Alessia Usardi

Genetic and Epigenetic Defects at the GNAS Locus Lead to Distinct Patterns of Skeletal Growth but Similar Early-Onset Obesity: DISTINCT PATTERNS OF FETAL AND POSTNATAL GROWTH IN GNAS-RELATED DISORDERS

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 parathyroid hormone (PTH) resistance, PHP1A and PHP1B patients may display early‐onset obesity. Because 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 postnatal 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 with significant overweight and obesity in adults (bodey mass index [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.

Progressive Development of PTH Resistance in Patients With Inactivating Mutations on the Maternal Allele of GNAS

Context Parathormone (PTH) resistance is characterized by hypocalcaemia, hyperphosphatemia, and elevated PTH in the absence of vitamin D deficiency. Pseudohypoparathyroidism type 1A [PHP1A, or inactivating parathormone (PTH)/PTHrp signaling disorder 2, according to the new classification (iPPSD2)], is caused by mutations in the maternal GNAS allele. Objective To assess PTH resistance over time in 20 patients affected by iPPSD2 (PHP1A), diagnosed because of family history, ectopic ossification, or short stature, and carrying a GNAS mutation. Methods We gathered retrospective data for calcium, phosphate, thyrotropin (TSH), and PTH levels at regular intervals. PTH infusion testing (teriparatide) was performed in 1 patient. Results Patients were diagnosed at a mean age of 3.9 years and had a mean follow-up of 2 years. TSH resistance was already present at diagnosis in all patients (TSH, 13.3 ± 9.0 mIU/L). Over time, PTH levels increased (179 to 306 pg/mL; P < 0.05), and calcium levels decreased (2.31 to 2.21 mmol/L; P < 0.05), but phosphate levels did not decrease with age as expected for healthy individuals. One patient born with ectopic ossifications showed an increase in cyclic adenosine monophosphate upon PTH infusion, similar to that of controls, at 7 months of age, but an impaired response at 4 years of age. Conclusions In patients with iPPSD2 (PHP1A), PTH resistance and hypocalcemia develop over time. These findings highlight the importance of screening for maternal GNAS mutations in the presence of ectopic ossifications or family history, even in the absence of PTH resistance and hypocalcemia. The follow-up of these patients should include regular assessments of calcium, phosphate, and PTH levels.

Diagnosis and management of pseudohypoparathyroidism and related disorders: first international Consensus Statement

This Consensus Statement covers recommendations for the diagnosis and management of patients with pseudohypoparathyroidism (PHP) and related disorders, which comprise metabolic disorders characterized by physical findings that variably include short bones, short stature, a stocky build, early-onset obesity and ectopic ossifications, as well as endocrine defects that often include resistance to parathyroid hormone (PTH) and TSH. The presentation and severity of PHP and its related disorders vary between affected individuals with considerable clinical and molecular overlap between the different types. A specific diagnosis is often delayed owing to lack of recognition of the syndrome and associated features. The participants in this Consensus Statement agreed that the diagnosis of PHP should be based on major criteria, including resistance to PTH, ectopic ossifications, brachydactyly and early-onset obesity. The clinical and laboratory diagnosis should be confirmed by a molecular genetic analysis. Patients should be screened at diagnosis and during follow-up for specific features, such as PTH resistance, TSH resistance, growth hormone deficiency, hypogonadism, skeletal deformities, oral health, weight gain, glucose intolerance or type 2 diabetes mellitus, and hypertension, as well as subcutaneous and/or deeper ectopic ossifications and neurocognitive impairment. Overall, a coordinated and multidisciplinary approach from infancy through adulthood, including a transition programme, should help us to improve the care of patients affected by these disorders.This Consensus Statement gives recommendations for the diagnosis and management of patients with pseudohypoparathyroidism and related disorders. A coordinated and multidisciplinary approach from infancy through adulthood is recommended to improve the care of these patients.

The Importance of Networking in Pseudohypoparathyroidism: EuroPHP Network and Patient Support Associations

Pseudohypoparathyroidism is a rare endocrine disorder with an estimated prevalence of 1/100,000. It is characterized by hypocalcemia and hyperphosphatemia in the absence of vitamin D deficiency or impaired renal function. Research studies during the last 20 years have led to the identification of the molecular underlying cause of the disease, the characterization of the clinical and biochemical characteristics and the observation of an overlap between genetic and clinical manifestations. The creation of networks both for specialists (including endocrinologists, pediatricians, dermatologists, geneticists, molecular biologists…) and patients support groups brings up the opportunity of research advance, synergism and common objectives for families and investigators, improving the quality of information about the disease and its outcome, that, at the end, will improve both the knowledge and life of the patients and their families.