Bone Abstracts

Background: Familial hypocalciuric hypercalcaemia type 3 (FHH3) is a genetically heterogenous autosomal dominant disorder caused by loss-of-function mutations in the AP2S1 gene. This gene encodes the alpha-2 subunit of the adaptor protein-2 complex, which facilitates endocytosis of plasma membrane constituents such as G-protein coupled receptors.

Objective: It has been suggested that FHH3 may be associated with cognitive deficits (1). We assessed our cohort of 5 children with genetically confirmed FHH3 for evidence of learning and behavioural issues, using formal (such as the Vineland Adaptive Behaviour Scales Second Edition) and informal assessments.

Results: Table 1 summarises the patient characteristics of our cohort of children with FHH3, as well as extent of learning disabilities (LD) and behavioural difficulties.

Discussion: Our case series demonstrates that children affected with FHH3 present with varying degrees of LD. Behavioural difficulties (autistic spectrum disorder and attention deficit hyperactivity disorder) were also observed in several cases. The mechanism by which FHH3 is associated with cognitive and behavioural dysfunction remains unclear. Reports of symptomatic hypercalcaemia in this group of patients could imply that the chronic hypercalcaemia itself may be contributory. It is also postulated that adaptor protein-2 complexes expressed in the brain may affect neurological development by another mechanism. A knock-out mouse model, currently in development, may elucidate the pathogenesis of this phenotype.

Conclusion: We report varying degrees of LD and behavioural issues in children diagnosed with FHH3 and therefore recommend assessing this key phenotype in all patients with FHH3, with provision of appropriate support.

Disclosure: The authors declared no competing interests.

Reference

1. Hannan et al., Hum Mol Genet 2015.