Novel myopathy in a newborn with Shwachman–Diamond syndrome and review of neonatal presentation

Abstract

Shwachman-Diamond-Bodian syndrome (SDS) is a pleiotropic disorder in which the main features are bone marrow dysfunction and pancreatic insufficiency. Skeletal changes can occur, and in rare cases manifest as severe congenital thoracic dystrophy. We report a newborn boy with asphyxia, narrow thorax, and severe hypotonia initially suggesting a neuromuscular disease. The muscle biopsy showed myopathic changes with prominent variability in muscle fiber size and abnormal expression of developmental isoforms of myosin. The myofibrils showed focal loss and disorganization of myofilaments, and thickening of the Z-discs including some abortive nemaline rods. The boy became permanently dependent on assisted ventilation. Pancreatic insufficiency was subsequently diagnosed, explaining the malabsorption and failure to thrive. Except transitory thrombocytopenia and leukopenia, no major hematological abnormalities were noted. He had bilateral nephrocalcinosis with preserved renal function. Transitory liver dysfunction with elevated transaminase levels and parenchymal changes on ultrasound were registered. The clinical diagnosis was confirmed by detection of compound heterozygous mutations in SBDS using whole-exome sequencing: a recurrent intronic mutation causing aberrant splicing (c.258+2T>C) and a novel missense variant in a highly conserved codon (c.41A>G, p.Asn14Ser), considered to be damaging for the protein structure by in silico prediction programs. The carrier status of the parents has been confirmed. This case illustrates the challenges in differential diagnosis of pronounced neonatal hypotonia with asphyxia and highlights the muscular involvement in SDS. To our knowledge, this is the first report of myopathy evidenced in a patient with clinically and molecularly confirmed SDS.

Shwachman-Diamond Syndrome With Congenital Myogenic Ptosis: Case Report of a Rare Association?

“…We hypothesized that the dysfunctional SBDS protein led to structural changes in the muscle fibers of the levator palpebrae superioris muscle, which contributed to the development of ptosis. In a case report on novel myopathy in SDS,7 muscle biopsies of the quadricep femoris showed variable hypotrophic and scattered muscle fibers with centrally located nuclei; similar findings were observed in the levator palpebrae superioris muscle biopsies of patients with congenital ptosis 8. Although these muscles are anatomically and functionally distinct, the nature of ribosomopathy may affect all skeletal muscles at a rudimentary level of protein synthesis.…”

A Case of Shwachman–Diamond Syndrome who Presented with Hypotonia

“…16 Topa et al reported myopathic changes in muscle biopsy of an infant with SDS who presented with neonatal thoracic dystrophy and severe hypotonia. 17 We did not perform a muscle biopsy in our patient; however, she had a less severe and transient hypotonia that improved with nutritional support. So, her hypotonia was less likely to be related with myopathic changes.…”

Genetic manifestations and phenotype spectrum of feeding difficulty of unknown etiology: a hospital-based cohort study

“…Patient No.15 presented with feeding di culty, failure to thrive and hypotonia, compound heterozygous variants of SBDS gene were identi ed and Shwachman-Diamond syndrome was diagnosed. During later follow-up, the patient gradually developed typical clinical manifestations of thrombocytopenia and neutropenia [20]. Some of our patients were incidentally found with other genetic diseases that had not yet appeared clinical symptoms, or to be carriers of recessive genetic diseases, suggesting more attention should be paid for those areas in the future.…”