No abstract

Background Pseudohypoparathyroidism (PHP) and related disorders newly referred to as inactivating PTH/PTHrP Signaling Disorders (iPPSD) are rare endocrine diseases. Many clinical features including obesity, neurocognitive impairment, brachydactyly, short stature, parathyroid hormone (PTH)-resistance, and resistance to other hormones such as thyroid-stimulating hormone (TSH) have been well described, yet they refer mainly to the full development of the disease during late childhood and adulthood. Objective A significant delay in diagnosis has been reported; therefore, our objective is to increase awareness on neonatal and early infancy presentation of the diseases. To do so, we analyzed a large cohort of iPPSD/PHP patients. Methods We included 136 patients diagnosed with iPPSD/PHP. We retrospectively collected data on birth and investigated the rate of neonatal complications occurring in each iPPSD/PHP category within the first month of life. Results Overall 36% of patients presented at least one neonatal complication, far more than the general population; when considering only the patients with iPPSD2/PHP1A, it reached 47% of the patients. Neonatal hypoglycemia and transient respiratory distress appeared significantly frequent in this latter group, i.e., 10.5% and 18.4%, respectively. The presence of neonatal features was associated with earlier resistance to TSH (p < 0.001) and with the development of neurocognitive impairment (p = 0.02) or constipation (p = 0.04) later in life. Conclusion Our findings suggest that iPPSD/PHP and especially iPPSD2/PHP1A newborns require specific care at birth, because of an increased risk of neonatal complications. These complications may predict a more severe course of the disease, however they are unspecific which likely explains the diagnostic delay.

Background Maternal inactivating GNAS mutations lead to pseudohypoparathyroidism 1A (PHP1A), newly classified as inactivating PTH/PTHrP signaling disorder type 2 of maternal inheritance (iPPSD2). Patients present with resistance to PTH and other hormones, subcutaneous ossifications, brachydactyly, short stature, and early-onset obesity. They can be born small for gestational age (SGA) and may present with growth hormone (GH) deficiency. The use of recombinant human GH (rhGH) therapy has been sporadically reported, yet we lack data on the long-term efficacy and safety of rhGH, as well as on adult height. Objectives Our multicenter, retrospective, observational study describes growth in patients treated with rhGH in comparison with untreated iPPSD2/PHP1A controls. Methods We included 190 patients; 26 received rhGH. Height, weight, body mass index (BMI) at various time-points, and adult height were documented. We analyzed the effect of rhGH on adult height by using linear mixed models. Results Adult height was available for 11/26 of rhGH-treated individuals and for 69/164 controls. Patients treated with rhGH showed a gain in height of 0.7 SDS after one year (CI +0.5 to +0.8, p<0.001) and of 1.5 SDS after 3 years (CI +1.0 to +2.0, p<0.001). Additionally, there was a clear beneficial impact of rhGH on adult height when compared to untreated controls, with a difference of 1.9 SDS (CI +1.1 to +2.7, p<0.001). BMI SDS did not vary significantly upon rhGH therapy. Conclusion rhGH treatment of iPPSD2/PHP1A patients with short stature improves growth and adult height. More studies are needed to confirm long-term efficacy and safety.