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

Disclosures •Grant funding from AISS (Italian SDS Association)

2

Cystic Fibrosis and Shwachman-Diamond Syndrome CF

SDS

Autosomal recessive

Autosomal recessive

Frequency 1:2500 live birth Carrier frequency1:25

Frequency 1:80.000-170.000 Carrier frequency 1:210

Gene defect: chromosome 7 Mutations: >2000 Protein involved: CFTR Function: cloride channel

Gene defect: chromosome 7 Mutations: ~20 Protein involved: SBDS Function: SBDS protein seems to be associated with the ribosomal RNA (rRNA) biogenesis. Thus, SDS is considered a ribosomopathy.

Phenotypic expression: polymorphic

Phenotypic expression: polymorphic

CF and SDS gene defect localized on the same chromosome CF

SDS

7 cen

SBDS

COL1A2

7q

305 Kb D7S15 PON

Chromosome 7

MET

CF J3.11 TCRB

SDCR2A

Theoretical model of CFTR and SBDS structures

A

• CFT R

• SBDS

A

1480 aminoacids 27 exons

250 aminoacids 5 exons Complete loss of SBDS is not compatible with life

Organ Involvement CF

SDS

CFTR Genotype

SBDS Genotype

Main features of SBDS pathology Pancreas

Fatty infiltration

Blood and bone marrow

Neutropenia, reduced platelets, bone marrow dysplasia  acute leukemia

Bone

Osteopenia with cortical thinning, osteoporosis, metaphysis enlargemen

Brain

Structural changes

Teeth

No specific studies on the pathophysiology of this problem

Main functional characteristics of SBDS Pancreas Blood and bone marrow

Pancreatic insufficiency at birth and during first years o f life Neutropiena causing recurrent infections, BM aplasia, BM dysplasia evolving to AML

Bone

Growth retadation, short final stature, narrow chest, short limbs, clynodactily, coxa valga, knee varus, stress fractures

Brain

Cognitive impairment (from mild to severe)

Teeth

Dental caries, delayed dental development, gengivitis

SBDS progression of haematologic disease All SDS 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?

Pancreas (1) Histological and pathophisiological characteristics

CF

SDS

•Fat infiltration

+

•Acinar atrophy and fibrosis

+

•Preservation ducts and ductules

–

+









•Ductal function •Exocrine enzyme secretion

+ –

Pancreas (2)

CF diagnosis

SDS diagnosis

subset

subset PI

PS of patients

No enzyme supplementation

PS

PI of patients

Enzyme Enzyme supplementation supplementation

No enzyme supplementation

SDS Growth retardation Length at birth and height at diagnosis 50°

25° 10° 5°

diagnosis

birth

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)

Growth charts for SDS, 0-8 yrs age Weight MALE: 48 patients Weight - Male

Weight - Male

kg

30

40

35

kg

97°

97°

15

75°

10

50° 25°

97° 50° 20

Weight (kg)

20

30

25

SDS Cacciari WHO

50°

3° 3°

0

0

5

10

3°

0

2

4

years

Age (years)

Personal data

6

8

0

2

4

years

Age (years)

6

8

Growth charts for SDS, 0-8 yrs age Height MALE: 48 patients Height - Male

Height - Male

cm

120

140

cm

3°

97° 50° 3°

40

40

60

60

3°

50°

100

Height (cm)

50° 25°

97°

80

100

75°

80

SDS Cacciari WHO

120

97°

0

2

4

years

Age (years)

Personal data

6

8

0

2

4

years

Age (years)

6

8

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

Respiratory disease is mainly related to neutropenia CF

SDS

Mucus abnormalities

Bronchial obstruction

Neutropenia

Reduced chemotaxis

Lung infections Bacterial infection Pulmonary damage worst in the early childhood

Inflammation

Pulmonary insufficiency

Improvement of lung function over the years

SDS Long term survival probability Analysis of patients included in the Italian Registry 1.00

SDS

Probability

0.75

0.50

0.25

Gender

Pts

Events

10 years EFS

20 years EFS

M

63

12

88 (76, 94)

88 (76, 94)

F

48

10

94 (81, 98)

75 (53, 88)

0.00 0

5

10

15

20

Age (year) Gender

M

F

25

30

Survival (2)

CF Primary Causes of Death 2009 (CFF data) Cause Cardiorespiratory Transplant complication Liver disease/failure Trauma Suicide Other Unknown

% 70.2 12.5 2.3 1.1 0.9 8.4 4.6

SDS Primary Causes of Death 2015 (Italian Data) Cause

%

Cardiorespiratory

3-5

LMA

10

Other

1-2

CF

SDS Exocrine Pancreas

MENDELIAN INHERITANCE

?

SBDS

?

SBDS

Skeleton

?

SBDS

Brain

?

SBDS

Liver

?

SBDS

Airways

?

SBDS

Teeth

?

SBDS

Kidney

?

SBDS

Blood

? Modifier genes CFTR/SBDS Environment

COMPLEX GENETICS

SDS 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 12-15 month – bone marrow aspiration)

And the Future? Exp #1

Exp #2

SBDS Control NT

Control Control 5 uM 10 uM

SDS NT

SDS 5 uM

SDS 10 uM

SDS 10 uM

Actin

SBDS SDS NT

SDS 5 uM

SDS 10 uM

Control NT

SDS NT

SDS 5 uM

SDS 10 uM

Control NT

Actin Control NT

Control Control 5 uM 10 uM

SDS NT

SDS 5 uM

SDS 10 uM

SDS 10 uM

Vr101 restores full length protein expression in LCLs

Vr101 (5 mM) restores SBDS protein expression in bone marrow CD34+ cells obtained from SDS patients SDS1 SDS NT

SDS2

SDS Vr101 5 mM

SDS NT

SDS Vr101 5 mM

SDS NT

SDS Vr101 5 mM

SBDS SBDS

In collaboration with Fondazione Tettamanti, Monza and University of Pavia

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