Beyond the textbook phenotype: Debunking myths in pseudohypoparathyroidism

Abstract

Background: Pseudohypoparathyroidism type 1A (PHP1A), now classified within the spectrum of inactivating PTH/PTHrP signaling disorders (iPPSD), is often recognized by the stereotypical Albright hereditary osteodystrophy (AHO) phenotype and parathyroid hormone (PTH) resistance. However, subtle or atypical phenotypic expression may lead to diagnostic delay or misdiagnosis. We present a case illustrating how seemingly unrelated clinical clues converged toward PHP1A when a high index of suspicion was maintained.

Case summary: A 16-year-old male presented with true seizures and was started on carbamazepine. Hypocalcemia was noted, and CT brain revealed extensive intracranial calcifications, leading to a working diagnosis of Fahr syndrome and referral to endocrinology. There was no family history of similar illness. He was born at term weighing 4.5 kg and had poor scholastic performance. On examination, height was 150 cm and weight 43 kg; multiple itchy nodular lesions over the abdomen and medial right ankle had previously been treated as eczema. Biochemistry showed hyperphosphatemia, markedly elevated PTH, sufficient vitamin D, subclinical hypothyroidism, normal renal function and magnesium. With PHP suspected, hand radiography revealed shortening of the 1st, 4th, and 5th metacarpals, while X-rays of the abdomen and ankle showed soft-tissue calcification corresponding to the nodules. Oral calcium and calcitriol were initiated. GNAS sequencing identified a novel heterozygous nonsense variant, c.559C>T (p.Gln187Ter), two codons upstream of the recognized mutational hotspot.

Conclusion: This case challenges assumptions that PHP1A is defined by obvious AHO, obesity, clinically apparent brachydactyly, or isolated PTH resistance. Seizures, intracranial calcifications, and cutaneous nodules may initially be attributed to neurological, Fahr syndrome, and dermatological disorders, respectively. Subtle skeletal abnormalities may only become apparent radiographically. Recognizing hypocalcemia, hyperphosphatemia, elevated PTH, and additional hormone resistance despite the absence of a textbook phenotype requires a high index of suspicion and can uncover an otherwise overlooked GNAS-related disorder.

[J Assoc Clin Endocrinol Diabetol Bangladesh, 2026;5(Suppl 1): S80]