Pseudohypoparathyroidism type 1A (PHP1A), pseudoPHP (PPHP), and PHP type 1B (PHP1B) are caused by maternal and paternal GNAS mutations, and abnormal methylation at maternal GNAS promoter(s), respectively. Adult PHP1A patients are reportedly obese and short, whereas most PPHP patients are born small. In addition to PTH resistance, PHP1A and PHP1B patients may display early-onset obesity. As early-onset and severe obesity and short stature are daily burdens for PHP1A patients, we aimed at improving knowledge on the contribution of the GNAS transcripts to fetal and postnatal growth and fat storage. Through an international collaboration, we collected growth and weight data from birth until adulthood for 306 PHP1A/PPHP and 220 PHP1B patients. PHP1A/PPHP patients were smaller at birth than healthy controls, especially PPHP (length z-score PHP1A: −1.1±1.8; PPHP: −3.0±1.5). Short stature is observed in 64% and 59% of adult PHP1A and PPHP patients. PHP1B patients displayed early post-natal overgrowth (height z-score at 1 year: 2.2±1.3 and 1.3±1.5 in autosomal dominant and sporadic PHP1B) followed by a gradual decrease in growth velocity resulting in normal adult height (z-score for both: −0.4±1.1). Early-onset obesity characterizes GNAS alterations and is associated to significant overweight and obesity in adults (BMI z-score: 1.4±2.6, 2.1±2.0, and 1.4±1.9 in PPHP, PHP1A, and PHP1B, respectively), indicating that reduced Gsα expression is a contributing factor.. The growth impairment in PHP1A/PPHP may be due to Gsα haploinsufficiency in the growth plates; the paternal XLαs transcript likely contributes to prenatal growth; for all disease variants, a reduced pubertal growth spurt may be due to accelerated growth plate closure. Consequently, early diagnosis and close follow-up is needed in patients with GNAS defects to screen and intervene in case of early-onset obesity and decreased growth velocity.

Background X-linked hypophosphatemic rickets (XLH) is the first cause of inherited hypophosphatemia and is caused by mutation in the PHEX gene, resulting in excessive expression of the phosphaturic factor FGF23. Symptoms are mainly related to rickets in children and osteomalacia in adults and cause several complications that can be highly invalidating. Due to its rarity, XLH is poorly known and diagnosis is frequently delayed. Conventional treatment is based on oral phosphate salts supplementation and activated vitamin D analogs, which however, cannot cure the disease in most cases. Objective Due to the low prevalence of XLH, an experts’ opinion survey was conducted across Italian centers to collect data on XLH and on its management. Methods A questionnaire was developed by a group of experts to collect data on XLH epidemiology, diagnosis and treatment in Italy. Results Data from 10 Italian centers (nine of which pediatric) on 175 patients, followed between 1998 and 2017, were included in the survey. Most patients were followed since childhood and 63 children became adults during the investigated period. The diagnosis was made before the age of 1 and between 1 and 5 years in 11 and 50% of cases, respectively. Clinically apparent bone deformities were present in 95% of patients. These were ranked moderate/severe in 75% of subjects and caused growth stunting in 67% of patients. Other frequent complications included bone pain (40%), dental abscesses (33%), and dental malpositions (53%). Treatment protocols varied substantially among centers. Nephrocalcinosis was observed in 34% of patients. Tertiary hyperparathyroidism developed in 6% of patients. Conclusions XLH remains a severe condition with significant morbidities.

Background: To date, there is no agreement about the frequency or the features of thyroid abnormalities in McCune-Albright syndrome (MAS). The aim of our study was to detect thyroid abnormalities in a cohort of MAS children and adolescents and to give indications for their treatment and follow-up. Methods: In 36 patients, 22 females and 14 males, thyroid function and sonographic features of thyroid were evaluated every 6–12 months. Results: Three males and 1 female had hyperthyroidism: 2 with nodular, 2 with diffuse goiters. They were treated with methimazole (0.2–0.5 mg/kg/day) with good clinical and biochemical responses. The remaining 32 patients were euthyroid, even if 7 displayed sonographic alterations, of whom 5 had nodular goiter with nodules >1 cm, and 2 micronodular goiter. Fine-needle aspiration biopsy was performed in 2 patients with nodules >1 cm, 1 showing hemorrhagic nodule and 1 colloid cystic nodule. Conclusions: Prevalence of thyroid alterations in the studied MAS series was 31%. 64% of 11 patients with thyroid alterations had nodular goiters, with nodules >1 cm. As the onset of thyroid disease ranged from 1 to 20 years, a strict monitoring of thyroid function is recommended every 6 months. Satisfactory treatment can be obtained and maintained with antithyroid drugs.

Children with HT may develop a deterioration of thyroid status during the first five years of disease. Such a trend may be observed, even in the patients who initially present with a mild biochemical picture (either SH or euthyroidism). A total of 57.1% of initially euthyroid children remain euthyroid, and 40.6% of patients with initial SH normalize thyroid function within five years after HT diagnosis. The patients presenting with SH are more prone to the risk of developing severe thyroid dysfunction over time.