Endocrine Abstracts

Introduction: Hypoparathyroidism-retardation-dysmorphism syndrome (HRD) is an autosomal recessive disorder characterized by distinct clinical, biochemical, and genetic abnormalities. HRD has almost exclusively been reported in children of Middle Eastern origin where the rate of consanguinity is high. The syndrome is characterized by severe short stature, the aetiology of which is unclear. Mutations in tubulin-specific chaperone E (TBCE), a gene encoding a chaperone required for the folding of α-tubulin and its heterodimerization with β-tubulin and implicated in the tubulin assembly pathway, have recently been described in association with this disorder. We now report magnetic resonance imaging (MRI) findings in our cohort (n=4) of children with HRD syndrome, all of whom also had GH insufficiency (GHI).

Aims: We aimed to describe the clinical features, assess pituitary function and evaluate MRI cranium features of children with HRD syndrome.

Methods: Diagnosis of HRD was based on clinical features and genetic analysis. Four children with clinical features of HRD syndrome (severe pre- and post-natal growth failure, characteristic facies and hypoparathyroidism) and a previously reported homozygous mutation in TBCE were further investigated with an MRI scan of the brain and standard pituitary function testing using the Glucagon stimulation test.

Results: All of the patients were found to have a previously described mutation (155–166del) in the TBCE gene. Glucagon provocation demonstrated a suboptimal GH response in 3 of the 4 children. IGF-1 concentrations were low in all 4 children. Cortisol responses were suboptimal (peak cortisol 316–502 nmol/l). Male children (n=3) had clinical and biochemical features of hypogonadotrophic hypogonadism. MRI of the brain revealed severe hypoplasia of the anterior pituitary and the corpus callosum with decreased white matter bulk.

Conclusion: We report GH insufficiency as one of the factors contributing to the extreme short stature in children with HRD syndrome. All individuals in our study were also noted to have decreased white matter bulk, delayed myelination and a hypoplastic anterior pituitary. The TBCE gene may therefore play a role in the development of the anterior pituitary, the corpus callosum and white matter of the developing brain, in addition to the parathyroid glands.