Introduction. Shwachman-Diamond Syndrome (SDS) is an autosomal-recessive disorder characterized by neutropenia, pancreatic exocrine insufficiency, skeletal dysplasia, and an increased risk for leukemic transformation. Biallelic mutations in the SBDS gene have been found in about 90% of patients. The clinical spectrum of SDS in patients is wide, and variability has been noticed between different patients, siblings, and even within the same patient over time. Herein, we present two SDS siblings (UPN42 and UPN43) carrying the same SBDS mutations and showing relevant differences in their phenotypic presentation. Study aim. We attempted to understand whether other germline variants, in addition to SBDS, could explain some of the clinical variability noticed between the siblings. Methods. Whole-exome sequencing (WES) was performed. Human Phenotype Ontology (HPO) terms were defined for each patient, and the WES data were analyzed using the eVai and DIVAs platforms. Results. In UPN43, we found and confirmed, using Sanger sequencing, a novel de novo variant (c.10663G > A, p.Gly3555Ser) in the KMT2A gene that is associated with autosomal-dominant Wiedemann–Steiner Syndrome. The variant is classified as pathogenic according to different in silico prediction tools. Interestingly, it was found to be related to some of the HPO terms that describe UPN43. Conclusions. We postulate that the KMT2A variant found in UPN43 has a concomitant and co-occurring clinical effect, in addition to SBDS mutation. This dual molecular effect, supported by in silico prediction, could help to understand some of the clinical variations found among the siblings. In the future, these new data are likely to be useful for personalized medicine and therapy for selected cases.

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.