Endocrine Abstracts

Backround: Pseudohypoparathyroidism (PHP) type 1A is a rare disorder characterized by end-organ resistance to the action of parathyroid hormone (PTH), resistance to other hormones that activate Gs-coupled receptors, such as TSH and gonadotropins and phenotypic features of Albright hereditary osteodystrophy (AHO), including short stature, obesity, round face, brachydactyly and subcutaneous ossifications. PHP type 1A is caused by heterozygous loss-of-function mutations in the gene encoding the α-subunit of Gs (GNAS), inherited from the mother or de novo. The clinical features and disease severity may vary considerably among affected individuals.

Objective: To describe the diversity of the clinical and endocrine features in 11 children with PHP seen in our Division between 2007 and 2018.

Methods: In the present retrospective study, the medical records of 11 PHP children were reviewed. Data collected included: a) clinical parameters: age at diagnosis, growth pattern, AHO features, abnormalities of male genitalia b) biochemical parameters: PTH, TSH, LH, FSH, PRL, ACTH, cortisol, calcium and phosphate levels, growth hormone (GH) response following GH stimulation tests, when performed c) bone age d) molecular analysis of the GNAS gene.

Results: The median age at diagnosis was 8.5 months (range: 40 days–9 years). Among 11 PHP patients (n=7 males), 9 were obese (81.8%). 8 out of 9 patients manifested early onset obesity (<2 years of age). Round face, brachydactyly and ectopic ossifications were present in 90.9%, 81.8% and 72.7% of patients, respectively. During follow-up, growth rate retardation was noted in 45.5% and adult short stature in another 18.2% of our PHP patients. 42.9% of male patients displayed abnormalities of external genitalia. Endocrine features included: increased PTH and TSH in all cases, low PRL in 80% (n=8/10), increased FSH in 10% (n=1/10), and elevated phosphate levels in 81.8%. Only three cases developed hypocalcemia. GH deficiency was diagnosed in 45.5% of patients. Increased ACTH levels were observed in 3 patients (27.3%). Two of them had normal cortisol concentrations. The third case, a 2-year old girl was diagnosed with adrenal insufficiency, first manifested as full-blown adrenal crisis, while undergoing adenoidectomy. Molecular analysis of GNAS gene was performed in 9 cases. Heterozygous mutations were identified in 8 patients (88.9%), one de novo and three inherited from the mother.

Conclusions: PHP disorders may exhibit wide phenotypic variability. Measurement of ACTH and cortisol levels should be always included in the assessment of PHP patients in order to promptly diagnose an associated adrenal insufficiency that can be fatal.