ESPE Abstracts

Introduction: Inactivating PTH/PTHrP signaling disorders (iPPSD) including pseudohypoparathyroidism 1A (PHP1A) represent a heterogenous group of endocrine conditions. Associated phenotypes are complex and may consist of resistance to hormones and neurotransmitters as well as short stature, osteoma cutis and skeletal findings. Cases with unusual and poorly understood presentations attributed to PHP1A have been reported. PHP1A manifests at variable ages and the occurrence and sequence of associated conditions is highly heterogenous, even within individuals who share the same GNAS variant. Neonatal complications were correlated with early (< 12 months) TSH-resistance in PHP1A-infants (1), possibly indicating that early complications may be associated with more severe disease. We report three unrelated patients with heterozygous GNAS -variants and infancy-onset of unusual PHP1A-manifestations.

Cases: Patient 1 (GNAS variant [NM_000516.7] c.140G>A, p.(Gly47Asp), ACMG 4, de novo) a presently 15 months old boy, presented with severe chronic noninfectious diarrhea beginning at 5 weeks of age, which lead to life-threatening dystrophy. Patient 2 (GNAS variant [NM_000516.7] c.470_472del, p.(Glu157del), ACMG 3, de novo) is a presently 4-year-old boy with a history of bronchopulmonary dysplasia inappropriate for gestational age and neonatal onset severe pulmonary complications including critical pulmonary bleeding, and recurring pulmonary infections. Patient 3 (GNAS variant [NM_000516.7] c.719-1G>C, p.(?), ACMG V, maternally inherited) is a presently 4-year-old girl who showed signs of PTH resistance and progressive osteoma cutis at an age of 1-2 weeks and obesity at the age of 3 months.

Discussion: The phenotypic spectrum of PHP1A in neonates and infancy may expand to severe gastrointestinal and pulmonary disease. The early onset of the unusual (patient 1 and 2) findings is likely related to PHP1A, but was not recognized as a sign for PHP1A, thereby delaying the correct diagnosis. These cases support the hypothesis that manifestations in early life may indicate a complicated course of the disease.

Conclusion: Elevated PTH or TSH in infants with unclear chronic symptoms or conditions should prompt evaluation for disorders of the IPPSD spectrum. In the absence of reliable predictors for the individual courses of PHP1A in depth clinical screening for possible manifestations beyond the classical spectrum is warranted even in infancy. 1: Del Sindaco, G., Berkenou, J., Pagnano, A., Rothenbuhler, A., Arosio, M., Mantovani, G., & Linglart, A. (2023). Neonatal and Early Infancy Features of Patients With Inactivating PTH/PTHrP Signaling Disorders/Pseudohypoparathyroidism. The Journal of Clinical Endocrinology & Metabolism, 108(11), 2961–2969. https://doi.org/10.1210/clinem/dgad236