Endocrine Abstracts

Background

Autosomal dominant hypocalcaemia, caused by either inherited or de novo mutations in calcium-sensing receptor gene (CASR), is biochemically characterized by the presence of hypocalcaemia, hypercalciuria and inappropriately low levels of PTH. Receptor-activating mutations induce an increase sensitivity to calcium by parathyroid and renal cells, leading to suppression of PTH synthesis and consequently hypocalcaemia. Clinical manifestations are variable: from asymptomatic individuals to severe disease forms with neonatal seizures. Some of the associated comorbidities include intellectual disability, neuropsychiatric symptoms, basal ganglia calcification, and nephrolithiasis.

Case report

Female child, referred to medical consultation at 11 years old due to poor growth (< p3). History of a 36 weeks delivery due to intrauterine growth restriction, and birth weight of 2050g (< p5). Past medical history of congenital kidney hydronephrosis submitted to surgery at 2 years old; double J-stent placement and lithotripsy due to renal pelvic stones at 13 years old. Followed by paediatric nephrology since age 10 due to bilateral renal lithiasis and recurrent UTIs. Deficient neurodevelopment due to intellectual disability. Bilateral pallidal, anterior frontal subcortical and cerebellar calcifications were also found, even though without specific associated neurological complaints. No family disease was found. Initial evaluation showed Tanner stage I, bone age of 10 years and absence of dysmorphisms. Analytical study revealed: Ca²⁺ 1.8 mmol/l (2.19–2.66), phosphate 2.02 mmol/l (0.95–1.75), hypomagnesemia and an inappropriately low PTH level of 13.1 pg/ml (16–87 pg/ml). A diagnosis of primary hypoparathyroidism was set. Supplementation with calcium carbonate/lactogluconate (875 mg + 1132 mg/day) and calcitriol 1µg/day was started. To perform an etiological study, a karyotype and a search for mutations in critical regions of 22q11 chromosome were made, but no changes were identified. At the age of 18, the patient started the follow up in a tertiary adulthood hospital centre. An additional molecular study revealed the presence of a possible pathogenic variant c.2459C > T(Ser820Phe) in the CASR gene, in heterozygosity. Currently, the patient remains under the same therapeutic regimen, without worsening of the hypocalcaemia.

Discussion and conclusion

Poor height progression was the basis for this patient’s study, allowing the diagnosis of hypocalcaemia and related complications. The identification of a c.2459C > T(Ser820Phe) CASR gene variant found in heterozygosity has been previously described in patients with hypocalcaemia and hypoparathyroidism, being classified as a probable pathogenic variant. Its more recent detection explained the clinical features showed, as well as provided an adequate genetic counselling for the patient and family.