Clinical Guidance

Disorders of GNAS inactivation include pseudohypoparathyroidism Ia (PHP-Ia), Ib (PHP-Ib), and Ic (PHP-Ic), as well as pseudopseudohypoparathyroidism (PPHP), progressive osseous heteroplasia (POH), and osteoma cutis (OC) . The term pseudohypoparathyroidism (PHP) refers to disorders with hypocalcemia and hyperphosphatemia (which are typical of hypoparathyroidism) that result from end-organ resistance to rather than deficiency of parathyroid hormone (PTH).

Pseudohypoparathyroidism Ia (PHP-Ia) and PHP-Ic

PHP-Ia and PHP-Ic have a similar phenotype and are distinguished only by ex vivo assays of Gs protein function that are based on hormone receptor activation of Gs; in these assays Gs activity is reduced by approximately 50% in PHP-Ia and normal in PHP-Ic. Endocrine.

Source: GeneReviews — "Disorders of GNAS Inactivation"

Clinical Guidance

No clear correlation appears to exist between the type and location of GNAS complex locus / STX16 pathogenic variants and disease onset, severity of endocrine resistance, or number of AHO features. However, two unique variants affecting both the stability and the activity of Gs have been described in three unrelated individuals with PHP1a who presented with additional clinical features reflecting enhanced Gs activity:

Source: GeneReviews — "Disorders of GNAS Inactivation"

Penetrance

Disorders of GNAS inactivation show complete penetrance, with manifestations typically appearing during childhood. However, the exact manifestations and severity vary significantly among individuals.

Source: GeneReviews — "Disorders of GNAS Inactivation"

Differential Diagnosis

Conditions to be considered in the differential diagnosis include the following:

Source: GeneReviews — "Disorders of GNAS Inactivation"

Clinical Guidance

Limit dietary intake of phosphorus (dairy products and meats) in persons with persistently elevated serum levels of phosphate.

Source: GeneReviews — "Disorders of GNAS Inactivation"

Therapies Under Investigation

Dr Emily Germain-Lee at the University of Connecticut is recruiting individuals with PHP-Ia and AHO to determine whether growth hormone therapy can improve short stature and obesity. Researchers at Vanderbilt University Medical Center are investigating whether theophylline treatment promotes weight loss, improves glucose tolerance, and slows growth plate closure in children and young adults. Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Source: GeneReviews — "Disorders of GNAS Inactivation"