Shwachman-Diamond syndrome: diagnosis, pathogenesis and prognosis

ABSTRACT

Introduction: Shwachman-Diamond Syndrome (SDS) is a rare autosomal recessive disease due to mutations in the SBDS and DNAJC21 genes, both involved in ribosome biogenesis. Patients affected by SDS show widely variable clinical features and have an increased risk to develop myelodysplastic syndrome, aplastic anemia and acute myeloid leukemia.

Areas covered: Clinical features from diagnosis to surveillance and treatment of SDS patients are presented. It is mainly addressed the necessity to monitor the haematological and cytogenetic picture of the bone marrow in order to early identify any possible dysplastic/neoplastic sign to quickly treat the condition. Since, hematopoietic stem cell transplant is the only therapy for hematological complications, the useful preparative regimens is extensively discussed. In addition, recent molecular and cytogenetic studies are reported.

Expert opinion: In our opinion, due to high variability of pathological phenotype presented by SDS patients, a prompt molecular diagnosis may help the management of the disease and may aim the cytological monitoring at bone marrow level, which could improve the surveillance of patients and, if necessary, carry to a prompt hematopoietic stem cell transplant.

KEYWORDS:

• Shwachman-Diamond syndrome
• SBDS
• DNAJC21
• bone marrow failure
• ribosomopathies
• leukemia
• HSCT

Article highlights

• SDS is a rare autosomal recessive disease mainly characterized by exocrine pancreatic insufficiency, skeletal alterations and bone marrow failure with an increased risk to develop myelodysplasia (MDS) and acute myelogenous leukemia (AML)

• Due to the postnatal pancreatic insufficiency, SDS enter frequently into differential diagnosis of cystic fibrosis

• Up to now, three genes have been associated with SDS. These genes cooperate to ribosome maturation leading to consider SDS a ribosomopathy.

• No specific drugs or chemical compounds are known to treat the molecular effects of SDS mutations.

• The only therapy of SDS patients are symptomatic treatments. The higher risk of develop MDS/AML suggests cytogenetic monitoring of the BM once per year. HSCT may be evaluated in presence of haematological complications

When to discuss the SDS diagnosis?

The classical phenotype is characterized by exocrine pancreatic insufficiency and bone marrow failure, but the presence and the severity of these defects are very variable between patients and in every patient during the time, as well as the presence of other minor signs. Indeed, neutropenia, confirmed in three subsequent blood count, may suggest SDS, even when exocrine pancreatic function is normal.

What is the proof of SDS?

Low levels of serum pancreatic enzymes, low faecal elastase with evidence of pancreatic lipomatosis are undoubtedly signs of SDS, particularly if they are associated with developmental delay and haematological dysfunction. It is a point of debate if the genetic analysis for the detection of causative mutations could be compulsory for SDS diagnosis.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded