Shwachman-Diamond syndromes: clinical, genetic, and biochemical insights from the rare variants

Abstract

Shwachman-Diamond syndrome is a rare inherited bone marrow failure syndrome characterized by neutropenia, exocrine pancreatic insufficiency, and skeletal abnormalities. In 10-30%, transformation to a myeloid neoplasm occurs. Approximately 90% of patients have biallelic pathogenic variants in the SBDS gene located on human chromosome 7q11. In the past several years, pathogenic variants in three other genes have been identified to cause similar phenotypes. These are DNAJC21, EFL1, and SRP54. Clinical manifestations involve multiple organ systems and those classically associated with the Shwachman-Diamond syndrome (bone, blood, and pancreas). Neurocognitive, dermatologic, and retinal changes may also be found. There are specific gene-phenotype differences. To date, SBDS, DNAJC21, and SRP54 variants have been associated with myeloid neoplasia. Common to SBDS, EFL1, DNAJC21, and SRP54 is their involvement in ribosome biogenesis or early protein synthesis. These four genes constitute a common biochemical pathway conserved from yeast to humans that involve early stages of protein synthesis and demonstrate the importance of this synthetic pathway in myelopoiesis. We propose to use the terms Shwachman-Diamond-like syndrome or Shwachman-Diamond syndromes.

Growth Charts for Shwachman–Diamond Syndrome at Ages 0 to 18 Years

“…Consistent with the previous study on patients with SDS in childhood, the 97th and 50th percentiles for height and weight of patients with SDS aged 0-18 years still correspond to the 50th and 3rd percentiles of the general population, respectively. In addition, we found that the median age at menarche of patients with SDS (12 years) was comparable with that of the Italian general population (12.4 years) [14]. In this regard, we observed that pubertal development did not modify the growth trend in females with SDS.…”

“…All patients enrolled in this study were diagnosed with SDS through a genetic analysis and showed biallelic mutations in SBDS. Patients carrying DNAJC21, SRP54, and EFL1 variants, described as subjects with an SDS-like condition [14], were not included in this study. Considering the rarity of SDS [26,27], this study's population is one of the largest cohort studies ever reported for this disease.…”

“…At a median age of 6.4 years (min-max 2.2-36.8), 19 patients (16.7%) underwent HSCT due to MDS (6), aplasia (6), leukemia (5), or for unknown reasons (2). The median age at menarche in females with SDS was 12 years (11)(12)(13)(14)(15), which is comparable with that of the Italian general population (12.4 years (95%CI, 12.4; 12.6), as previously described [25]. It was not possible to retrieve the age at pubarche.…”

“…Exocrine pancreatic insufficiency is another feature of this disease. Pancreatic dysfunction is due to pancreatic acinar cell atrophy followed by adipocyte replacement, in the absence of appreciable inflammation [14]. Of note, a recent study of Sbds mutant zebrafish phenocopying the SDS condition has shown that mutant larvae exhibit hepatocyte and pancreatic lobular exocrine atrophy, with reduced size of zymogen granules [15].…”

The Molecular and Genetic Mechanisms of Inherited Bone Marrow Failure Syndromes: The Role of Inflammatory Cytokines in Their Pathogenesis

“…More than 90% of patients diagnosed with SDS carry biallelic mutations in the Shwachman–Bodian–Diamond Syndrome ( SBDS ) gene. However, other genes have been recently associated with SDS or SDS-like conditions, including DnaJ heat shock protein family (Hsp40) member C21 ( DNAJC21 ), signal recognition particle 54 ( SRP54 ), and elongation factor-like GTPase 1 ( EFL1 ), as we recently reviewed [ 71 ]. Since SBDS, EFL1, DNAJC21, and SRP54 are all involved in ribosome biogenesis or affect the total protein synthesis, SDS has been classified as a ribosomopathy.…”