Shwachman-Diamond syndrome

Shwachman-Diamond syndrome (SDS; Shwachman-Bodian-Diamond syndrome) typically manifests in infancy, most often within the first six months of life, with poor weight gain and growth failure secondary to exocrine pancreatic insufficiency. Clinical presentation is highly variable: nearly half of individuals in the North American SDS Registry present without neutropenia or steatorrhoea, while neonatal presentations may include life-threatening infections or severe bone marrow failure. Persistent or intermittent neutropenia is recognised in 88-100% of affected children, frequently preceding the formal diagnosis. Additional haematologic features include anaemia, thrombocytopenia, and macrocytic red cells. Characteristic skeletal manifestations – including metaphyseal dysostosis, delayed bone maturation, and thoracic dystrophy – are present in all individuals with a molecularly confirmed diagnosis, although severity varies. Hepatic involvement, immune dysfunction, endocrine, dental, and dermatologic features may occur. Approximately 20% of children with SDS demonstrate intellectual disability in at least one domain, with perceptual reasoning most affected.

The estimated prevalence is between 1/77,000.

SDS is caused by biallelic germline pathogenic variants in one of four genes encoding proteins central to ribosome biogenesis and function. SBDS (7q11.21) accounts for ~92% of cases; DNAJC21 (5p13.2), EFL1 (15q25.2), and SRP54 (14q13.2) each account for <1%.1 SBDS and EFL1 cooperate in maturation of the 60S ribosomal subunit and assembly of the active 80S ribosome; DNAJC21 supports 60S biogenesis; and SRP54 mediates signal-recognition-particle-dependent co-translational protein targeting to the endoplasmic reticulum. Molecular analysis of SBDS is complicated by the highly homologous pseudogene SBDSP, and more than 90% of affected individuals carry at least one SBDS exon-2 variant arising through gene conversion with SBDSP.

SDS associated with SBDS is inherited in an autosomal recessive manner; parents of an affected individual are typically heterozygous carriers, and the recurrence risk for siblings is 25%. Prenatal molecular testing is technically possible once the familial pathogenic variants have been identified.

Diagnosis is supported by demonstration of exocrine pancreatic dysfunction in combination with haematologic evidence of bone marrow dysfunction. Biochemical markers include low serum trypsinogen (in children aged under three years) or low serum isoamylase (in individuals aged over three years), and/or low faecal elastase. Haematologic assessment documents cytopenia, macrocytic red cells, and/or characteristic bone marrow findings. Pancreatic imaging by ultrasound, CT, or MRI typically shows lipomatosis (small pancreas with fatty infiltration and retained ductal and islet components), although imaging may be normal early in the disease course.

Main differential diagnoses include:

• Pearson syndrome: exocrine pancreatic and bone marrow dysfunction overlap with SDS, but marrow shows normal cellularity with distinct cytoplasmic vacuolisation in myeloid precursors; large mitochondrial DNA deletions (mtDNA)
• : upper-respiratory infections with exocrine pancreatic dysfunction, elevated sweat chloride values, and no primary bone marrow failure; CFTR
• : progressive pancytopenia with positive chromosome breakage studies and no primary exocrine pancreatic dysfunction; FANCA, FANCC, FANCG and others

• Establishing the diagnosis: molecular genetic testing confirms the clinical suspicion and distinguishes SDS from phenotypically overlapping bone marrow failure syndromes.
• Specific and individualised surveillance: identification of the underlying pathogenic variant(s) is a prerequisite for the targeted medical care, including structured haematologic surveillance for emerging myelodysplastic syndrome or acute myeloid leukaemia, that is determined by the treating physicians in consultation with the affected individual.
• Family member testing: once the familial pathogenic variants are known, predictive and carrier testing of at-risk relatives becomes technically possible.

• Nelson A, Myers K. Shwachman-Diamond Syndrome. GeneReviews. 2024 Sep 19. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. PMID: 20301722. Available from:
• Goobie S, Popovic M, Morrison J, Ellis L, Ginzberg H, Boocock GR, et al. Shwachman-Diamond syndrome with exocrine pancreatic dysfunction and bone marrow failure maps to the centromeric region of chromosome 7. American journal of human genetics. 2001;68(4):1048-54. doi: 10.1086/319505. PMID: . PMCID: PMC1275624.
• Dror Y, Donadieu J, Koglmeier J, Dodge J, Toiviainen-Salo S, Makitie O, et al. Draft consensus guidelines for diagnosis and treatment of Shwachman-Diamond syndrome. Annals of the New York Academy of Sciences. 2011;1242:40-55. doi: 10.1111/j.1749-6632.2011.06349.x. PMID: .
• Furutani E, Liu S, Galvin A, Steltz S, Malsch MM, Loveless SK, et al. Hematologic complications with age in Shwachman-Diamond syndrome. Blood advances. 2022;6(1):297-306. doi: 10.1182/bloodadvances.2021005539. PMID: . PMCID: PMC8753194.