One in a billion: a patient with Marfan syndrome and familial hypocalciuric hypercalcaemia

Abstract

Summary Marfan syndrome is an autosomal dominant multisystem disorder that has an estimated incidence of 1 in 5000. It is caused by mutations in the FBN1 gene, which encodes the extracellular matrix protein type 1 fibrillin. Familial hypocalciuric hypercalcaemia (FHH), also inherited in an autosomal dominant pattern, is a rare benign disorder characterised by hypercalcaemia, hypocalciuria and relative hyperparathyroidism with normal or high plasma PTH levels, with an estimated incidence of between 1 in 10 000 to 1 in 100 000. We report a unique case of a 26-year-old man referred for investigation of hypercalcaemia, who also had clinical features of Marfan syndrome but no previous genetic investigations. Calculated fractional urinary excretion of calcium was low (0.0005) following correction of vitamin D deficiency, raising the possibility of FHH. Genetic testing for Marfan syndrome and FHH, via a hyperparathyroidism multiplex gene panel test, revealed a novel truncating variant in the FBN1 gene (c.8481T>G; p.(Tyr2827Ter)), consistent with Marfan syndrome; and a pathogenic truncating variant in the CaSR gene (c.741dupT; p.[Asp248Ter]), which confirmed the diagnosis of FHH. The patient’s mother was subsequently found to have mild hypercalcaemia (adjusted calcium 2.76 mmol/L) and is also heterozygous for the same CaSR mutation. Genetic testing of his father confirmed the presence of the same FBN1 gene mutation. This case illustrates the importance of making robust diagnoses in the era of modern genomic medicine, confirming FHH as the cause of hypercalcaemia means that no treatment is warranted and the patient can be reassured. Learning points Familial hypocalciuric hypercalcaemia (FHH) should always be excluded during the investigation of hypercalcaemia by measuring urinary calcium: creatinine clearance ratio. Diagnosing FHH is important as the condition is benign and misdiagnosing patients with primary hyperparathyroidism could potentially lead to unnecessary morbidity from parathyroid surgery. Genetic testing is increasingly available for a variety of inherited conditions including Marfan syndrome and FHH. Patients who present with clinical features suggestive of a particular genetic condition should undergo prompt, appropriate confirmatory testing wherever possible. Taking a thorough family history is vital when assessing patients presenting with endocrine conditions, as this could prompt cascade testing and appropriate genetic counselling where necessary.