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

Abstract

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.

A paternally inherited non‐sense variant c.424G>T (p.G142*) in the first exon of XLαs in an adult patient with hypophosphatemia and osteopetrosis

“…In the present family, proband's father and daughter did not show obvious clinical signs, possibly due to the variable expressivity of the phenotype. Interfamilial and intrafamilial variability has been found for the same GNAS mutations . However, other causes leading to relevant clinical manifestations in the proband could not be excluded.…”

“…Epigenetic events contribute to tissue‐specific imprinting of Gsα, which leads to phenotypic variability in GNAS mutations. Heterozygous, maternally inherited inactivating mutations in one of the 13 GNAS exons encoding Gsα lead to pseudohypoparathyroidism type 1a (PHP1A), characterized by hypocalcemia and hyperphosphatemia due to kidney resistance to parathyroid hormone (PTH), together with the features of Albright's hereditary osteodystrophy (AHO) including short stature, obesity, round face, brachydactyly, subcutaneous ossifications, and mental retardation . However, paternal inheritance of the same mutations causes pseudopseudohypoparathyroidism (PPHP), characterized by AHO alone without hormonal resistance, or progressive osseous heteroplasia (POH), characterized by severe heterotopic ossification (HO) …”

GNAS, PDE4D, and PRKAR1A Mutations and GNAS Methylation Changes Are Not a Common Cause of Isolated Early-Onset Severe Obesity Among Finnish Children

“…Differential diagnosis between these disorders can be challenging because of their overlapping clinical and/or laboratory phenotypes. The clinical features can be difficult to identify by physical examination and some patients show only minor clinical abnormalities that furthermore can vary with age (13). Furthermore, PTH-resistance in PHP1B may remain undetected until symptomatic hypocalcemia develops (2).…”

DNA Methylation in the Diagnosis of Monogenic Diseases

“…Pseudohypoparathyroidism (PHP) represents a group of disorders characterized by resistance to the parathyroid hormone (PTH) leading to hypocalcemia and hyperphosphataemia [83]. PHP is also defined by several clinical features such as brachydactyly, short stature, stocky build, obesity, round face and subcutaneuous ossification, also known as Albright hereditary osteodsystrophy (AHO).…”