EYH Ng, JCK Chan, CFY Shih, SKL Ho, HM Luk

What is the diagnosis?

The clinical features are compatible with Shwachman-Diamond syndrome (SDS) (OMIM #260400), a rare genetic disorder characterised by a classical triad of exocrine pancreatic dysfunction, bone marrow dysfunction and skeletal abnormalities, first described in the 1960s.¹

Exome sequencing found a heterozygous variant NM_016038.2(SBDS):c.183_184delinsCT p.(Lys62*) and a homozygous variant NM_016038.2(SBDS):c.258+2T>C p.(Cys84Tyrfs*4).

The variant c.183_184delinsCT is a reported pathogenic variant in literature^2,3 that causes dinucleotide replacement of TA by CT at positions 183-184, leading to a change at the 62nd amino acid from Lysine to a stop codon (Lys62*), and subsequent loss-of-function. The variant c.258+2T>C is also a reported variant in literature.^2-4 This variant is predicted to disrupt the donor splice site of intron 2 and causes an 8-bp deletion consistent with the activation of an upstream cryptic splice donor site at positions 251-252, leading to a frameshift change at the 84th codon from Cysteine to Tyrosine, and subsequent premature stop at the 87th position, also resulting in loss of function. c.[183_184delinsCT;258+2T>C] is a common haplotype resulting from gene conversion with a neighbouring pseudogene.² According to American College of Medical Genetics (ACMG) guidelines, both variants were classified as Pathogenic. Parental testing showed that c.258+2T>C was paternally inherited, while c.[183_184delinsCT;258+2T>C] was maternally inherited. The genetic diagnosis of Shwachman-Diamond syndrome was substantiated.

SBDS Sanger sequencing of the affected eldest sister showed that she carried both c.[183_184delinsCT;258+2T>C] and c.258+2T>C in a compound heterozygous state. Another unaffected elder sister was a carrier for c.[183_184delinsCT;258+2T>C] (Figure 2).

Figure 2 Pedigree of the proband.

What are the clinical features?

SDS is a rare genetic condition characterised by a combination of haematological, pancreatic, and skeletal abnormalities. It is estimated to occur in approximately 1 in 77,000 to 200,000 live births.^5,6 Symptoms of SDS typically manifest in infancy, while some features may only become apparent during early childhood. The features observed in SDS patients are as follows:⁶

Key clinical features include cytopenia in more than 95% of patients, primarily presenting as neutropenia and susceptibility to recurrent infections. Over 90% exhibit exocrine pancreatic dysfunction, leading to malabsorption, steatorrhea and failure to thrive. Approximately 80% have short stature, often attributed to feeding difficulties and recurrent infections. Skeletal abnormalities affect about 60% of patients, including delayed epiphyseal ossification and metaphyseal dysplasia.

Other associated features may include delayed development or intellectual disability in about 20%, as well as congenital structural abnormalities including cardiac, gastrointestinal, urogenital, ocular, and auditory structures. Eczema and ichthyosis are also frequently reported, along with hepatomegaly and deranged liver function.

Patients with SDS are at increased risk of developing myelodysplastic syndromes or acute myeloid leukaemia, with estimated occurrence of approximately 10%.

What is the genetic basis of SDS?

SDS is primarily caused by alterations in the SBDS gene located on chromosome 7q11, and demonstrates an autosomal recessive inheritance pattern.⁷ If both parents are heterozygous carriers of a pathogenic SBDS variant, each offspring has 25% chance of being affected, 50% chance of being a clinically asymptomatic carrier, and 25% chance of being unaffected.

Around 90% of individuals with SDS exhibit biallelic pathogenic variants in the SBDS gene. These alterations often lead to reduced amount or functionality of the SBDS protein, which plays a crucial role in ribosome biogenesis and RNA metabolism.⁷ Common variants include those resulting from gene conversion with a neighbouring pseudogene, which can lead to significant protein truncation and loss of function.^2,8

The SBDS protein is integral to the assembly and function of ribosomes, which are essential for protein synthesis. Deficiency in functional SBDS protein disrupts ribosome formation, thereby affecting protein production and various developmental processes across multiple organ systems, including the pancreas and bone marrow.⁹

Biallelic pathogenic variants in other genes such as DNAJC21, EFL1, and heterozygous pathogenic variants in SRP54 have also been associated with similar phenotypes, albeit accounting for a smaller percentage of cases.⁷ These genes are also involved in ribosome biogenesis and early protein synthesis, highlighting a shared biochemical pathway relevant to the disorder.

What is the management of SDS?

Management of SDS requires a multidisciplinary team of specialists, including paediatricians, haematologists, endocrinologists, gastroenterologists, pulmonary specialists, orthopaedic surgeons and clinical geneticists.

Exocrine pancreatic insufficiency is managed with oral pancreatic enzymes and supplementation of fat-soluble vitamins. Blood and platelet transfusions may be necessary for patients experiencing anaemia and thrombocytopenia. In cases of severe recurrent infections with persistently low absolute neutrophil counts, granulocyte-colony stimulating factor (G-CSF) can be considered to boost white blood cell production. Hematopoietic stem cell transplantation (HSCT) should be evaluated for patients with severe bone marrow failure, myelodysplastic syndrome, or acute myeloid leukaemia. Early referrals to pulmonary and orthopaedic specialists are crucial for managing thoracic dystrophy and other skeletal abnormalities. Regular assessments of nutritional status, serum fat-soluble vitamin levels, complete blood counts, and monitoring for orthopaedic complications are essential components of ongoing care. Additionally, neuropsychological evaluations and developmental support should be integrated into the management plan.

At-risk individuals shall be referred to clinical geneticists for counselling to discuss genetic testing options that may identify those who could benefit from early intervention or preventive measures. After appropriate reproductive counselling, prenatal diagnosis and preimplantation genetic testing can be considered for at-risk individuals. Early identification can facilitate monitoring of the condition and support informed family planning decisions.

Acknowledgement

We would like to thank the patient and the family for their contribution and Tuen Mun Hospital for conducting the imaging procedures and providing the radiographic images.

Funding

This research did not receive any specific funding from the public, commercial, or non-profit sectors.

Conflict of Interest

The authors declare that there is no conflict of interest.

References

1. Hall GW, Dale P, Dodge JA. Shwachman-Diamond syndrome: UK perspective. Arch Dis Child 2006;91:521-4.

2. Boocock GR, Morrison JA, Popovic M, et al. Mutations in SBDS are associated with Shwachman-Diamond syndrome. Nat Genet 2003;33:97-101.

3. Donadieu J, Fenneteau O, Beaupain B, et al. Classification of and risk factors for hematologic complications in a French national cohort of 102 patients with Shwachman-Diamond syndrome. Haematologica 2012;97:1312-9.

4. Peretto L, Tonetto E, Maestri I, et al. Counteracting the Common Shwachman-Diamond Syndrome-Causing SBDS c.258+2T>C Mutation by RNA Therapeutics and Base/Prime Editing. Int J Mol Sci 2023;24:4024.s

5. Minelli A, Nicolis E, Cannioto Z, et al. Incidence of Shwachman-Diamond syndrome. Pediatr Blood Cancer 2012;59:1334-5.

6. Nelson A, Myers K. Shwachman-diamond syndrome. GeneReviews [internet], 2024 [cited 2025 Jan 08]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1756/

7. Kawashima N, Oyarbide U, Cipolli M, Bezzerri V, Corey SJ. Shwachman-Diamond syndromes: clinical, genetic, and biochemical insights from the rare variants. Haematologica 2023;108:2594-605.

8. Woloszynek JR, Rothbaum RJ, Rawls AS, et al. Mutations of the SBDS gene are present in most patients with Shwachman-Diamond syndrome. Blood 2004;104:3588-90.

9. Zambetti NA, Bindels EM, Van Strien PM, et al. Deficiency of the ribosome biogenesis gene Sbds in hematopoietic stem and progenitor cells causes neutropenia in mice by attenuating lineage progression in myelocytes. Haematologica 2015;100:1285-93.