Ossifications in Albright Hereditary Osteodystrophy: Role of Genotype, Inheritance, Sex, Age, Hormonal Status, and BMI

Abstract

Abstract Context Albright hereditary osteodystrophy (AHO) is caused by heterozygous inactivating mutations in GNAS. Depending on the parental origin of the mutated allele, patients develop either pseudohypoparathyroidism type 1A (PHP1A), with multihormone resistance and severe obesity, or pseudopseudohypoparathyroidism (PPHP), without hormonal abnormalities or marked obesity. Subcutaneous ossifications (SCOs) are a source of substantial morbidity in both PHP1A and PPHP. Objective This study investigated the previously undetermined prevalence of SCO formation in PHP1A vs PPHP as well as possible correlations with genotype, sex, age, hormonal resistance, and body mass index (BMI). Design This study evaluated patients with AHO for SCOs by physical examination performed by one consistent physician over 16 years. Setting Albright Clinic, Kennedy Krieger Institute; Institute for Clinical and Translational Research, Johns Hopkins Hospital; Albright Center, Connecticut Children’s Medical Center. Patients We evaluated 67 patients with AHO (49 with PHP1A, 18 with PPHP) with documented mutations in GNAS. Main Outcome Measures Relationships of SCOs to genotype, sex, age, hormonal resistance, and BMI. Results Forty-seven of 67 participants (70.1%) had SCOs. Patients with PHP1A and PPHP had similar prevalences and degrees of ossification formation. Patients with frameshift and nonsense mutations had much more extensive SCOs than those with missense mutations. Males were affected more than females. There was no correlation with hormonal status or BMI. Conclusions There is a similar prevalence of SCOs in PHP1A and PPHP, and the extent of SCO formation correlates with the severity of the mutation. Males are affected more extensively than females, and the SCOs tend to worsen with age.