Prevalence and incidence of rare diseases: Bibilographic data

2 March 2016 Prevalence and incidence of rare diseases: Bibilographic data s listed by decreasing prevalence, incidence or number of published cases www.orpha.net www.orphadata.org

Methodology Orphanet carries out a systematic survey of literature in order to estimate the prevalence and incidence of rare diseases. This study aims to collect new data regarding point prevalence, birth prevalence and incidence, and to update already published data according to new scientific studies or other available data. This data is presented in the following reports published biannually: Prevalence, incidence or number of published cases listed by diseases (in alphabetical order) ; s listed by decreasing prevalence, incidence or number of published cases ; Data collection A number of different sources are used : Registries (RARECARE, EUROCAT, etc) ; National/international health institutes and agencies (Institut National de Veille Sanitaire (French Institute of Health Surveillance); American Center of Control and Prevention, American National Cancer Institute, European Medicines Agency, World Health Organization etc) ; Medline is consulted using the following search algorithm : «names» AND Epidemiology[MeSH:NoExp] OR Incidence[Title/abstract] OR Prevalence[Title/ abstract] OR Epidemiology[Title/abstract]; Medical texts, grey literature and reports from experts ; Orphanet collaborating experts. Data characteristics The data published in this document are worldwide estimations, or European estimations if a worldwide estimation is not available. The published data is raw collected data or extrapolations of raw data at worldwide or European level when no genetic founder effect is suspected as a cause of a disease. If a range of national data is available, the average is calculated to estimate the worldwide or European prevalence or incidence. When a range of data sources is available, the most recent data source that meets a certain number of quality criteria is favoured (registries, meta-analyses, population-based studies, large cohorts studies). For congenital diseases, the prevalence is estimated, so that: Prevalence = birth prevalence x (patient life expectancy/general population life expectancy). When only incidence data is documented, the prevalence is estimated when possible, so that : Prevalence = incidence x disease mean duration. When neither prevalence nor incidence data is available, which is the case for very rare diseases, the number of cases or families documented in the medical literature is provided. Limitations of the study The prevalence and incidence data presented in this report are only estimations and cannot be considered to be absolutely correct. The average values presented in this report do not take into account the heterogeneous nature of the methodologies employed by the studies considered in the literature survey. The validity and exactitude of raw data sources is taken for granted and have not been verified. Thus, confusion between terms such as incidence and prevalence and/or birth prevalence is possible due to the interchangeable use of these terms in certain sources. It is possible that prevalence is overestimated in some cases as epidemiological studies are generally based on hospital data in regions with higher prevalence. Data presentation Without specification, published figures are worldwide. An asterisk * indicates European data.. Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 2

List of diseases or groups of diseases by decreasing prevalence prevalence (/,000) 79457 Maculopapular cutaneous mastocytosis 450.0 BP* 1480 Ventricular septal defect 272.0 BP* 853 Fetal and neonatal alloimmune thrombocytopenia 112.5 BP* 268810 Posterior meningocele.0 BP* 3388 Neural tube defect 91.05 BP* 91349 Non-functioning pituitary adenoma 80.025 * 648 Noonan 70.0 BP* 182130 Tumor of endocrine glands 64.0 * 2014 Cleft palate 53.6 BP* 535 Cutaneous lupus erythematosus 50.0 * 706 Patent arterial duct 50.0 BP* 8 47,XYY 50.0 BP* 48 Congenital bilateral absence of vas deferens 50.0 * 63259 Iniencephaly 50.0 * Pneumonia caused by Pseudomonas 90066 aeruginosa infection 50.0 * 93 Renal agenesis, unilateral 50.0 BP 67037 Squamous cell carcinoma of head and neck 49.0 * 2185 Congenital hydrocephalus 46.5 BP* Congenital isolated thyroxine-binding 209893 globulin 46.0 * 275555 Preeclampsia 45.0 * 93108 Renal dysplasia 43.5 BP* 3375 Trisomy X 42.5 * 801 Scleroderma 42.0 217071 Renal cell carcinoma 42.0 * 363999 Non-immune hydrops fetalis 42.0 BP 1646 Partial chromosome Y deletion 41.65 73247 Eosinophilic esophagitis 40.08 768 Familial long QT 40.0 BP* 294 Fetal cytomegalovirus 40.0 * 98497 Genetic peripheral neuropathy 40.0 97292 Cardiogenic shock 40.0 * 101016 Romano-Ward 40.0 * 3189 Congenital pulmonary valve stenosis 39.3 BP* 442 Congenital hypothyroidism 38.0 BP* 98715 Uveitis 38.0 * 90056 Moderate and severe traumatic brain injury 37.8 * 567 22q11.2 deletion 37.5 BP 226295 Primary congenital hypothyroidism 37.5 * Acute sensorineural hearing loss by acute 90059 acoustic trauma or sudden deafness or surgery induced acoustic trauma 37.0 * Non-papillary transitional cell carcinoma of 209989 the bladder 37.0 * 545 Follicular lymphoma 36.0 * 97230 Solar urticaria 36.0 * prevalence (/,000) 1457 Aorta coarctation 35.6 BP* 2764 Osteochondritis dissecans 35.0 * 1048 Isolated anencephaly/exencephaly 35.0 BP* 70475 Radiation proctitis 35.0 * 94059 Uremic pruritus 35.0 * 3303 Tetralogy of Fallot 34.0 BP 636 Neurofibromatosis type 1 33.3 BP 226292 Permanent congenital hypothyroidism 33.3 BP* 858 Congenital toxoplasmosis 33.0 BP* 439167 Placental insufficiency 33.0 908 Fragile X 32.5 70476 Vernal keratoconjunctivitis 32.0 * 90051 Sepsis in premature infants 32.0 * 90058 Spinal cord injury 32.0 * 216675 Transposition of the great arteries 31.7 BP* 2140 Congenital diaphragmatic hernia 30.0 BP 563 Peripartum cardiomyopathy 30.0 BP 1330 Partial atrioventricular canal 30.0 * 729 Polycythemia vera 30.0 * 213500 Ovarian cancer 30.0 * 301 Wild type ATTR amyloidosis 30.0 * Non-acquired combined pituitary hormone 467 29.0 BP* 411527 Central retinal vein occlusion 28.0 * 1656 Dermatitis herpetiformis 27.0 * 67038 B-cell chronic lymphocytic leukemia 27.0 * 791 Retinitis pigmentosa 26.7 70568 Posttransplant lymphoproliferative disease 26.2 * 54057 Thrombotic thrombocytopenic purpura 25.5 * Cytomegalovirus disease in patients with 137698 impaired cell mediated immunity deemed at 25.5 * risk 166 Charcot-Marie-Tooth disease 25.0 * 2 Immune thrombocytopenic purpura 25.0 * 701 Alopecia universalis 25.0 * 145 Hereditary breast and ovarian cancer 25.0 * 2073 Narcolepsy-cataplexy 25.0 * 95719 Thyroid hemiagenesis 25.0 93402 Syndactyly type 1 25.0 BP* Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 3

94058 Neovascular glaucoma 24.4 * prevalence (/,000) 1199 Esophageal atresia 24.3 BP* 1531 Craniosynostosis 24.3 BP* Congenitally uncorrected transposition of the 860 24.25 BP* great arteries 2248 Hypoplastic left heart 24.0 BP 171901 Primary cutaneous T-cell lymphoma 24.0 * 2368 Gastroschisis 23.7 BP* 3394 Soft tissue sarcoma 23.7 * 2137 Chronic autoimmune hepatitis 23.5 1851 Multicystic dysplastic kidney 23.26 BP 97363 Unilateral multicystic dysplastic kidney 23.2 BP 228113 Anal fistula 23.0 * Scarring in glaucoma filtration surgical 90080 procedures 22.0 * 217067 Pouchitis 22.0 * Pulmonary fungal infections in patients 217080 deemed at risk 22.0 * 636 Neurofibromatosis type 1 21.3 * Congenital hypothyroidism due to 95711 developmental anomaly 21.3 * 186 Primary biliary cirrhosis 21.05 85410 Oligoarticular juvenile arthritis 20.5 * 60 Alpha-1-antitrypsin 20.0 * 70 Proximal spinal muscular atrophy 20.0 BP* 3389 Tuberculosis 20.0 * 1329 Complete atrioventricular canal 20.0 BP* 557 Isolated anorectal malformation 20.0 BP 130 Brugada 20.0 * 35122 Congenital sucrase-isomaltase 20.0 * 1330 Partial atrioventricular canal 20.0 BP* 247 Arrhythmogenic right ventricular cardiomyopathy 20.0 70587 Infant acute respiratory distress 20.0 * 90062 Acute liver failure 20.0 * 90081 AIDS wasting 20.0 * 261197 Proximal 16p11.2 microdeletion 20.0 * 823 Isolated spina bifida 18.6 BP* 30391 Biliary atresia 18.5 BP 704 Pemphigus vulgaris 18.0 * 90061 Non-infectious posterior uveitis 18.0 * 154 Familial isolated dilated cardiomyopathy 17.5 * 65753 Charcot-Marie-Tooth disease type 1 17.5 3380 Trisomy 18 16.7 BP 2032 Idiopathic pulmonary fibrosis 16.7 77240 Primary lymphedema 16.7 * 461 Recessive X-linked ichthyosis 16.6 * 774 Hereditary hemorrhagic telangiectasia 16.0 * prevalence (/,000) 1201 Atresia of small intestine 16.0 BP* 36258 Buerger disease 16.0 544 Diffuse large B-cell lymphoma 16.0 * Primary membranoproliferative 54370 glomerulonephritis 16.0 * 90064 Acute peripheral arterial occlusion 16.0 * 137599 Stromal keratitis 16.0 * 83463 Microtia 15.5 BP 90291 Systemic sclerosis 15.4 * 98896 Duchenne muscular dystrophy 15.1 BP* 558 Marfan 15.0 232 Sickle cell anemia 15.0 * 2382 Lennox-Gastaut 15.0 * 2828 Young-onset Parkinson disease 15.0 * 88673 Hepatocellular carcinoma 15.0 * 94093 Neuroleptic malignant 15.0 * 221061 Familial cerebral cavernous malformation 15.0 163934 Atopic keratoconjunctivitis 15.0 * 166260 Dentinogenesis imperfecta type 2 14.6 * 49042 Dentinogenesis imperfecta 14.5 * 95712 Thyroid ectopia 14.3 * 214 Cystinuria 14.0 101959 Chronic primary adrenal insufficiency 14.0 * 2162 Holoprosencephaly 13.4 BP* 3193 Supravalvular aortic stenosis 13.3 * 44890 Gastrointestinal stromal tumor 13.0 * 70589 Bronchopulmonary dysplasia 13.0 * 423461 Mucolipidosis type III alpha/beta 13.0 088 Thyroid carcinoma 12.7 3376 Triploidy 12.6 BP* 273 Steinert myotonic dystrophy 12.5 797 Sarcoidosis 12.5 285 Ehlers-Danlos, hypermobility type 12.5 * 903 Von Willebrand disease 12.5 2415 Lymphatic malformation 12.5 * 85138 Addison disease 12.5 * Medium chain acyl-coa dehydrogenase 42 12.0 BP* 95426 Chronic pain requiring intraspinal analgesia 12.0 * 29073 Multiple myeloma 11.9 * 660 Omphalocele 11.7 BP* 1866 Focal, segmental or multifocal dystonia 11.7 * 98878 Hemophilia A 11.25 BP 70573 Small cell lung cancer 11.2 * 635 Neuroblastoma 11.0 * Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 4

prevalence (/,000) 3109 Mayer-Rokitansky-Küster-Hauser 11.0 BP 890 Hepatic veno-occlusive disease 11.0 * 85443 AL amyloidosis 11.0 * 388 Hirschsprung disease 10.9 BP* 904 Williams 10.8 BP 700 Alopecia totalis 10.5 * 827 Stargardt disease 10.0 * 1146 Digitotalar dysmorphism 10.0 2612 Linear nevus sebaceus 10.0 BP* 716 Phenylketonuria 10.0 BP* 418 Congenital adrenal hyperplasia 10.0 * 805 Tuberous sclerosis complex 10.0 BP* 654 Nephroblastoma 10.0 BP* 569 Familial or sporadic hemiplegic migraine 10.0 * 233 Duane retraction 10.0 * 3157 Septo-optic dysplasia spectrum 10.0 BP* 412 Hyperlipoproteinemia type 3 10.0 3260 Hypereosinophilic of undetermined significance 10.0 * 3286 Catecholaminergic polymorphic ventricular tachycardia 10.0 * 31112 Dermatofibrosarcoma protuberans 10.0 * 64740 Recurrent acute pancreatitis 10.0 * Acquired aneurysmal subarachnoid 90065 hemorrhage 10.0 * 90076 Partial deep dermal and full thickness burns 10.0 * Polymalformative genetic with 183422 increased risk of developing cancer 10.0 * 182067 Glial tumor 10.0 * 1114 Aplasia cutis congenita 10.0 BP 70482 Carcinoma of esophagus 9.8 223727 Bone sarcoma 9.29 * 79665 Gardner 9.1 BP 2443 Mitochondrial oxidative phosphorylation disorder due to nuclear DNA anomalies 9.0 * 900 Granulomatosis with polyangiitis 9.0 * 1203 Duodenal atresia 9.0 * 1203 Duodenal atresia 9.0 BP* 98292 Mastocytosis 9.0 * Congenital total pulmonary venous return 99125 anomaly 9.0 BP 137914 Choanal atresia 8.6 BP* 99981 Apnea of prematurity 8.5 * 3280 Syringomyelia 8.4 * 98555 Anophthalmia - microphthalmia 8.3 BP* 2444 Congenital pulmonary airway malformation 8.2 BP* 171 Primary sclerosing cholangitis 8.1 579 Mucopolysaccharidosis type 1 8.0 * 930 Idiopathic achalasia 8.0 3451 West 8.0 * prevalence (/,000) 194 Ocular coloboma 8.0 BP* 90290 CREST 8.0 * Juvenile rheumatoid factor-negative 85408 polyarthritis 8.0 * 88991 Congenital heart malformation 7.8 BP* 589 Myasthenia gravis 7.77 448 Hemophilia 7.7 * Sporadic adult-onset ataxia of unknown 247234 7.6 * etiology 72 Angelman 7.5 666 Osteogenesis imperfecta 7.5 * 4 Laryngo-tracheo-esophageal cleft 7.5 BP* 1464 Univentricular heart 7.5 BP Classic congenital adrenal hyperplasia due to 315306 21-hydroxylase, salt wasting form 7.5 * Classic congenital adrenal hyperplasia due to 315306 7.5 BP* 21-hydroxylase, salt wasting form 586 Cystic fibrosis 7.4 * 821 Sotos 7.1 BP 732 Polymyositis 7.1 * 705 Pendred 7.0 * 1332 Medullary thyroid carcinoma 7.0 * Classic congenital adrenal hyperplasia due to 90794 7.0 BP 21-hydroxylase Classic congenital adrenal hyperplasia due to 90794 7.0 * 21-hydroxylase Recurrent hepatitis C virus induced liver 90052 disease in liver transplant recipients 7.0 * 95432 Primary progressive aphasia 7.0 261236 16p13.11 microdeletion 7.0 BP 2059 Fryns 7.0 BP* 42 Medium chain acyl-coa dehydrogenase 6.85 580 Mucopolysaccharidosis type 2 6.7 * 418 Congenital adrenal hyperplasia 6.7 BP* 3366 Isolated trigonocephaly 6.7 BP* 57145 SUNCT 6.7 * 238468 Hypohidrotic ectodermal dysplasia 6.7 * 206647 Myotonic dystrophy 6.7 42062 Iminoglycinuria 6.68 * 42062 Iminoglycinuria 6.67 BP* 50839 Cat-scratch disease 6.6 * 138 CHARGE 6.5 BP 553 Cushing 6.5 * 52759 Vasculitis 6.3 * Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 5

prevalence (/,000) 887 VACTERL/VATER association 6.25 BP* 363958 17q21.31 microdeletion 6.25 * 733 Familial adenomatous polyposis 6.0 * 790 Retinoblastoma 6.0 BP 221 Dermatomyositis 6.0 * 683 Progressive supranuclear palsy 6.0 521 Chronic myeloid leukemia 6.0 * 609 Tibial muscular dystrophy 6.0 * 46724 Cerebral arteriovenous malformation 6.0 * 252164 Benign schwannoma 6.0 * 524 Li-Fraumeni 6.0 55 Oculocutaneous albinism 5.9 635 Neuroblastoma 5.8 BP* 1037 Arthrogryposis multiplex congenita 5.7 BP* 85438 Enthesitis-related arthritis 5.7 * 881 Turner 5.5 BP* 963 Acromegaly 5.5 2440 Split hand-split foot malformation 5.4 BP* 2542 Isolated anophthalmia - microphthalmia 5.3 BP* 738 Porphyria 5.25 778 Rett 5.0 BP* 792 X-linked retinoschisis 5.0 469 Hereditary fructose intolerance 5.0 * 718 Isolated Pierre Robin 5.0 BP* 287 Ehlers-Danlos, classic type 5.0 244 Primary ciliary dyskinesia 5.0 BP* 685 Hereditary spastic paraplegia 5.0 * 43 X-linked adrenoleukodystrophy 5.0 BP 251 Multiple epiphyseal dysplasia 5.0 * 90309 Ehlers-Danlos type 1 5.0 * 85414 Systemic-onset juvenile idiopathic arthritis 5.0 * 280062 Calciphylaxis 5.0 * 98878 Hemophilia A 4.85 886 Usher 4.8 * 88629 Tritanopia 4.8 * 98896 Duchenne muscular dystrophy 4.78 60041 Congenital heart block 4.54 BP 269 Facioscapulohumeral dystrophy 4.5 * 85446 Wild type ABeta2M amyloidosis 4.5 * 175 Cartilage-hair hypoplasia 4.34 BP* 104 Leber hereditary optic neuropathy 4.3 1143 Neurogenic arthrogryposis multiplex congenita 4.3 BP* 3384 Truncus arteriosus 4.3 BP 2116 Hartnup disease 4.2 prevalence (/,000) 1209 Tricuspid atresia 4.2 BP* Juvenile rheumatoid factor-positive 85435 polyarthritis 4.2 * 85436 Juvenile psoriatic arthritis 4.2 * 2130 Hemimelia 4.15 * 93110 Posterior urethral valve 4.125 BP* 778 Rett 4.0 * 15 Achondroplasia 4.0 BP 564 Meckel 4.0 BP 819 Smith-Magenis 4.0 884 Tetrasomy 12p 4.0 BP* 1928 Congenital lobar emphysema 4.0 BP 3193 Supravalvular aortic stenosis 4.0 BP* 52417 MALT lymphoma 4.0 * 79140 Cutaneous neuroendocrine carcinoma 4.0 * 96169 Koolen-De Vries 4.0 * 96253 Cushing disease 4.0 * 95716 Familial thyroid dyshormonogenesis 4.0 * 101330 Porphyria cutanea tarda 4.0 * 99013 Spastic paraplegia type 7 4.0 * 178029 Central diabetes insipidus 4.0 * 96092 8p inverted duplication/deletion 3.9 BP* 803 Amyotrophic lateral sclerosis 3.85 79126 Acute interstitial pneumonia 3.8 * 98848 Indolent systemic mastocytosis 3.8 * 2467 Systemic mastocytosis 3.75 478 Kallmann 3.75 * 3378 Trisomy 13 3.7 BP* 3451 West 3.7 BP 2932 Chronic inflammatory demyelinating polyneuropathy 3.7 * 3465 Worster-Drought 3.7 * 818 Smith-Lemli-Opitz 3.7 BP* 60015 Enlarged parietal foramina 3.7 98976 Congenital glaucoma 3.6 BP* 640 Hereditary neuropathy with liability to pressure palsies 3.5 * 1880 Ebstein malformation 3.5 BP* 2655 Thanatophoric dysplasia 3.5 BP* 3205 Sturge-Weber 3.5 BP* 2103 Guillain-Barré 3.5 * 81 Antisynthetase 3.5 102 Multiple system atrophy 3.5 52416 Mantle cell lymphoma 3.5 * 95713 Athyreosis 3.5 * 95720 Thyroid hypoplasia 3.5 Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 6

217074 Rare carcinoma of pancreas 3.5 104008 Short bowel 3.4 * 218 Darier disease 3.4 * 652 Multiple endocrine neoplasia type 1 3.3 * 905 Wilson disease 3.3 429 Hypochondroplasia 3.3 * 1172 Autosomal recessive cerebellar ataxia 3.3 98672 Autosomal dominant optic atrophy 3.3 prevalence (/,000) 98723 Hypoplastic right heart 3.3 BP* 182090 Pulmonary arterial hypertension 3.3 * 926 Acatalasemia 3.2 * 158 Systemic primary carnitine 3.2 BP* 075 Gastric endocrine tumor 3.2 * 2322 Kabuki 3.1 * 50251 Pleural mesothelioma 3.1 * Acute inflammatory demyelinating 98916 polyradiculoneuropathy 3.1 * 93930 Bladder exstrophy 3.05 BP 673 Malaria 3.0 * 794 Saethre-Chotzen 3.0 BP* 136 CADASIL 3.0 * 282 Frontotemporal dementia 3.0 * 767 Polyarteritis nodosa 3.0 * 2745 Opitz G/BBB 3.0 * 36234 Bacterial toxic-shock 3.0 824 Myelofibrosis with myeloid metaplasia 3.0 * Chronic thromboembolic pulmonary 70591 hypertension 3.0 * Congenitally corrected transposition of the 216694 great arteries 3.0 BP Ileal pouch anal anastomosis related faecal 238621 incontinence 3.0 * 171673 Limbal stem cell 3.0 * 653 Multiple endocrine neoplasia type 2 2.9 * 739 Prader-Willi 2.8 BP* 374 Goldenhar 2.8 BP* 506 Leigh 2.8 BP* 169802 Severe hemophilia A 2.8 * 626 Large congenital melanocytic nevus 2.75 * 399 Huntington disease 2.7 99 Autosomal dominant cerebellar ataxia 2.7 49382 Achromatopsia 2.7 6 3-methylcrotonyl-CoA carboxylase 2.65 BP* 79432 Oculocutaneous albinism type 2 2.55 358 Gitelman 2.5 * 1034 Amniotic bands 2.5 BP* 1872 Cone rod dystrophy 2.5 * 2138 46,XX ovotesticular disorder of sex development 2.5 BP 2337 Non-epidermolytic palmoplantar keratoderma 2.5 * 65 Leber congenital amaurosis 2.5 BP 758 Pseudoxanthoma elasticum 2.5 * 94 Astrocytoma 2.5 * 393 46,XX testicular disorder of sex development 2.5 33069 Dravet 2.5 BP 75249 Familial isolated restrictive cardiomyopathy 2.5 * 97927 Peripheral resistance to thyroid hormones 2.5 * 93571 Dense deposit disease 2.5 070 Progressive non-fluent aphasia 2.5 * Classic congenital adrenal hyperplasia due to 315311 21-hydroxylase, simple virilizing 2.5 * form 65 Leber congenital amaurosis 2.5 352731 Oculocutaneous albinism type 1 2.5 70588 Meconium aspiration 2.44 * prevalence (/,000) 93928 Epispadias 2.4 BP* 98933 Multiple system atrophy, parkinsonian type 2.4 * 116 Beckwith-Wiedemann 2.3 BP* 39812 Graft versus host disease 2.3 * 315 Lead poisoning 2.3 * 905 Wilson disease 2.2 BP 2869 Peutz-Jeghers 2.2 BP 304 Epidermolysis bullosa simplex 2.2 BP* 137605 Legius 2.2 BP 98895 Becker muscular dystrophy 2.2 BP* 217 Isolated Dandy-Walker malformation 2.1 * 70567 Cholangiocarcinoma 2.1 95 Friedreich ataxia 2.0 * 480 Kearns-Sayre 2.0 * 607 Nemaline myopathy 2.0 BP* 280 Wolf-Hirschhorn 2.0 BP* 126 Blepharophimosis - epicanthus inversus - ptosis 2.0 861 Treacher-Collins 2.0 BP* 352 Galactosemia 2.0 BP* 3346 Tracheal agenesis 2.0 BP* 63 Alport 2.0 * 3129 Sarcosinemia 2.0 BP 1699 Trisomy 12p 2.0 BP 2017 Sternal cleft 2.0 BP* 185 Scimitar 2.0 BP* Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 7

2345 Isolated Klippel-Feil 2.0 * 54595 Craniopharyngioma 2.0 * 93323 Fibular hemimelia 2.0 * 98841 Anaplastic large cell lymphoma 2.0 * 217064 5-fluorouracil poisoning 2.0 * 157835 Paroxysmal hemicrania 2.0 * 168782 Childhood disintegrative disorder 2.0 * 657 Congenital isolated hyperinsulinism 2.0 BP 93110 Posterior urethral valve 2.0 * 363203 Ring chromosome 2.0 BP 199 Cornelia de Lange 1.9 * prevalence (/,000) 10 48,XXYY 1.9 BP* 79361 Inherited epidermolysis bullosa 1.9 BP* 35808 Malignant sex cord stromal tumor of ovary 1.85 * 304 Epidermolysis bullosa simplex 1.8 675 Annular pancreas 1.8 BP* 53271 Muenke 1.8 BP* 664 Ornithine transcarbamylase 1.77 BP 77 Aniridia 1.75 251076 8p23.1 microduplication 1.72 2182 Hydrocephalus with stenosis of the aqueduct 1.7 BP of Sylvius 2182 Hydrocephalus with stenosis of the aqueduct 1.7 of Sylvius 637 Neurofibromatosis type 2 1.7 * 2152 Mowat-Wilson 1.7 BP* 1848 Renal agenesis, bilateral 1.7 BP* 98879 Hemophilia B 1.7 * 394 Classic homocystinuria 1.65 * 899 Walker-Warburg 1.65 BP* 183660 Severe combined immuno 1.65 BP* 1915 Fetal alcohol 1.6 BP* 64747 X-linked Charcot-Marie-Tooth disease 1.6 * 79241 Biotinidase 1.6 * 79241 Biotinidase 1.6 BP 98895 Becker muscular dystrophy 1.53 192 Coffin-Lowry 1.5 131 Budd-Chiari 1.5 * 180 Choroideremia 1.5 * 2019 Femur-fibula-ulna complex 1.5 BP* 389 Langerhans cell histiocytosis 1.5 * 137 Congenital disorder of glycosylation 1.5 BP* 35689 Primary lateral sclerosis 1.5 * 641 Multifocal motor neuropathy 1.5 71211 Neuromyelitis optica 1.5 * 45453 Incessant infant ventricular tachycardia 1.5 BP* prevalence (/,000) 45452 Idiopathic neonatal atrial flutter 1.5 BP* 92050 Intestinal epithelial dysplasia 1.5 BP* 98757 Spinocerebellar ataxia type 3 1.5 98756 Spinocerebellar ataxia type 2 1.5 98755 Spinocerebellar ataxia type 1 1.5 168811 Malignant peritoneal mesothelioma 1.5 * 168956 Hypereosinophilic 1.5 * 183 Eosinophilic granulomatosis with polyangiitis 1.5 512 Metachromatic leukodystrophy 1.47 BP* 79269 Sanfilippo type A 1.4 BP 195 Cat-eye 1.35 BP* 247525 Citrullinemia type I 1.35 * 355 Gaucher disease 1.3 BP 79434 Oculocutaneous albinism type 1B 1.3 79431 Oculocutaneous albinism type 1A 1.3 281090 Syndromic X-linked ichthyosis 1.3 * 1880 Ebstein malformation 1.25 * 2481 Neurocutaneous melanocytosis 1.25 * 628 Diastrophic dwarfism 1.2 * 2750 Orofaciodigital type 1 1.2 BP* 46485 Superficial pemphigus 1.2 * Autosomal recessive polycystic kidney 731 1.17 * disease 263432 Nevus of Ito 1.17 * 72 Angelman 1.1 BP* 289 Ellis Van Creveld 1.1 BP 2911 Poland 1.1 BP* 224 Neonatal diabetes mellitus 1.1 BP* 140874 Joubert and related disorders 1.1 BP 275766 Idiopathic pulmonary arterial hypertension 1.1 * 377 Gorlin 1.1 487 Krabbe disease 1.0 * 614 Thomsen and Becker disease 1.0 16 Blue cone monochromatism 1.0 16 Blue cone monochromatism 1.0 BP 681 Hypokalemic periodic paralysis 1.0 * 53 Albers-Schönberg osteopetrosis 1.0 199 Cornelia de Lange 1.0 BP* 370 Glycogen storage disease due to phosphorylase kinase 1.0 BP* 217 Isolated Dandy-Walker malformation 1.0 BP* 33 Isovaleric acidemia 1.0 * 2308 Jacobsen 1.0 BP* 606 Proximal myotonic myopathy 1.0 * 355 Gaucher disease 1.0 * Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 8

364 Glycogen storage disease due to glucose-6- phosphatase 1.0 BP 646 Niemann-Pick disease type C 1.0 * 2134 Atypical hemolytic-uremic 1.0 * 267 Autosomal recessive limb-girdle muscular dystrophy type 2A 1.0 * 1552 Currarino triad 1.0 * 189 Hidrotic ectodermal dysplasia 1.0 * prevalence (/,000) 254 Spondylometaphyseal dysplasia 1.0 BP* 2578 Mayer-Rokitansky-Küster-Hauser type 2 1.0 BP* 296 Enchondromatosis 1.0 * 647 Nijmegen breakage 1.0 BP 2924 Isolated polycystic liver disease 1.0 * Idiopathic and/or familial pulmonary arterial 422 1.0 * hypertension 3403 Uhl anomaly 1.0 BP 3449 Weill-Marchesani 1.0 616 Medulloblastoma 1.0 * 360 Glioblastoma 1.0 1900 Ehlers-Danlos, kyphoscoliotic type 1.0 BP 286 Ehlers-Danlos, vascular type 1.0 * 531 Miller-Dieker 1.0 BP* 396 Chronic hiccup 1.0 * 5 Long chain 3-hydroxyacyl-CoA dehydrogenase 1.0 BP* 25 Glutaryl-CoA dehydrogenase 1.0 BP 177 Rhizomelic chondrodysplasia punctata 1.0 * Autosomal recessive limb-girdle muscular 34515 dystrophy type 2I 1.0 * 67043 Acanthamoeba keratitis 1.0 * 51577 Cobblestone lissencephaly 1.0 BP* 79435 Oculocutaneous albinism type 4 1.0 Glycogen storage disease due to glucose-6-79258 phosphatase type a 1.0 BP* 77259 Gaucher disease type 1 1.0 * 91378 Hereditary angioedema 1.0 * 90060 Diffuse alveolar hemorrhage 1.0 * 98863 X-linked Emery-Dreifuss muscular dystrophy 1.0 98863 X-linked Emery-Dreifuss muscular dystrophy 1.0 BP 96263 48,XXXY 1.0 BP* Congenital hypothyroidism due to 95715 transplacental passage of maternal TSHbinding inhibitory antibodies 1.0 * 94068 Spondyloepiphyseal dysplasia congenita 1.0 BP* 93685 Localized Castleman disease 1.0 99789 Dentin dysplasia type I 1.0 * 163703 Febrile infection-related epilepsy 1.0 * prevalence (/,000) 180242 Malignant tumor of fallopian tubes 1.0 * Glycogen storage disease due to liver 264580 phosphorylase kinase 1.0 BP* 141 Canavan disease 1.0 BP 577 Mucolipidosis type III 1.0 BP* 444490 Familial chylomicronemia 1.0 * 33226 Waldenström macroglobulinemia 1.0 * 87503 Mal de Meleda 1.0 3169 Sirenomelia 0.98 BP 79278 Autosomal erythropoietic protoporphyria 0.92 * 207 Crouzon disease 0.9 BP* 2131 Alternating hemiplegia of childhood 0.9 BP* 882 Tyrosinemia type 1 0.9 BP 48162 Lewis-Sumner 0.9 * 581 Mucopolysaccharidosis type 3 0.87 BP* 576 Mucolipidosis type II 0.84 BP* 99429 Complete androgen insensitivity 0.83 579 Mucopolysaccharidosis type 1 0.82 BP Glycogen storage disease due to acid maltase 365 0.8 BP* 2346 Angioosteohypertrophic 0.8 BP* 813 Silver-Russell 0.8 BP* 1461 Criss-cross heart 0.8 BP* 79361 Inherited epidermolysis bullosa 0.8 * 169793 Severe hemophilia B 0.8 * 3312 Thalidomide embryopathy 0.77 213 Cystinosis 0.75 BP 181 X-linked hypohidrotic ectodermal dysplasia 0.75 BP* 354 GM1 gangliosidosis 0.75 BP* 667 Autosomal recessive malignant osteopetrosis 0.75 BP* 1501 Adrenocortical carcinoma 0.75 * Congenital adrenal hyperplasia due to 11-90795 beta-hydroxylase 0.75 BP* Congenital adrenal hyperplasia due to 95699 cytochrome P450 oxidoreductase 0.75 BP* 487 Krabbe disease 0.7 BP 464 Incontinentia pigmenti 0.7 BP* 392 Holt-Oram 0.7 BP* 726 Alpers-Huttenlocher 0.7 BP* 110 Bardet-Biedl 0.7 * 303 Dystrophic epidermolysis bullosa 0.7 216804 Osteogenesis imperfecta type 2 0.7 BP* 93473 Hurler 0.7 BP* 580 Mucopolysaccharidosis type 2 0.68 BP 796 Sandhoff disease 0.67 BP* 124 Blackfan-Diamond anemia 0.67 BP* Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 9

prevalence (/,000) 511 Maple syrup urine disease 0.67 BP 2591 Infantile myofibromatosis 0.67 BP* 3282 Multifocal atrial tachycardia 0.67 BP 1335 Pentalogy of Cantrell 0.67 BP 90053 Hematopoietic stem cell transplantation 0.65 * 84 Fanconi anemia 0.62 BP* 783 Rubinstein-Taybi 0.6 BP* 474 Jeune 0.6 BP* 3287 Takayasu arteritis 0.6 * 994 Fetal akinesia deformation sequence 0.6 BP* 2345 Isolated Klippel-Feil 0.6 BP* 79168 Disorder of bile acid synthesis 0.6 * 79098 Sympathetic ophthalmia 0.6 * 98809 Paroxysmal kinesigenic dyskinesia 0.6 Progressive supranuclear palsy - corticobasal 240103 0.6 * 248111 Juvenile Huntington disease 0.6 * 169796 Moderately severe hemophilia B 0.6 * 169799 Mild hemophilia B 0.6 * 54 X-linked recessive ocular albinism 0.58 BP* Pulmonary arterial hypertension associated 275803 0.57 * with congenital heart disease 562 McCune-Albright 0.55 * 313 Lamellar ichthyosis 0.55 * 96264 49,XXXXY 0.55 BP* 79276 Acute intermittent porphyria 0.54 * 93929 Cloacal exstrophy 0.54 BP 682 Hyperkalemic periodic paralysis 0.5 * 23 Argininosuccinic aciduria 0.5 * 255 Dopa-responsive dystonia 0.5 611 Inclusion body myositis 0.5 * 828 Stickler 0.5 BP* 634 Netherton 0.5 BP* 634 Netherton 0.5 * 902 Werner 0.5 * 3427 Double outlet left ventricle 0.5 BP 811 Shwachman-Diamond 0.5 BP 747 Autoimmune pulmonary alveolar proteinosis 0.5 782 Axenfeld-Rieger 0.5 * Combined of factor V and factor 35909 0.5 * VIII 122 Birt-Hogg-Dubé 0.5 * 64742 Pleuropulmonary blastoma 0.5 BP* 79269 Sanfilippo type A 0.5 * 79242 Holocarboxylase synthetase 0.5 BP* 98249 Ehlers-Danlos 0.5 BP* 281097 Autosomal recessive congenital ichthyosis 0.5 * 93473 Hurler 0.5 * 201 Cowden 0.5 * prevalence (/,000) Ataxia-telangiectasia 0.49 * Congenital adrenal hyperplasia due to 11-90795 0.47 * beta-hydroxylase 379 Chronic granulomatous disease 0.46 BP 23 Argininosuccinic aciduria 0.46 BP 676 Hereditary chronic pancreatitis 0.43 * 52 Alagille 0.4 BP* 2869 Peutz-Jeghers 0.4 * 1452 Cleidocranial dysplasia 0.4 BP* 915 Aarskog-Scott 0.4 BP* 1215 Autosomal dominant optic atrophy plus 0.4 * 2315 Johanson-Blizzard 0.4 BP* 8 Pyruvate carboxylase 0.4 BP* 256 Early-onset generalized limb-onset dystonia 0.4 * 503 Autosomal dominant Larsen 0.4 BP* 42738 Severe congenital neutropenia 0.4 BP* 88 Idiopathic aplastic anemia 0.4 * 77293 Niemann-Pick disease type B 0.4 * 217085 Mucopolysaccharidosis type 2, severe form 0.4 BP* Non-acquired isolated growth hormone 631 0.39 99885 Permanent neonatal diabetes mellitus 0.38 BP* 3440 Waardenburg 0.37 BP* 290 Congenital rubella 0.35 BP* 43393 Lambert-Eaton myasthenic 0.35 510 Lesch-Nyhan 0.34 BP* 96 Ataxia with vitamin E 0.33 * 565 Menkes disease 0.33 BP* 327 Congenital factor VII 0.33 * 140 Campomelic dysplasia 0.33 BP* 98850 Aggressive systemic mastocytosis 0.33 * 79473 Porphyria variegata 0.32 * 147 Carbamoyl-phosphate synthetase 1 0.31 261 Emery-Dreifuss muscular dystrophy 0.3 * 394 Classic homocystinuria 0.3 BP 258 Congenital muscular dystrophy type 1A 0.3 * 84 Fanconi anemia 0.3 1 Autosomal dominant popliteal pterygium 0.3 4 Mirror polydactyly - vertebral segmentation - 0.3 * limbs defects 633 Laron 0.3 * Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 10

prevalence (/,000) 2299 Aortic arch interruption 0.3 BP* 277 Severe combined immuno due to adenosine deaminase 0.3 BP* 590 Congenital myasthenic 0.3 * 219 Autosomal recessive limb-girdle muscular dystrophy type 2F 0.3 * 56970 Transmissible spongiform encephalopathy 0.3 * Congenital non-bullous ichthyosiform 79394 erythroderma 0.3 * 90647 Jervell and Lange-Nielsen 0.3 90079 Anthracycline extravasations 0.3 * 229717 Isolated agammaglobulinemia 0.3 182050 MYH9-related disease 0.3 * 294963 Popliteal pterygium 0.3 * 324964 Chronic recurrent multifocal osteomyelitis 0.3 99886 Transient neonatal diabetes mellitus 0.3 BP* 845 Tay-Sachs disease 0.28 BP 811 Shwachman-Diamond 0.28 191 Cockayne 0.27 BP* 702 Pelizaeus-Merzbacher disease 0.25 * 528 Berardinelli-Seip congenital lipodystrophy 0.25 * 678 Papillon-Lefèvre 0.25 X-linked dominant chondrodysplasia 35173 punctata 0.25 BP* 77292 Niemann-Pick disease type A 0.25 BP* Pulmonary arterial hypertension associated 275798 with connective tissue disease 0.25 * 910 Xeroderma pigmentosum 0.23 BP* 324 Fabry disease 0.22 BP* 47 X-linked agammaglobulinemia 0.22 111 Barth 0.22 * 436 Hypophosphatasia 0.21 BP* 447 Paroxysmal nocturnal hemoglobinuria 0.2 * 534 Oculocerebrorenal of Lowe 0.2 893 WAGR 0.2 BP 385 Neurodegeneration with brain iron accumulation 0.2 * 235 Dubowitz 0.2 BP* 3320 Thrombocytopenia - absent radius 0.2 BP* 6 Pyridoxine-dependent epilepsy 0.2 BP* 2052 Fraser 0.2 BP* 110 Bardet-Biedl 0.2 BP* 277 Severe combined immuno due to adenosine deaminase 0.2 * 35 Propionic acidemia 0.2 * 353 Autosomal recessive limb-girdle muscular dystrophy type 2C 0.2 * prevalence (/,000) Hypohidrotic ectodermal dysplasia with 98813 immuno 0.2 BP* 93598 Primary hyperoxaluria type 1 0.2 * 99870 Letterer-Siwe disease 0.2 * 238583 Hyperphenylalaninemia 0.2 178478 Infant botulism 0.2 BP* 209916 Extraskeletal myxoid chondrosarcoma 0.2 * 1361 Carnosinemia 0.2 BP 1456 Atypical coarctation of aorta 0.17 BP* 407 Glycine encephalopathy 0.17 * 79404 Junctional epidermolysis bullosa, Herlitz type 0.17 BP 280219 Pelizaeus-Merzbacher disease, classic form 0.17 * 583 Mucopolysaccharidosis type 6 0.16 BP* 85 Congenital dyserythropoietic anemia 0.16 BP* 335 Congenital fibrinogen 0.15 * 538 Lymphangioleiomyomatosis 0.15 223 Nephrogenic diabetes insipidus 0.15 * 79430 Hermansky-Pudlak 0.15 Pantothenate kinase-associated 157850 neurodegeneration 0.15 * 118 Beta-mannosidosis 0.14 BP* 763 Pycnodysostosis 0.13 3463 Wolfram 0.13 183669 Agammaglobulinemia 0.13 * 1308 C 0.11 * Autosomal dominant medullary cystic kidney 34149 0.11 * disease with or without hyperuricemia 61 Alpha-mannosidosis 0.1 * 367 Glycogen storage disease due to glycogen branching enzyme 0.1 BP 512 Metachromatic leukodystrophy 0.1 * 906 Wiskott-Aldrich 0.1 * 628 Diastrophic dwarfism 0.1 BP* 205 Crigler-Najjar 0.1 BP* 773 Refsum disease 0.1 * 1452 Cleidocranial dysplasia 0.1 1775 Dyskeratosis congenita 0.1 * 204 Creutzfeldt-Jakob disease 0.1 * 1959 Evans 0.1 * 3198 Stiff person and related disorders 0.1 * 326 Congenital factor V 0.1 * 507 Leishmaniasis 0.1 * 3329 Tibial aplasia - ectrodactyly 0.1 * 329 Congenital factor XI 0.1 * 2686 Cyclic neutropenia 0.1 * 298 Mitochondrial neurogastrointestinal encephalomyopathy 0.1 * Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 11

225 Maternally-inherited diabetes and deafness 0.1 * prevalence (/,000) 209 Cutis laxa 0.1 BP* 31824 Colchicine poisoning 0.1 * 119 Autosomal recessive limb-girdle muscular dystrophy type 2E 0.1 * 142 Anaplastic thyroid carcinoma 0.1 * 73274 Acquired hemophilia 0.1 * Congenital adrenal hyperplasia due to 17-90793 alpha-hydroxylase 0.1 * 93262 Crouzon - acanthosis nigricans 0.1 BP 93322 Tibial hemimelia 0.1 BP* 86834 Juvenile myelomonocytic leukemia 0.1 * 98810 Paroxysmal non-kinesigenic dyskinesia 0.1 99842 Leukocyte adhesion type I 0.1 * 247257 Inhalational anthrax 0.1 * Adult-onset proximal spinal muscular 209335 0.1 * atrophy, autosomal dominant Mitochondrial membrane protein-associated 289560 0.1 neurodegeneration 391665 Homozygous familial hypercholesterolemia 0.1 2485 Melorheostosis 0.09 * 48818 Aceruloplasminemia 0.09 79270 Sanfilippo type B 0.09 * Cushing due to macronodular 189427 adrenal hyperplasia 0.08 * 275777 Heritable pulmonary arterial hypertension 0.08 * 726 Alpers-Huttenlocher 0.07 * 42738 Severe congenital neutropenia 0.07 Neonatal acute respiratory distress due to 217563 SP-B 0.067 BP 337 Fibrodysplasia ossificans progressiva 0.05 2442 X-linked lymphoproliferative disease 0.05 * 2788 Osteoporosis - pseudoglioma 0.05 * 325 Congenital factor II 0.05 * 331 Congenital factor XIII 0.05 * 77261 Gaucher disease type 3 0.05 * 309294 Sialidosis 0.05 BP* 99718 Leber plus disease 0.04 * Primary pigmented nodular adrenocortical 189439 0.04 * disease 69087 Naegeli-Franceschetti-Jadassohn 0.035 * Congenital muscular dystrophy with integrin 34520 0.03 * alpha-7 280210 Pelizaeus-Merzbacher disease, connatal form 0.03 * Pelizaeus-Merzbacher disease, transitional 280224 0.03 * form 93976 Anotia 0.028 BP* 740 Hutchinson-Gilford progeria 0.025 BP prevalence (/,000) 227 Diphallia 0.02 BP 584 Mucopolysaccharidosis type 7 0.01 * 3169 Sirenomelia 0.01 77260 Gaucher disease type 2 0.01 * 90308 Klippel-Trénaunay 0.007 * 740 Hutchinson-Gilford progeria 0.005 Poliomyelitis in patients with 309 immunodeficiencies deemed at risk 8.0E-4 * 391474 Frontorhiny 0.0 Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 12

List of diseases or groups of diseases by decreasing incidence 69665 Intrahepatic cholestasis of pregnancy 0.0* 178045 Transient congenital hypothyroidism 0.0* 99828 Dengue fever 714.0 94093 Neuroleptic malignant 170.0 874 Adult heart tumor 140.9* 3389 Tuberculosis 139.0 673 Malaria 73.0 418959 Squamous cell carcinoma of stomach 55.0 65250 Perineural cyst 50.0* 558 Marfan 25.0* 2810 Idiopathic facial palsy 25.0 507 Leishmaniasis 25.0 178320 Acute lung injury 25.0* 91546 Lyme disease 21.9 63443 Rare epithelial tumor of stomach 18.6* 98715 Uveitis 17.0* 813 Silver-Russell 15.5* 461 Recessive X-linked ichthyosis 15.0* 418 Congenital adrenal hyperplasia 13.35* 268316 Complication in hemodialysis 13.0* Carcinoma of gallbladder and 56044 extrahepatic biliary tract 12.0 547 Non-Hodgkin lymphoma 11.6* 1546 Cryptococcosis 11.0* 435 Ito hypomelanosis 10.85* 137839 Lemierre 10.0* 2209 Maternal phenylketonuria 10.0* 3467 Hereditary xanthinuria 9.05* Squamous cell carcinoma of head and 67037 neck 8.7 94 Astrocytoma 8.0* 1941 Juvenile absence epilepsy 7.5* 70482 Carcinoma of esophagus 7.0 2 Immune thrombocytopenic purpura 6.75* 448 Hemophilia 6.25* 29073 Multiple myeloma 6.0 58220 Microscopic colitis 6.0* 182095 Interstitial lung disease 5.4* 146 Differentiated thyroid carcinoma 5.25 171901 Primary cutaneous T-cell lymphoma 5.2* 99977 Squamous cell carcinoma of esophagus 5.2 incidence(/,000) 3099 Rheumatic fever 5.0* 70567 Cholangiocarcinoma 4.2 217074 Rare carcinoma of pancreas 3.9 2929 Juvenile polyposis 3.85* 2032 Idiopathic pulmonary fibrosis 3.81* 182130 Tumor of endocrine glands 3.75* 548 Leprosy 3.7 Infant acute respiratory distress 70587 3.5* 36205 Collagenous colitis 3.35 087 Thyroid tumor 3.2 363472 Tumor of testis and paratestis 3.15* 088 Thyroid carcinoma 3.1 186 Primary biliary cirrhosis 3.0 360 Glioblastoma 3.0 96061 Mosaic trisomy 8 3.0* 99745 Typhoid 3.0* Complete androgen insensitivity 99429 3.0* Familial isolated dilated 154 cardiomyopathy 2.91* 513 Acute lymphoblastic leukemia 2.75* 95716 Familial thyroid dyshormonogenesis 2.67 70 Proximal spinal muscular atrophy 2.6* 877 Endocrine tumor 2.53* 2038 Pulmonary arteriovenous fistula 2.5 519 Acute myeloid leukemia 2.5 Chronic recurrent multifocal 324964 osteomyelitis 2.5 98293 Hodgkin lymphoma 2.4* 391 Classic Hodgkin lymphoma 2.38* 352 Galactosemia 2.1* 79239 Classic galactosemia 2.1* 98375 Autoimmune hemolytic anemia 2.02* 1866 Focal, segmental or multifocal dystonia 2.0* 729 Polycythemia vera 1.9* 50251 Pleural mesothelioma 1.9* 102 Multiple system atrophy 1.8 Testicular seminomatous germ cell 842 tumor 1.71* 355 Gaucher disease 1.7* 139417 Acute transverse myelitis 1.6 553 Cushing 1.55* 512 Metachromatic leukodystrophy 1.5* 92 Juvenile idiopathic arthritis 1.5* 35 Propionic acidemia 1.5 618 Familial melanoma 1.5* incidence(/,000) Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 13

26106 Hereditary diffuse gastric cancer 1.5* 52688 Myelodysplastic 1.5* 2103 Guillain-Barré 1.45 801 Scleroderma 1.41 803 Amyotrophic lateral sclerosis 1.35 250923 Isolated aniridia 1.31* 77 Aniridia 1.3* 635 Neuroblastoma 1.26 521 Chronic myeloid leukemia 1.25* Proximal spinal muscular atrophy type 83418 1.23* 2 Non-seminomatous germ cell tumor of 363494 1.21* testis 2137 Chronic autoimmune hepatitis 1.2 Epstein-Barr virus-associated gastric 313920 carcinoma 1.2 549 Legionellosis 1.1* Proximal spinal muscular atrophy type 83419 1.1* 3 398043 Malignant tumor of penis 1.075* 91349 Non-functioning pituitary adenoma 1.05 848 Beta-thalassemia 1.0 710 Pfeiffer 1.0* 727 Microscopic polyangiitis 1.0* Malignant peripheral nerve sheath 3148 tumor 1.0 400 Cystic echinococcosis 1.0* 2781 Osteopetrosis 1.0* 44890 Gastrointestinal stromal tumor 1.0 824 Myelofibrosis with myeloid metaplasia 1.0* 69078 Liposarcoma 1.0* 54595 Craniopharyngioma 1.0 157798 Hyperplastic polyposis 1.0 209964 Solitary rectal ulcer 1.0* 2023 Undifferentiated pleomorphic sarcoma 0.9* 2467 Systemic mastocytosis 0.9* 33226 Waldenström macroglobulinemia 0.81* 223727 Bone sarcoma 0.8* 930 Idiopathic achalasia 0.77 542 Primary cutaneous lymphoma 0.75* 900 Granulomatosis with polyangiitis 0.7* 46484 Oligodendroglial tumor 0.7* 070 Progressive non-fluent aphasia 0.7* 99976 Adenocarcinoma of esophagus 0.7 683 Progressive supranuclear palsy 0.65 171 Primary sclerosing cholangitis 0.65 79139 Japanese encephalitis 0.65* incidence(/,000) 83597 Acute disseminated encephalomyelitis 0.6* 101330 Porphyria cutanea tarda 0.6* 780 Rhabdomyosarcoma 0.59* 178566 Mycosis fungoides and variants 0.59* 732 Polymyositis 0.585* 398058 Squamous cell carcinoma of penis 0.57* 221 Dermatomyositis 0.55* 99892 ACTH-dependent Cushing 0.55 589 Myasthenia gravis 0.53 99971 Well-differentiated liposarcoma 0.51* 191 Cockayne 0.5* 2584 Classic mycosis fungoides 0.5* 980 Absence of the pulmonary artery 0.5* 39044 Uveal melanoma 0.5* 820 Sneddon 0.4* T-cell large granular lymphocyte 86872 leukemia 0.4* 101959 Chronic primary adrenal insufficiency 0.4* 399 Huntington disease 0.38 83484 St. Louis encephalitis 0.38* 36426 Stevens-Johnson 0.36* 963 Acromegaly 0.35 728 Relapsing polychondritis 0.35 49041 IgG4-related retroperitoneal fibrosis 0.35* 329217 Cerebral sinovenous thrombosis 0.35* 33276 Kaposi sarcoma 0.34* 533 Listeriosis 0.337 1070 Anisakiasis 0.32 Proximal spinal muscular atrophy type 83420 0.32* 4 1930 Herpes simplex encephalitis 0.3 Hereditary pheochromocytomaparaganglioma 29072 0.3 873 Desmoid tumor 0.3* 52417 MALT lymphoma 0.3* 178478 Infant botulism 0.3* Acute generalized exanthematous 293173 pustulosis 0.3 93672 Juvenile dermatomyositis 0.295 58017 Hairy cell leukemia 0.29* 79140 Cutaneous neuroendocrine carcinoma 0.27 99970 Dedifferentiated liposarcoma 0.27* Proximal spinal muscular atrophy type 83330 0.26* 1 168999 Malignant melanoma of the mucosa 0.26* 97279 Insulinoma 0.25 139423 Idiopathic acute transverse myelitis 0.25* incidence(/,000) Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 14

329977 Classic endocrine tumor of appendix 0.25 55880 Chondrosarcoma 0.24* 668 Osteosarcoma 0.23* 1332 Medullary thyroid carcinoma 0.22* 97253 Pancreatic endocrine tumor 0.21* 301 Ependymal tumor 0.2* 96253 Cushing disease 0.2* 251636 Ependymoma 0.2* Primary hepatic neuroendocrine 085 carcinoma 0.2 3287 Takayasu arteritis 0.19* 95455 Toxic epidermal necrolysis 0.19 Primary cutaneous CD30+ T-cell 541 lymphoproliferative disease 0.18* Eosinophilic granulomatosis with 183 polyangiitis 0.18* 543 Burkitt lymphoma 0.17* 3398 Thymic epithelial neoplasm 0.17* 142 Anaplastic thyroid carcinoma 0.17* 284 Alveolar echinococcosis 0.16* 204 Creutzfeldt-Jakob disease 0.15 2495 Meningioma 0.15* Transmissible spongiform 56970 encephalopathy 0.15* 33402 Pediatric hepatocellular carcinoma 0.15* 654 Nephroblastoma 0.14* 99867 Thymoma 0.14* 319 Ewing sarcoma 0.13* Malignant sex cord stromal tumor of 35808 ovary 0.13* 182114 Rare urogenital tumor 0.13* 913 Zollinger-Ellison 0.125 2086 Optic pathway glioma 0.12 Nodular lymphocyte predominant 86893 0.12 Hodgkin lymphoma 616 Medulloblastoma 0.11* 520 Acute promyelocytic leukemia 0.11* 112 Bartter 0.1* 509 Leptospirosis 0.1* Autosomal dominant hyper-ige 2314 0.1* 2382 Lennox-Gastaut 0.1* 514 Acute monoblastic leukemia 0.1* Cardiodysrhythmic potassium-sensitive 37553 0.1* periodic paralysis 26790 Pseudomyxoma peritonei 0.1 53035 Caroli disease 0.1 99967 Myxoid/round cell liposarcoma 0.1* incidence(/,000) 98919 Miller-Fisher 0.1* 228371 Foodborne botulism 0.1* 178475 Wound botulism 0.1* Anti-glomerular basement membrane 375 disease 0.08* 35807 Malignant germ cell tumor of ovary 0.08* 73274 Acquired hemophilia 0.08 79277 Congenital erythropoietic porphyria 0.065* 790 Retinoblastoma 0.05* 1267 Botulism 0.05* 99969 Pleomorphic liposarcoma 0.05* 99931 Idiopathic pulmonary hemosiderosis 0.0425* 331 Congenital factor XIII 0.04* 248111 Juvenile Huntington disease 0.04* 385 Pituitary carcinoma 0.04* Autoimmune pulmonary alveolar 747 proteinosis 0.04 357034 Non-hereditary retinoblastoma 0.038* 2573 Moyamoya disease 0.035* 290 Congenital rubella 0.03* 1501 Adrenocortical carcinoma 0.03* 33355 Reticular dysgenesis 0.03* 46487 Acquired epidermolysis bullosa 0.03* 99865 Spermatocytic seminoma 0.03* 329984 Goblet cell carcinoma 0.025 449 Hepatoblastoma 0.02* 1957 Esthesioneuroblastoma 0.02* 1183 Opsoclonus-myoclonus 0.02* 143 Parathyroid carcinoma 0.02* 99928 Placental site trophoblastic tumor 0.02* 251909 Pineoblastoma 0.02* 251679 Astroblastoma 0.02* 363489 Sex cord-stromal tumor of testis 0.02* 31837 Pulmonary venoocclusive disease 0.015* 538 Lymphangioleiomyomatosis 0.0135 79276 Acute intermittent porphyria 0.013* Autosomal erythropoietic 79278 protoporphyria 0.012* 2030 Fibrosarcoma 0.01* 55881 Adamantinoma 0.01* 251899 Choroid plexus carcinoma 0.01* 79473 Porphyria variegata 0.008* Pleuropulmonary blastoma family 284343 tumor susceptibility 0.007 97280 Glucagonoma 0.005* 97283 Somatostatinoma 0.0025* incidence(/,000) Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 15

List of diseases or groups of diseases by decreasing number of published cases or families of published cases 319218 Ebola hemorrhagic fever 50918 Kikuchi-Fujimoto disease 2309 Pachyonychia congenita 158014 Rosaï-Dorfman disease 64 Alström 1917 Fetal methylmercury 83312 Rickettsialpox 85 Congenital dyserythropoietic anemia 99825 Nipah virus disease 167 Chédiak-Higashi 26 Methylmalonic acidemia with homocystinuria 2138 46,XX ovotesticular disorder of sex development 2930 Cronkhite-Canada 3261 Autoimmune lymphoproliferative 34526 Familial primary hypomagnesemia 42642 PFAPA 35687 Erdheim-Chester disease 69077 Rhabdoid tumor 73256 Central neurocytoma 79282 Methylmalonic acidemia with homocystinuria, type cblc 99826 Marburg hemorrhagic fever 85448 AGel amyloidosis 22 4-hydroxybutyric aciduria 28220 1052 0 0 950 800 800 740 556 500 500 500 500 500 500 500 500 500 500 500 500 475 450 Vitamin B12-unresponsive methylmalonic 450 79312 acidemia type mut- 404 411593 Insulin autoimmune 400 649 Norrie disease 400 125 Bloom 400 35125 Epidermal nevus 400 025 Alpha-heavy chain disease 400 3348 Tracheobronchopathia osteochondroplastica 400 352540 Oncogenic osteomalacia 390 238606 Primary orthostatic tremor 380 83453 Vulvovaginal gingival 350 2968 Leukocyte adhesion 350 64741 Pulmonary blastoma 85458 Hereditary cerebral hemorrhage with amyloidosis 350 304 838 Susac 1556 Cutis marmorata telangiectatica congenita 570 Moebius 3071 Costello 157 Carnitine palmitoyltransferase II 184 Cherubism 1340 Cardiofaciocutaneous 1328 Camurati-Engelmann disease 1896 EEC 2092 Focal dermal hypoplasia 2909 Rothmund-Thomson 1467 Cogan 2330 Kasabach-Merritt 3347 Mounier-Kühn Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 16

530 Lipoid proteinosis 41 Dyschromatosis symmetrica hereditaria 482 Kimura disease 525 Lichen planopilaris 840 Syringocystadenoma papilliferum 73 Gorham-Stout disease 83469 Desmoplastic small round cell tumor 99147 Acquired von Willebrand Carnitine palmitoyl transferase II, 228302 myopathic form 247245 Superficial siderosis 167635 Scleromyxedema 206569 Autoimmune necrotizing myopathy 237 Duplication of urethra 501 Lafora disease 500 Noonan with multiple lentigines Acute encephalopathy with biphasic seizures and 363549 late reduced diffusion 2070 Eosinophilic gastroenteritis Capillary malformation - arteriovenous 137667 malformation 2908 Kindler 79087 Partial acquired lipodystrophy 006 ABeta amyloidosis, Dutch type 98954 Meesmann corneal dystrophy 163634 Maffucci 373 Simpson-Golabi-Behmel 90283 Lupus erythematosus tumidus 199318 15q13.3 microdeletion 2710 Oculodentodigital dysplasia 296 283 280 261 250 250 250 250 250 250 250 246 243 241 169105 Good Megacystis-microcolon-intestinal hypoperistalsis 230 2241 220 65285 Lhermitte-Duclos disease 205 587 Muir-Torre 204 2796 Pachydermoperiostosis 203 2510 Micro 201 33364 Trichothiodystrophy 1598 Monosomy 18p 193 Cohen 1059 Blue rubber bleb nevus 3165 Eosinophilic fasciitis Alpha-thalassemia-X-linked intellectual disability 847 1986 Gollop-Wolfgang complex 1980 Bilateral striopallidodentate calcinosis 2616 3M 575 Muckle-Wells 559 Marinesco-Sjögren 343 Hyperimmunoglobulinemia D with periodic fever 414 Gyrate atrophy of choroid and retina 1451 CINCA 452 X-linked lissencephaly with abnormal genitalia 317 Erythrokeratodermia variabilis 302 Epidermodysplasia verruciformis 2088 Glycogen storage disease due to GLUT2 1063 Tufted angioma 220 Denys-Drash 36412 Hypocomplementemic urticarial vasculitis Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 17

523 Hereditary leiomyomatosis and renal cell cancer 679 Malignant atrophic papulosis 66630 Congenital pseudoarthrosis of clavicle 48377 Subcorneal pustular dermatosis 48686 Primary effusion lymphoma 48652 Monosomy 22q13 79277 Congenital erythropoietic porphyria 79255 GM1 gangliosidosis type 1 75563 X-linked sideroblastic anemia 91385 Acquired angioedema 97360 Robinow 97231 Ligneous conjunctivitis 139436 Multicentric reticulohistiocytosis 139491 Hemochromatosis type 4 137867 Madras motor neuron disease 99050 Pulmonary artery coming from the aorta 220407 Limited systemic sclerosis 221016 Rothmund-Thomson type 2 199267 Infantile digital fibromatosis 293848 Right temporal lobar atrophy Familial primary hypomagnesemia with 306516 hypercalciuria and nephrocalcinosis 1540 Jackson-Weiss 402035 Eosinophilic colitis 28 Vitamin B12-responsive methylmalonic acidemia 1465 Coffin-Siris 293381 Epithelial recurrent erosion dystrophy 1475 Renal coloboma 196 192 190 186 180 254509 Iatrogenic botulism 98960 Thiel-Behnke corneal dystrophy Celiac disease, epilepsy and cerebral calcification 1459 Megalencephaly-capillary malformationpolymicrogyria 60040 97685 17q11 microdeletion 252212 Malignant triton tumor 324636 Autoerythrocyte sensitization 1522 Craniometaphyseal dysplasia 1359 Carney complex 48431 Congenital cataracts - facial dysmorphism - neuropathy 324 Persistent polyclonal B-cell lymphocytosis 226 Dihydropteridine reductase 3467 Hereditary xanthinuria 3103 Roberts 2048 Foix-Chavany-Marie 2108 Hallermann-Streiff 3197 Hereditary hyperekplexia 3265 Humero-radial synostosis 2637 Microcephalic osteodysplastic primordial dwarfism type II 662 Yellow nail 35069 Infantile neuroaxonal dystrophy 28378 Tyrosinemia type 2 37748 Schnitzler 188 Systemic capillary leak 71274 Disseminated peritoneal leiomyomatosis 52503 X-linked creatine transporter 79259 Glycogen storage disease due to glucose-6- phosphatase type b 180 173 170 170 170 170 170 160 160 160 154 150 150 150 150 150 150 150 150 150 150 150 150 150 150 150 150 Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 18

150 84142 Isaac 150 93682 Pediatric Castleman disease 150 139411 Carney triad 150 168816 Peritoneal cystic mesothelioma 150 314777 Familial isolated pituitary adenoma 150 284454 Acute zonal occult outer retinopathy 148 135 CACH 147 398166 Focal facial dermal dysplasia 145 166113 Bazex 143 113 Bazex-Dupré-Christol 140 2576 MULIBREY nanism 140 83450 Regional odontodysplasia 140 79314 L-2-hydroxyglutaric aciduria 140 90003 IgG4-related hepatopathy Mendelian susceptibility to mycobacterial diseases 140 319552 due to complete IL12RB1 137 2290 Microvillus inclusion disease Immune dysregulation-polyendocrinopathyenteropathy-x-linked 136 37042 130 3400 Aorto-ventricular tunnel 130 178307 Reticulate acropigmentation of Kitamura 130 834 Free sialic acid storage disease Leukoencephalopathy with brain stem and spinal 127 137898 cord involvement - high lactate 125 650 LCAT 123 1305 Feingold 120 2343 Isolated cloverleaf skull 120 51 Aicardi-Goutières Hereditary motor and sensory neuropathy, 120 90117 Okinawa type 120 026 Gamma-heavy chain disease 120 391641 Feingold type 1 Combined hamartoma of the retina and retinal 120 440727 pigment epithelium 117 3138 Ulnar-mammary 117 398073 Prader-Willi-like 115 48918 Focal myositis 115 98967 Schnyder corneal dystrophy 114 261494 Kleefstra Postaxial polydactyly-anterior pituitary anomaliesfacial dysmorphism 112 420584 Hyperornithinemia-hyperammonemiahomocitrullinuria 111 415 110 245 Nager Familial primary hypomagnesemia with 110 31043 hypercalciuria and nephrocalcinosis without severe ocular involvement 106 86909 Myoclonic epilepsy of infancy 88637 Hypomyelination-hypogonadotropichypogonadism-hypodontia 105 105 221150 Pitt-Hopkins-like 349 Fucosidosis 800 Schwartz-Jampel 45 Adenosine monophosphate deaminase 833 Encephalopathy due to sulfite oxidase 2053 Freeman-Sheldon 2785 Osteopetrosis with renal tubular acidosis 2414 Congenital pulmonary lymphangiectasia 477 KID 291 Fetal varicella 2882 Sitosterolemia 274 Bernard-Soulier 869 Triple A 981 Internal carotid agenesis Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 19

1507 Autosomal recessive Robinow 672 Pallister-Hall 2222 Hypertrichosis lanuginosa congenita 1826 Frontometaphyseal dysplasia 2780 Osteopathia striata - cranial sclerosis 2697 Arthrogryposis - renal dysfunction - cholestasis 2704 Ochoa 2342 Haim-Munk 3107 Autosomal dominant Robinow 572 Immuno by defective expression of HLA class 2 746 Mitochondrial trifunctional protein 24 Fumaric aciduria 332 Congenital intrinsic factor 3243 Sweet 3319 Congenital amegakaryocytic thrombocytopenia 1929 Rasmussen subacute encephalitis 2478 Megalencephalic leukoencephalopathy with subcortical cysts 33110 Autosomal agammaglobulinemia 31150 Tangier disease 30924 Primary hypomagnesemia with secondary hypocalcemia 42775 PHACE 35708 Aromatic L-amino acid decarboxylase 898 Wagner disease 724 Idiopathic acute eosinophilic pneumonia 71517 Rapid-onset dystonia-parkinsonism 70593 Immuno due to selective antipolysaccharide antibody 59306 McLeod neuroacanthocytosis 79403 Junctional epidermolysis bullosa - pyloric atresia 79409 Recessive dystrophic epidermolysis bullosa inversa 77258 Trichorhinophalangeal type 1 and 3 75326 Retinal arterial tortuosity 79086 Acquired generalized lipodystrophy Monoclonal Ig light chain-associated Fanconi 91136 89937 Autosomal dominant hypophosphatemic rickets 86813 Helicoid peripapillary chorioretinal degeneration 94087 Cytophagic histiocytic panniculitis 93686 Multicentric Castleman disease 139380 Recessive hereditary methemoglobinemia type 2 99015 Spastic paraplegia type 2 228 Rothmund-Thomson type 1 238769 1q44 microdeletion 254478 Lichen planus pemphigoides 140957 Autosomal dominant macrothrombocytopenia 168569 H 199241 Pulmonary capillary hemangiomatosis 306741 Hemidystonia-hemiatrophy 1293 Brachyolmia 1310 Caffey disease 1221 Cheilitis glandularis 351 Galactosialidosis 352723 Attenuated Chédiak-Higashi 65748 Multiple self-healing squamous epithelioma 502 Langer-Giedion 79493 Brooke-Spiegler Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 20

261476 Monosomy Xp21 Autosomal dominant neovascular inflammatory 329211 vitreoretinopathy 99 71276 Silent sinus 98 293181 Malignant migrating partial seizures of infancy 94 52368 Mohr-Tranebjaerg 91 1885 Isolated ectopia lentis 90 742 Prolidase 90 Progressive non-infectious anterior vertebral 2062 fusion 90 276198 Spinocerebellar ataxia type 36 90 2473 McKusick-Kaufman 90 59 Allan-Herndon-Dudley 89 347 Frasier 88 2044 Floating-Harbor 87 96147 Kleefstra due to 9q34 microdeletion 86 3403 Uhl anomaly 84 Glycogen storage disease due to LAMP-2 34587 84 2635 Metatropic dysplasia 81 79133 Focal facial dermal dysplasia type I 81 98961 Reis-Bücklers corneal dystrophy 81 333 Farber disease 80 1935 Early myoclonic encephalopathy 80 526 Liddle 80 955 Acroosteolysis dominant type 80 709 Peters plus 80 382 Guanidinoacetate methyltransferase 80 3342 Arterial tortuosity 80 901 Wells 80 49 Penile agenesis 80 Thiamine-responsive megaloblastic anemia 49827 80 79315 D-2-hydroxyglutaric aciduria 80 97229 Riboflavin transporter 80 Autosomal recessive early-onset inflammatory 238569 bowel disease 80 231401 Alpha-thalassemia-myelodysplastic 80 950 Acrodysostosis 80 2396 Encephalocraniocutaneous lipomatosis 77 1393 Cerebro-costo-mandibular 75 79230 Hemochromatosis type 2 74 209981 IRIDA 74 622 Homocystinuria without methylmalonic aciduria 73 Mutilating palmoplantar keratoderma with 659 periorificial keratotic plaques 73 2196 Familial primary hypomagnesemia with 72 hypercalciuria and nephrocalcinosis with severe ocular involvement 2671 Neu-Laxova 72 1830 Schimke immuno-osseous dysplasia 71 1442 Ring chromosome 18 70 760 Purine nucleoside phosphorylase 70 2123 Diffuse neonatal hemangiomatosis 70 6 Median cleft lip/mandibule 70 2484 Melnick-Needles 70 756 Pseudohypoaldosteronism type 1 70 65759 Carpenter 70 46489 Bullous systemic lupus erythematosus 70 79293 Familial LCAT 70 79257 GM1 gangliosidosis type 3 70 Autosomal dominant mendelian susceptibility to 319581 mycobacterial diseases due to partial IFNgammaR1 70 404546 DITRA 70 357043 Amyotrophic lateral sclerosis type 4 70 Congenital adrenal hyperplasia due to 3-betahydroxysteroid dehydrogenase 90791 68 98975 Congenital hereditary endothelial dystrophy type I 68 2554 Ear-patella-short stature 67 160148 Cap polyposis 67 2268 ICF 66 32 Glutathione synthetase 65 2333 Kenny-Caffey 65 51636 WHIM 65 90354 Brittle cornea 65 Hereditary hyperferritinemia with congenital 163 cataracts 64 3242 Renpenning 64 75392 Ehlers-Danlos, periodontitis type 62 2855 Perrault 61 3051 Intellectual disability - sparse hair - brachydactyly 61 699 Pearson 60 239 Dyggve-Melchior-Clausen disease 60 677 Pancreatoblastoma 60 381 Griscelli disease 60 969 Acromicric dysplasia 60 1270 Bowen-Conradi 60 1667 Wolcott-Rallison 60 139 CHILD 60 2065 Galloway-Mowat 60 2462 Shprintzen-Goldberg 60 708 Peters anomaly 60 159 Carnitine-acylcarnitine translocase 60 Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 21

3338 Toriello-Carey 60 3411 Double uterus - hemivagina - renal agenesis 60 2221 Acquired hypertrichosis lanuginosa 60 721 Gray platelet 60 52530 Pseudo-von Willebrand disease 60 63455 Paraneoplastic pemphigus 60 Vitamin B12-responsive methylmalonic acidemia 79310 type cbla 60 Mandibulofacial dysostosis-microcephaly 79113 60 90349 Autosomal recessive cutis laxa type 1 60 99803 Haddad 60 158029 Sea-blue histiocytosis 60 493 Sagliker 60 773 Refsum disease 60 2332 KBG 59 79320 ALG6-CDG 58 293642 Blepharophimosis-intellectual disability 58 88644 Autosomal recessive ataxia, Beauce type 57 Autosomal recessive severe congenital 331176 neutropenia due to G6PC3 57 46 Adenylosuccinate lyase 56 71 Chylomicron retention disease 55 2556 Microphthalmia with linear skin defects 55 826 Sporotrichosis 55 57782 Mazabraud 54 83628 PELVIS 54 Autosomal recessive spastic ataxia with 314603 leukoencephalopathy 54 79099 Interstitial granulomatous dermatitis with arthritis 53 251515 Distal arthrogryposis type 10 53 178509 Perry 53 398088 Hereditary cryohydrocytosis with normal stomatin 53 3473 Zimmermann-Laband 52 251671 Angiocentric glioma 52 98767 Spinocerebellar ataxia type 11 51 585 Multiple sulfatase 50 868 Triose phosphate-isomerase 50 1414 Cholestasis-lymphedema 50 2801 Juvenile Paget disease 50 3111 Rotor 50 574 Monosomy 21 50 808 Seckel 50 871 Familial progressive cardiac conduction defect 50 897 Waardenburg-Shah 50 1444 Ring chromosome 20 50 40 Acromesomelic dysplasia, Maroteaux type 50 156 Carnitine palmitoyl transferase 1A 50 1253 Ascher 50 127 Borjeson-Forssman-Lehmann 50 1297 Branchio-oculo-facial 50 1125 Ocular motor apraxia, Cogan type 50 1118 Fibular aplasia - ectrodactyly 50 1573 Hypotrichosis with juvenile macular degeneration 50 1440 Ring chromosome 14 50 1425 Desbuquois 50 165 Neutral lipid storage disease 50 2078 Geroderma osteodysplastica 50 2143 Donnai-Barrow 50 2136 Hennekam 50 1997 Blepharo-cheilo-odontic 50 2028 Juvenile hyaline fibromatosis 50 2632 Langer mesomelic dysplasia 50 2461 Marden-Walker 50 2407 LOC 50 2896 Pitt-Hopkins 50 2805 Partial pancreatic agenesis 50 Hemolytic anemia due to glucophosphate 712 isomerase 50 851 Paris-Trousseau thrombocytopenia 50 3231 Deafness-onychodystrophy 50 3253 Zlotogora-Ogur 50 361 Familial glucocorticoid 50 1902 Ehrlichiosis 50 33111 Granulomatous slack skin 50 29822 Spontaneous periodic hypothermia 50 71518 Benign paroxysmal torticollis of infancy 50 59315 Rhombencephalosynapsis 50 53540 Goldmann-Favre 50 79500 DOORS 50 79143 Isolated congenital anonychia 50 79256 GM1 gangliosidosis type 2 50 75382 Oguchi disease 50 91496 Snowflake vitreoretinal degeneration 50 90342 Xeroderma pigmentosum variant 50 90348 Autosomal dominant cutis laxa 50 86816 Congenital analbuminemia 50 Cystic leukoencephalopathy without 85136 megalencephaly 50 85212 Fetal Gaucher disease 50 98811 Paroxysmal exertion-induced dyskinesia 50 Glycogen storage disease due to phosphoglycerate 97234 50 mutase 93600 Primary hyperoxaluria type 3 50 Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 22

137888 Auriculocondylar 50 101150 Autosomal recessive dopa-responsive dystonia 50 102069 Hepatic amyloidosis with intrahepatic cholestasis 50 012 Lissencephaly with cerebellar hypoplasia type B 50 99872 Hashimoto-Pritzker 50 217385 17p13.3 microduplication 50 221046 Poikiloderma with neutropenia 50 157846 Neuroferritinopathy 50 171929 Trisomy 10p 50 208513 Spinocerebellar ataxia type 29 50 206583 Adult polyglucosan body disease 50 512 Onychomatricoma 50 Xeroderma pigmentosum complementation group 276255 50 C 284448 CLIPPERS 50 Multicentric osteolysis-nodulosis-arthropathy 371428 spectrum 50 404507 Chondromyxoid fibroma 50 352636 Phalangeal microgeodic 50 79147 Familial reactive perforating collagenosis 50 Keratoderma hereditarium mutilans with 79395 ichthyosis 50 1873 Jalili 49 54251 Corticosteroid-sensitive aseptic abscess 49 Mendelian susceptibility to mycobacterial diseases 319558 49 due to complete IL12B 255229 Navajo neurohepatopathy 49 3447 Weaver 48 2897 Pityriasis rubra pilaris 48 Rapid-onset childhood obesity - hypothalamic 293987 dysfunction - hypoventilation - autonomic dysregulation 48 989 Hypoglossia-hypodactyly 47 1509 Coxopodopatellar 47 216828 Osteogenesis imperfecta type 5 47 250994 1q21.1 microduplication 46 798 Schinzel-Giedion 46 86788 X-linked severe congenital neutropenia 45 99749 Kostmann 45 209932 Cone dystrophy with supernormal rod response 45 279947 Postorgasmic illness 45 284984 Aneurysm-osteoarthritis 45 Mitochondrial DNA depletion, 254875 myopathic form 45 84064 Syndromic diarrhea 44 Seborrhea-like dermatitis with psoriasiform 168606 elements Dopa-responsive dystonia due to sepiapterin 70594 reductase 44 43 1052 Mosaic variegated aneuploidy 41 254351 Distal 7q11.23 microdeletion 41 398156 Oculoauriculofrontonasal 41 2301 Congenital short bowel 41 2771 Bruck 40 9 Tetrasomy X 40 Congenital cataract - hypertrophic cardiomyopathy 1369 40 - mitochondrial myopathy 2971 Peroxisomal acyl-coa oxidase 40 1745 Distal trisomy 6p 40 1742 Trisomy 5p 40 1699 Trisomy 12p 40 Congenital generalized hypertrichosis, Ambras 1023 type 40 1923 Methimazole embryofetopathy 40 859 Transcobalamin 40 1517 Hypertrichotic osteochondrodysplasia, Cantu type 40 2273 Ichthyosis follicularis - alopecia - photophobia 40 2470 Matthew-Wood 40 2457 Mandibuloacral dysplasia 40 2962 De Barsy 40 Epidermolysis bullosa simplex with muscular 257 dystrophy 40 Autosomal dominant hypohidrotic ectodermal 1810 dysplasia 40 51188 Ethylmalonic encephalopathy 40 79134 DEND 40 90350 Autosomal recessive cutis laxa type 2 40 96102 Distal trisomy 10q 40 96148 Distal monosomy 10q 40 95159 Hepatoerythropoietic porphyria 40 210548 Macrocephaly-autism 40 228384 5q14.3 microdeletion 40 210122 Congenital alveolar capillary dysplasia 40 314422 Ameloblastic carcinoma 40 263534 Acral peeling skin 40 280785 Bullous diffuse cutaneous mastocytosis 40 280651 Acrodysostosis with multiple hormone resistance 40 281190 Congenital reticular ichthyosiform erythroderma 40 411777 Generalized eruptive keratoacanthoma 40 1515 Cranioectodermal dysplasia 39 1647 Oculocerebrocutaneous 38 2067 GAPO 38 55654 Hypotrichosis simplex 38 Autosomal dominant rhegmatogenous retinal 209867 detachment 38 314621 Duplication of the pituitary gland 38 Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 23

1993 Pai 37 3208 Isolated succinate-coq reductase 37 79406 Late-onset junctional epidermolysis bullosa 37 1766 Dysequilibrium 37 1855 Spondyloenchondrodysplasia 36 98955 Lisch epithelial corneal dystrophy 36 Hereditary North American Indian childhood 168583 cirrhosis 36 573 Polymicrogyria due to TUBB2B mutation 36 Benign infantile focal epilepsy with midline spikes 166308 36 and wave during sleep 446 Neonatal hemochromatosis 35 2040 Congenital bronchobiliary fistula 35 Hereditary sensory and autonomic neuropathy 970 type 2 35 53721 Cobb 35 96125 Distal monosomy 6p 35 024 Mu-heavy chain disease 35 293621 X-linked endothelial corneal dystrophy 35 36 Acrocallosal 34 1437 Ring chromosome 1 34 83 Antley-Bixler 34 1532 Gómez-López-Hernández 34 943 Malonic aciduria 34 69126 Pyogenic arthritis - pyoderma gangrenosum - acne 34 217031 Obesity due to MC3R 34 2874 Phakomatosis pigmentokeratotica 34 363528 Intellectual disability-strabismus 34 Short stature-optic atrophy-pelger-huët anomaly 391677 34 398097 Neonatal antiphospholipid 34 93269 Short rib-polydactyly, Majewski type 34 2406 Locked-in 33 1388 Catel-Manzke 33 2783 Autosomal dominant osteopetrosis type 1 33 561 Marshall-Smith 33 3102 Richieri Costa-Pereira 33 2170 Methylcobalamin type cblg 33 832 Succinyl-CoA:3-ketoacid CoA transferase 33 3322 Hoyeraal-Hreidarsson 33 2795 Polycystic ovaries - urethral sphincter dysfunction 33 123 Björnstad 33 225123 Hemochromatosis type 3 33 3163 SHORT 32 3255 Filippi 32 35664 ALDH18A1-related De Barsy 32 67039 Segmental odontomaxillary dysplasia 32 141096 Supernumerary nostril 32 293843 3MC 32 Chronic diarrhea due to guanylate cyclase 2C 314373 overactivity 32 Autosomal recessive ataxia due to ubiquinone 139485 31 Lower motor neuron with late-adult 276435 onset 31 96173 Ring chromosome 9 31 Glycogen storage disease due to muscle 371 phosphofructokinase 30 246 Postaxial acrofacial dysostosis 30 29 Mevalonic aciduria 30 Aniridia-cerebellar ataxia-intellectual disability 1065 30 2746 Opsismodysplasia 30 Glycogen storage disease due to muscle 715 phosphorylase kinase 30 1752 Trisomy 8q 30 957 Acropectorovertebral dysplasia 30 2615 Nakajo-Nishimura 30 1229 Congenital intrauterine infection-like 30 1225 Baller-Gerold 30 1662 Restrictive dermopathy 30 1545 Crisponi 30 1525 Cranio-osteoarthropathy 30 1427 Otospondylomegaepiphyseal dysplasia 30 2036 Scalp-ear-nipple 30 2763 Osteocraniostenosis 30 2733 Omodysplasia 30 Blepharophimosis-intellectual disability, 2728 30 Ohdo type Microcephalic osteodysplastic primordial dwarfism 2636 30 types I and III 2399 Nasopalpebral lipoma - coloboma - telecanthus 30 5 Pyle disease 30 2834 Wrinkly skin 30 669 Otopalatodigital 30 3266 Humero-radio-ulnar synostosis 30 3258 Cenani-Lenz 30 3352 Tricho-dento-osseous 30 2995 Baraitser-Winter 30 3448 Weaver-Williams 30 3464 Woodhouse-Sakati 30 2849 Perlman 30 35705 Neurometabolic disorder due to serine 30 66628 Obesity due to congenital leptin 30 79411 Transient bullous dermolysis of the newborn 30 Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 24

79456 Diffuse cutaneous mastocytosis 30 79292 Fish-eye disease 30 79155 Encephalopathy due to hydroxykynureninuria 30 79157 2-methylbutyryl-CoA dehydrogenase 30 Anophthalmia/microphthalmia - esophageal 77298 atresia 30 77301 Monosomy 9q22.3 30 91481 Ring dermoid of cornea 30 Spondylometaphyseal dysplasia, 'corner fracture' 93315 type 30 Spondyloepimetaphyseal dysplasia congenita, 93346 Strudwick type 30 Autosomal dominant polycystic kidney disease 88924 type 1 with tuberous sclerosis 30 90045 Hereditary folate malabsorption 30 Camptodactyly - tall stature - scoliosis - hearing 85164 loss 30 85278 Christianson 30 85202 Keutel 30 98764 Spinocerebellar ataxia type 27 30 97297 Bohring-Opitz 30 93940 Laryngo-tracheo-esophageal cleft type 3 30 140933 Linear atrophoderma of Moulin 30 98970 Fleck corneal dystrophy 30 Xeroderma pigmentosum-cockayne 220295 complex 30 Carnitine palmitoyl transferase II, 228305 severe infantile form 30 228116 Hughes-Stovin 30 228236 Linear focal dermal elastosis 30 238446 15q11q13 microduplication 30 163746 Neurologic Waardenburg-Shah 30 141163 Glossopalatine ankylosis 30 Severe neonatal-onset encephalopathy with 209370 microcephaly 30 209943 IRVAN 30 294049 Reunion Island's Larsen 30 275523 Dianzani autoimmune lymphoproliferative disease 30 Xeroderma pigmentosum complementation group 276258 30 D 91396 Isolated cryptophthalmia 30 1943 Infant epilepsy with migrant focal crisis 29 1314 Symmetrical thalamic calcifications 29 2753 Orofaciodigital type 4 29 Leukoencephalopathy with bilateral anterior 139444 temporal lobe cysts 29 2220 Hypertrichosis cubiti - short stature 28 3459 Wilson-Turner 28 50814 Craniolenticulosutural dysplasia 28 Autosomal dominant Charcot-Marie-Tooth disease 228174 28 type 2N Gastric adenocarcinoma and proximal polyposis of 314022 28 the stomach 329466 Autosomal dominant focal dystonia, DYT25 28 Familial episodic pain with 391392 28 predominantly lower limb involvement 466 Fatal familial insomnia 27 1040 Metaphyseal anadysplasia 27 2169 Methylcobalamin type cble 27 Noonan -like disorder with loose anagen 2701 27 hair 2623 Geleophysic dysplasia 27 69085 Limb-mammary 27 99812 LIG4 27 251287 Benign concentric annular macular dystrophy 27 Hereditary diffuse leukoencephalopathy with 313808 axonal spheroids and pigmented glia 27 X-linked central congenital hypothyroidism with 329235 late-onset testicular enlargement 27 1262 Böök 26 40366 Acitretin/etretinate embryopathy 26 98771 Spinocerebellar ataxia type 18 26 Multiple congenital anomalies due to 14q32.2 254519 maternally expressed gene defect 26 Motor developmental delay due to 14q32.2 254516 paternally expressed gene defect 26 Syndactyly - camptodactyly and clinodactyly of 357332 fifth fingers - bifid toes 26 7 3C 25 Palmoplantar keratoderma-spastic paralysis 2201 25 1955 Spinocerebellar ataxia type 34 25 2499 Metachondromatosis 25 3455 Wiedemann-Rautenstrauch 25 3472 Yunis-Varon 25 39041 Omenn 25 50944 Schöpf-Schulz-Passarge 25 54028 Plummer-Vinson 25 56305 Atelosteogenesis type III 25 56304 Atelosteogenesis type II 25 Hepatic veno-occlusive disease - 79124 immuno 25 93109 Congenital megacalycosis 25 85173 IMAGe 25 251019 2q32q33 microdeletion 25 166286 Porokeratotic eccrine ostial and dermal duct nevus 25 314597 Chudley-McCullough 25 268249 Mycophenolate mofetil embryopathy 25 Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 25

281122 Self-healing collodion baby 25 Autosomal dominant childhood-onset proximal 363454 spinal muscular atrophy with contractures 25 1715 Trisomy 18p 25 1234 Bartsocas-Papas 24 1186 Infantile onset spinocerebellar ataxia 24 1361 Carnosinemia 24 3275 Spondylocarpotarsal synostosis 24 Distal myopathy with early respiratory muscle 34521 involvement 24 98972 Central cloudy dystrophy of Francois 24 Hyperphosphatasia-intellectual disability 247262 24 171607 X-linked spastic paraplegia type 34 24 Hypercholesterolemia due to cholesterol 7alphahydroxylase 209902 24 Pyogenic bacterial infections due to MyD88 183713 24 525 Pseudohypoaldosteronism type 2D 24 Autosomal dominant cerebellar ataxia, deafness 314404 and narcolepsy 24 Familial cutaneous telangiectasia and 313846 oropharyngeal predisposition cancer 24 PURA-related severe neonatal hypotonia-seizuresencephalopathy due to a point mutation 438216 24 1617 2q24 microdeletion 23 52022 Potocki-Shaffer 23 93329 Autosomal recessive omodysplasia 23 101028 Transaldolase 23 238475 Familial hypercholanemia 23 261652 Kleefstra due to a point mutation 23 411493 Pontocerebellar hypoplasia type 10 23 Combined immuno due to LRBA 445018 23 2670 Pierson 22 2953 Ehlers-Danlos, musculocontractural type 22 71271 Split hand - split foot - deafness 22 Autosomal dominant deafness-onychodystrophy 79499 22 Familial thoracic aortic aneurysm and aortic 91387 dissection 22 85201 Genitopatellar 22 85203 Acro-pectoral 22 93953 Familial thyroglossal duct cyst 22 228423 Monocytopenia with susceptibility to infections 22 Generalized congenital lipodystrophy with 228429 myopathy 22 163690 Hypotonia-cystinuria 22 209908 Childhood apraxia of speech 22 314718 Lethal arteriopathy due to fibulin-4 22 Developmental delay with autism spectrum 329195 disorder and gait instability 22 269229 Pontine tegmental cap dysplasia 22 Xeroderma pigmentosum complementation group 276264 22 F Childhood-onset autosomal recessive myopathy 363677 with external ophthalmoplegia 22 398173 Focal facial dermal dysplasia type II 22 431255 Scapuloperoneal spinal muscular atrophy 22 445038 3-methylglutaconic aciduria type 7 22 2588 Myhre 21 1578 Dehydratase 21 230 Dopamine beta-hydroxylase 21 69082 Odonto-tricho-ungual-digito-palmar 21 Autosomal dominant intermediate Charcot-Marie- 93114 21 Tooth disease type E Nephrogenic of inappropriate 93606 antidiuresis 21 217330 Hyperuricemia - anemia - renal failure 21 168593 Sudden infant death - dysgenesis of the testes 21 Isolated autosomal dominant hypomagnesemia, 199326 Glaudemans type 21 Autosomal dominant focal non-epidermolytic 403 21 palmoplantar keratoderma with plantar blistering Fatal multiple mitochondrial dysfunction 401869 type 1 21 Familial episodic pain with 391389 predominantly upper body involvement 21 398189 Focal facial dermal dysplasia type IV 21 30 Hereditary orotic aciduria 20 3137 Alpha-N-acetylgalactosaminidase 20 1358 Carey-Fineman-Ziter 20 971 Acrorenal 20 Hypertrichosis-acromegaloid facial appearance 966 20 965 Acromegaloid facial appearance 20 1807 Focal facial dermal dysplasia type III 20 1519 Hypertelorism, Teebi type 20 1513 Craniodiaphyseal dysplasia 20 1493 Vici 20 1387 Cataract - intellectual disability - hypogonadism 20 1466 COFS 20 455 Superficial epidermolytic ichthyosis 20 2755 Orofaciodigital type 8 20 Laryngeal abductor paralysis - intellectual 2375 disability 20 2363 Lacrimoauriculodentodigital 20 3021 RAPADILINO 20 Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 26

Blepharophimosis-intellectual disability, 3047 20 SBBYS type 2847 Pericardial and diaphragmatic defect 20 3226 Deafness - lymphedema - leukemia 20 3387 Isolated anterior cervical hypertrichosis 20 1134 Arrhinia 20 2394 Pyruvate dehydrogenase E3 20 198 Occipital horn 20 33445 Neuroectodermal melanolysosomal disease 20 26137 Juvenile temporal arteritis 20 91 Aromatase 20 69084 Pure hair and nail ectodermal dysplasia 20 67046 3-methylglutaconic aciduria type 1 20 69723 Tyrosinemia type 3 20 65283 Timothy 20 Radio-ulnar synostosis - amegakaryocytic 71289 thrombocytopenia 20 Bleeding diathesis due to a collagen receptor 73271 defect 20 63442 Angel-shaped phalango-epiphyseal dysplasia 20 83616 Rubella panencephalitis 20 79319 MPI-CDG 20 79154 2-aminoadipic 2-oxoadipic aciduria 20 79084 Familial partial lipodystrophy, Köbberling type 20 Channelopathy-associated congenital insensitivity 88642 20 to pain 86797 Atypical lichen myxedematosus 20 88628 Posterior column ataxia - retinitis pigmentosa 20 86919 Keratosis palmaris et plantaris - clinodactyly 20 85192 Calvarial doughnut lesions - bone fragility 20 Alpha-thalassemia-intellectual disability 98791 20 linked to chromosome 16 98773 Spinocerebellar ataxia type 21 20 98768 Spinocerebellar ataxia type 13 20 97232 Fingerprint body myopathy 20 93941 Laryngo-tracheo-esophageal cleft type 4 20 139455 Autosomal recessive bestrophinopathy 20 137678 Czech dysplasia, metatarsal type 20 101110 Spinocerebellar ataxia type 20 20 976 Bathing suit ichthyosis 20 Autosomal dominant Charcot-Marie-Tooth disease 228179 20 type 2M 228247 Acquired pseudoxanthoma elasticum 20 247522 Primary ciliary dyskinesia - retinitis pigmentosa 20 Localized junctional epidermolysis bullosa, non- 251393 Herlitz type 20 251028 2q33.1 microdeletion 20 140966 Palmoplantar keratoderma, Nagashima type 20 178364 Syndromic microphthalmia type 5 20 209905 Brain-lung-thyroid 20 309854 Cirrhosis-dystonia-polycythemiahypermanganesemia 20 352328 MEGDEL 20 261243 16p13.11 microduplication 20 RAS-associated autoimmune leukoproliferative 268114 disease 20 280779 Cutaneous collagenous vasculopathy 20 289863 Atypical glycine encephalopathy 20 Mitochondrial DNA depletion, 369897 encephalomyopathic form with variable craniofacial anomalies 20 420179 Malan overgrowth 20 3339 Toriello-Lacassie-Droste 19 1541 Craniosynostosis, Boston type 19 Hereditary myopathy with lactic acidosis due to 43115 ISCU 19 75857 6q terminal deletion 19 Hereditary inclusion body myopathy - joint 79091 contractures - ophthalmoplegia 19 89838 KRT14-related epidermolysis bullosa simplex 19 Hypomyelination with atrophy of basal ganglia and 139441 19 cerebellum 139447 Progressive cavitating leukoencephalopathy 19 228410 Polyvalvular heart disease 19 251046 6p22 microdeletion 19 178487 Adult intestinal botulism 19 Polyneuropathy - hearing loss - ataxia - retinitis 171848 pigmentosa - cataract 19 293812 Fixed pigmented erythema 19 Congenital muscular dystrophy due to 280671 phosphatidylcholine biosynthesis defect 19 401973 MEND 19 363558 New-onset refractory status epilepticus 19 2353 Schilbach-Rott 18 2460 Van den Ende-Gupta 18 Autosomal dominant primary hypomagnesemia 34528 with hypocalciuria 18 88630 Terminal osseous dysplasia - pigmentary defects 18 Spondylometaphyseal dysplasia - cone-rod 85167 dystrophy 18 Carnitine palmitoyl transferase II, 228308 neonatal form 18 228402 2q23.1 microdeletion 18 319 Charcot-Marie-Tooth disease type 2P 18 324588 Familial dyskinesia and facial myokymia 18 397596 Activated PIK3-delta 18 Methylmalonic acidemia with homocystinuria, 369962 type cblx 18 Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 27

370046 Didymosis aplasticosebacea 18 363417 Temtamy preaxial brachydactyly 18 2318 Joubert with oculorenal defect 17 560 Marshall 17 1325 Camptodactyly - taurinuria 17 1954 Congenital lethal erythroderma 17 1908 Aminopterin/methotrexate embryofetopathy 17 69744 Circumscribed palmoplantar hypokeratosis 17 Methylmalonic acidemia with homocystinuria, 79283 type cbld 17 93282 Spondyloepimetaphyseal dysplasia, PAPSS2 type 17 99844 Leukocyte adhesion type III 17 231573 Congenital erosive and vesicular dermatosis 17 163696 Action myoclonus-renal failure 17 530 Pseudohypoaldosteronism type 2E 17 324381 Hereditary inclusion body myopathy type 4 17 Autoimmune lymphoproliferative due 436159 to CTLA4 haploinsuffiency 17 Chronic atrial and intestinal dysrhythmia 435988 17 99853 Ovarioleukodystrophy 17 1195 Congenital atransferrinemia 16 2102 GTP cyclohydrolase I 16 1438 Ring chromosome 10 16 920 Ablepharon macrostomia 16 1974 Autosomal recessive facio-digito-genital 16 2752 Orofaciodigital type 3 16 Glycogen storage disease due to hepatic glycogen 2089 synthase 16 2538 Microgastria - limb reduction defect 16 33067 Metaphyseal chondrodysplasia, Jansen type 16 Obesity due to prohormone convertase I 71528 16 52994 Orbital leiomyoma 16 85198 Dysspondyloenchondromatosis 16 93972 Juberg-Marsidi 16 99901 Acyl-CoA dehydrogenase 9 16 238455 Infantile dystonia-parkinsonism 16 Hypoplastic pancreas-intestinal atresia-hypoplastic 293864 16 gallbalder Intestinal obstruction in the newborn due to 314376 guanylate cyclase 2C 16 314566 Primary progressive apraxia of speech 16 319171 Distal 17p13.1 microdeletion 16 279943 Hereditary neutrophilia 16 Congenital sideroblastic anemia-b-cell 369861 immuno-periodic fever-developmental delay 16 2721 Odonto-onycho-dermal dysplasia 15 2731 Taurodontia - absent teeth - sparse hair 15 3097 Meacham 15 3405 Umbilical cord ulceration - intestinal atresia 15 3439 Von Voss-Cherstvoy 15 Congenital membranous nephropathy due to 69063 maternal anti-neutral endopeptidase alloimmunization 15 Immuno due to interleukin-1 receptorassociated kinase-4 70592 15 Methylmalonic acidemia with homocystinuria type 79284 15 cblf 79327 ALG1-CDG 15 Scleromyxedema without monoclonal 90400 gammopathy 15 88620 Isolated congenital anosmia 15 103908 Congenital sodium diarrhea 15 Hereditary sclerosing poikiloderma with tendon 221043 and pulmonary involvement 15 140944 CLOVE 15 Congenital muscular dystrophy due to LMNA 157973 mutation 15 171680 Lissencephaly due to TUBA1A mutation 15 314432 Spigelian hernia-cryptorchidism 15 Non-progressive cerebellar ataxia with intellectual 314647 15 disability 329324 Inverse Klippel-Trénaunay 15 261236 16p13.11 microdeletion 15 280133 Complement component 3 15 Severe intellectual disability and progressive 280763 spastic paraplegia 15 Peripheral neuropathy-myopathy-hoarsenesshearing loss 397744 15 397615 Obesity due to CEP19 15 401768 Proximal myopathy with extrapyramidal signs 15 Intrauterine growth restriction-short stature-early 436144 15 adult-onset diabetes 436169 Thrombomodulin-related bleeding disorder 15 98949 Complete cryptophthalmia 15 978 ADULT 14 1193 Atkin-Flaitz 14 1658 Absence of fingerprints - congenital milia 14 1660 Dermo-odonto dysplasia 14 1516 Craniofacial dyssynostosis 14 2789 Lateral meningocele 14 1441 Ring chromosome 17 14 Autosomal recessive limb-girdle muscular 34514 dystrophy type 2G 14 36355 P2Y12 defect 14 79322 DPM1-CDG 14 75378 Oligocone trichromacy 14 Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 28

90390 Anonychia - onychodystrophy 14 93356 Spondyloepimetaphyseal dysplasia, Missouri type 14 228415 5q35 microduplication 14 238750 4q21 microdeletion 14 Autosomal recessive limb-girdle muscular 206549 dystrophy type 2L 14 199351 Adult-onset dystonia-parkinsonism 14 306507 LAMB2-related infantile-onset nephrotic 14 Short stature-onychodysplasia-facial 314394 dysmorphism-hypotrichosis 14 Autosomal recessive mendelian susceptibility to 319569 mycobacterial diseases due to partial IFNgammaR1 14 261257 Distal 17p13.3 microdeletion 14 Retinal dystrophy with inner retinal dysfunction 397758 and ganglion cell anomalies 14 401849 Autosomal spastic paraplegia type 72 14 Microcornea-myopic chorioretinal atrophytelecanthus 369970 14 Autosomal recessive severe congenital 423384 neutropenia due to JAGN1 14 431272 X-linked scapuloperoneal muscular dystrophy 14 1394 Cerebro-facio-thoracic dysplasia 13 2021 Fibrochondrogenesis 13 50945 Blomstrand lethal chondrodysplasia 13 101102 Charcot-Marie-Tooth disease type 2H 13 Acute infantile liver failure due to synthesis defect 217371 13 of mtdna-encoded proteins Non-acquired combined pituitary hormone 231720 with spine abnormalities 13 158025 Hereditary progressive mucinous histiocytosis 13 Osteosclerosis-developmental delaycraniosynostosis 178377 13 171612 Autosomal dominant spastic paraplegia type 37 13 Hypertelorism-preauricular sinus-punctual pitsdeafness 293958 13 Congenital hereditary facial paralysis with variable 306530 13 hearing loss 313936 PENS 13 X-linked mendelian susceptibility to mycobacterial 319605 13 diseases Severe early-onset obesity-insulin resistance 329249 due to SH2B1 13 Familial steroid-resistant nephrotic with 280406 13 sensorineural deafness 284160 8q21.11 microdeletion 13 Tall stature-intellectual disability-facial 404443 dysmorphism 13 401953 Episodic ataxia with slurred speech 13 356978 D,L-2-hydroxyglutaric aciduria 13 357008 Atypical hemolytic-uremic with DGKE 13 352665 9q21 microdeletion 13 Pseudoxanthoma elasticum-like skin 436274 manifestations with retinis pigmentosa 13 435438 Progressive myoclonic epilepsy type 7 13 443098 Hyperostosis cranialis interna 13 Intellectual disability-expressive aphasia-facial 436151 dysmorphism 13 844 Atrial tachyarrhythmia with short PR interval 12 956 Acro-pectoro-renal dysplasia 12 Uveal coloboma-cleft lip and palate-intellectual 1473 disability 12 Alopecia-epilepsy-pyorrhea-intellectual disability 8 12 1190 Atelosteogenesis type I 12 1458 CODAS 12 1471 Coloboma of macula - brachydactyly type B 12 2237 Hypoparathyroidism - deafness - renal disease 12 2224 Hypertryptophanemia 12 3460 Torg-Winchester 12 600 Distal myopathy with vocal cord weakness 12 59303 Ichthyosis - hypotrichosis - sclerosing cholangitis 12 Distal myopathy with posterior leg and anterior 63273 hand involvement 12 X-linked intellectual disability - macrocephaly - 85320 macroorchidism 12 Hemolytic anemia due to adenylate kinase 86817 12 98772 Spinocerebellar ataxia type 19/22 12 93395 Ballard 12 Hereditary sensory and autonomic neuropathy 139578 with spastic paraplegia 12 217346 19q13.11 microdeletion 12 217377 Microduplication Xp11.22-p11.23 12 210571 Dystonia 16 12 228387 Spondylo-megaepiphyseal-metaphyseal dysplasia 12 247794 Juvenile cataract - microcornea - renal glucosuria 12 171829 6q16 deletion 12 199340 Muscular dystrophy, Selcen type 12 Cortical dysgenesis with pontocerebellar 570 hypoplasia due to TUBB3 mutation 12 547 Autosomal recessive infantile hypercalcemia 12 Leukoencephalopathy-thalamus and brainstem 314051 anomalies-high lactate 12 314585 15q overgrowth 12 314588 Distal tetrasomy 15q 12 Mendelian susceptibility to mycobacterial diseases 319547 12 due to complete IFNgammaR2 261250 16q24.3 microdeletion 12 Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 29

261323 21q22.11q22.12 microdeletion 12 261272 17q12 microduplication 12 268261 21q22.13q22.2 microdeletion 12 Recessive intellectual disability - motor 280384 dysfunction - multiple joint contractures 12 280620 Progressive myoclonic epilepsy type 6 12 284460 Acute annular outer retinopathy 12 PRKAR1B-related neurodegenerative dementia 412066 with intermediate filaments 12 Hypohidrosis-enamel hypoplasia-palmoplantar 363523 keratoderma-intellectual disability 12 MYH7-related late-onset scapuloperoneal 437572 muscular dystrophy 12 2253 Foveal hypoplasia - presenile cataract 11 1231 Barber-Say 11 Amelogenesis imperfecta-nephrocalcinosis 1031 11 1757 Fibular dimelia - diplopodia 11 1497 X-linked complicated corpus callosum dysgenesis 11 1487 Cooks 11 2016 Cleft palate-lateral synechia 11 Atrial septal defect - atrioventricular conduction 1479 defects 11 3063 X-linked intellectual disability, Snyder type 11 2987 Antecubital pterygium 11 2832 Short tarsus - absence of lower eyelashes 11 2854 Fuhrmann 11 Trichomegaly - retina pigmentary degeneration - 3363 dwarfism 11 79324 ALG12-CDG 11 79076 Juvenile polyposis of infancy 11 88619 Familial acute necrotizing encephalopathy 11 Combined immuno due to DOCK8 217390 11 238744 Mammary-digital-nail 11 Autosomal dominant limb-girdle muscular 238755 dystrophy type 1H 11 238722 Familial congenital mirror movements 11 Hyperandrogenism due to cortisone reductase 168588 11 Familial scaphocephaly, McGillivray 168624 type 11 166272 Goldblatt 11 166282 Familial sick sinus 11 Leukonychia totalis - acanthosis-nigricans-like 210133 lesions - abnormal hair 11 313850 Infantile cerebellar-retinal degeneration 11 261183 15q11.2 microdeletion 11 280553 Fatal infantile hypertonic myofibrillar myopathy 11 397937 Polyglucosan body myopathy 11 Facial dysmorphism - immuno - livedo - 352712 short stature 11 Combined oxidative phosphorylation 444013 type 23 11 443988 Ventriculomegaly-cystic kidney disease 11 444051 20q11.2 microdeletion 11 1627 Deletion 5q35 10 968 Acromesomelic dysplasia, Hunter-Thomson type 10 916 Aase-Smith 10 1313 Infantile choroidocerebral calcification 10 1336 Hyperkeratosis-hyperpigmentation 10 1263 Boomerang dysplasia 10 1 2q37 microdeletion 10 Autosomal dominant palmoplantar keratoderma 1010 and congenital alopecia 10 1150 Arthrogryposis multiplex congenita - whistling face 10 1952 Pacman dysplasia 10 1824 Lowry-Wood 10 X-linked intellectual disability - Dandy-Walker 1568 malformation - basal ganglia disease - Seizures 10 1788 Acrofacial dysostosis, Rodríguez type 10 1490 Corneal dystrophy - perceptive deafness 10 1426 Greenberg dysplasia 10 Pancreatic hypoplasia - diabetes - congenital heart 2255 10 disease 2319 Juberg-Hayward 10 2081 Cerebral gigantism - jaw cysts 10 Gaucher disease - ophthalmoplegia - 2072 cardiovascular calcification 10 2047 Flynn-Aird 10 2658 Lenz-Majewski hyperostotic dwarfism 10 Muscular atrophy - ataxia - retinitis pigmentosa - 2579 diabetes mellitus 10 Hereditary myoclonus - progressive distal muscular 2590 10 atrophy 2439 Patterson-Stevenson-Fontaine 10 2371 Lethal Larsen-like 10 2329 Karsch-Neugebauer 10 3032 NPHP3-related Meckel-like 10 2959 Progeria - short stature - pigmented nevi 10 2872 Cardiocranial, Pfeiffer type 10 2839 Pelvis-shoulder dysplasia 10 2880 Phosphoenolpyruvate carboxykinase 10 Cerebellar ataxia - areflexia - pes cavus - optic 1171 atrophy - sensorineural hearing loss 10 3317 Thoracolaryngopelvic dysplasia 10 3469 XK aprosencephaly 10 39 Acromelanosis 10 69739 Athabaskan brainstem dysgenesis 10 Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 30

66637 Diaphanospondylodysostosis 10 66625 Cerebro-oculo-nasal 10 Hyperinsulinism due to short chain 3-hydroxylacyl- 71212 10 CoA dehydrogenase 46627 Char 10 79279 Alpha-N-acetylgalactosaminidase type 1 10 79280 Alpha-N-acetylgalactosaminidase type 2 10 79281 Alpha-N-acetylgalactosaminidase type 3 10 79321 ALG3-CDG 10 79083 PPARG-related familial partial lipodystrophy 10 Localized lichen myxedematosus with mixed 90398 features of different subtypes 10 Body skin hyperlaxity due to vitamin K-dependent 91135 10 coagulation factor Centripetalis recessive dystrophic epidermolysis 89841 bullosa 10 85336 X-linked neurodegenerative, Hamel type 10 X-linked intellectual disability - hypotonia - facial 85329 dysmorphism - aggressive behavior 10 Diffuse palmoplantar keratoderma-acrocyanosis 86918 10 85174 Pseudodiastrophic dysplasia 10 85191 Singleton-Merten dysplasia 10 85163 Hypomyelination - congenital cataract 10 85274 Syndromic X-linked intellectual disability 7 10 97340 Hunter-McAlpine craniosynostosis 10 97240 Zebra body myopathy 10 93599 Primary hyperoxaluria type 2 10 93406 Syndactyly type 5 10 139406 Encephalopathy due to prosaposin 10 139426 Perioral myoclonia with absences 10 101111 Spinocerebellar ataxia type 25 10 99954 Charcot-Marie-Tooth disease type 4H 10 013 Lissencephaly with cerebellar hypoplasia type C 10 99843 Leukocyte adhesion type II 10 220465 Laron with immuno 10 Ehlers-Danlos due to tenascin-x 230839 10 Syndromic multisystem autoimmune disease due 228426 to Itch 10 Progressive supranuclear palsy - progressive non 240112 fluent aphasia 10 Dominant hypophosphatemia with nephrolithiasis 244305 10 or osteoporosis Familial clubfoot due to 17q23.1q23.2 238578 microduplication 10 254504 Inhalational botulism 10 254411 Annular atrophic lichen planus 10 X-linked dominant chondrodysplasia, Chassaing- 163966 Lacombe type 10 140969 Saldino-Mainzer 10 147 Orofaciodigital type 9 10 168796 Heart-hand, Slovenian type 10 Combined immuno due to CRAC channel 169090 10 dysfunction 166073 Pontocerebellar hypoplasia type 6 10 168486 Congenital neuronal ceroid lipofuscinosis 10 178330 Heinz body anemia 10 171881 Cap myopathy 10 Sterile multifocal osteomyelitis with periostitis and 210115 10 pustulosis Benign familial nocturnal alternating hemiplegia of 209973 10 childhood 294016 Microcephaly-capillary malformation 10 Transient infantile hypertriglyceridemia and 293 hepatosteatosis 10 313906 Congenital pancreatic cyst 10 Segmental progressive overgrowth with 314662 10 fibroadipose hyperplasia Autosomal recessive congenital cerebellar ataxia 324262 due to MGLUR1 10 325004 CANDLE 10 261211 16p11.2p12.2 microdeletion 10 263458 Hyperinsulinism due to INSR 10 263482 Spondyloepiphyseal dysplasia, Maroteaux type 10 Xeroderma pigmentosum complementation group 276261 10 E Xeroderma pigmentosum complementation group 276267 10 G 276280 Hemihyperplasia-multiple lipomatosis 10 280615 Hemoglobinopathy Toms River 10 Pseudoxanthomatous diffuse cutaneous 280794 mastocytosis 10 Multiple congenital anomalies - hypotonia - 280633 seizures 10 284227 TEMPI 10 ADNP-related multiple congenital anomaliesintellectual disability-autism spectrum disorder 404448 10 Huntington disease-like due to C9ORF72 401901 10 expansions Hypomyelination with brain stem and spinal cord 363412 involvement and leg spasticity 10 352629 16q24.1 microdeletion 10 Autosomal recessive cerebellar ataxia with lateonset spasticity 352641 10 352734 Minimal pigment oculocutaneous albinism type 1 10 Temperature-sensitive oculocutaneous albinism 352737 type 1 10 353320 Pyruvate carboxylase, benign type 10 Intellectual disability-severe speech delay-mild 391372 dysmorphism 10 Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 31

Autoimmune encephalopathy with parasomnia 420789 and obstructive sleep apnea 10 309246 GM2 gangliosidosis, AB variant 10 Fatal congenital hypertrophic cardiomyopathy due 439854 10 to glycogen storage disease 1345 Cardiomyopathy - cataract - hip spine disease 9 1264 Tricho-retino-dento-digital 9 Brachymorphism - onychodysplasia - 1292 dysphalangism 9 1553 Curry-Jones 9 2213 Hypertelorism-microtia-facial clefting 9 8 Acro-cardio-facial 9 2707 Oculocerebrofacial, Kaufman type 9 2557 Mietens 9 33574 Gamma-glutamylcysteine synthetase 9 3-hydroxy-3-methylglutaryl-CoA synthase 35701 9 35704 L-Arginine:glycine amidinotransferase 9 35107 Desmosterolosis 9 69737 Bosley-Salih-Alorainy 9 79405 Junctional epidermolysis bullosa inversa 9 79333 COG7-CDG 9 93317 Spondylometaphyseal dysplasia, Sedaghatian type 9 85338 X-linked intellectual disability - ataxia - apraxia 9 Macrostomia - preauricular tags - external 83619 ophthalmoplegia 9 85277 X-linked intellectual disability, Cantagrel type 9 85199 Craniosynostosis - anal anomalies - porokeratosis 9 85286 X-linked intellectual disability, Shashi type 9 137871 Laminopathy type Decaudain-Vigouroux 9 137628 Cardiac anomalies - heterotaxy 9 Combined immuno T+ B+ due to partial 231154 RAG1 9 X-linked intellectual disability - spastic 163982 quadriparesis 9 46,XY disorder of sex development - adrenal 168558 insufficiency due to CYP11A1 9 209951 Autosomal recessive spastic paraplegia type 18 9 293939 Distal Xq28 microduplication 9 293948 1p21.3 microdeletion 9 314466 Atypical Meigs 9 Developmental and speech delay due to SOX5 313892 9 314679 Cerebro-facio-articular 9 Autosomal dominant intermediate Charcot-Marie- 324585 9 Tooth disease with neuropathic pain 329478 Adult-onset distal myopathy due to VCP mutation 9 261279 17q23.1q23.2 microdeletion 9 261349 2p15p16.1 microdeletion 9 263487 COG5-CDG 9 Moyamoya angiopathy-short stature-facial 280679 dysmorphism-hypergonadotropic hypogonadism 9 Periodic paralysis with later-onset distal motor 397750 neuropathy 9 1120 Lung agenesis - heart defect - thumb anomalies 9 401945 Moyamoya disease with early-onset achalasia 9 363710 Spinocerebellar ataxia type 37 9 352745 Oculocutaneous albinism type 7 9 Congenital microcephaly-severe encephalopathyprogressive cerebral atrophy 391376 9 Ketoacidosis due to monocarboxylate transporter- 438075 9 1 STING-associated vasculopathy with onset in 425120 infancy 9 1226 Bamforth-Lazarus 8 1318 Campomelia, Cumming type 8 1327 Camptodactyly, Guadalajara type 1 8 1278 Brachydactyly - preaxial hallux varus 8 1188 Ataxia-deafness-intellectual disability 8 Autosomal recessive palmoplantar keratoderma 1366 and congenital alopecia 8 1454 Joubert with hepatic defect 8 Hydrocephalus - costovertebral dysplasia - 2180 Sprengel anomaly 8 2206 Ankylosing vertebral hyperostosis with tylosis 8 2107 Hall-Riggs 8 2563 MOMO 8 2561 Ackerman 8 X-linked intellectual disability - dysmorphism - 2958 cerebral atrophy 8 3219 Fountain 8 2326 Kallmann - heart disease 8 3474 CHIME 8 33572 5-oxoprolinase 8 Autosomal dominant familial hematuria - retinal 73229 arteriolar tortuosity - contractures 8 79325 ALG8-CDG 8 85282 MEHMO 8 85273 X-linked intellectual disability, Abidi type 8 85289 X-linked intellectual disability, Vitale type 8 137639 Leukoencephalopathy-ataxia-hypodontiahypomyelination 8 210144 Lethal polymalformative, Boissel type 8 221054 Acrocephalopolydactyly 8 Microcornea - posterior megalolenticonus - 231736 persistent fetal vasculature - coloboma 8 251295 Pigmented paravenous retinochoroidal atrophy 8 251290 Parietal foramina with cleidocranial dysplasia 8 Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 32

140936 Lelis 8 178506 Brain calcification, Rajab type 8 178389 Osteopetrosis - hypogammaglobulinemia 8 Amelogenesis imperfecta-gingival hyperplasia 171836 8 183678 Hermansky-Pudlak with neutropenia 8 Sodium channelopathy-related small fiber 306577 neuropathy 8 Porencephaly-microcephaly-bilateral congenital 306547 cataract 8 314811 Short stature due to GHSR 8 Mitochondrial hypertrophic cardiomyopathy with 314637 lactic acidosis due to MTO1 8 324321 Sinoatrial node dysfunction and deafness 8 Mendelian susceptibility to mycobacterial diseases 319595 8 due to partial STAT1 Autosomal dominant Charcot-Marie-Tooth disease 329258 8 type 2Q Autosomal recessive limb-girdle muscular 352479 dystrophy type 2U 8 261483 Xq27.3q28 duplication 8 263665 NK-cell enteropathy 8 Premature aging appearance-developmental 276432 delay-cardiac arrhythmia 8 280325 Distal monosomy 12p 8 Autosomal recessive limb-girdle muscular 280333 dystrophy type 2P 8 Joubert with Jeune asphyxiating 397715 thoracic dystrophy 8 Alacrimia-choreoathetosis-liver dysfunction 404454 8 401942 Familial median cleft of the upper and lower lips 8 397590 Silver-Russell due to a point mutation 8 Brain dopamine-serotonin vesicular transport 352649 8 disease Digital anomalies - intellectual disability - short 352487 8 stature Autosomal dominant intermediate Charcot-Marie- 352670 8 Tooth disease type F 352675 X-linked Charcot-Marie-Tooth disease type 6 8 Autism spectrum disorder-epilepsy-arthrogryposis 370943 8 Severe combined immuno due to CTPS1 420573 8 Lethal neonatal spasticity-epileptic 435845 8 encephalopathy 420686 Woolly hair-palmoplantar keratoderma 8 399096 Distal anoctaminopathy 8 435638 3p25.3 microdeletion 8 438274 GCGR-related hyperglucagonemia 8 0 Ocular albinism with late-onset sensorineural deafness 7 958 Acro-renal-mandibular 7 2598 Mitochondrial myopathy and sideroblastic anemia 7 1131 X-linked mandibulofacial dysostosis 7 1842 Bone dysplasia, lethal Holmgren type 7 1574 Retinal degeneration - nanophthalmos - glaucoma 7 Primary hypergonadotropic hypogonadism - 2232 partial alopecia 7 2095 Gorlin-Chaudhry-Moss 7 Möbius - axonal neuropathy - 2560 hypogonadotropic hypogonadism 7 3194 Stern-Lubinsky-Durrie 7 3087 Retinohepatoendocrinologic 7 Severe X-linked intellectual disability, Gustavson 3078 type 7 2920 Oliver 7 Torticollis - keloids - cryptorchidism - renal 3341 dysplasia 7 1901 Ehlers-Danlos, dermatosparaxis type 7 33573 Gamma-glutamyl transpeptidase 7 38874 Dihydropyrimidinuria 7 338 Familial multiple fibrofolliculoma 7 Woolly hair-palmoplantar keratoderma-dilated 65282 cardiomyopathy 7 66631 CEDNIK 7 71526 Obesity due to pro-opiomelanocortin 7 79323 MPDU1-CDG 7 79094 Grange 7 93316 Spondylometaphyseal dysplasia, Schmidt type 7 X-linked neurodegenerative, Bertini 85334 type 7 Congenital malabsorptive diarrhea due to paucity 83620 of enteroendocrine cells 7 93382 Brachydactyly type A6 7 139474 17q11.2 microduplication 7 101078 X-linked Charcot-Marie-Tooth disease type 4 7 211067 Episodic ataxia type 5 7 228379 Virus-associated trichodysplasia spinulosa 7 Patent ductus arteriosus - bicuspid aortic valve - 228190 hand anomalies 7 228169 Autosomal dominant striatal neurodegeneration 7 247198 Progressive cerebello-cerebral atrophy 7 254531 Paternal 14q32.2 hypomethylation 7 251383 CK 7 163693 2p21 microdeletion 7 163976 X-linked intellectual disability, Van Esch type 7 X-linked intellectual disability - craniofacioskeletal 163979 7 178338 UV-sensitive 7 209970 Episodic ataxia type 7 7 Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 33

Deficiency in anterior pituitary function-variable 293978 immuno 7 Progeroid and marfanoid aspect-lipodystrophy 382 7 Combined immuno due to STK4 314689 7 Severe neonatal hypotonia-seizuresencephalopathy due to 5q31.3 314655 microdeletion 7 X-linked immuno with magnesium 317476 defect, Epstein-Barr virus infection and neoplasia 7 329329 Autosomal recessive frontotemporal pachygyria 7 Microcephalic primordial dwarfism due to ZNF335 329228 7 324632 Hendra virus infection 7 329802 5p13 microduplication 7 261229 14q11.2 microduplication 7 263347 MRCS 7 Autosomal semi-dominant severe lipodystrophic 280365 laminopathy 7 Skin fragility-woolly hair-palmoplantar 293165 keratoderma 7 397695 3q27.3 microdeletion 7 Intellectual disability-coarse face-macrocephalycerebellar hypotrophy 397709 7 Intellectual disability-facial dysmorphism 404440 due to SETD5 haploinsufficiency 7 Multisystemic smooth muscle dysfunction 404463 7 401785 Autosomal recessive spastic paraplegia type 62 7 397941 MAN1B1-CDG 7 Intellectual disability-seizures-macrocephalyobesity 369950 7 Severe motor and intellectual disabilitiessensorineural deafness-dystonia 369939 7 Ataxia-intellectual disability-oculomotor apraxiacerebellar cysts 370022 7 Congenital neutropenia-myelofibrosisnephromegaly 369852 7 363396 High myopia-sensorineural deafness 7 357001 19p13.13 microdeletion 7 Autosomal recessive congenital cerebellar ataxia 363432 due to GRID2 7 352490 Autism spectrum disorder due to AUTS2 7 Focal epilepsy-intellectual disability-cerebrocerebellar malformation 352587 7 352582 Familial infantile myoclonic epilepsy 7 353298 Roifman 7 420561 Temple-Baraitser 7 439822 PDE4D haploinsufficiency 7 Familial atrial tachyarrhythmia-infra-hisian cardiac 436242 7 conduction disease Autosomal dominant Charcot-Marie-Tooth disease 435387 7 type 2 due to VCP mutation Primary immuno due to STAT2 431166 7 3204 Stormorken-Sjaastad-Langslet 6 1951 Epilepsy telangiectasia 6 991 PAGOD 6 Thumb stiffness - brachydactyly - intellectual 1078 disability 6 1115 Recessive aplasia cutis congenita of limbs 6 Hidrotic ectodermal dysplasia, Christianson-Fourie 1808 6 type 1786 Acrofacial dysostosis, Catania type 6 Cutis gyrata - acanthosis nigricans - 1555 craniosynostosis 6 2306 Isotretinoin-like 6 1051 Ramos-Arroyo 6 Hypogonadotropic hypogonadism - frontoparietal 2230 alopecia 6 Blepharophimosis - ptosis - esotropia - syndactyly - 2057 6 short stature 2117 Hartsfield-Bixler-Demyer 6 2824 Paraplegia - intellectual disability - hyperkeratosis 6 2339 Keratosis follicularis - dwarfism - cerebral atrophy 6 3175 Spasticity - intellectual disability - X-linked epilepsy 6 X-linked intellectual disability - psychosis - 3077 macroorchidism 6 2934 Polysyndactyly - cardiac malformation 6 2804 W 6 3220 Deafness - enamel hypoplasia - nail defects 6 Symphalangism with multiple anomalies of hands 3246 and feet 6 66518 Short fifth metacarpals - insulin resistance 6 Megalencephaly - polymicrogyria - postaxial 83473 polydactyly - hydrocephalus 6 79106 Eiken 6 85337 X-linked intellectual disability, Zorick type 6 85276 X-linked intellectual disability, Armfield type 6 93973 Carpenter-Waziri 6 108 Autosomal recessive spastic paraplegia type 28 6 211017 Spinocerebellar ataxia type 30 6 230851 Ehlers-Danlos, cardiac valvular type 6 Severe combined immuno due to 228003 CORO1A 6 244310 RFT1-CDG 6 254525 Paternal 14q32.2 microdeletion 6 254528 Maternal 14q32.2 microdeletion 6 Autosomal recessive spastic ataxia - optic atrophy 254343 6 - dysarthria 254346 19p13.12 microdeletion 6 Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 34

Autosomal recessive limb-girdle muscular 254361 dystrophy type 2Q 6 247820 Ectodermal dysplasia - syndactyly 6 Syndactyly - telecanthus - anogenital and renal 140952 malformations 6 157820 Cold-induced sweating 6 Ehlers-Danlos, spondylocheirodysplastic 157965 6 type 46,XY gonadal dysgenesis - motor and sensory 168563 neuropathy 6 168984 CLAPO 6 169464 Primary CD59 6 178303 8q22.1 microdeletion 6 199332 Endocrine-cerebro-osteodysplasia 6 Ehlers-Danlos, kyphoscoliotic and 179 deafness type 6 314399 Autosomal dominant aplasia and myelodysplasia 6 313884 12p12.1 microdeletion 6 Combined immuno due to ORAI1 317428 6 324569 Pontocerebellar hypoplasia type 8 6 Progressive external ophthalmoplegia - myopathy 352447 6 - emaciation 231537 Hermansky-Pudlak type 8 6 Fatal multiple mitochondrial dysfunction 401874 type 2 6 401777 Optic atrophy-intellectual disability 6 398069 Prader-Willi due to point mutation 6 Acute infantile liver failure-multisystemic 370088 involvement 6 Leukoencephalopathy with mild cerebellar ataxia 363540 and white matter edema 6 Severe neurodegenerative with 363400 lipodystrophy 6 Nail and teeth abnormalities-marginal 423454 palmoplantar keratoderma-oral hyperpigmentation 6 398127 Neonatal scleroderma 6 Autoimmune hemolytic anemia-autoimmune 444463 thrombocytopenia-primary immuno 6 Severe intellectual disability-hypotoniastrabismus-coarse face-planovalgus 436141 6 Contractures-developmental delay-pierre Robin 436003 6 929 Achalasia - microcephaly 5 5 Alopecia-contractures-dwarfism-intellectual disability 5 Choanal atresia-hearing loss-cardiac defectscraniofacial dysmorphism 1 5 1094 Anonychia - microcephaly 5 1113 Aphalangy - syndactyly - microcephaly 5 1811 Odontomicronychial dysplasia 5 1657 Dermatoosteolysis, Kirghizian type 5 1784 Acro-fronto-facio-nasal dysostosis 5 1514 Craniodigital - intellectual disability 5 1562 Dacryocystitis - osteopoikilosis 5 1535 Craniosynostosis - dysmorphism - brachydactyly 5 2085 Glaucoma - sleep apnea 5 2077 German 5 2111 Cystic hamartoma of lung and kidney 5 2714 Oculo-palato-cerebral 5 Nephrosis - deafness - urinary tract - digital 2669 malformations 5 2668 Nephropathy-deafness-hyperparathyroidism 5 2571 X-linked immunoneurologic disorder 5 2565 Mononen-Karnes-Senac 5 2558 Mikati-Najjar-Sahli 5 2496 Mesomelia-synostoses 5 2351 Kousseff 5 3168 Sillence 5 3128 Sakati-Nyhan 5 Intellectual disability - balding - patella luxation - 3041 acromicria 5 3 Pyknoachondrogenesis 5 2823 Paraplegia - brachydactyly - cone-shaped epiphysis 5 Fallot complex - intellectual disability - growth 3304 delay 5 Cholestasis-pigmentary retinopathy-cleft palate 1415 5 1272 Fine-Lubinsky 5 Arachnodactyly - abnormal ossification - 1129 intellectual disability 5 69736 Acute bilateral depigmentation of the iris 5 65287 Beta-ureidopropionase 5 Growth delay due to insulin-like growth factor 73272 type 1 5 50815 Branchiogenic deafness 5 83472 CAMOS 5 75374 Bradyopsia 5 79095 Congenital bile acid synthesis defect type 4 5 90646 Deafness - hypogonadism 5 Localized lichen myxedematosus with monoclonal 90399 5 gammopathy or systemic symptoms Acanthosis nigricans - Insulin resistance - muscle 90301 cramps - acral enlargement 5 Lissencephaly type 3 - familial fetal akinesia 86821 sequence 5 86914 Lymphedema - cerebral arteriovenous anomaly 5 85112 Palmoplantar keratoderma - XX sex reversal - 5 Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 35

predisposition to squamous cell carcinoma 85175 Astley-Kendall dysplasia 5 X-linked intellectual disability - cubitus valgus - 85280 dysmorphism 5 85295 HSD10 disease, atypical type 5 85297 X-linked spinocerebellar ataxia type 3 5 85284 BRESEK 5 97341 Persistent placoid maculopathy 5 94056 Humero-ulnar synostosis 5 93975 Renier-Gabreels-Jasper 5 139515 Charcot-Marie-Tooth disease type 4J 5 137834 Frank-Ter Haar 5 Microcephaly - facio-cardio-skeletal, 217026 Hadziselimovic type 5 210141 Inherited congenital spastic tetraplegia 5 Frontonasal dysplasia with alopecia and genital 228390 anomaly 5 228227 Late-onset focal dermal elastosis 5 238766 Ptosis - syndactyly - learning difficulties 5 Recurrent infections - inflammatory due 251523 5 to zinc metabolism disorder 157954 ANE 5 169079 Cernunnos-XLF 5 168443 Spondyloepimetaphyseal dysplasia - hypotrichosis 5 Autosomal recessive lower motor neuron disease 206580 with childhood onset 5 199343 EAST 5 Hypoinsulinemic hypoglycemia and body 293964 hemihypertrophy 5 Childhood encephalopathy due to thiamine 293955 pyrophosphokinase 5 293462 Pre-Descemet corneal dystrophy 5 Multiple congenital anomalies-hypotonia-seizures 496 5 type 2 504 Onychocytic matricoma 5 552 Follicular cholangitis and pancreatitis 5 Congenital cataract-hearing loss-severe 313 developmental delay 5 314555 Craniofacial dysplasia-osteopenia 5 314667 TMEM165-CDG 5 314652 Variant ABeta2M amyloidosis 5 Combined oxidative phosphorylation defect type 324535 11 5 Autosomal recessive mendelian susceptibility to 319574 mycobacterial diseases due to partial IFNgammaR2 5 Beta-propeller protein-associated 329284 neurodegeneration 5 Methylmalonic aciduria due to transcobalamin 280183 receptor defect 5 Familial omphalocele with facial 280403 dysmorphism 5 Severe neonatal lactic acidosis due to NFS1-ISD11 397593 complex 5 Infantile cerebral and cerebellar atrophy with 402364 postnatal progressive microcephaly 5 401986 1p31p32 microdeletion 5 98676 Autosomal recessive isolated optic atrophy 5 369920 Pontocerebellar hypoplasia type 9 5 Combined oxidative phosphorylation defect type 369913 17 5 363654 X-linked parkinsonism-spasticity 5 363618 LMNA-related cardiocutaneous progeria 5 Intellectual disability-hyperkinetic movementtruncal ataxia 369847 5 Cryptosporidiosis - chronic cholangitis - liver 357329 disease 5 352596 Progressive myoclonic epilepsy with dystonia 5 Autoimmune enteropathy and endocrinopathysusceptibility to chronic infections 391487 5 423275 Spinocerebellar ataxia type 40 5 444002 11q22.2q22.3 microdeletion 5 Juvenile-onset diabetes mellitus-central and 445062 peripheral neurodegeneration 5 Craniosynostosis - Dandy-Walker malformation - 1538 hydrocephalus 4 1135 Arrhinia - choanal atresia - microphthalmia 4 2431 Central bilateral macrogyria 4 921 Abruzzo-Erickson 4 1240 Metaphyseal acroscyphodysplasia 4 1307 Distal limb deficiencies - micrognathia 4 1261 Bonnemann-Meinecke-Reich 4 1104 Anophthalmia plus 4 Aortic arch anomaly - peculiar facies - intellectual 1110 disability 4 1117 Aplasia cutis - myopia 4 1816 Ectodermal dysplasia, Berlin type 4 1809 Hidrotic ectodermal dysplasia, Halal type 4 1790 Hypomandibular faciocranial dysostosis 4 1682 Arterial dissection - lentiginosis 4 1508 Coxoauricular 4 1435 Choroideremia - deafness - obesity 4 Ichthyosis - alopecia - eclabion - ectropion - 2269 intellectual disability 4 2150 Hirschsprung disease - type D brachydactyly 4 Malignant hyperthermia - arthrogryposis - 2215 torticollis 4 2050 Cole-Carpenter 4 Diaphragmatic defect - limb - skull 2141 defect 4 Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 36

1973 Faciocardiorenal 4 Cleft lip/palate - intestinal malrotation - 1 cardiopathy 4 2723 Odontotrichomelic 4 2676 Neuroectodermal-endocrine 4 2589 Myoclonus-cerebellar ataxia-deafness 4 Leukoencephalopathy-palmoplantar keratoderma 2386 4 2328 Kapur-Toriello 4 Intellectual disability - dysmorphism - 3044 4 hypogonadism - diabetes mellitus 3052 X-linked intellectual disability - seizures - psoriasis 4 Non-eruption of teeth - maxillary hypoplasia - 2972 4 genu valgum 2946 Brachydactyly - long thumb 4 2865 Short stature - webbed neck - heart disease 4 2919 Orofaciodigital type 5 4 2820 Spastic paraplegia - nephritis - deafness 4 2168 Homocarnosinosis 4 3355 Trichoodontoonychial dysplasia 4 1884 Ectopia lentis - chorioretinal dystrophy - myopia 4 1768 Familial caudal dysgenesis 4 1423 Lethal recessive chondrodysplasia 4 806 Scott 4 69735 Hypotrichosis-lymphedema-telangiectasia-renal defect 4 Autosomal dominant multiple pterygium 65743 4 Permanent neonatal diabetes mellitus - pancreatic 65288 4 and cerebellar agenesis 71269 Benign exophthalmos 4 46059 Lathosterolosis 4 79329 MGAT2-CDG 4 79132 Sparse hair - short stature - skin anomalies 4 Primary immuno with natural-killer cell 75391 and adrenal insufficiency 4 79022 Simpson-Golabi-Behmel type 2 4 77295 Odontoleukodystrophy 4 91131 DK1-CDG 4 91132 Ichthyosis-hypotrichosis 4 93333 Pelviscapular dysplasia 4 Neurodegeneration due to 3-hydroxyisobutyryl- 88639 CoA hydrolase 4 Primary immuno due to p14 90023 4 X-linked intellectual disability - corpus callosum 85330 agenesis - spastic quadriparesis 4 X-linked intellectual disability - hypogonadism - 85331 ichthyosis - obesity - short stature 4 85326 X-linked intellectual disability, Stoll type 4 85325 X-linked intellectual disability, Stevenson type 4 85323 X-linked intellectual disability, Seemanova type 4 Myopathy due to calsequestrin and SERCA1 88635 protein overload 4 Leukoencephalopathy - metaphyseal 83629 chondrodysplasia 4 Microcephalic osteodysplastic dysplasia, Saul- 85172 Wilson type 4 85186 Endosteal sclerosis - cerebellar hypoplasia 4 85162 Facial onset sensory and motor neuronopathy 4 Severe achondroplasia - developmental delay - 85165 acanthosis nigricans 4 X-linked intellectual disability, Miles-Carpenter 85283 type 4 85285 X-linked intellectual disability, Schimke type 4 Spondylocostal dysostosis - anal and genitourinary 94095 4 malformations 94063 12q14 microdeletion 4 94065 15q24 microdeletion 4 93946 Hamel cerebro-palato-cardiac 4 93405 Syndactyly type 4 4 93352 Spondyloepimetaphyseal dysplasia, Shohat type 4 Hereditary sensory and autonomic neuropathy 139573 with deafness and global delay 4 137911 Autism - facial port-wine stain 4 Progressive demyelinating neuropathy with 217396 bilateral striatal necrosis 4 Hereditary hypotrichosis with recurrent skin 217407 vesicles 4 210163 Congenital lethal myopathy, Compton-North type 4 Pulmonary fibrosis - hepatic hyperplasia - bone 210136 marrow hypoplasia 4 Severe early-onset axonal neuropathy due to NEFL 228374 4 228399 8q12 microduplication 4 228240 Elastoderma 4 Cutis laxa with severe pulmonary, gastrointestinal 221145 4 and urinary anomalies 247604 Juvenile primary lateral sclerosis 4 Glaucoma secondary to spherophakia/ectopia 238763 lentis and megalocornea 4 Infantile onset panniculitis with uveitis and 251304 systemic granulomatosis 4 Microphthalmia - retinitis pigmentosa - 251279 foveoschisis - optic disc drusen 4 251061 7q31 microdeletion 4 251056 6q25 microdeletion 4 250984 Autosomal recessive Stickler 4 250972 Polymicrogyria with optic nerve hypoplasia 4 Ectodermal dysplasia - cutaneous syndactyly 247827 4 Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 37

247790 FTH1-related iron overload 4 158687 Lethal acantholytic epidermolysis bullosa 4 163649 Spondyloepiphyseal dysplasia, Nishimura type 4 163668 Spondyloepiphyseal dysplasia, MacDermot type 4 163654 Spondyloepiphyseal dysplasia, Cantu type 4 163971 X-linked intellectual disability, Cilliers type 4 140963 Bilateral microtia - deafness - cleft palate 4 140976 RHYNS 4 166024 Multiple epiphyseal dysplasia, Al-Gazali type 4 Microcephaly - polymicrogyria - corpus callosum 171703 agenesis 4 Craniosynostosis - hydrocephalus - Arnold-Chiari 171839 malformation type I - radioulnar synostosis 4 171844 Blindness-scoliosis-arachnodactyly 4 210128 Urocanic aciduria 4 209967 Episodic ataxia type 6 4 199337 Pancreatic insufficiency - anemia - hyperostosis 4 Lethal occipital encephalocele-skeletal dysplasia 293925 4 293825 Congenital dyserythropoietic anemia type IV 4 Hypogonadotropic hypogonadism-severe 293967 microcephaly-sensorineural hearing lossdysmorphism 4 Painful orbital and systemic neurofibromasmarfanoid habitus 501 4 306550 FADD-related immuno 4 313781 20p13 microdeletion 4 313795 Jawad 4 Hereditary sensory and autonomic neuropathy 314381 type 6 4 313855 FGFR2-related bent bone dysplasia 4 314721 Atypical dentin dysplasia due to SMOC2 4 314632 Parkinsonism due to ATP13A2 4 324313 9p13 microdeletion 4 X-linked mendelian susceptibility to mycobacterial 319612 4 diseases due to IKBKG Blepharophimosis-intellectual disability 329255 4 due to UBE3B 324581 Benign Samaritan congenital myopathy 4 Mitochondrial DNA deletion with 352470 progressive myopathy 4 Microcephaly-cerebellar hypoplasia-cardiac 329332 conduction defect 4 329341 Limbic encephalitis with DPP6 antibodies 4 261102 Distal 7q11.23 microduplication 4 261190 15q14 microdeletion 4 Infantile spams - psychomotor retardation - 263410 progressive brain atrophy - basal ganglia disease 4 264 14q22q23 microdeletion 4 280142 Severe combined immuno due to LCK 4 Hereditary sensorimotor neuropathy with 280598 hyperelastic skin 4 Chondrodysplasia with joint dislocations, gpapp 280586 type 4 280558 Warsaw breakage 4 280654 Autosomal recessive nail dysplasia 4 284339 Pontocerebellar hypoplasia type 7 4 Periodic paralysis with transient compartment-like 397755 4 Severe combined immuno due to IKK2 397787 4 Short stature-auditory canal atresia-mandibular 397623 hypoplasia-skeletal anomalies 4 Diffuse cerebral and cerebellar atrophy-intractable 404437 4 seizures-progressive microcephaly AHDC1-related intellectual disability-obstructive 412069 sleep apnea-mild dysmorphism 4 Autosomal recessive spondylometaphyseal 401979 dysplasia, Mégarbané type 4 Severe intellectual disability-progressive spastic 404473 diplegia 4 404466 Female infertility due to zona pellucida defect 4 Hyperammonemic encephalopathy due to 401948 carbonic anhydrase VA 4 401780 Autosomal recessive spastic paraplegia type 61 4 401810 Autosomal recessive spastic paraplegia type 64 4 401835 Autosomal recessive spastic paraplegia type 70 4 1819 Epimetaphyseal skeletal dysplasia 4 398079 Prader-Willi-like due to point mutation 4 Sacral agenesis-abnormal ossification of the 397927 vertebral bodies-persistent notochordal canal 4 Microcephaly-thin corpus callosum-intellectual 397951 disability 4 369942 CADDS 4 Cardiac anomalies-developmental delay-facial 369891 dysmorphism 4 Severe intellectual disability-poor languagestrabismus-grimacing face-long fingers 363686 4 Mandibular hypoplasia-deafness-progeroid 363649 4 Intellectual disability-seizures-hypotoniaophthalmologic-skeletal anomalies 369837 4 363969 Autosomal recessive cerebral atrophy 4 Ichthyosis-short stature-brachydactylymicrospherophakia 363992 4 363965 Koolen-De Vries due to a point mutation 4 Short ulna - dysmorphism - hypotonia - intellectual 357175 4 disability 356961 SLC35A2-CDG 4 356947 3q26q27 microdeletion 4 Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 38

Developmental delay-microcephaly-facial 363444 dysmorphism, Hutterite type 4 Severe feeding difficulties - failure to thrive - 352577 microcephaly due to ASXL3 4 Cobblestone lissencephaly without muscular or 352682 ocular involvement 4 352709 CLN13 disease 4 Progressive retinal dystrophy due to retinol 352718 transport defect 4 Autosomal recessive severe congenital 420702 neutropenia due to CSF3R 4 PCNA-related progressive neurodegenerative 438134 photosensitivy 4 424027 Progressive myoclonic epilepsy type 8 4 Lethal fetal brain malformation-duodenal atresiabilateral renal hypoplasia 444069 4 Peeling skin-leukonuchia-acral punctate keratosescheilitis-knuckle pads 444138 4 443995 Mandibulofacial dysostosis with alopecia 4 178400 Distal myopathy with anterior tibial onset 4 Periodic fever-infantile enterocolitisautoinflammatory 436166 4 RARS-related autosomal recessive 438114 hypomyelinating leukodystrophy 4 999 Ermine phenotype 3 Congenital osteogenesis imperfecta - microcephaly 2772 3 - cataracts Disorder of sex development - intellectual 2983 disability 3 1259 Blepharoptosis - myopia - ectopia lentis 3 Camptodactyly - fibrous tissue hyperplasia - 1321 skeletal dysplasia 3 1342 Heart-hand type 3 3 1299 Branchio-skeleto-genital 3 1027 Autosomal recessive amelia 3 Aniridia - ptosis - intellectual disability - familial 1067 obesity 3 1133 AREDYLD 3 1069 Aniridia-absent patella 3 Aphalangy - hemivertebrae - urogenital-intestinal 1112 dysgenesis 3 Aplasia cutis congenita - intestinal 1116 lymphangiectasia 3 Hypohidrotic ectodermal dysplasia - 1882 hypothyroidism - ciliary dyskinesia 3 Intellectual disability - hypoplastic corpus callosum 1495 3 - preauricular tag 1529 Craniofacial-deafness-hand 3 1521 Craniofrontonasal dysplasia - Poland anomaly 3 Hair defect - photosensitivity - intellectual 1408 disability 3 1389 Cortical blindness - intellectual disability - 3 polydactyly 2153 Hirschsprung disease-nail hypoplasia-dysmorphism 3 2218 Cervical hypertrichosis - peripheral neuropathy 3 Posterior fusion of lumbosacral vertebrae - 2064 blepharoptosis 3 2091 Multinodular goiter - cystic kidney - polydactyly 3 Glaucoma - ectopia - microspherophakia - stiff 2084 joints - short stature 3 1972 Lethal faciocardiomelic dysplasia 3 Facial dysmorphism - macrocephaly - myopia - 1970 Dandy-Walker malformation 3 2736 Lethal omphalocele-cleft palate 3 2751 Orofaciodigital type 2 3 2713 Oculoosteocutaneous 3 2613 Nail-patella-like renal disease 3 2608 N 3 2515 Microcephaly - cardiomyopathy 3 2521 Microcephaly - cleft palate 3 Microcephaly - cardiac defect - lung 2516 malsegmentation 3 2437 Czeizel-Losonci 3 Hypergonadotropic hypogonadism - cataract 2410 3 2409 Lowry-MacLean 3 3172 Eyebrow duplication - syndactyly 3 3210 Summitt 3 3086 Autosomal dominant vitreoretinochoroidopathy 3 3088 Revesz 3 3010 Qazi-Markouizos 3 Retinal ischemic - digestive tract small 3018 vessel hyalinosis - diffuse cerebral calcifications 3 Absent thumb-short stature-immuno 2951 3 2881 Cutaneous photosensitivity - lethal colitis 3 Osteoporosis - oculocutaneous hypopigmentation 2786 3 3326 Thymic-renal-anal-lung dysplasia 3 3328 Absent tibia - polydactyly - arachnoid cyst 3 3238 Cardiospondylocarpofacial 3 3404 Ulbright-Hodes 3 Trigonocephaly - short stature - developmental 3369 delay 3 Short stature - intellectual disability - eye 2649 anomalies - cleft lip/palate 3 3433 Microcephaly - brachydactyly - kyphoscoliosis 3 Anophthalmia - megalocornea - cardiopathy - 1101 skeletal anomalies 3 1383 Cataract - deafness - hypogonadism 3 Müllerian derivatives - lymphangiectasia - 1655 polydactyly 3 Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 39

Arachnodactyly - intellectual disability - 1130 dysmorphism 3 Short stature due to growth hormone qualitative 629 anomaly 3 69125 Anonychia with flexural pigmentation 3 Sensorineural hearing loss - early graying - 66633 essential tremor 3 65798 Goodman 3 Global developmental delay - osteopenia - 73223 ectodermal defect 3 50811 Lipodystrophy - intellectual disability - deafness 3 52054 Craniosynostosis - intracranial calcifications 3 83617 Agammaglobulinemia-microcephalycraniosynostosis-severe dermatitis 3 79328 ALG9-CDG 3 79330 GCS1-CDG 3 Seizures - intellectual disability due to 79156 hydroxylysinuria 3 Osteosclerosis - ichthyosis - premature ovarian 75325 failure 3 77299 Microphthalmia - brain atrophy 3 93267 Cloverleaf skull - multiple congenital anomalies 3 Hemolytic anemia due to glutathione reductase 90030 3 85324 X-linked intellectual disability, Shrimpton type 3 Deafness - intellectual disability, Martin-Probst 85321 type 3 86309 DPAGT1-CDG 3 Psychomotor retardation due to S- 88618 adenosylhomocysteine hydrolase 3 86915 Lymphedema - atrial septal defects - facial changes 3 83642 Microcytic anemia with liver iron overload 3 85291 X-linked intellectual disability, Wittwer type 3 X-linked intellectual disability - 85317 hypogammaglobulinemia - progressive neurological deterioration 3 X-linked intellectual disability - precocious puberty 85318 3 - obesity 85290 X-linked intellectual disability, Wilson type 3 93970 Holmes-Gang 3 93971 Chudley-Lowry-Hoar 3 93947 X-linked intellectual disability, Golabi-Ito-Hall type 3 139466 SERKAL 3 Microcephaly - intellectual disability - phalangeal 137658 and neurological anomalies 3 Hypotonia with lactic acidemia and 137908 hyperammonemia 3 103910 Congenital enterocyte heparan sulfate 3 Intractable diarrhea - choanal atresia - eye 137622 anomalies 3 137625 Glycogen storage disease due to muscle and heart 3 glycogen synthase 98908 Neutral lipid storage myopathy 3 217335 RIN2 3 Neurodegenerative due to cerebral 217382 folate transport 3 217017 Zechi-Ceide 3 230845 Ehlers-Danlos, vascular-like type 3 Ptosis - upper ocular movement limitation - 228396 absence of lacrimal punctum 3 254534 Maternal 14q32.2 hypermethylation 3 251066 8p11.2 deletion 3 163665 Spondyloepiphyseal dysplasia tarda, Kohn type 3 163961 X-linked intellectual disability, Kroes type 3 166068 Pontocerebellar hypoplasia type 5 3 166277 Suarez-Stickler 3 168448 Spondyloepimetaphyseal dysplasia, Bieganski type 3 168544 Spondylometaphyseal dysplasia, Golden type 3 168549 Axial spondylometaphyseal dysplasia 3 Hemorrhagic disease due to alpha-1-antitrypsin 178396 Pittsburgh mutation 3 171860 Intellectual disability - cataracts - kyphosis 3 171866 Spondyloepimetaphyseal dysplasia, aggrecan type 3 Autosomal recessive limb-girdle muscular 206554 dystrophy type 2M 3 373 Familial infantile gigantism 3 Severe congenital hypochromic anemia with 298 ringed sideroblasts 3 Nephrotic -deafness-pretibial 333 epidermolysis bullosa 3 Primary microcephaly-epilepsy-permanent 306558 neonatal diabetes 3 313800 Optic nerve edema-splenomegaly 3 Congenital nephrotic -interstitial lung 306504 disease-epidermolysis bullosa 3 Frontonasal dysplasia-severe microphthalmiasevere facial clefting 306542 3 314389 Xq12-q13.3 duplication 3 Young adult-onset distal hereditary motor 314485 neuropathy 3 Autosomal recessive leukoencephalopathy with 314572 ischemic stroke-retinitis pigmentosa 3 Hypertrophic cardiomyopathy and renal tubular 324525 disease due to mitochondrial DNA mutation 3 324290 Early-onset Lafora body disease 3 Mendelian susceptibility to mycobacterial diseases 319563 3 due to complete ISG15 Autoinflammatory with pyogenic 329173 bacterial infection and amylopectinosis 3 Congenital muscular dystrophy with intellectual 329178 disability and severe epilepsy 3 324999 JMP 3 Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 40

Congenital cataract - progressive muscular 354 hypotonia - hearing loss - developmental delay 3 261120 14q11.2 microdeletion 3 261144 14q12 microdeletion 3 261295 20p12.3 microdeletion 3 263508 COG1-CDG 3 263516 Progressive myoclonic epilepsy type 3 3 280356 PLIN1-related familial partial lipodystrophy 3 280640 Occipital pachygyria and polymicrogyria 3 412035 13q12.3 microdeletion 3 Early onset epileptic encephalopathy-cortical 411986 blindness-intellectual disability-facial dysmorphism 3 Epidermolysis bullosa simplex due to exophilin 5 412189 3 Autosomal recessive cerebellar ataxia-epilepsyintellectual disability due to TUD 404493 3 402082 Progressive myoclonic epilepsy type 5 3 FBLN1-related developmental delay-central 404451 nervous system anomaly-syndactyly 3 401859 Lipoic acid synthetase 3 401866 Spasticity-ataxia-gait anomalies 3 401935 14q24.1q24.3 microdeletion 3 401795 Autosomal recessive spastic paraplegia type 59 3 Severe intellectual disability-progressive postnatal 397933 microcephaly- midline stereotypic hand 3 movements 397922 Ferro-cerebro-cutaneous 3 Combined immuno due to MALT1 397964 3 Severe dermatitis-multiple allergies-metabolic 369992 wasting 3 370127 Medich giant platelet 3 370052 SCALP 3 Intellectual disability-facial dysmorphism-hand 370010 anomalies 3 Acroosteolysis-keloid-like lesions-premature aging 363665 3 Intellectual disability-feeding difficultiesdevelopmental delay-microcephaly 363611 3 Autosomal recessive intermediate Charcot-Marie- 369867 Tooth disease type C 3 Autosomal recessive limb-girdle muscular 369840 dystrophy type 2S 3 363981 Charcot-Marie-Tooth disease type 4B3 3 Intellectual disability - hypotonia - spasticity - 356996 sleep disorder 3 Mitochondrial DNA depletion, 363534 hepatocerebrorenal form 3 Fetal akinesia-cerebral and retinal hemorrhage 363409 3 Early-onset progressive neurodegeneration - 352654 blindness - ataxia - spasticity 3 370938 Salt-and-pepper 3 Severe intellectual disability-short staturebehavioral troubles-facial dysmorphism 3 391307 Infantile-onset mesial temporal lobe epilepsy with 391316 3 severe cognitive regression 391351 SURF1-related Charcot-Marie-Tooth disease type 4 3 Hereditary sensory and autonomic neuropathy 391397 type 7 3 Primary microcephaly-mild intellectual disabilityyoung-onset diabetes 391408 3 391457 HSD10 disease, neonatal type 3 391646 Feingold type 2 3 420566 Bleeding disorder due to CalDAG-GEFI 3 420794 Cono-spondylar dysplasia 3 Muscular dystrophy with progressive weakness, 424261 distal contractures and rigid spine 3 Autosomal recessive intermediate Charcot-Marie- 435998 Tooth disease type D 3 Retinitis pigmentosa-juvenile cataract-short 436245 stature-intellectual disability 3 Microcephaly-complex motor and sensory axonal 423894 neuropathy 3 398117 Neonatal dermatomyositis 3 444048 46,XX ovarian dysgenesis-short stature 3 Combined oxidative phosphorylation 444458 type 24 3 Cognitive impairment-coarse facies-heart defectsobesity-pulmonary involvement-short stature- 444077 skeletal dysplasia 3 Cataract-growth hormone -sensory 436174 neuropathy-sensorineural hearing loss-skeletal dysplasia 3 Colobomatous optic disc-macular atrophychorioretinopathy 435930 3 X-linked microcephaly-growth retardationprognathism-cryptorchidism 435938 3 Progeroid features-hepatocellular carcinoma 435953 predisposition 3 Severe intellectual disability-epilepsy-cataract 438178 due to fatty acyl-coa reductase 1 3 Autosomal recessive primary immuno 437552 with defective spontaneous natural killer cell cytotoxicity 3 Multiple epiphyseal dysplasia, with severe 166029 proximal femoral dysplasia 3 Osteogenesis imperfecta - retinopathy - seizures - 2773 intellectual disability 2 1488 Cooper-Jabs 2 1770 Gonadal dysgenesis, XY type - associated anomalies 2 Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 41

1046 Lethal hemolytic anemia - genital anomalies 2 Hypogonadism - mitral valve prolapse - intellectual 2233 2 disability Mitochondrial DNA depletion, 1933 encephalomyopathic form with methylmalonic aciduria 2 2135 Hennekam-Beemer 2 1422 Chondrodysplasia - disorder of sex development 2 Multiple sclerosis - ichthyosis - factor VIII 3151 2 1948 Epilepsy - microcephaly - skeletal dysplasia 2 1354 Heart defects - limb shortening 2 949 Acrocraniofacial dysostosis 2 1227 Bangstad 2 1237 Beemer-Ertbruggen 2 1326 Camptodactyly, Guadalajara type 2 2 Brachytelephalangy - dysmorphism - Kallmann 1295 2 1021 Amaurosis-hypertrichosis 2 1068 Aniridia-intellectual disability 2 1064 Aniridia - renal agenesis - psychomotor retardation 2 3 Scalp defects - postaxial polydactyly 2 Alopecia-intellectual disability-hypergonadotropic 1014 2 hypogonadism 1659 Dermatoleukodystrophy 2 1806 Ectodermal dysplasia - blindness 2 Dandy-Walker malformation - postaxial 1566 polydactyly 2 1563 Dahlberg-Borer-Newcomer 2 Cryptomicrotia - brachydactyly - excess fingertip 1547 arch 2 1533 Craniosynostosis - fibular aplasia 2 1380 Cataract - nephropathy - encephalopathy 2 1368 Cataract - ataxia - deafness 2 Contractures - ectodermal dysplasia - cleft 1484 lip/palate 2 1453 Cleidorhizomelic 2 1433 Choroidal atrophy - alopecia 2 Hypogonadotropic hypogonadism - retinitis 2235 pigmentosa 2 Male hypergonadotropic hypogonadism - 2234 intellectual disability - skeletal anomalies 2 Hyposmia - nasal and ocular hypoplasia - 2250 hypogonadotropic hypogonadism 2 2249 Ulna hypoplasia - intellectual disability 2 2266 Hypotrichosis-intellectual disability, Lopes type 2 2272 Ichthyosis - oral and digital anomalies 2 2271 Congenital ichthyosis - microcephalus - tetraplegia 2 2274 Ichthyosis - hepatosplenomegaly - cerebellar degeneration 2 Dysmorphism - short stature - deafness - disorder 2282 of sex development 2 2155 Hirschsprung disease - deafness - polydactyly 2 Microcephaly - glomerulonephritis - marfanoid 2172 habitus 2 2181 Hydrocephaly - tall stature - joint laxity 2 2119 HEC 2 1995 Cleft lip - retinopathy 2 Alar cartilages hypoplasia-coloboma-telecanthus 7 2 2010 Cleft palate - stapes fixation - oligodontia 2 2025 Gingival fibromatosis - facial dysmorphism 2 2718 Oculotrichodysplasia 2 2513 Microcephaly - albinism - digital anomalies 2 2511 Microbrachycephaly - ptosis - cleft lip 2 2390 Lichstenstein 2 2347 Lethal Kniest-like dysplasia 2 2324 Kaler-Garrity-Stern 2 3177 Corneal-cerebellar 2 3199 Stimmler 2 Deaf blind hypopigmentation, Yemenite 3214 2 type 3105 Robinow-like 2 3132 Say-Barber-Miller 2 3134 SCARF 2 Spastic tetraplegia - retinitis pigmentosa - 3011 intellectual disability 2 46,XX disorder of sex development - skeletal 2975 anomalies 2 Pterygium colli - intellectual disability - digital 2988 anomalies 2 2985 Pseudoprogeria 2 2888 Pierre Robin - faciodigital anomaly 2 2867 Short stature, Brussels type 2 2876 PHAVER 2 2892 Pilodental dysplasia - refractive errors 2 2825 PARC 2 2826 Spastic paraplegia - precocious puberty 2 3262 Syngnathia multiple anomalies 2 3291 Teebi-Shaltout 2 3323 Thrombocytopenia - Robin sequence 2 3327 Thyrocerebrorenal 2 Deafness - genital anomalies - metacarpal and 3224 metatarsal synostosis 2 3239 Deafness - vitiligo - achalasia 2 3365 Trigonocephaly - broad thumbs 2 3368 Trigonocephaly - bifid nose - acral anomalies 2 3 Stoll-Alembik-Finck 2 Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 42

3167 Siegler-Brewer-Carey 2 2352 Kozlowski-Brown-Hardwick 2 Microcephaly - seizures - intellectual disability - 2519 heart disease 2 Osteochondrodysplatic nanism - deafness - 2653 retinitis pigmentosa 2 Adult familial nephronophthisis - spastic 2666 quadriparesia 2 1485 Arthrogryposis - hyperkeratosis, lethal form 2 2729 Okamoto 2 Atherosclerosis - deafness - diabetes - epilepsy - 1192 nephropathy 2 2015 Cleft palate - short stature - vertebral anomalies 2 2427 Macrocephaly - short stature - paraplegia 2 2898 X-linked intellectual disability - plagiocephaly 2 2183 Hydrocephalus - obesity - hypogonadism 2 Central nervous system calcification - deafness - 3240 tubular acidosis - anemia 2 Anhidrotic ectodermal dysplasiaimmuno-osteopetrosis-lymphedema 69088 2 Congenital brain dysgenesis due to glutamine 71278 synthetase 2 73224 Tubular renal disease - cardiomyopathy 2 Ossification anomalies - psychomotor 73230 development delay 2 Spinal muscular atrophy - Dandy-Walker 73245 malformation - cataracts 2 Visceral neuropathy - brain anomalies - facial 73246 dysmorphism - developmental delay 2 71270 Auriculoocular anomalies - cleft lip 2 Dentinogenesis imperfecta - short stature - hearing 71267 2 loss - intellectual disability Zellweger-like without peroxisomal 50812 anomalies 2 50817 Duane anomaly - myopathy - scoliosis 2 50809 Talo-patello-scaphoid osteolysis 2 50810 Microlissencephaly - micromelia 2 52047 Braddock 2 Agenesis of the corpus callosum-intellectual 52055 disability-coloboma-micrognathia 2 64542 Acrofacial dysostosis, Kennedy-Teebi type 2 79302 Congenital bile acid synthesis defect type 3 2 79332 B4GALT1-CDG 2 Brain malformation - congenital heart disease - 75389 postaxial polydactyly 2 Developmental malformations - deafness - 79107 dystonia 2 Neonatal diabetes - congenital hypothyroidism - 79118 congenital glaucoma - hepatic fibrosis - polycystic kidneys 2 Not NOTCH3-related small vessel disease of the 77304 brain 2 Auricular abnormalities - cleft lip with or without 77 cleft palate - ocular abnormalities 2 Osteopenia - myopia - hearing loss - intellectual 91133 disability - facial dysmorphism 2 91130 Cardiomyopathy - hypotonia - lactic acidosis 2 91494 Macular coloboma-cleft palate-hallux valgus 2 Obesity - colitis - hypothyroidism - cardiac 88643 hypertrophy - developmental delay 2 90022 Cardiomyopathy - renal anomalies 2 X-linked intellectual disability - acromegaly - 85327 hyperactivity 2 86822 Lissencephaly type 3 - metacarpal bone dysplasia 2 Hypercoagulability due to 83639 glycosylphosphatidylinositol 2 X-linked intellectual disability - epilepsy - 85319 progressive joint contractures - dysmorphism 2 Familial papillary thyroid carcinoma with renal 97290 papillary neoplasia 2 95428 COG8-CDG 2 Severe intellectual disability-epilepsy-anal 94066 anomalies-distal phalangeal hypoplasia 2 139414 Congenital panfollicular nevus 2 Microcephaly - digital anomalies - intellectual 137653 disability 2 Lung fibrosis - immuno - 46,XX gonadal 137631 dysgenesis 2 103912 Epithelio-exfoliative colitis - deafness 2 Resistance to thyrotropin-releasing hormone 99832 2 Univentricular heart with single atrio-ventricular 99069 valve 2 217399 Congenital insensitivity to pain with hyperhidrosis 2 238523 Atypical hypotonia - cystinuria 2 238505 Autosomal recessive lymphoproliferative disease 2 Severe X-linked mitochondrial 238329 encephalomyopathy 2 Late-onset localized junctional epidermolysis 231556 bullosa - intellectual disability 2 Autosomal recessive ataxia due to PEX10 247815 2 Leukoencephalopathy - dystonia - motor 163684 neuropathy 2 163985 Hyperekplexia - epilepsy 2 Hypospadias - hypertelorism - coloboma and 157788 deafness 2 Hereditary cryohydrocytosis with reduced 168577 stomatin 2 Fatal mitochondrial disease due to combined 168566 oxidative phosphorylation 3 2 168555 Spondylometaphyseal dysplasia, A4 type 2 Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 43

Brain demyelination due to methionine 168598 adenosyltransferase 2 169 Immuno due to CD25 2 166038 Metaphyseal chondrodysplasia, Kaitila type 2 Metaphyseal chondrodysplasia - retinitis 166035 pigmentosa 2 FASTKD2-related infantile mitochondrial 166105 encephalomyopathy 2 Spondyloepimetaphyseal dysplasia - abnormal 168451 dentition 2 Spondyloepimetaphyseal dysplasia, Geneviève 168454 type 2 Spondylometaphyseal dysplasia - bowed forearms 168552 2 - facial dysmorphism 183707 Neutrophil immuno 2 199348 Thiamine-responsive encephalopathy 2 199329 Congenital myopathy, Paradas type 2 293807 Ketamine-induced biliary dilatation 2 294026 2q31.1 microduplication 2 294023 Neonatal inflammatory skin and bowel disease 2 313772 Early-onset spastic ataxia-neuropathy 2 306511 Autosomal recessive spastic paraplegia type 48 2 313947 2q23.1 microduplication 2 Contractures-webbed neck-micrognathiahypoplastic nipples 314002 2 314034 7p22.1 microduplication 2 314029 High bone mass osteogenesis imperfecta 2 Marfanoid habitus - inguinal hernia - advanced 314041 bone age 2 314629 CLN11 disease 2 Intellectual disability-hypotonia-brachycephalypyloric stenosis-cryptorchidism 314575 2 Autoinflammation-PLCG2-associated antibody 324530 -immune dysregulation 2 Aphonia - deafness - retinal dystrophy - bifid 324540 halluces - intellectual disability 2 Muscular hypertrophy - hepatomegaly - 324416 polyhydramnios 2 X-linked intellectual disability - cardiomegaly - 324410 congestive heart failure 2 324307 Severe lateral tibial bowing with short stature 2 Multiple paragangliomas associated with 324299 polycythemia 2 T-cell immuno with epidermodysplasia 324294 verruciformis 2 Mendelian susceptibility to mycobacterial diseases 319600 2 due to partial IRF8 Autosomal dominant mendelian susceptibility to 319589 mycobacterial diseases due to partial IFNgammaR2 2 Spondylocostal dysostosis - hypospadias - 329252 intellectual disability 2 Congenital chronic diarrhea with protein-losing 329242 enteropathy 2 Intellectual disability - craniofacial dysmorphism - 329224 cryptorchidism 2 324575 Hyperinsulinism due to HNF1A 2 Congenital ichthyosis-intellectual disability-spastic 352333 2 quadriplegia 261304 Paternal 20q13.2q13.3 microdeletion 2 261534 49,XXXYY 2 263501 COG4-CDG 2 263463 CHST3-related skeletal dysplasia 2 276556 Hyperinsulinism due to UCP2 2 276405 Hyperbiliverdinemia 2 280071 ALG11-CDG 2 280576 Nestor-Guillermo progeria 2 280397 Familial Alzheimer-like prion disease 2 280663 Hermansky-Pudlak type 9 2 281127 Acral self-healing collodion baby 2 397725 COASY protein-associated neurodegeneration 2 Autosomal dominant Charcot-Marie-Tooth disease 397735 2 type 2U 231531 Hermansky-Pudlak type 7 2 2575 Cystic fibrosis - gastritis - megaloblastic anemia 2 412217 Dystonia-aphonia 2 Epidermolysis bullosa simplex due to BP230 412181 2 Autosomal recessive cerebellar ataxia-epilepsyintellectual disability due to KIAA0226 404499 2 Global developmental delay-lung cystsovergrowth-wilms tumor 404476 2 401862 Lipoyl transferase 1 2 401923 9q31.1q31.3 microdeletion 2 Partial corpus callosum agenesis-cerebellar vermis 401959 2 hypoplasia with posterior fossa cysts 401764 Pancytopenia-developmental delay 2 401805 Autosomal recessive spastic paraplegia type 63 2 401815 Autosomal recessive spastic paraplegia type 66 2 401820 Autosomal recessive spastic paraplegia type 67 2 401830 Autosomal recessive spastic paraplegia type 69 2 397959 TCR-alpha-beta-positive T-cell 2 397946 Autosomal recessive spastic paraplegia type 58 2 Intellectual disability-obesity-prognathism-eye and 397973 2 skin anomalies Finger hyperphalangy-toe anomalies-severe pectus 369979 2 excavatum Methylmalonic acidemia with homocystinuria, 369955 2 type cblj Aldosterone-producing adenoma with seizures and 369929 2 neurological abnormalities Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 44

Early infantile epileptic encephalopathy without 369894 2 suppression burst 369881 2p21 microdeletion without cystinuria 2 370921 STT3A-CDG 2 370039 Angora hair nevus 2 370015 Spondyloepimetaphyseal dysplasia, Isidor type 2 Spondylometaphyseal dysplasia, Czarny-Ratajczak 370019 2 type 363680 2p13.2 microdeletion 2 Autosomal recessive limb-girdle muscular 363623 dystrophy type 2T 2 Autosomal recessive limb-girdle muscular 363543 dystrophy type 2R 2 Severe combined immuno due to 357237 CARD11 2 Mandibulofacial dysostosis - macroblepharon - 357158 macrostomia 2 Hypotonia-cerebral atrophy-hyperglycinemia 363424 2 Corneal intraepithelial dyskeratosis-palmoplantar 352662 hyperkeratosis-laryngeal dyskeratosis 2 Intellectual disability - obesity - brain 352530 malformations - facial dysmorphism 2 Infantile hypertrophic cardiomyopathy due to 352563 MRPL44 2 370930 XYLT1-CDG 2 Muscle-eye-brain disease with bilateral multicystic 370997 2 leucodystrophy 391343 Fatal post-viral neurodegenerative disorder 2 Growth and developmental delay-hypotonia-vision 391348 2 impairment-lactic acidosis Growth retardation-mild developmental delaychronic hepatitis 391366 2 420741 RIDDLE 2 Combined oxidative phosphorylation 420728 type 20 2 Autosomal recessive severe congenital 420699 neutropenia due to CXCR2 2 439232 AApoAIV amyloidosis 2 Combined oxidative phosphorylation 420733 type 21 2 424107 Congenital myopathy with myasthenic-like onset 2 Microcephaly-short stature-intellectual disabilityfacial dysmorphism 423306 2 X-linked intellectual disability-limb spasticityretinal dystrophy-diabetes insipidus 423479 2 Autosomal dominant Charcot-Marie-Tooth disease 435819 2 type 2 due to TFG mutation 431329 Autosomal recessive spastic paraplegia type 57 2 398109 Neonatal autoimmune hemolytic anemia 2 440713 Isolated sedoheptulokinase 2 436182 Microcephalic primordial dwarfism-insulin 2 resistance Lethal fetal cerebrorenogenitourinary 439897 agenesis/hypoplasia 2 435660 LIPE-related familial partial lipodystrophy 2 Severe autosomal recessive 438207 macrothrombocytopenia 2 Progressive encephalopathy with leukodystrophy 431361 due to DECR 2 440731 L-ferritin 2 443950 Charcot-Marie-Tooth disease type 2T 2 Limb-girdle muscular dystrophy due to POMK 445110 2 166032 Multiple epiphyseal dysplasia, with miniepiphyses 2 79326 ALG2-CDG 1 Case Glycogen storage disease due to muscle betaenolase 99849 1 Case 243343 Dimethylglycine dehydrogenase 1 Case 238459 SLC35A1-CDG 1 Case Autosomal recessive intermediate Charcot-Marie- 254334 Tooth disease type B 1 Case 250977 AICA-ribosiduria 1 Case 536 DDOST-CDG 1 Case 324422 ALG13-CDG 1 Case 329 Hypotrichosis-deafness 1 Case Lethal encephalopathy due to mitochondrial and 350 peroxisomal fission defect 1 Case Transient neonatal multiple acyl-coa 329942 dehydrogenase 1 Case Glycogen storage disease due to glycogenin 263297 1 Case 263494 DPM3-CDG 1 Case Spinal muscular atrophy with respiratory distress 404521 type 2 1 Case 411712 Maternal riboflavin 1 Case 401800 Autosomal recessive spastic paraplegia type 60 1 Case 401825 Autosomal recessive spastic paraplegia type 68 1 Case 401840 Autosomal recessive spastic paraplegia type 71 1 Case 397968 Charcot-Marie-Tooth disease type 2R 1 Case 370924 STT3B-CDG 1 Case 370097 Oculocutaneous albinism type 6 1 Case 370927 SSR4-CDG 1 Case 440706 Ribose-5-P isomerase 1 Case 435934 COG2-CDG 1 Case Combined immuno due to OX40 431149 1 Case 435651 CIDEC-related familial partial lipodystrophy 1 Case Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 45

of published families of families 250 1652 Dent disease 1949 Benign familial neonatal epilepsy 1416 Familial calcium pyrophosphate deposition 89843 Dystrophic epidermolysis bullosa pruriginosa 98759 Spinocerebellar ataxia type 17 Autosomal dominant nocturnal frontal lobe 98784 epilepsy 81 2524 Pontocerebellar hypoplasia type 2 80 757 Pseudohypoaldosteronism type 2 52 60030 Loeys-Dietz 50 627 Nance-Horan 2526 Microcephaly - lymphedema - chorioretinopathy 50 50 98934 Huntington disease-like 2 46,XY disorder of sex development due to 5-50 753 alpha-reductase 2 40 2254 Pontocerebellar hypoplasia type 1 40 79410 Pretibial dystrophic epidermolysis bullosa 40 98762 Spinocerebellar ataxia type 12 40 263548 Peeling skin type A 35 1106 Microphthalmia with limb anomalies 35 79501 Punctate palmoplantar keratoderma type 1 35 163937 X-linked intellectual disability, Najm type 35 418 Immuno with factor I anomaly Autosomal recessive axonal neuropathy with 33 324442 neuromyotonia Glycogen storage disease due to 30 713 phosphoglycerate kinase 1 2848 Camptodactyly-arthropathy-coxa-varapericarditis 30 30 425 Apolipoprotein A-I Phosphoribosylpyrophosphate synthetase 30 3222 superactivity 3237 Multiple synostoses 30 of families 30 90026 Primary erythermalgia Hereditary combined of vitamin K- 30 98434 dependent clotting factors 30 217012 Spinocerebellar ataxia type 31 MITF-related melanoma and renal cell carcinoma 30 293822 predisposition 30 263553 Peeling skin type B 28 33108 Lethal multiple pterygium Familial hyperthyroidism due to mutations in TSH 28 424 receptor 24 85293 X-linked intellectual disability, Cabezas type 20 643 Giant axonal neuropathy 20 959 Acro-renal-ocular Dilated cardiomyopathy - hypergonadotropic 20 2229 hypogonadism 20 3203 Overhydrated hereditary stomatocytosis Familial platelet with predisposition to 20 71290 acute myelogenous leukemia 20 98763 Spinocerebellar ataxia type 14 20 97286 Carney-Stratakis 998 Autosomal dominant spastic paraplegia type 17 20 99027 Adult-onset autosomal dominant leukodystrophy 20 20 3202 Dehydrated hereditary stomatocytosis 19 99791 Dentin dysplasia type II Non-spherocytic hemolytic anemia due to 17 90031 hexokinase Infantile-onset ascending hereditary spastic 17 293168 paralysis 16 88621 Ichthyosis prematurity 16 84090 Fibronectin glomerulopathy 2950 Triphalangeal thumb - polysyndactyly 15 15 25980 X-linked myopathy with excessive autophagy X-linked distal arthrogryposis multiplex 14 1145 congenita X-linked intellectual disability - cerebellar 12 137831 hypoplasia Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 46

of families 12 228277 Familial anetoderma 12 401996 Karyomegalic interstitial nephritis 11 93974 Smith-Fineman-Myers 11 99955 Charcot-Marie-Tooth disease type 4B1 11 98971 Posterior amorphous corneal dystrophy 11 439218 KCNQ2-related epileptic encephalopathy 10 931 Acheiropodia 10 1276 Brachydactyly-arterial hypertension 10 1062 Hereditary neurocutaneous angioma 10 1412 Tarsal-carpal coalition 10 2238 Familial isolated hypoparathyroidism Palmoplantar keratoderma-esophageal 10 2198 carcinoma 10 2202 Palmoplantar keratoderma-deafness 10 2791 Otodental 10 3412 VACTERL with hydrocephalus 90001 X-linked cone dysfunction with myopia 10 Syndromic X-linked intellectual disability due to 10 85279 JARID1C mutation 10 140927 Benign familial neonatal-infantile seizures 994 Autosomal dominant spastic paraplegia type 13 10 993 Autosomal dominant spastic paraplegia type 12 10 991 Autosomal dominant spastic paraplegia type 10 10 10 989 Autosomal dominant spastic paraplegia type 8 10 988 Autosomal dominant spastic paraplegia type 6 10 106 Autosomal recessive spastic paraplegia type 26 10 996 Autosomal recessive spastic paraplegia type 15 10 158673 Acral dystrophic epidermolysis bullosa 10 158676 Dystrophic epidermolysis bullosa, nails only of families 10 166063 Pontocerebellar hypoplasia type 4 Hereditary proximal myopathy with early 10 178464 respiratory failure Xeroderma pigmentosum complementation 10 276252 group B Autosomal recessive cerebellar ataxia due to 10 412057 STUB1 71291 Hereditary vascular retinopathy 9 008 ACys amyloidosis 9 217266 BNAR 9 1377 Cataract-microcornea 8 1832 Lethal osteosclerotic bone dysplasia 8 66629 Goldberg-Shprintzen megacolon 8 Autosomal recessive intermediate Charcot- 217055 Marie-Tooth disease type A 8 306527 Isolated hereditary congenital facial paralysis 8 1897 EEM 7 1777 Temtamy 7 990 Autosomal dominant spastic paraplegia type 9 7 251274 Familial hyperaldosteronism type III 7 Autosomal recessive systemic lupus 345 erythematosus 7 329457 Distal arthrogryposis type 5D 7 281139 Annular epidermolytic ichthyosis 7 Foveal hypoplasia-optic nerve decussation 397618 defect-anterior segment dysgenesis 7 93561 ALys amyloidosis 7 1799 Familial developmental dysphasia 6 79503 Ichthyosis hystrix of Curth-Macklin 6 79401 Epidermolysis bullosa simplex, Ogna type 6 75381 Cystoid macular dystrophy 6 Deafness with labyrinthine aplasia, microtia, and 90024 6 microdontia X-linked reticulate pigmentary disorder with 85453 systemic manifestations 6 140917 Stapes ankylosis with broad thumbs and toes 6 137634 Overgrowth - macrocephaly - facial dysmorphism 6 Mesoaxial synostotic syndactyly with phalangeal 157801 6 reduction Hypopigmentation-punctate palmoplantar 324561 6 keratoderma 391411 Atypical juvenile parkinsonism 6 2118 Hawkinsinuria 5 1428 Familial chondromalacia patellae 5 1836 Mesomelic dysplasia, Kantaputra type 5 2802 X-linked sideroblastic anemia and ataxia 5 3248 Distal symphalangism 5 3351 Trichodental 5 Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 47

of families Intellectual disability-developmental delaycontractures 3454 5 Familial primary hypomagnesemia with 34527 normocalciuria and normocalcemia 5 Autosomal dominant limb-girdle muscular 34517 dystrophy type 1E 5 Autosomal dominant limb-girdle muscular 34516 dystrophy type 1D 5 Short stature - pituitary and cerebellar defects - 85442 small sella turcica 5 Familial encephalopathy with neuroserpin 85110 inclusion bodies 5 X-linked hereditary sensory and autonomic 139583 neuropathy with deafness 5 Female restricted epilepsy with intellectual 101039 disability 5 101068 Congenital stromal corneal dystrophy 5 Autosomal dominant Charcot-Marie-Tooth 99940 disease type 2F 5 231108 Familial rhabdoid tumor 5 178333 Åland Islands eye disease 5 Autism-epilepsy due to branched chain 308410 5 ketoacid dehydrogenase kinase Ocular albinism with congenital sensorineural 352740 deafness 5 1879 Melorheostosis with osteopoikilosis 5 391330 X-linked osteoporosis with fractures 5 Colobomatous microphthalmia-rhizomelic 424099 dysplasia 5 Autoimmune interstitial lung disease-arthritis 444092 5 86789 Patella aplasia/hypoplasia 5 1275 Brachydactyly - elbow wrist dysplasia 4 2307 IVIC 4 2947 Triphalangeal thumbs - brachyectrodactyly 4 46348 Paroxysmal extreme pain disorder 4 77297 Majeed 4 97239 Reducing body myopathy 4 101108 Spinocerebellar ataxia type 23 4 98890 Early-onset X-linked isolated optic atrophy 4 Progressive sensorineural hearing loss - 228012 hypertrophic cardiomyopathy 4 171851 MEDNIK 4 293936 EDICT 4 Facial dysmorphism-lens dislocation-anterior 412022 segment abnormalities-spontaneous filtering blebs 4 AXIN2-related attenuated familial adenomatous 401911 polyposis 4 Hyperuricemia-pulmonary hypertension-renal 363694 failure-alkalosis 4 of families 423296 Spinocerebellar ataxia type 38 4 399103 Nebulin-related early-onset distal myopathy 4 1252 Blepharonasofacial malformation 3 1266 Dermato-cardio-skeletal, Borrone type 3 1074 Ankyloblepharon filiforme - imperforate anus 3 Hypertelorism - hypospadias - polysyndactyly 2211 3 2699 Median nodule of the upper lip 3 Adducted thumbs-arthrogryposis, 2952 Christian type 3 3421 Cerebroretinal vasculopathy 3 3466 WT limb-blood 3 Gamma-aminobutyric acid transaminase 2066 3 162 Cataract-glaucoma 3 X-linked intellectual disability with isolated 67045 growth hormone 3 Thrombocytopenia with congenital 67044 dyserythropoietic anemia 3 67036 Autosomal dominant optic atrophy and cataract 3 98870 Congenital dyserythropoietic anemia type III 3 98766 Spinocerebellar ataxia type 5 3 97249 Pontocerebellar hypoplasia type 3 3 Autosomal recessive cerebellar ataxia - blindness 95433 3 - deafness 94064 Deafness-infertility 3 101010 Autosomal recessive spastic paraplegia type 30 3 Autosomal dominant Charcot-Marie-Tooth 99944 disease type 2K 3 157832 Craniorhiny 3 PLCG2-associated antibody and 359 immune dysregulation 3 314978 X-linked non progressive cerebellar ataxia 3 Hereditary thrombocytosis with transverse limb 329319 defect 3 276193 Spinocerebellar ataxia type 35 3 Familial progressive hyper- and 280628 hypopigmentation 3 Autosomal dominant Charcot-Marie-Tooth 401964 disease type 2 with giant axons 3 Short stature-advanced bone age-early onset 435804 osteoarthritis 3 444072 Cerebellar-facial-dental 3 Maternally-inherited cardiomyopathy and 1349 hearing loss 2 Retinitis pigmentosa - intellectual disability - 3085 deafness - hypogenitalism 2 Congenital absence/hypoplasia of fingers 973 excluding thumb, unilateral 2 1241 Bencze 2 114 Auriculoosteodysplasia 2 Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 48

of families 1187 Lethal ataxia with deafness and optic atrophy 2 1867 Bullous dystrophy, macular type 2 1350 Heart-hand type 2 2 1436 Skeletal dysplasia - intellectual disability 2 Familial isolated hypoparathyroidism due to 2239 agenesis of parathyroid gland 2 2027 Gingival fibromatosis - progressive deafness 2 2754 Joubert with orofaciodigital defect 2 Metaphyseal dysplasia - maxillary hypoplasia - 2504 brachydacty 2 2405 Thickened earlobes - conductive deafness 2 Spastic paraplegia - glaucoma - intellectual 2818 disability 2 42665 Tietz 2 Autosomal dominant limb-girdle muscular 266 dystrophy type 1A 2 63261 HERNS 2 Autosomal dominant limb-girdle muscular 55596 dystrophy type 1G 2 79141 Hereditary painful callosities 2 79136 Episodic ataxia type 4 2 75497 X-linked Ehlers-Danlos 2 75327 North Carolina macular dystrophy 2 75373 Progressive bifocal chorioretinal atrophy 2 Alport -intellectual disability-midface 86818 hypoplasia-elliptocytosis 2 85287 X-linked intellectual disability, Siderius type 2 94083 Partington 2 93409 Brachydactyly-syndactyly, Zhao type 2 93389 Brachydactyly type A5 2 139471 Microphthalmia with brain and digit anomalies 2 139480 Autosomal recessive spastic paraplegia type 39 2 Hereditary sensory and autonomic neuropathy 139564 type 1B 2 107 Autosomal recessive spastic paraplegia type 27 2 Sensorineural deafness with dilated 217622 cardiomyopathy 2 576 Oligodontia - cancer predisposition 2 Tall stature - scoliosis - macrodactyly of the great 329191 2 toes Spectrin-associated autosomal recessive 352403 cerebellar ataxia 2 439254 ITM2B amyloidosis 2 434179 Orofaciodigital type 14 2 998 Albinism-deafness 1 Family 1876 Oculogastrointestinal muscular dystrophy 1 Family 1228 Banki 1 Family 1319 Camptobrachydactyly 1 Family 1144 Arthrogryposis-like hand anomaly - sensorineural 1 Family of families deafness Lipodystrophy due to peptidic growth factors 1979 1 Family Steroid dehydrogenase - dental 3196 anomalies 1 Family 1765 Dyschondrosteosis - nephritis 1 Family 1527 Craniosynostosis, Philadelphia type 1 Family Woolly hair - hypotrichosis - everted lower lip - 1409 outstanding ears 1 Family 2186 Hydrocephalus - blue sclerae - nephropathy 1 Family 2709 Oculodental, Rutherfurd type 1 Family 2674 Cyprus facial-neuromusculoskeletal 1 Family 2391 Congenitally short costocoracoid ligament 1 Family 2999 Ptosis - strabismus - ectopic pupils 1 Family 2890 Pili torti - onychodysplasia 1 Family 2917 Polydactyly-myopia 1 Family 3408 Upington disease 1 Family 3417 Van den Bosch 1 Family 1246 Brachydactyly - nystagmus - cerebellar ataxia 1 Family 52056 Ulnar/fibula ray defect - brachydactyly 1 Family Autosomal dominant limb-girdle muscular 55595 dystrophy type 1F 1 Family 79135 Episodic ataxia type 3 1 Family 79129 Trichodysplasia - amelogenesis imperfecta 1 Family 75501 Ehlers-Danlos, fibronectinemic type 1 Family 79085 AKT2-related familial partial lipodystrophy 1 Family 93283 Spondyloepiphyseal dysplasia, Kimberley type 1 Family 85335 Fried 1 Family 85322 X-linked intellectual disability, Pai type 1 Family X-linked recessive intellectual disability - 83648 macrocephaly - ciliary dysfunction 1 Family 85168 Craniofacial conodysplasia 1 Family 85292 X-linked spinocerebellar ataxia type 4 1 Family X-linked intellectual disability, Stocco Dos Santos 85288 1 Family type Autosomal recessive cerebellar ataxia - saccadic 95434 intrusion 1 Family 93397 Brachydactyly type A7 1 Family Microtia-eye coloboma-imperforation of the 139450 nasolacrimal duct 1 Family 139512 Neuropathy with hearing impairment 1 Family 101101 Charcot-Marie-Tooth disease type 2B2 1 Family 101112 Spinocerebellar ataxia type 26 1 Family 995 Autosomal recessive spastic paraplegia type 14 1 Family 105 Autosomal recessive spastic paraplegia type 25 1 Family 103 Autosomal recessive spastic paraplegia type 23 1 Family 104 Autosomal recessive spastic paraplegia type 24 1 Family 999 Autosomal dominant spastic paraplegia type 19 1 Family 997 X-linked spastic paraplegia type 16 1 Family Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 49

of families 109 Autosomal dominant spastic paraplegia type 29 1 Family Autosomal dominant Charcot-Marie-Tooth 99941 disease type 2G 1 Family Autosomal dominant Charcot-Marie-Tooth 99945 disease type 2L 1 Family 99806 Oculootodental 1 Family 98959 Subepithelial mucinous corneal dystrophy 1 Family Epibulbar lipodermoid - preauricular appendage - 231742 1 Family polythelia 163662 Spondyloepiphyseal dysplasia, Reardon type 1 Family 163988 Developmental delay - deafness, Hildebrand type 1 Family Spondyloepimetaphyseal dysplasia, matrilin-3 156728 type 1 Family 166011 Multiple epiphyseal dysplasia, Beighton type 1 Family 166108 Intellectual disability, Birk-Barel type 1 Family 178461 X-linked myopathy with postural muscle atrophy 1 Family 171617 Autosomal dominant spastic paraplegia type 38 1 Family 171622 Autosomal recessive spastic paraplegia type 32 1 Family 171629 Autosomal recessive spastic paraplegia type 35 1 Family 293375 Grayson-Wilbrandt corneal dystrophy 1 Family 305 11p15.4 microduplication 1 Family Autosomal dominant proximal renal tubular 314889 acidosis 1 Family 329883 Non-hypoproteinemic hypertrophic gastropathy 1 Family 329475 Spastic paraplegia - Paget disease of bone 1 Family Autoimmune lymphoproliferative with 275517 1 Family recurrent viral infections 276183 Spinocerebellar ataxia type 32 1 Family 370131 White platelet 1 Family 370091 Oculocutaneous albinism type 5 1 Family X-linked dyserythropoetic anemia with abnormal 363727 1 Family platelets and neutropenia 391320 East Texas bleeding disorder 1 Family 391327 X-linked calvarial hyperostosis 1 Family Autosomal dominant myopia-midfacial retrusionsensorineural hearing loss-rhizomelic dysplasia 1 Family 440354 444099 Autosomal dominant spastic paraplegia type 73 1 Family X-linked colobomatous microphthalmiamicrocephaly-intellectual disability-short stature 1 Family 431140 Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - March 2016-2 50

For any questions or comments, please contact us: contact.orphanet@inserm.fr Editor-in-chief :Ana Rath Editor of the report:stéphanie Stéphanie Nguengang Wakap Technical support : Samuel Demarest and Valérie Lanneau The correct form when quoting this document is : «Prevalence of rare diseases: Bibliographic data», Orphanet Report Series, Rare s collection, March 2016, 2 : s listed by decreasing prevalence, incidence or number of published cases This Orphanet Report Series is part of the joint action 677024 RD-ACTION which has received funding from the European Union s Health Programme (2014-2020). The content of this Orphanet Report Series represents the views of the author only and is his/her sole responsibility; it can not be considered to reflect the views of the European Commission and/or the Consumers, Health, Agriculture and Food Executive Agency or any other body of the European Union. The European Commission and the Agency do not accept any responsibility for use that may be made of the information it contains.