Discussion

We report the first case of a young woman diagnosed with both the Shwachman–Diamond syndrome and partial atrioventricular septal defect.

In our patient, exploration of asymptomatic bicytopaenia led to diagnosis of the Shwachman–Diamond syndrome. Described first in 1964,Reference Shwachman, Diamond, Oski and Khaw ¹ this multi-system disease is mainly characterised by haematological abnormalities but can also involve other systems, making the diagnosis challenging at times. It is an autosomal recessive disorder. Approximately 90% of patients with some of these clinical issues have various biallellic mutations in the Shwachman–Bodian–Diamond syndrome gene located on the long arm of chromosome 7.Reference Costa and Santos ² These mutations lead to defects in a protein that participates in several essential cellular processes. Haematological abnormalitiesReference Dror, Donadieu and Koglmeier ³ , including cytopaenia, are usually discovered early in life and are the most common findings revealing this syndrome. When considering haematological findings, neutropaenia occurs in more than 80% of cases, either chronic or intermittent, thrombocytopenia in 24–88%, and mild anaemia in up to 80% of patients. Pancytopaenia has been reported in up to 10–65% of cases. Neutropaenia, although not the only one, may contribute to the increased susceptibility to infections, emphasising the need for cautious prevention of potential systemic infections, particularly when prophylaxis of infective endocarditis is considered. The prognosis of these patients is impaired by the increased risk of developing myelodysplastic syndrome and secondary acute myeloid leukaemia, thus emphasising the need for a careful follow-up. Most patients have skeletal abnormalities,Reference Dror, Donadieu and Koglmeier ³ including metaphyseal dysostosis, frequently involving femoral heads even if they remain usually asymptomatic at this level. The most commonly reported gastrointestinal impairment is exocrine pancreatic insufficiency of varying severity, due to extensive fatty replacement of pancreatic acinar tissue,Reference Dror, Donadieu and Koglmeier ³ as documented in our patient, and may result in malabsorption, steatorrhoea, and failure to thrive in children. Cardiac abnormalities, although infrequently reported, have mostly been described through case reportsReference Savilahti and Rapola ^{4 –} Reference Graham, Walson, Paplanus and Payne ⁶ and include myocardial fibrosis and histopathological necrosis, possibly contributing to early deaths and cardiac failure. These features are of great interest when cardiotoxic chemotherapy is needed in case of stem cell transplantation.Reference Toiviainen-Salo, Pitkänen and Holmström ⁷ Recently, a case of dilated cardiomyopathy with refractory cardiac failure was reported in a child with Shwachman–Diamond syndrome.Reference Kopel, Gutierrez and Lage ⁸ A large series of 102 patients with genetically demonstrated Shwachman–Diamond syndrome revealed that 11% of patients had cardiac abnormalities: six patients had cardiomyopathy and six had congenital heart disease. All congenital heart defects had been diagnosed within the first year of life and included two ostium secondum atrial septal defects, one ventricular septal defect, one double aortic arch, and one tetralogy of Fallot. Surgery was performed in four patients, whereas surveillance was chosen for the two remaining ones.Reference Hauet, Beaupain and Michaud ⁹

Systematic cardiac evaluation in our patient revealed typical partial atrioventricular septal defect. The estimated incidence of atrioventricular septal defect ranges from 0.24/1000 live births to 0.31/1000 live births. This defect is usually associated with Down syndrome – trisomy 21 – but the responsible gene(s) on chromosome 21 have not been identified yet. When not associated with trisomy 21, atrioventricular septal defect usually occurs sporadically, with a multigenic pattern: some mutations in cysteine-rich with epidermal growth factor domains (CRELD) 1, located on chromosome 3, have recently been involved but are not sufficient to cause the defect when isolated.Reference Maslen ¹⁰ Therefore, no genetic relation can so far be assumed between atrioventricular septal defect and Shwachman–Diamond syndrome.

In the absence of a familial history of congenital heart disease and Down syndrome, the partial atrioventricular septal defect diagnosed in our patient is likely to be the first described case in association with Shwachman–Diamond syndrome. The wide range of cardiac abnormalities diagnosed in such patients emphasises the need for a systematic cardiac screening of cardiac malformations and a regular monitoring of the cardiac function.