Prevalence of rare diseases: Bibliographic data

Prevalence distribution of rare diseases 200 180 160 140 diseases 120 100 80 60 40 May November 2014 2009 1 20 0 0 5 10 15 20 25 30 35 40 45 50 (/100000) Prevalence of rare diseases: Bibliographic data Listed in alphabetical order of disease or group of diseases www.orpha.net

Methodology A systematic survey of the literature is being performed in order to provide an estimate of the of rare diseases in Europe. An updated report will be regularly and will replace the previous version. This update contains new epidemiological data and modifications to existing data for which new information has been made available. Search strategy The search strategy is carried out using several data sources: - Websites: Orphanet, e-medicine, GeneClinics, EMA and OMIM ; - Registries, RARECARE - Medline is consulted using the search algorithm: «Disease names» AND Epidemiology[MeSH:NoExp] OR Incidence[Title/abstract] OR Prevalence[Title/ abstract] OR Epidemiology[Title/abstract] ; - Medical books, grey literature and reports from experts are also important sources of data. Updated Data New information from available data sources: EMA, new scientific publications, grey literature, expert opinion. Limitation of the study The exact rate of each rare disease is difficult to assess from the available data sources. There is a low level of consistency between studies, a poor documentation of methods used, confusion between incidence and, and/or confusion between incidence at birth and life-long incidence. The validity of the studies is taken for granted and not assessed. It is likely that there is an overestimation for most diseases as the few surveys are usually done in regions of higher and are usually based on hospital data. Therefore, these estimates are an indication of the assumed but may not be accurate. Collected data Prevalence values provided are the mean of the highest and lowest values collected. When is not documented we calculate it using incidence: - For congenital diseases with birth-onset, = incidence at birth x (patient life expectancy/ general population life expectancy) ; - For the other rare diseases, = incidence x rare disease mean duration ; When no or incidence data are available, the number of or reported in the literature is provided. The * sign indicates a life time. The ** sign indicates a birth. It was used when the birth was the only data available and a estimate was not possible because of a large variability in the duration of the disease. NB: Life expectancy of the French population (81 years) is used as the general population life expectancy. For any questions or comments, please contact us: contact.orphanet@inserm.fr Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - May 2014-1 2

Prevalence or reported number of listed in alphabetical order of disease or group of diseases or 94063 12q14 microdeletion 4 199318 15q13.3 microdeletion 150 94065 15q24 microdeletion 4 1606 1p36 deletion 15** 268261 21q22.13q22.2 microdeletion 12 567 22q11.2 deletion 5.6** 79157 2-methylbutyryl-CoA dehydrogenase < 30 163693 2p21 microdeletion 7 1617 2q24 microdeletion 23 251019 2q32q33 microdeletion < 25 1001 2q37 microdeletion 10 7 3C 25 35701 3-hydroxy-3-methylglutaryl-CoA synthase 9 2616 3M 40 67046 3-methylglutaconic aciduria 1 20 2975 46,XX disorder of sex development - skeletal anomalies 2138 46,XX ovotesticular disorder of sex development 168558 46,XY disorder of sex development - adrenal insufficiency due to CYP11A1 752 46,XY disorder of sex development due to 17-beta-hydroxysteroid dehydrogenase 3 168563 46,XY gonadal dysgenesis - motor and sensory neuropathy 0.68 10 48,XXYY 1.9** 2 > 500 9 6 22 4-hydroxybutyric aciduria 450 33572 5-oxoprolinase 8 75857 6q terminal deletion 19 171829 6q16 deletion 7 178303 8q22.1 microdeletion 4 915 Aarskog-Scott 0.4** 916 Aase-Smith < 10 920 Ablepharon macrostomia 15 921 Abruzzo-Erickson 4 1658 Absence of fingerprints - congenital milia 14 2951 Absent thumb - short stature - immuno 67043 Acanthamoeba keratitis 1 90301 Acanthosis nigricans - Insulin resistance - muscle cramps - acral enlargement 3 5 926 Acatalasemia 3.2 48818 Aceruloplasminemia 0.1 or 929 Achalasia - microcephaly 5 931 Acheiropodia < 10 932 Achondrogenesis 2.8** 15 Achondroplasia 2.6** 49382 Achromatopsia 2.7 2561 Ackerman 8 79086 Acquired generalized lipodystrophy > 100 73274 Acquired hemophilia 0.1 2221 Acquired hypertrichosis lanuginosa 60 99147 Acquired Von Willebrand 300 36 Acrocallosal 34 2008 Acro-cardio-facial 9 949 Acrocraniofacial dysostosis 2 37 Acrodermatitis enteropathica 0.2 1786 Acrofacial dysostosis, Catania 6 64542 Acrofacial dysostosis, Kennedy-Teebi 2 1787 Acrofacial dysostosis, Palagonia 4 1788 Acrofacial dysostosis, Rodríguez < 10 1784 Acro-fronto-facio-nasal dysostosis 5 965 Acromegaloid facial appearance < 20 963 Acromegaly 6 964 Acromegaly - cutis verticis gyrata - corneal leukoma 16 39 Acromelanosis < 10 953 Acromesomelic dysplasia, Brahimi-Bacha 3 968 Acromesomelic dysplasia, Hunter-Thomson 10 40 Acromesomelic dysplasia, Maroteaux 50 969 Acromicric dysplasia < 40 955 Acroosteolysis dominant 50 85203 Acro-pectoral 22 956 Acro-pectoro-renal dysplasia 12 957 Acropectorovertebral dysplasia < 30 971 Acrorenal 20 958 Acro-renal-mandibular 7 959 Acro-renal-ocular < 20 * Lifetime ** Prevalence at birth Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - May 2014-1 3

or 163696 Action myoclonus - renal failure 17 69736 Acute bilateral depigmentation of the iris 5 98916 Acute inflammatory demyelinating polyradiculoneuropathy 3.1 79276 Acute intermittent porphyria 0.54 79126 Acute interstitial pneumonia 3.8 90062 Acute liver failure 23 98918 Acute motor axonal neuropathy 0.1 98917 Acute motor-sensory axonal neuropathy 0.1 519 Acute myeloid leukemia 11* 55881 Adamantinoma 0.11* 2952 Adducted thumbs - arthrogryposis, Christian 45 Adenosine monophosphate deaminase 3 > 100 46 Adenylosuccinate lyase 50 1501 Adrenocortical carcinoma 1 2666 Adult familial nephronophthisis - spastic quadriparesia 2 178487 Adult intestinal botulism 19 829 Adult Still's disease 1.25 978 ADULT 14 209335 Adult-onset proximal spinal muscular atrophy, autosomal dominant 83617 Agammaglobulinemia - microcephaly - craniosynostosis - severe dermatitis 52055 Agenesis of the corpus callosum - intellectual disability - coloboma - micrognathia 0.1 98850 Aggressive systemic mastocytosis 0.2 3 2 990 Agnathia - holoprosencephaly - situs inversus 30 50 Aicardi 1** 51 Aicardi-Goutières 120 52 Alagille 0.4** 178333 Åland Islands eye disease > 5 2007 Alar cartilages hypoplasia - coloboma - telecanthus 53 Albers-Schönberg osteopetrosis 5 2 998 Albinism-deafness 35664 ALDH18A1-related De Barsy 32 58 Alexander disease 300 79324 ALG12-CDG 11 79327 ALG1-CDG 15 79326 ALG2-CDG 1 case 79321 ALG3-CDG 10 79320 ALG6-CDG 58 79325 ALG8-CDG 8 79328 ALG9-CDG 3 139477 Al-Gazali-Dattani 3 56 Alkaptonuria 0.5 or 59 Allan-Herndon-Dudley 89 1005 Alopecia - contractures - dwarfism - intellectual disability 1008 Alopecia - epilepsy - pyorrhea - intellectual disability 700 Alopecia totalis 10.5 701 Alopecia universalis 25 726 Alpers 0.7** 60 Alpha-1-antitrypsin 25 61 Alpha-mannosidosis 0.2** 5 12 3137 Alpha-N-acetylgalactosaminidase < 20 847 Alpha-thalassemia - X-linked intellectual disability 63 Alport 2 2131 Alternating hemiplegia of childhood 0.9** > 200 284 Alveolar echinococcosis < 1000 1021 Amaurosis - hypertrichosis 2 1946 Amelo-cerebro-hypohidrotic 39 171836 Amelogenesis imperfecta and gingival hyperplasia 4 1908 Aminopterin/methotrexate embryofetopathy 17 1034 Amniotic bands 4** 69 Amyloidosis 30 803 Amyotrophic lateral sclerosis 5.2 228113 Anal fistula 23 98841 Anaplastic large cell lymphoma 2 142 Anaplastic thyroid carcinoma 0.1 157954 ANE 5 72 Angelman 1.1 63442 Angel-shaped phalango-epiphyseal dysplasia 15 2346 Angio-osteohypertrophic 0.8** 69088 Anhidrotic ectodermal dysplasia - immuno - osteopetrosis - lymphedema 2 1069 Aniridia - absent patella 3 1065 Aniridia - cerebellar ataxia - intellectual disability 1067 Aniridia - ptosis - intellectual disability - familial obesity 1064 Aniridia - renal agenesis - psychomotor retardation > 10 3 2 1068 Aniridia-intellectual disability 2 1070 Anisakiasis 3.8 1074 Ankyloblepharon filiforme - imperforate anus 2 2206 Ankylosing vertebral hyperostosis with tylosis 8 675 Annular pancreas 1.8** 1094 Anonychia - microcephaly 5 * Lifetime ** Prevalence at birth Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - May 2014-1 4

or 69125 Anonychia with flexural pigmentation 3 91129 Anophthalmia - heart and pulmonary anomalies - intellectual disability 1102 Anophthalmia - hypothalamo-pituitary insufficiency 1101 Anophthalmia - megalocornea - cardiopathy - skeletal anomalies 2 30 3 1104 Anophthalmia plus 4 77298 Anophthalmia/microphthalmia - esophageal atresia 30 2987 Antecubital pterygium 11 83 Antley-Bixler 34 63269 Antley-Bixler with genital anomaly and disorder of steroidogenesis 1110 Aortic arch anomaly - peculiar facies - intellectual disability 2299 Aortic arch interruption 0.3** 88636 Aortic dilatation - joint hypermobility - arterial tortuosity < 50 4 22 3400 Aorto-ventricular tunnel 130 87 Apert 1.25 1112 Aphalangy - hemivertebrae - urogenitalintestinal dysgenesis 3 1113 Aphalangy - syndactyly - microcephaly 1117 Aplasia cutis - myopia 4 1116 Aplasia cutis congenita - intestinal lymphangiectasia 99981 Apnea of prematurity 8.5 1129 Arachnodactyly - abnormal ossification - intellectual disability 1130 Arachnodactyly - intellectual disability - dysmorphism 3 5 3 1133 AREDYLD 3 35704 Arginine:glycine amidinotransferase 9 23 Argininosuccinic aciduria 0.45 91 Aromatase 13 1134 Arrhinia 20 1135 Arrhinia - choanal atresia - microphthalmia 4 247 Arrhythmogenic right ventricular dysplasia 43.5 1682 Arterial dissection - lentiginosis 4 3342 Arterial tortuosity < 80 1485 Arthrogryposis - hyperkeratosis, lethal form 2 2697 Arthrogryposis - renal dysfunction - cholestasis 1037 Arthrogryposis multiplex congenita 5.7** 1150 Arthrogryposis multiplex congenita - whistling face 1144 Arthrogryposis-like hand anomaly - sensorineural deafness < 100 10 1253 Ascher 50 or 85175 Astley-Kendall dysplasia 5 94 Astrocytoma 2.5 1188 Ataxia-deafness-retardation 8 100 Ataxia-telangiectasia 1 1190 Atelosteogenesis I 12 56304 Atelosteogenesis II 25 56305 Atelosteogenesis III < 25 69739 Athabaskan brainstem dysgenesis 10 1192 Atherosclerosis - deafness - diabetes - epilepsy - nephropathy 95713 Athyreosis 3.5 2 1193 Atkin-Flaitz 14 163934 Atopic keratoconjunctivitis 15 1201 Atresia of small intestine 16 1479 Atrial septal defect - atrioventricular conduction defects 11 844 Atrial tachyarrhythmia with short PR interval 12 1456 Atypical coarctation of aorta 0.17** 2134 Atypical hemolytic uremic 1 3095 Atypical Rett 2.22 77300 Auricular abnormalities - cleft lip with or without cleft palate - ocular abnormalities 2 71270 Auriculoocular anomalies - cleft lip 2 114 Auriculoosteodysplasia 2 137911 Autism - facial port-wine stain 4 3261 Autoimmune lymphoproliferative > 500 99 Autosomal dominant cerebellar ataxia 3 99940 Autosomal dominant Charcot-Marie-Tooth disease 2F 99941 Autosomal dominant Charcot-Marie-Tooth disease 2G 99944 Autosomal dominant Charcot-Marie-Tooth disease 2K 99945 Autosomal dominant Charcot-Marie-Tooth disease 2L 73229 Autosomal dominant familial hematuria - retinal arteriolar tortuosity - contractures 1810 Autosomal dominant hypohidrotic ectodermal dysplasia 89937 Autosomal dominant hypophosphatemic rickets 93114 Autosomal dominant intermediate Charcot- Marie-Tooth disease E 503 Autosomal dominant Larsen 0.4** 266 Autosomal dominant limb-girdle muscular dystrophy 1A 264 Autosomal dominant limb-girdle muscular dystrophy 1B 0.2 3 8 40 < 100 10 2 * Lifetime ** Prevalence at birth Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - May 2014-1 5

34516 Autosomal dominant limb-girdle muscular dystrophy 1D 34517 Autosomal dominant limb-girdle muscular dystrophy 1E 55595 Autosomal dominant limb-girdle muscular dystrophy 1F 55596 Autosomal dominant limb-girdle muscular dystrophy 1G 65743 Autosomal dominant multiple pterygium 67036 Autosomal dominant optic atrophy and cataract or 5 5 4 14 2783 Autosomal dominant osteopetrosis 1 33 1010 Autosomal dominant palmoplantar keratoderma and congenital alopecia 88924 Autosomal dominant polycystic kidney disease 1 with tuberous sclerosis 34528 Autosomal dominant primary hypomagnesemia with hypocalciuria 209867 Autosomal dominant rhegmatogenous retinal detachment 10 30 3 38 3107 Autosomal dominant Robinow 100 100991 Autosomal dominant spastic paraplegia 10 100993 Autosomal dominant spastic paraplegia 12 100994 Autosomal dominant spastic paraplegia 13 100998 Autosomal dominant spastic paraplegia 17 101009 Autosomal dominant spastic paraplegia 29 171612 Autosomal dominant spastic paraplegia 37 171617 Autosomal dominant spastic paraplegia 38 < 10 < 10 < 10 < 20 13 100988 Autosomal dominant spastic paraplegia 6 10 100989 Autosomal dominant spastic paraplegia 8 < 10 100990 Autosomal dominant spastic paraplegia 9 1027 Autosomal recessive amelia 3 88644 Autosomal recessive ataxia, Beauce 57 1172 Autosomal recessive cerebellar ataxia 7 95433 Autosomal recessive cerebellar ataxia - blindness - deafness 95434 Autosomal recessive cerebellar ataxia - saccadic intrusion 267 Autosomal recessive limb girdle muscular dystrophy 2A 268 Autosomal recessive limb-girdle muscular dystrophy 2B 353 Autosomal recessive limb-girdle muscular dystrophy 2C 1 0.13 0,2 3 119 Autosomal recessive limb-girdle muscular dystrophy 2E 219 Autosomal recessive limb-girdle muscular dystrophy 2F 34514 Autosomal recessive limb-girdle muscular dystrophy 2G 34515 Autosomal recessive limb-girdle muscular dystrophy 2I 206549 Autosomal recessive limb-girdle muscular dystrophy 2L 206554 Autosomal recessive limb-girdle muscular dystrophy 2M 206580 Autosomal recessive lower motor neuron disease with childhood onset 667 Autosomal recessive malignant osteopetrosis 0.75** 0,1 0.3 1 or 14 14 3 5 93329 Autosomal recessive omodysplasia 23 731 Autosomal recessive polycystic kidney disease 1.2 1507 Autosomal recessive Robinow < 100 100995 Autosomal recessive spastic paraplegia 14 100996 Autosomal recessive spastic paraplegia 15 < 10 209951 Autosomal recessive spastic paraplegia 18 9 101003 Autosomal recessive spastic paraplegia 23 101004 Autosomal recessive spastic paraplegia 24 101005 Autosomal recessive spastic paraplegia 25 101006 Autosomal recessive spastic paraplegia 26 2 101007 Autosomal recessive spastic paraplegia 27 2 101008 Autosomal recessive spastic paraplegia 28 6 101010 Autosomal recessive spastic paraplegia 30 171622 Autosomal recessive spastic paraplegia 32 171629 Autosomal recessive spastic paraplegia 35 139480 Autosomal recessive spastic paraplegia 39 2 782 Axenfeld-Rieger 0.5 168549 Axial spondylometaphyseal dysplasia 3 79332 B4GALT1-CDG 1 case 36234 Bacterial toxic-shock 3 93395 Ballard 12 1226 Bamforth 5 1227 Bangstad 2 1228 Banki 2995 Baraitser-Winter 30 1231 Barber-Say 10 110 Bardet-Biedl 0.7 111 Barth 0.22 1234 Bartsocas-Papas 24 166113 Bazex 145 113 Bazex-Dupré-Christol 143 67038 B-cell chronic lymphocytic leukemia 27 * Lifetime ** Prevalence at birth Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - May 2014-1 6

116 Beckwith-Wiedemann 2.3** or 1237 Beemer-Ertbruggen 2 117 Behçet disease 4 1241 Bencze 2 71269 Benign exophthalmos 4 140927 Benign familial neonatal-infantile seizures 10 209973 Benign familial nocturnal alternating hemiplegia of childhood < 10 71518 Benign paroxysmal torticollis of infancy 50 528 Berardinelli-Seip congenital lipodystrophy 0.25 274 Bernard-Soulier 100 118 Beta-mannosidosis 0.14** 848 Beta-thalassemia 0.5 65287 Beta-ureidopropionase 5 610 Bethlem myopathy 0.77 140963 Bilateral microtia - deafness - cleft palate 4 1848 Bilateral renal agenesis 2** 1980 Bilateral striopallidodentate calcinosis < 200 30391 Biliary atresia 2.9** 122 Birt-Hogg-Dubé 0.5 123 Björnstad 33 124 Blackfan-Diamond anemia 0.67** 93930 Bladder exstrophy 2.8 73271 Bleeding diathesis due to a collagen receptor defect < 20 1997 Blepharo-cheilo-odontic > 50 1251 Blepharofacioskeletal 2 1252 Blepharonasofacial malformation 2 2057 Blepharophimosis - ptosis - esotropia - syndactyly - short stature 3047 Blepharophimosis-intellectual disability, SBBYS 6 < 20 1259 Blepharoptosis - myopia - ectopia lentis 3 171844 Blindness - scoliosis - arachnodactyly 4 125 Bloom 265 16 Blue cone monochromatism 1 1059 Blue rubber bleb nevus > 200 91135 Body skin hyperlaxity due to vitamin K-dependent coagulation factor 6 97297 Bohring-Opitz < 20 1842 Bone dysplasia, lethal Holmgren 4 1261 Bonnemann-Meinecke-Reich 4 1262 Böök 26 1263 Boomerang dysplasia 10 69737 Bosley-Salih-Alorainy 9 1267 Botulism 0.05 83313 Boutonneuse fever 17 or 1276 Brachydactyly - arterial hypertension > 10 2946 Brachydactyly - long thumb 4 1246 Brachydactyly - nystagmus - cerebellar ataxia 1278 Brachydactyly - preaxial hallux varus 8 93389 Brachydactyly A5 2 93382 Brachydactyly A6 7 1292 Brachymorphism - onychodysplasia - dysphalangism 1295 Brachytelephalangy - dysmorphism - Kallmann 9 2 52047 Braddock 2 75374 Bradyopsia 5 178506 Brain calcification, Rajab 8 168598 Brain demyelination due to methionine adenosyltransferase 75389 Brain malformation - congenital heart disease - postaxial polydactyly 36414 Brain stem tumor 3.5 2 2 209905 Brain-lung-thyroid < 20 50815 Branchiogenic deafness 5 1297 Branchio-oculo-facial < 50 1299 Branchio-skeleto-genital 3 85284 BRESEK 2 70589 Bronchopulmonary dysplasia 13 2771 Bruck < 40 130 Brugada 20 131 Budd-Chiari 1.5 36258 Buerger disease 16 1867 Bullous dystrophy, macular 2 703 Bullous pemphigoid 2.5 46489 Bullous systemic lupus erythematosus 70 1306 Buschke-Ollendorff 5 85293 Cabezas 135 CACH 148 136 CADASIL 3 280062 Calciphylaxis 5 85192 Calvarial doughnut lesions - bone fragility 20 83472 CAMOS 5 1318 Campomelia, Cumming 8 140 Campomelic dysplasia 0.33** 1319 Camptobrachydactyly 1321 Camptodactyly - fibrous tissue hyperplasia - skeletal dysplasia 3 * Lifetime ** Prevalence at birth Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - May 2014-1 7

85164 Camptodactyly - tall stature - scoliosis - hearing loss or 30 1325 Camptodactyly - taurinuria 4 1327 Camptodactyly, Guadalajara 1 8 1326 Camptodactyly, Guadalajara 2 2 2848 Camptodactyly-arthropathy-coxa-varapericarditis < 30 1328 Camurati-Engelmann disease > 300 1335 Cantrell pentalogy 0.55** 171881 Cap myopathy < 10 160148 Cap polyposis 20 147 Carbamoylphosphate synthetase 0.03 137628 Cardiac anomalies - heterotaxy 9 2872 Cardiocranial, Pfeiffer < 10 1340 Cardiofaciocutaneous 250 1345 Cardiomyopathy - cataract - hip spine disease 9 91130 Cardiomyopathy - hypotonia - lactic acidosis 2 90022 Cardiomyopathy - renal anomalies 2 3238 Cardiospondylocarpofacial 3 1358 Carey-Fineman-Ziter < 20 2998 Carnevale 2 1359 Carney complex 160 139411 Carney triad 150 157 Carnitine palmitoyl transferase II > 300 159 Carnitine-acylcarnitine translocase 40 1361 Carnosinemia 30 53035 Caroli disease < 250 65759 Carpenter > 70 93973 Carpenter-Waziri 6 2767 Carpotarsal osteochondromatosis < 10 1368 Cataract - ataxia - deafness 2 1383 Cataract - deafness - hypogonadism 3 1387 Cataract - intellectual disability - hypogonadism < 20 1380 Cataract - nephropathy - encephalopathy 2 162 Cataract-glaucoma 3 1377 Cataract-microcornea 8 717 Catecholamine-producing tumor 10 3286 Catecholaminergic polymorphic ventricular tachycardia 1388 Catel-Manzke > 33 195 Cat-eye 1.35 50839 Cat-scratch disease 6.6 66631 CEDNIK 7 10 1459 Celiac disease, epilepsy and cerebral calcification or 170 3258 Cenani-Lenz < 30 75377 Central areolar choroidal dystrophy 3.33 2431 Central bilateral macrogyria 4 597 Central core disease 0.4 3240 Central nervous system calcification - deafness - tubular acidosis - anemia 2 73256 Central neurocytoma > 100 1171 Cerebellar ataxia - areflexia - pes cavus - optic atrophy - sensorineural hearing loss 46724 Cerebral arteriovenous malformation 6 2 2081 Cerebral gigantism - jaw cysts < 10 1393 Cerebro-costo-mandibular 75 66625 Cerebro-oculo-nasal 10 3421 Cerebroretinal vasculopathy 3 909 Cerebrotendinous xanthomatosis 2 2218 Cervical hypertrichosis - peripheral neuropathy 3 1401 CHAND > 10 88642 Channelopathy-associated congenital insensitivity to pain 20 46627 Char 10 166 Charcot-Marie-Tooth disease 22 101101 Charcot-Marie-Tooth disease 2B2 101102 Charcot-Marie-Tooth disease 2H 13 99955 Charcot-Marie-Tooth disease 4B1 11 99954 Charcot-Marie-Tooth disease 4H 10 139515 Charcot-Marie-Tooth disease 4J 5 167 Chédiak-Higashi 200 139 CHILD 60 209908 Childhood apraxia of speech 22 168782 Childhood disintegrative disorder 2 3474 CHIME 8 137914 Choanal atresia 8.6** 1200 Choanal atresia - deafness - cardiac defects - dysmorphism 70567 Cholangiocarcinoma 2.1 5 1414 Cholestasis - lymphedema 50 1415 Cholestasis - pigmentary retinopathy - cleft palate 1422 Chondrodysplasia - disorder of sex development 5 2 50945 Chondrodysplasia, Blomstrand 13 55880 Chondrosarcoma 3.55 178 Chordoma 0.05 1433 Choroidal atrophy - alopecia 2 * Lifetime ** Prevalence at birth Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - May 2014-1 8

180 Choroideremia 1.5 or 1435 Choroideremia - deafness - obesity 4 85278 Christianson < 30 2137 Chronic autoimmune hepatitis 0.75 379 Chronic granulomatous disease 0.4** 396 Chronic hiccup 1 2932 Chronic inflammatory demyelinating polyneuropathy 521 Chronic myeloid leukemia 6 70591 Chronic thromboembolic pulmonary hypertension 93971 Chudley-Lowry-Hoar 3 1451 CINCA 100 69744 Circumscribed palmoplantar hypokeratosis 17 3.7 187 Citrullinemia 14.4 168984 CLAPO 6 394 Classical homocystinuria 1.65 1995 Cleft lip - retinopathy 2 2001 Cleft lip/palate - intestinal malrotation - cardiopathy 2015 Cleft palate - short stature - vertebral anomalies 3 4 2 2010 Cleft palate - stapes fixation - oligodontia 2 2016 Cleft palate-lateral synechia 7 1453 Cleidorhizomelic 2 93929 Cloacal exstrophy 0.75 53721 Cobb 35 51577 Cobblestone lissencephaly 1** 191 Cockayne 200 1458 CODAS 3 192 Coffin-Lowry 1.5 1465 Coffin-Siris < 100 1466 COFS < 20 79333 COG7-CDG 9 95428 COG8-CDG 2 1467 Cogan 200 193 Cohen 200 31824 Colchicine poisoning 0.1 157820 Cold-induced sweating 6 2050 Cole-Carpenter 4 36205 Collagenous colitis 10.5 1471 Coloboma of macula - brachydactyly B 12 1474 Colobomatous - microphthalmia - heart disease - hearing loss 35909 Combined of factor V and factor VIII 0.5 10 1572 Common variable immuno 4 1329 Complete atrioventricular canal 20** or 209932 Cone dystrophy with supernormal rod response 45 1872 Cone rod dystrophy 2.5 973 Congenital absence/hypoplasia of fingers excluding thumb, unilateral 418 Congenital adrenal hyperplasia 10 < 10 210122 Congenital alveolar capillary dysplasia < 60 86816 Congenital analbuminemia < 50 1195 Congenital atransferrinemia 12 48 Congenital bilateral absence of vas deferens 50 79302 Congenital bile acid synthesis defect 3 2 79095 Congenital bile acid synthesis defect 4 5 71278 Congenital brain dysgenesis due to glutamine synthetase 2 2040 Congenital bronchobiliary fistula 23 1369 Congenital cataract - hypertrophic cardiomyopathy - mitochondrial myopathy 48431 Congenital cataracts - facial dysmorphism - neuropathy 2140 Congenital diaphragmatic hernia 21.2** 137 Congenital disorder of glycosylation 1.5** 85 Congenital dyserythropoietic anemia 1 103910 Congenital enterocyte heparan sulfate 40 160 3 79277 Congenital erythropoietic porphyria > 200 325 Congenital factor II 0.05 326 Congenital factor V 0.1 327 Congenital factor VII 0.33 328 Congenital factor X 0.2 329 Congenital factor XI 0.1 331 Congenital factor XIII 0.05 335 Congenital fibrinogen 0.15 1023 Congenital generalized hypertrichosis, Ambras 174590 Congenital hypogonadotropic hypogonadism 20 442 Congenital hypothyroidism 29 95711 Congenital hypothyroidism due to developmental anomaly 95715 Congenital hypothyroidism due to transplacental passage of maternal TSHbinding inhibitory antibodies 2271 Congenital ichthyosis - microcephalus - tetraplegia 1229 Congenital intrauterine infection-like 21.3 657 Congenital isolated hyperinsulinism 20 1 40 2 > 30 * Lifetime ** Prevalence at birth Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - May 2014-1 9

209893 Congenital isolated thyroxine-binding globulin or 1954 Congenital lethal erythroderma 17 210163 Congenital lethal myopathy, Compton-North 83620 Congenital malabsorptive diarrhea due to paucity of enteroendocrine cells 46 4 3 93109 Congenital megacalycosis > 50 97242 Congenital muscular dystrophy 5 157973 Congenital muscular dystrophy due to LMNA mutation 258 Congenital muscular dystrophy 1A 0.3 34520 Congenital muscular dystrophy with integrin alpha-7 0.03 75840 Congenital muscular dystrophy, Ullrich 0.13 590 Congenital myasthenic s 0.3 97245 Congenital myopathy 3.8 2772 Congenital osteogenesis imperfecta - microcephaly - cataracts 15 3 66630 Congenital pseudoarthrosis of clavicle > 200 2414 Congenital pulmonary lymphangiectasia > 100 3189 Congenital pulmonary valve stenosis 28.4** 290 Congenital rubella 0.29** 35122 Congenital sucrase-isomaltase 20 858 Congenital toxoplasmosis 33** 216694 Congenitally corrected transposition of the great arteries 0.3** 2391 Congenitally short costocoracoid ligament 1484 Contractures - ectodermal dysplasia - cleft lip/ palate 2 1487 Cooks 11 1488 Cooper-Jabs 2 1051 Corneal anesthesia - deafness - intellectual disability 2 1490 Corneal dystrophy - perceptive deafness < 10 3177 Corneal-cerebellar 2 199 Cornelia de Lange 1** 94062 Coronary artery disease - hyperlipidemia - hypertension - diabetes - osteoporosis 1389 Cortical blindness - intellectual disability - polydactyly 278 Corticobasal degeneration 4 54251 Corticosteroid-sensitive aseptic abscesses 3 49 3071 Costello 300 201 Cowden 0.45 1508 Coxoauricular 4 or 1509 Coxo-podo-patellar 47 1513 Craniodiaphyseal dysplasia < 20 1514 Craniodigital - intellectual disability 5 1515 Cranioectodermal dysplasia 15 85168 Craniofacial conodysplasia 1529 Craniofacial-deafness-hand 3 1521 Craniofrontonasal dysplasia - Poland anomaly 3 50814 Craniolenticulosutural dysplasia 28 1522 Craniometaphyseal dysplasia 70 1525 Cranio-osteoarthropathy 30 54595 Craniopharyngioma 2 63260 Craniorachischisis 5 157832 Craniorhiny 3 1538 Craniosynostosis - Dandy-Walker malformation - hydrocephalus 1535 Craniosynostosis - dysmorphism - brachydactyly 4 5 1533 Craniosynostosis - fibular aplasia 2 171839 Craniosynostosis - hydrocephalus - Chiari I malformation - radioulnar synostosis 4 52054 Craniosynostosis - intracranial calcifications 3 1541 Craniosynostosis, Boston 19 1527 Craniosynostosis, Philadelphia 1534 Craniosynostosis-radial aplasia, Imaizumi 2 90290 CREST 8 204 Creutzfeldt-Jakob disease 0.1 205 Crigler-Najjar 0.1** 1545 Crisponi < 30 1461 Criss-cross heart 0.8** 2930 Cronkhite-Canada 500 207 Crouzon disease 0.9 1547 Cryptomicrotia - brachydactyly - excess fingertip arch 1549 Cryptosporidiosis 34 1552 Currarino triad 1 2 1553 Curry-Jones 9 96253 Cushing disease 4 553 Cushing 6.5 535 Cutaneous lupus erythematosus 50 66646 Cutaneous mastocytosis 0.75 79140 Cutaneous neuroendocrine carcinoma 4 2881 Cutaneous photosensitivity - lethal colitis 3 1555 Cutis gyrata - acanthosis nigricans - craniosynostosis 209 Cutis laxa 0.1** 6 1556 Cutis marmorata telangiectatica congenita 300 1557 Cutis verticis gyrata - intellectual disability 1.02 * Lifetime ** Prevalence at birth Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - May 2014-1 10

2686 Cyclic neutropenia 0.1 or 2674 Cyprus facial-neuromusculoskeletal 212 Cystathioninuria 7 586 Cystic fibrosis 12.6 2111 Cystic hamartoma of lung and kidney < 5 85136 Cystic leukoencephalopathy without megalencephaly 213 Cystinosis 0.5** 214 Cystinuria 14 < 50 75381 Cystoid macular dystrophy 6 94087 Cytophagic histiocytic panniculitis < 100 137678 Czech dysplasia, metatarsal < 20 1562 Dacryocystitis - osteopoikilosis 5 1563 Dahlberg-Borer-Newcomer 2 1566 Dandy-Walker malformation - postaxial polydactyly 218 Darier disease 2 2 1831 De Hauwere 2 3214 Deaf blind hypopigmentation, Yemenite 2 3220 Deafness - enamel hypoplasia - nail defects 6 3224 Deafness - genital anomalies - metacarpal and metatarsal synostosis 85321 Deafness - intellectual disability, Martin-Probst 2 3 3226 Deafness - lymphedema - leukemia < 10 3231 Deafness - onychodystrophy < 50 3239 Deafness - vitiligo - achalasia 2 90024 Deafness with labyrinthine aplasia, microtia, and microdontia 6 94064 Deafness-infertility 3 1578 Dehydratase 21 79134 DEND 14 1652 Dent disease 250 101 Dentatorubral pallidoluysian atrophy 0.48 71267 Dentinogenesis imperfecta - short stature - hearing loss - intellectual disability 2 220 Denys-Drash 150 1656 Dermatitis herpetiformis 27 1266 Dermato-cardio-skeletal, Borrone 31112 Dermatofibrosarcoma protuberans 10 2 1659 Dermatoleukodystrophy 2 221 Dermatomyositis 6 1657 Dermatoosteolysis, Kirghizian 5 1660 Dermo-odonto dysplasia 14 or 1425 Desbuquois > 40 35107 Desmosterolosis 2 163988 Developmental delay - deafness, Hildebrand 79107 Developmental malformations - deafness - dystonia 2 66637 Diaphanospondylodysostosis < 10 2141 Diaphragmatic defect - limb - skull defect 628 Diastrophic dwarfism 1.2 220393 Diffuse cutaneous systemic sclerosis 4 544 Diffuse large B-cell lymphoma 20 4 2123 Diffuse neonatal hemangiomatosis < 70 86918 Diffuse palmoplantar keratodermaacrocyanosis 10 1674 Digitorenocerebral < 10 1146 Digitotalar dysmorphism 10 226 Dihydropteridine reductase > 150 38874 Dihydropyrimidinuria 7 1678 Dincsoy-Salih-Patel 2 166291 Dirofilariasis 25 79168 Disorder of bile acid synthesis 0.6 2983 Disorder of sex development - intellectual disability 1307 Distal limb deficiencies - micrognathia 3 4 96148 Distal monosomy 10q 40 1627 Distal monosomy 5q 10 96125 Distal monosomy 6p > 35 34521 Distal myopathy with early respiratory muscle involvement 63273 Distal myopathy with posterior leg and anterior hand involvement 24 12 600 Distal myopathy with vocal cord weakness 12 3248 Distal symphalangism < 5 96102 Distal trisomy 10q 40 1745 Distal trisomy 6p 40 91131 DK1-CDG 4 2143 Donnai-Barrow 50 230 Dopamine beta-hydroxylase 12 255 Dopa-responsive dystonia 0.3 70594 Dopa-responsive dystonia due to sepiapterin reductase 43 3427 Double outlet left ventricle 32 3411 Double uterus - hemivagina - renal agenesis < 60 86309 DPAGT1-CDG 3 * Lifetime ** Prevalence at birth Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - May 2014-1 11

or 79322 DPM1-CDG 14 50817 Duane anomaly - myopathy - scoliosis 2 233 Duane retraction 10 235 Dubowitz 0.2** 98896 Duchenne muscular dystrophy 5 1203 Duodenal atresia 9 178503 Dursun 2 239 Dyggve-Melchior-Clausen disease 60 1765 Dyschondrosteosis - nephritis 1775 Dyskeratosis congenita 0.1 2282 Dysmorphism - short stature - deafness - disorder of sex development 2 210571 Dystonia 16 7 1934 Early infantile epileptic encephalopathy 88 1935 Early myoclonic encephalopathy 30 1177 Early-onset cerebellar ataxia with retained tendon reflexes 256 Early-onset generalized limb-onset dystonia 0.4 2554 Ear-patella-short stature 42 1880 Ebstein malformation 3.5** 1235 Ectodermal dysplasia - absent dermatoglyphs < 30 1806 Ectodermal dysplasia - blindness 2 1816 Ectodermal dysplasia, Berlin 4 1884 Ectopia lentis - chorioretinal dystrophy - myopia 1888 Ectrodactyly - ectodermal dysplasia without clefting 1 4 5 1897 EEM 7 98249 Ehlers-Danlos 0.5** 90309 Ehlers-Danlos 1 5 287 Ehlers-Danlos, classic 3.5 1901 Ehlers-Danlos, dermatosparaxis 7 75501 Ehlers-Danlos, fibronectinemic 285 Ehlers-Danlos, hypermobility 12.5 1900 Ehlers-Danlos, kyphoscoliotic 1** 2953 Ehlers-Danlos, musculocontractural 157965 Ehlers-Danlos, spondylocheirodysplastic 286 Ehlers-Danlos, vascular 1 22 6 1902 Ehrlichiosis < 50 79106 Eiken 6 289 Ellis Van Creveld 0.3** 261 Emery-Dreifuss muscular dystrophy 0.3 2396 Encephalocraniocutaneous lipomatosis 45 71277 Encephalopathy due to GLUT1 84 79155 Encephalopathy due to hydroxykynureninuria < 30 or 139406 Encephalopathy due to prosaposin < 10 833 Encephalopathy due to sulfite oxidase 296 Enchondromatosis 1 > 100 85186 Endosteal sclerosis - cerebellar hypoplasia 4 1937 Eng-Strom 2 85438 Enthesitis-related arthritis 5.7 73247 Eosinophilic esophagitis 50 3165 Eosinophilic fasciitis 200 2070 Eosinophilic gastroenteritis 1 183 Eosinophilic granulomatosis with polyangiitis 1 301 Ependymal tumor 3.85 35125 Epidermal nevus > 400 304 Epidermolysis bullosa simplex 2.4 257 Epidermolysis bullosa simplex with muscular dystrophy > 40 1948 Epilepsy - microcephaly - skeletal dysplasia 2 1951 Epilepsy telangiectasia 6 79135 Episodic ataxia 3 79136 Episodic ataxia 4 2 211067 Episodic ataxia 5 7 209967 Episodic ataxia 6 4 209970 Episodic ataxia 7 7 103912 Epithelio-exfoliative colitis - deafness 2 35687 Erdheim-Chester disease > 500 999 Ermine pheno 3 1955 Erythrokeratodermia - ataxia 25 317 Erythrokeratodermia variabilis > 200 79278 Erythropoietic protoporphyria 0.9 1199 Esophageal atresia 24.3 70482 Esophageal carcinoma 12.2* 3318 Essential thrombocythemia 24 1957 Esthesioneuroblastoma 1200 51188 Ethylmalonic encephalopathy < 40 1959 Evans 0.1 319 Ewing sarcoma 2.33 209916 Extraskeletal myxoid chondrosarcoma 0.2 3172 Eyebrow duplication - syndactyly 3 324 Fabry disease 0.22** 1970 Facial dysmorphism - macrocephaly - myopia - Dandy-Walker malformation 3 85162 Facial onset sensory and motor neuronopathy 4 269 Facioscapulohumeral dystrophy 4 * Lifetime ** Prevalence at birth Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - May 2014-1 12

or 88619 Familial acute necrotizing encephalopathy 11 733 Familial adenomatous polyposis 6 1768 Familial caudal dysgenesis 4 47045 Familial cold urticaria 0.1 1799 Familial developmental dysphasia 6 1764 Familial dysautonomia 550 85110 Familial encephalopathy with neuroserpin inclusion bodies > 5 361 Familial glucocorticoid 50 154 Familial isolated dilated cardiomyopathy 17.5 2238 Familial isolated hypoparathyroidism < 10 2239 Familial isolated hypoparathyroidism due to agenesis of parathyroid gland 75249 Familial isolated restrictive cardiomyopathy 2.5 768 Familial long QT 40** 2 338 Familial multiple fibrofolliculoma 7 569 Familial or sporadic hemiplegic migraine 10 79083 Familial partial lipodystrophy associated with PPARG mutations 79085 Familial partial lipodystrophy due to AKT2 mutations 10 2348 Familial partial lipodystrophy, Dunnigan 300 79084 Familial partial lipodystrophy, Köbberling < 20 71290 Familial platelet with predisposition to acute myelogenous leukemia 34527 Familial primary hypomagnesemia with normocalcuria and normocalcemia 168624 Familial scaphocephaly, McGillivray < 20 2 11 166282 Familial sick sinus 11 95716 Familial thyroid dyshormonogenesis 4 84 Fanconi anemia 0.3 166105 FASTKD2-related infantile mitochondrial encephalomyopathy 2 466 Fatal familial insomnia 27 168566 Fatal mitochondrial disease due to combined oxidative phosphorylation 3 2 1305 Feingold < 50 2019 Femur-fibula-ulna complex 1.5 994 Fetal akinesia deformation sequence 0.6** 1915 Fetal alcohol 1.6** 294 Fetal cytomegalovirus 40 85212 Fetal Gaucher disease 0.01 1917 Fetal methylmercury 800 291 Fetal varicella > 100 2021 Fibrochondrogenesis 11 337 Fibrodysplasia ossificans progressiva 0.05 or 1118 Fibular aplasia - ectrodactyly < 50 1757 Fibular dimelia - diplopodia 11 93323 Fibular hemimelia 2 3255 Filippi < 25 1272 Fine-Lubinsky 5 97232 Fingerprint body myopathy < 20 2044 Floating-Harbor 87 2047 Flynn-Aird 10 2092 Focal dermal hypoplasia 300 79133 Focal facial dermal dysplasia I 81 48918 Focal myositis 115 1866 Focal, segmental or multifocal dystonia 11.7 545 Follicular lymphoma 36 3219 Fountain 8 2253 Foveal hypoplasia - presenile cataract 11 908 Fragile X 20 137834 Frank-Ter Haar 5 2052 Fraser 0.2** 347 Frasier > 50 2053 Freeman-Sheldon 100 85335 Fried 95 Friedreich ataxia 2 1826 Frontometaphyseal dysplasia < 30 282 Frontotemporal dementia 3 348 Fructose-1,6-bisphosphatase 5** 2059 Fryns 7** 349 Fucosidosis 100 2854 Fuhrmann 11 24 Fumaric aciduria < 100 97295 Furlong 2 352 Galactosemia 2** 2065 Galloway-Mowat 40 2066 Gamma-aminobutyric acid transaminase 2 33573 Gamma-glutamyl transpeptidase 7 33574 Gamma-glutamylcysteine synthetase 9 2067 GAPO 27 63443 Gastric cancer 49.2 44890 Gastrointestinal stromal tumor 13 2368 Gastroschisis 23.7** 355 Gaucher disease 1 2072 Gaucher disease - ophthalmoplegia - cardiovascular calcification 77259 Gaucher disease 1 1 < 10 * Lifetime ** Prevalence at birth Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - May 2014-1 13

77260 Gaucher disease 2 0.01 77261 Gaucher disease 3 0.05 or 79330 GCS1-CDG 2 2623 Geleophysic dysplasia 27 85201 Genitopatellar 7 2077 German 5 643 Giant axonal neuropathy 20 2027 Gingival fibromatosis - progressive deafness 2 358 Gitelman 2.5 2084 Glaucoma - ectopia - microspherophakia - stiff joints - short stature 3 2085 Glaucoma - sleep apnea 5 182067 Glial tumor 10 360 Glioblastoma 1 73223 Global developmental delay - osteopenia - ectodermal defect 2087 Glomerulonephritis - sparse hair - telangiectasis 3 < 10 141163 Glossopalatine ankylosis 30 35710 Glucose-galactose malabsorption 300 25 Glutaryl-CoA dehydrogenase 1** 32 Glutathione synthetase 65 407 Glycine encephalopathy 0.17 365 Glycogen storage disease due to acid maltase 2088 Glycogen storage disease due to GLUT2 367 Glycogen storage disease due to glycogen branching enzyme 2089 Glycogen storage disease due to hepatic glycogen synthase 34587 Glycogen storage disease due to LAMP-2 137625 Glycogen storage disease due to muscle and heart glycogen synthase 371 Glycogen storage disease due to muscle phosphofructokinase 715 Glycogen storage disease due to muscle phosphorylase kinase 713 Glycogen storage disease due to phosphoglycerate kinase 1 97234 Glycogen storage disease due to phosphoglycerate mutase 0.8** 0.1** < 200 16 84 3 < 30 < 30 30 < 50 66629 Goldberg-Shprintzen megacolon 10 166272 Goldblatt 11 374 Goldenhar 2.8 53540 Goldmann-Favre < 50 1986 Gollop-Wolfgang complex 200 1532 Gómez-López-Hernández 34 1770 Gonadal dysgenesis, XY - associated anomalies or 2 65798 Goodman 3 73 Gorham-Stout disease < 300 377 Gorlin 1.8 2095 Gorlin-Chaudhry-Moss 7 53693 GRACILE 2** 39812 Graft versus host disease 2.76 79094 Grange 7 900 Granulomatosis with polyangiitis 10 3274 Granulomatous arthritis of childhood 40 33111 Granulomatous slack skin < 50 35858 Gräsbeck-Imerslund disease 300 721 Gray platelet 60 1426 Greenberg dysplasia < 10 380 Greig cephalopolysyndactyly 100 381 Griscelli disease 60 2055 Growth - brachydactyly - dysmorphism 73272 Growth delay due to insulin-like growth factor 1 2 4 2102 GTP cyclohydrolase I 17 382 Guanidinoacetate methyltransferase 52 2103 Guillain-Barré 3.45 168569 H 100 2342 Haim-Munk < 100 1408 Hair defect - photosensitivity - intellectual disability 58017 Hairy cell leukemia 3.12* 3 2108 Hallermann-Streiff < 100 457 Harlequin ichthyosis < 100 2116 Hartnup 4 2117 Hartsfield-Bixler-Demyer 6 99872 Hashimoto-Pritzker < 50 1354 Heart defects - limb shortening 2 2119 HEC 2 178330 Heinz body anemia < 10 86813 Helicoid peripapillary chorioretinal degeneration 2130 Hemimelia 4.15 86817 Hemolytic anemia due to adenylate kinase 100 12 * Lifetime ** Prevalence at birth Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - May 2014-1 14

712 Hemolytic anemia due to glucophosphate isomerase 90030 Hemolytic anemia due to glutathione reductase 448 Hemophilia 7.7 98878 Hemophilia A 7 98879 Hemophilia B 2 178396 Hemorrhagic disease due to alpha-1- antitrypsin Pittsburgh mutation or 50 3 3 2136 Hennekam > 50 2135 Hennekam-Beemer 2 890 Hepatic veno-occlusive disease 11 79124 Hepatic veno-occlusive disease - immuno 449 Hepatoblastoma 0.54 88673 Hepatocellular carcinoma 1 86882 Hepatosplenic T-cell lymphoma 0.03 91378 Hereditary angioedema 1 145 Hereditary breast and ovarian cancer 25 676 Hereditary chronic pancreatitis 0.3 168577 Hereditary cryohydrocytosis with reduced stomatin 288 Hereditary elliptocytosis 35 < 25 2 90045 Hereditary folate malabsorption 30 469 Hereditary fructose intolerance 5 774 Hereditary hemorrhagic telangiectasia 16 163 Hereditary hyperferritinemia with congenital cataracts 79091 Hereditary inclusion body myopathy - joint contractures - ophthalmoplegia 2590 Hereditary myoclonus - progressive distal muscular atrophy 43115 Hereditary myopathy with lactic acidosis due to ISCU > 64 19 < 10 19 1062 Hereditary neurocutaneous angioma < 10 168583 Hereditary North American Indian childhood cirrhosis 36 30 Hereditary orotic aciduria < 20 158025 Hereditary progressive mucinous histiocytosis 13 178464 Hereditary proximal myopathy with early respiratory failure 970 Hereditary sensory and autonomic neuropathy 2 139573 Hereditary sensory and autonomic neuropathy with deafness and global delay 685 Hereditary spastic paraplegia 5 822 Hereditary spherocytosis 20 745 Hereditary thrombophilia due to congenital protein C 0.2 < 10 35 4 743 Hereditary thrombophilia due to congenital protein S or 71291 Hereditary vascular retinopathy 3467 Hereditary xanthinuria 150 0.2 79430 Hermansky-Pudlak 0.15 183678 Hermansky-Pudlak with neutropenia 8 63261 HERNS 3 189 Hidrotic ectodermal dysplasia 1 1808 Hidrotic ectodermal dysplasia, Christianson- Fourie 6 1809 Hidrotic ectodermal dysplasia, Halal 4 388 Hirschsprung disease 12.1** 2155 Hirschsprung disease - deafness - polydactyly 2 2153 Hirschsprung disease - nail hypoplasia - dysmorphism 3 2150 Hirschsprung disease - D brachydactyly 4 98293 Hodgkin lymphoma 10 93970 Holmes-Gang 3 2162 Holoprosencephaly 13.4** 392 Holt-Oram 0.4** 2168 Homocarnosinosis 4 622 Homocystinuria without methylmalonic aciduria 73 85295 HSD10 disease, atypical 5 3265 Humero-radial synostosis 150 3266 Humero-radio-ulnar synostosis 30 1792 Humerospinal dysostosis 5 94056 Humero-ulnar synostosis 5 97340 Hunter-McAlpine craniosynostosis 10 399 Huntington disease 7 93473 Hurler 0.57 93476 Hurler-Scheie 0.23 740 Hutchinson-Gilford progeria 0.005 2186 Hydrocephalus - blue sclerae - nephropathy 2180 Hydrocephalus - costovertebral dysplasia - Sprengel anomaly 2182 Hydrocephalus with stenosis of aqueduct of Sylvius 8 2181 Hydrocephaly - tall stature - joint laxity 2 1.7 2189 Hydrolethalus 5** 168588 Hyperandrogenism due to cortisone reductase 209902 Hypercholesterolemia due to cholesterol 7alpha-hydroxylase 83639 Hypercoagulability due to glycosylphosphatidylinositol 11 24 2 163985 Hyperekplexia - epilepsy 2 168956 Hypereosinophilic 1.5 * Lifetime ** Prevalence at birth Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - May 2014-1 15

343 Hyperimmunoglobulinemia D with periodic fever 682 Hyperkalemic periodic paralysis 0.5 or 200 1336 Hyperkeratosis-hyperpigmentation 10 411 Hyperlipoproteinemia 1 0.1 412 Hyperlipoproteinemia 3 7.8 73267 Hypernychthemeral 18.5 415 Hyperornithinemia-hyperammonemiahomocitrullinuria 157798 Hyperplastic polyposis 50 1519 Hypertelorism, Teebi 20 2220 Hypertrichosis cubiti - short stature 28 2222 Hypertrichosis lanuginosa congenita < 100 966 Hypertrichosis-acromegaloid facial appearence 12 < 20 2765 Hypertrichotic osteochondrodysplasia 18 1517 Hypertrichotic osteochondrodysplasia, Cantu 429 Hypochondroplasia 3.3 40 36412 Hypocomplementemic urticarial vasculitis < 200 989 Hypoglossia - hypodactyly < 50 2235 Hypogonadotropic hypogonadism - retinitis pigmentosa 1882 Hypohidrotic ectodermal dysplasia - hypothyroidism - ciliary dyskinesia 681 Hypokalemic periodic paralysis 1 2 3 1790 Hypomandibular faciocranial dysostosis 4 85163 Hypomyelination - congenital cataract 10 88637 Hypomyelination - hypogonadotropic hypogonadism - hypodontia 139441 Hypomyelination with atrophy of basal ganglia and cerebellum 4 19 2237 Hypoparathyroidism - deafness - renal disease 12 436 Hypophosphatasia 0.21** 2244 Hypopituitarism - microphthalmia < 10 2245 Hypopituitarism - postaxial polydactyly 6 2248 Hypoplastic left heart 15.1** 157788 Hypospadias - hypertelorism - coloboma and deafness 2 163690 Hypotonia - cystinuria 22 137908 Hypotonia with lactic acidemia and hyperammonemia 3 69735 Hypotrichosis - lymphedema - telangiectasia 4 55654 Hypotrichosis simplex 38 1573 Hypotrichosis with juvenile macular degeneration 2266 Hypotrichosis-intellectual disability, Lopes 50 2 or 254509 Iatrogenic botulism > 180 453 IBIDS 15 2268 ICF 50 2269 Ichthyosis - alopecia - eclabion - ectropion - intellectual disability 2274 Ichthyosis - hepatosplenomegaly - cerebellar degeneration 59303 Ichthyosis - hypotrichosis - sclerosing cholangitis 4 2 < 20 2272 Ichthyosis - oral and digital anomalies 2 2273 Ichthyosis follicularis - alopecia - photophobia > 40 88621 Ichthyosis prematurity 16 91132 Ichthyosis-hypotrichosis 4 930 Idiopathic achalasia 10 724 Idiopathic acute eosinophilic pneumonia > 100 422 Idiopathic and/or familial pulmonary arterial hypertension 1.5 88 Idiopathic aplastic anemia 0.4 3260 Idiopathic hypereosinophilic 10 45452 Idiopathic neonatal atrial flutter 2** 2032 Idiopathic pulmonary fibrosis 11.5 69061 Idiopathic steroid-sensitive nephrotic 85173 IMAGe < 20 42062 Iminoglycinuria 6.68 37042 Immune dysregulation-polyendocrinopathyenteropathy-x-linked 3002 Immune thrombocytopenic purpura 25 572 Immuno by defective expression of HLA class 2 18 136 100 169100 Immuno due to CD25 2 70592 Immuno due to interleukin-1 receptor-associated kinase-4 70593 Immuno due to selective antipolysaccharide antibody 75391 Immuno with natural-killer cell and adrenal insufficiency 83449 Inappropriate antidiuretic hormone secretion 45453 Incessant infant ventricular tachycardia 1.5** 611 Inclusion body myositis 0.49 464 Incontinentia pigmenti 0.7** 98848 Indolent systemic mastocytosis 3.8 < 15 100 4 2 1943 Infant epilepsy with migrant focal crisis 29 1313 Infantile choroidocerebral calcification 10 * Lifetime ** Prevalence at birth Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - May 2014-1 16

or 35069 Infantile neuroaxonal dystrophy > 150 1186 Infantile onset spinocerebellar ataxia 24 90003 Inflammatory pseudotumor of the liver 143 254504 Inhalational botulism 10 210141 Inherited congenital spastic tetraplegia 5 79361 Inherited epidermolysis bullosa 0.8 171860 intellectual disability - cataracts - kyphosis 3 3044 intellectual disability - dysmorphism - hypogonadism - diabetes mellitus 1495 intellectual disability - hypoplastic corpus callosum - preauricular tag 3051 intellectual disability - sparse hair - brachydactyly 4 3 6 166108 intellectual disability, Birk-Barel 85327 intellectual disability, X-linked - acromegaly - hyperactivity 163979 intellectual disability, X-linked - craniofacioskeletal 85280 intellectual disability, X-linked - cubitus valgus - dysmorphism 1568 intellectual disability, X-linked - Dandy-Walker malformation - basal ganglia disease - Seizures 2958 intellectual disability, X-linked - dysmorphism - cerebral atrophy 85319 intellectual disability, X-linked - epilepsy - progressive joint contractures - dysmorphism 85317 intellectual disability, X-linked - hypogammaglobulinemia - progressive neurological deterioration 85331 intellectual disability, X-linked - hypogonadism - ichthyosis - obesity - short stature 85329 intellectual disability, X-linked - hypotonia - facial dysmorphism - aggressive behavior 85320 intellectual disability, X-linked - macrocephaly - macro-orchidism 2 7 5 16 8 2 3 4 10 12 2898 intellectual disability, X-linked - plagiocephaly 2 85318 intellectual disability, X-linked - precocious puberty - obesity 3077 intellectual disability, X-linked - psychosis - macroorchidism 3052 intellectual disability, X-linked - seizures - psoriasis 3 6 4 85273 intellectual disability, X-linked, Abidi 8 85276 intellectual disability, X-linked, Armfield 6 85277 intellectual disability, X-linked, Cantagrel 9 163961 intellectual disability, X-linked, Kroes 3 85283 intellectual disability, X-linked, Miles- Carpenter 4 85322 intellectual disability, X-linked, Pai 85285 intellectual disability, X-linked, Schimke 4 85323 intellectual disability, X-linked, Seemanova or 4 85286 intellectual disability, X-linked, Shashi 9 85324 intellectual disability, X-linked, Shrimpton 3 85287 intellectual disability, X-linked, Siderius 4 3063 intellectual disability, X-linked, Snyder 11 85325 intellectual disability, X-linked, Stevenson 4 85288 intellectual disability, X-linked, Stocco Dos Santos 4 85289 intellectual disability, X-linked, Vitale 8 85290 intellectual disability, X-linked, Wilson 3 85291 intellectual disability, X-linked, Wittwer 3 85337 intellectual disability, X-linked, Zorick 6 3454 Intellectual disability-developmental delaycontractures 6 981 Internal carotid agenesis 100 79099 Interstitial granulomatous dermatitis with arthritis 137622 Intractable diarrhea - choanal atresia - eye anomalies 53 3 209981 IRIDA 50 209943 IRVAN < 30 6 Isolated 3-methylcrotonyl-CoA carboxylase 2.3** 1048 Isolated anencephaly/exencephaly 35** 250923 Isolated aniridia 1.38 2542 Isolated anophthalmia - microphthalmia 5.3 557 Isolated anorectal malformation 24 3387 Isolated anterior cervical hypertrichosis < 20 35099 Isolated brachycephaly 5 2343 Isolated cloverleaf skull 150 88620 Isolated congenital anosmia < 15 217 Isolated Dandy-Walker malformation 2.1** 2345 Isolated Klippel-Feil 2 718 Isolated Pierre Robin 5** 35098 Isolated plagiocephaly 10 35093 Isolated scaphocephaly 20 823 Isolated spina bifida 18.6** 3366 Isolated trigonocephaly 6.7 2306 Isotretinoin-like 6 33 Isovaleric acidemia 1 2307 IVIC 4 1540 Jackson-Weiss 2 2308 Jacobsen 150 1873 Jalili 49 * Lifetime ** Prevalence at birth Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - May 2014-1 17

90647 Jervell and Lange-Nielsen 0.3 or 2315 Johanson-Blizzard 23 475 Joubert 1 140874 Joubert and related disorders 1.1** 1454 Joubert with hepatic defect 8 2754 Joubert with orofaciodigital defect 29 2319 Juberg-Hayward 10 93972 Juberg-Marsidi 16 305 Junctional epidermolysis bullosa 0.06 2778 Juvenile chronic recurrent multifocal osteomyelitis > 260 2028 Juvenile hyaline fibromatosis 50 86834 Juvenile myelomonocytic leukemia 0.1 79264 Juvenile neuronal ceroid lipofuscinosis 0.46 2801 Juvenile Paget disease 50 79076 Juvenile polyposis of infancy 11 85436 Juvenile psoriatic arthritis 4.2 85408 Juvenile rheumatoid factor-negative polyarthritis 85435 Juvenile rheumatoid factor-positive polyarthritis 26137 Juvenile temporal arteritis 20 8 4.2 2322 Kabuki 3.1 168972 Kahrizi 3 2324 Kaler-Garrity-Stern 2 478 Kallmann 3.75 2326 Kallmann - heart disease 8 33276 Kaposi's sarcoma 2.11 2328 Kapur-Toriello 4 2330 Kasabach-Merritt > 175 2332 KBG 59 480 Kearns-Sayre 2 481 Kennedy disease 1.7** 2339 Keratosis follicularis - dwarfism - cerebral atrophy 6 86919 Keratosis palmaris et plantaris - clinodactyly < 20 134 Ketoacidosis due to beta-ketothiolase 60 477 KID < 100 482 Kimura disease 200 2352 Kozlowski-Brown-Hardwick 2 487 Krabbe disease 1** 2355 Kumar-Levick 2363 Lacrimo-auriculo-dento-digital 20 43393 Lambert-Eaton myasthenic 1 137871 Laminopathy Decaudain-Vigouroux 9 389 Langerhans cell histiocytosis 2 626 Large congenital melanocytic nevus 2 633 Laron 0.2 or 220465 Laron with immuno < 10 2375 Laryngeal abductor paralysis - intellectual disability 2004 Laryngo-tracheo-esophageal cleft 7.5** < 20 46059 Lathosterolosis < 5 650 LCAT 125 65 Leber congenital amaurosis 10 104 Leber hereditary optic neuropathy 1.5 99718 Leber 'plus' disease 0.04 549 Legionellosis 1.5 506 Leigh 2.75** 140936 Lelis 8 2382 Lennox-Gastaut 15 2658 Lenz-Majewski hyperostotic dwarfism 9 500 LEOPARD 200 510 Lesch-Nyhan 0.34** 1187 Lethal ataxia with deafness and optic atrophy 12 1972 Lethal faciocardiomelic dysplasia 3 1046 Lethal hemolytic anemia - genital anomalies 2 2347 Lethal Kniest-like dysplasia 2 2371 Lethal Larsen-like < 10 33108 Lethal multiple pterygium 28 2736 Lethal omphalocele-cleft palate 3 1832 Lethal osteosclerotic bone dysplasia 8 210144 Lethal polymalformative, Boissel 8 1423 Lethal recessive chondrodysplasia 4 1662 Lethal restrictive dermopathy 30 99870 Letterer-Siwe disease 0.2 2968 Leukocyte adhesion < 350 99843 Leukocyte adhesion II < 10 99844 Leukocyte adhesion III 17 137639 Leukoencephalopathy - ataxia - hypodontia - hypomyelination 163684 Leukoencephalopathy - dystonia - motor neuropathy 83629 Leukoencephalopathy - metaphyseal chondrodysplasia 139444 Leukoencephalopathy with bilateral anterior temporal lobe cysts 137898 Leukoencephalopathy with brain stem and spinal cord involvement - high lactate 2386 Leukoencephalopathy-palmoplantar keratoderma 8 2 4 29 39 4 * Lifetime ** Prevalence at birth Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - May 2014-1 18

210133 Leukonychia totalis - acanthosis-nigricans-like lesions - abnormal hair or 11 2389 Lewis-Pashayan 3 48162 Lewis-Sumner 0.9 65285 Lhermitte-Duclos disease 220 2390 Lichstenstein 2 526 Liddle 80 97231 Ligneous conjunctivitis 1.1 2369 Limb body wall complex 2** 263 Limb-girdle muscular dystrophy 0.8 69085 Limb-mammary 27 220402 Limited cutaneous systemic sclerosis 8 140933 Linear atrophoderma of Moulin < 30 50811 Lipodystrophy - intellectual disability - deafness 3 530 Lipoid proteinosis > 280 171680 Lissencephaly due to TUBA1A mutation < 15 86821 Lissencephaly 3 - familial fetal akinesia sequence 86822 Lissencephaly 3 - metacarpal bone dysplasia 5 2 60030 Loeys-Dietz 10 5 Long chain 3-hydroxyacyl-CoA dehydrogenase 2621 Low birth weight - dwarfism - dysgammaglobulinemia 1** 2 1824 Lowry-Wood < 10 137631 Lung fibrosis - immuno - 46,XX gonadal dysgenesis 538 Lymphangioleiomyomatosis 0.56 2415 Lymphatic malformation 12.5 86915 Lymphedema - atrial septal defects - facial changes 2 3 86914 Lymphedema - cerebral arteriovenous anomaly 5 470 Lysinuric protein intolerance 1.7** 94061 Macrocephaly - immune - anemia 2 2427 Macrocephaly - short stature - paraplegia 2 210548 Macrocephaly-autism < 40 83619 Macrostomia - preauricular tags - external ophthalmoplegia 9 91494 Macular coloboma - cleft palate - hallux valgus 2 98969 Macular corneal dystrophy 1 137867 Madras motor neuron disease 154 163634 Maffucci 250 556 Malakoplakia > 700 673 Malaria 3 or 679 Malignant atrophic papulosis > 200 2023 Malignant fibrous histiocytoma 2.4 2215 Malignant hyperthermia - arthrogryposis - torticollis 168811 Malignant peritoneal mesothelioma 1.5 180242 Malignant tumor of fallopian tubes 1 4 943 Malonic aciduria 34 52417 MALT lymphoma 4 2457 Mandibuloacral dysplasia 37 79113 Mandibulofacial dysostosis-microcephaly 52416 Mantle cell lymphoma 4 4 2461 Marden-Walker < 50 558 Marfan 20 444 Marie Unna hereditary hypotrichosis > 30 559 Marinesco-Sjögren 200 560 Marshall > 12 42642 Marshall with periodic fever 41 561 Marshall-Smith 33 137862 Martínez-Frías 11 98292 Mastocytosis 9 2209 Maternal hyperphenylalaninemia 1.25 225 Maternally-inherited diabetes and deafness 0.1 2470 Matthew-Wood 5 3109 Mayer-Rokitansky-Küster-Hauser 11 57782 Mazabraud 54 562 McCune-Albright 0.55 59306 McLeod neuroacanthocytosis 150 3097 Meacham < 15 564 Meckel 0.2** 70588 Meconium aspiration 2.44 2006 Median cleft lip/mandibule 70 42 Medium chain acyl-coa dehydrogenase 12** 171851 MEDNIK 4 1332 Medullary thyroid carcinoma 7 2241 Megacystis-microcolon-intestinal hypoperistalsis 2478 Megalencephalic leukoencephalopathy with subcortical cysts 83473 Megalencephaly - polymicrogyria - postaxial polydactyly - hydrocephalus 60040 Megalencephaly-capillary malformationpolymicrogyria 230 < 100 6 170 * Lifetime ** Prevalence at birth Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - May 2014-1 19

or 85282 MEHMO 7 2485 Melorheostosis 300 45360 Ménière disease 42.5 565 Menkes disease 0.33** 551 MERRF 0.9 157801 Mesoaxial synostotic syndactyly with phalangeal reduction 50251 Mesothelioma 3.1 2 2499 Metachondromatosis 25 512 Metachromatic leukodystrophy 0.1 1240 Metaphyseal acroscyphodysplasia 4 1040 Metaphyseal anadysplasia 27 166035 Metaphyseal chondrodysplasia - retinitis pigmentosa 2 33067 Metaphyseal chondrodysplasia, Jansen 16 166038 Metaphyseal chondrodysplasia, Kaitila 2 2635 Metatropic dysplasia 80 1923 Methimazole embryofetopathy 40 2169 Methylcobalamin cble 27 2170 Methylcobalamin cblg 33 26 Methylmalonic acidemia with homocystinuria > 500 79282 Methylmalonic acidemia with homocystinuria, cblc 79283 Methylmalonic acidemia with homocystinuria, cbld 79284 Methylmalonic acidemia with homocystinuria, cblf 500 17 15 29 Mevalonic aciduria 30 79329 MGAT2-CDG 4 2506 Michels 7 2510 Micro 8 2511 Microbrachycephaly - ptosis - cleft lip 2 85172 Microcephalic osteodysplastic dysplasia, Saul- Wilson 2636 Microcephalic osteodysplastic primordial dwarfism s I and III 4 < 30 3433 Microcephaly - brachydactyly - kyphoscoliosis 3 2515 Microcephaly - cardiomyopathy 3 2521 Microcephaly - cleft palate 3 137653 Microcephaly - digital anomalies - intellectual disability 2172 Microcephaly - glomerulonephritis - marfanoid habitus 137658 Microcephaly - intellectual disability - phalangeal and neurological anomalies 171703 Microcephaly - polymicrogyria - corpus callosum agenesis 2519 Microcephaly - seizures - intellectual disability - heart disease 2 2 3 4 2 or 83642 Microcytic anemia with liver iron overload 3 2538 Microgastria - limb reduction defect 16 50810 Microlissencephaly - micromelia 2 77299 Microphthalmia - brain atrophy 3 139471 Microphthalmia with brain and digit anomalies 2 1106 Microphthalmia with limb anomalies > 30 2556 Microphthalmia with linear skin defects 83463 Microtia 13** 139450 Microtia - eye coloboma - imperforation of the nasolacrimal duct 169808 Mild hemophilia A 2.8 169799 Mild hemophilia B 0.6 531 Miller-Dieker 1** 3004 Mirror polydactyly - vertebral segmentation - limbs defects 1933 Mitochondrial DNA depletion, encephalomyopathic form with methylmalonic aciduria 2598 Mitochondrial myopathy and sideroblastic anemia 298 Mitochondrial neurogastrointestinal encephalomyopathy 2443 Mitochondrial oxidative phosphorylation disorder due to nuclear DNA anomalies 0.3** 0.1 809 Mixed connective tissue disease 3.8 < 50 2 7 71516 Mixed dystonia 3 45448 Miyoshi myopathy 0.26 169805 Moderately severe hemophilia A 1.4 169796 Moderately severe hemophilia B 0.6 570 Moebius 300 52368 Mohr-Tranebjaerg > 91 91136 Monoclonal Ig light chain-associated Fanconi 9 100 2565 Mononen-Karnes-Senac 5 1598 Monosomy 18p < 200 574 Monosomy 21 < 50 48652 Monosomy 22q13 > 200 281 Monosomy 5p 4** 77301 Monosomy 9q22.3 30 2569 Moore-Federman 6 1052 Mosaic variegated aneuploidy 41 3347 Mounier-Kühn > 300 2152 Mowat-Wilson < 200 2573 Moyamoya disease 0.33 * Lifetime ** Prevalence at birth Orphanet Report Series - Prevalence of rare diseases: Bibliographic data - May 2014-1 20