ESPE Abstracts

Background: Pseudohypoparathyroidism (PHP) encompasses a group of rare disorders defined by target organ unresponsiveness to parathyroid hormone (PTH). Patients with PHP type 1A carry heterozygous mutations of the maternal GNAS gene that encodes the α-subunit of the G protein. This protein is coupled to the PTH receptor as well as to other heptahelical receptors - TSH, GHRH and gonadotropins receptors.

Objective and hypotheses: To describe a case of PHP type 1A due to a novel de-novo GNAS mutation.

Method: The patient was born at 36 weeks gestation weighing 3535 g after an uncomplicated pregnancy. Physical examination at birth was unremarkable except for umbilical hernia. At the fifth day of life, he developed hypothermia. Blood tests revealed TSH 76 mIU/l (normal range: 0.7–9.8), FT₄ 9.9 pmol/l (7–16) and FT₃ 4 pmol/l (3.8–6). Thyroid scan showed a normally located thyroid gland. Levothyroxine treatment was initiated with normalization of TSH, FT₄ and FT₃ levels. However, excessive weight gain ensued and at 6 months he weighed 11.3 kg (+3.3 SDS for his age). Therefore, further workup was performed and revealed: PTH 91.8, 129 and 211 pg/ml in sequential blood tests (nl=16–87), calcium 9.7 mg/dl, phosphorus 6.7 mg/dl, 25-hydroxy vitamin D 21.9 ng/ml and calcium/creatinine ratio in the urine 0.02. Both parents had unremarkable physical examination and lab results. DNA was extracted from whole blood and full sequencing of the coding regions of the GNAS gene was performed.

Results: Sequence analysis revealed a novel heterozygous frameshift mutation with a premature stop codon in exon 7 (c.518_521delACTG). This mutation has not been previously reported and is predicted to be deleterious. Neither parent carried the mutation.

Conclusion: This case presents a novel de-novo GNAS mutation. Physicians should consider the rare diagnosis of PHP among neonates with congenital hypothyroidism with normally located gland and marked obesity in the newborn period.