Shwachman-Diamond Syndrome: update on diagnosis and management

Transcription

1 Shwachman-Diamond Syndrome: update on diagnosis and management Marco Cipolli, MD Cystic Fibrosis Center, Ancona-Italy Montreal, October 5-8, 2016

2 Disclosures Grant funding from AISS (Italian Association) 2

3 Cystic Fibrosis and Shwachman-Diamond Syndrome CF Autosomal recessive Frequency 1:2500 live birth Carrier frequency1:25 Gene defect: chromosome 7 Mutations: >2000 Protein involved: CFTR Autosomal recessive Frequency 1: Carrier frequency 1:210 Gene defect: chromosome 7 Mutations: ~20 Protein involved: Function: cloride channel Function: protein seems to be associated with the ribosomal RNA (rrna) biogenesis. Thus, is considered a ribosomopathy. Phenotypic expression: polymorphic Phenotypic expression: polymorphic

4 CF and gene defect localized on the same chromosome CF 7 cen 7q COL1A2 D7S15 PON 305 Kb SDCR2A Chromosome 7 MET CF J3.11 TCRB

5 Theoretical model of CFTR and structures A CFT R A 1480 aminoacids 27 exons 250 aminoacids 5 exons Complete loss of is not compatible with life

6 Organ Involvement CF CFTR Genotype Genotype

7 Main features of pathology Pancreas Blood and bone marrow Bone Brain Teeth Fatty infiltration Neutropenia, reduced platelets, bone marrow dysplasia acute leukemia Osteopenia with cortical thinning, osteoporosis, metaphysis enlargemen Structural changes No specific studies on the pathophysiology of this problem

8 Main functional characteristics of Pancreas Blood and bone marrow Bone Brain Teeth Pancreatic insufficiency at birth and during first years o f life Neutropiena causing recurrent infections, BM aplasia, BM dysplasia evolving to AML Growth retadation, short final stature, narrow chest, short limbs, clynodactily, coxa valga, knee varus, stress fractures Cognitive impairment (from mild to severe) Dental caries, delayed dental development, gengivitis

9 progression of haematologic disease All patients exhibit bone marrow changes although to different degrees There are no longitudinal data on the incidence of MDS and AML but the prevalence clearly increases with age Severe bone marrow failure Aplastic anemia Clonal transformation MDS Malignant transformation AML (Estimated up to 20-25%) Cytogenetic clonal abnormalities (on chromosome 7 particularly) Associated with poor prognosis?

10 Pancreas (1) Histological and pathophisiological characteristics Fat infiltration Acinar atrophy and fibrosis Preservation ducts and ductules Ductal function Exocrine enzyme secretion CF

11 Pancreas (2) CF diagnosis diagnosis PS subset of patients PI PI subset of patients PS No enzyme supplementation Enzyme supplementation Enzyme supplementation No enzyme supplementation

12 Growth retardation Length at birth and height at diagnosis diagnosis birth

13 Exocrine Pancreas and Growth: how is the trajectory of weight and height during years? Birth Thin and short Pancreatic Insufficiency Diagnosis Even thinner and shorter Pancreatic Enzyme Replacement Therapy Follow up Improvement of weight and height with parallel and uniform trend (Z scores -1/-2 DS) 50% Pancreatic Sufficiency (> 4 yrs of age)

14 Growth charts for, 0-8 yrs age Weight (kg) Weight MALE: 48 patients kg Weight - Male kg Weight - Male Cacciari WHO years Age (years) years Age (years) Personal data

15 Growth charts for, 0-8 yrs age Height (cm) Height MALE: 48 patients cm Height - Male cm Height - Male Cacciari WHO years Age (years) years Age (years) Personal data

16 In conclusion The problem in growth is stature not nutrition PI might have a major role only until diagnosis The short stature is inherent to the syndrome Growth velocity appears normal No necessity for a high fat, high calory diet

17 Respiratory disease is mainly related to neutropenia CF Mucus abnormalities Bronchial obstruction Neutropenia Reduced chemotaxis Bacterial infection Lung infections Inflammation Pulmonary insufficiency Pulmonary damage worst in the early childhood Improvement of lung function over the years

18 Probability Long term survival probability Analysis of patients included in the Italian Registry Gender Pts Events 10 years EFS 20 years EFS 0.25 M (76, 94) F (81, 98) 88 (76, 94) 75 (53, 88) Age (year) Gender M F

19 Survival (2) CF Primary Causes of Death 2009 (CFF data) Cause % Primary Causes of Death 2015 (Italian Data) Cause % Cardiorespiratory Transplant complication Liver disease/failure Trauma Suicide Other Unknown Cardiorespiratory 3-5 LMA 10 Other 1-2

20 CF MENDELIAN INHERITANCE Exocrine Pancreas Blood Skeleton Brain Liver Airways Teeth Kidney???????? Modifier genes CFTR/ Environment? COMPLEX GENETICS

21 TREATMENT No specific treatment available The current treatment : Pancreatic enzyme replacement Vitamins Bone surgery to correct bone malformations Bone marrow transplantation in case of AML development Clinical follow up: Periodic check of body growth and osteogenesis Twice yearly blood count Periodic evaluation of cognitive development Check of bone marrow failure syndrome (every month bone marrow aspiration)

22 And the Future? Exp #1 Exp #2 Actin Control NT Control 5 um Control 10 um NT 5 um 10 um 10 um Actin NT 5 um 10 um Control NT Control NT Control 5 um Control 10 um NT 5 um 10 um 10 um NT 5 um 10 um Control NT Vr101 restores full length protein expression in LCLs

23 Vr101 (5 mm) restores protein expression in bone marrow CD34+ cells obtained from patients 1 2 NT Vr101 5 mm NT Vr101 5 mm NT Vr101 5 mm In collaboration with Fondazione Tettamanti, Monza and University of Pavia

24 Thanks to CF Center, University Hospital, Verona ITA Tettamanti Foundation, University Milano Bicocca ITA Genetic Department, University of Pavia ITA CF Center, University Hospital, Ancona ITA