Disorders of GNAS Inactivation

Clinical characteristics: Disorders of GNAS inactivation include the phenotypes pseudohypoparathyroidism Ia, Ib, and Ic (PHP-Ia, -Ib, -Ic), pseudopseudohypoparathyroidism (PPHP), progressive osseous heteroplasia (POH), and osteoma cutis (OC).

PHP-Ia and PHP-Ic are characterized by:

1. End-organ resistance to endocrine hormones including parathyroid hormone (PTH), thyroid-stimulating hormone (TSH), gonadotropins (LH and FSH), growth hormone-releasing hormone (GHRH), and CNS neurotransmitters (leading to obesity and variable degrees of intellectual disability and developmental delay); and

2. The Albright hereditary osteodystrophy (AHO) phenotype (short stature, round facies, and subcutaneous ossifications) and brachydactyly type E (shortening mainly of the 4th and/or 5th metacarpals and metatarsals and distal phalanx of the thumb).

Although PHP-Ib is characterized principally by PTH resistance, some individuals also have partial TSH resistance and mild features of AHO (e.g., brachydactyly).

PPHP, a more limited form of PHP-Ia, is characterized by various manifestations of the AHO phenotype without the hormone resistance or obesity.

POH and OC are even more restricted variants of PPHP:

1. POH consists of dermal ossification beginning in infancy, followed by increasing and extensive bone formation in deep muscle and fascia.

2. OC consists of extra-skeletal ossification that is limited to the dermis and subcutaneous tissues.

Diagnosis/testing: The diagnosis of a disorder of GNAS inactivation is established in a proband with all or some of the characteristic clinical and endocrine findings and evidence on molecular genetic testing of a genetic or epigenetic alteration resulting in lack of expression/function of the GNAS complex locus.

PHP-Ia,.-Ib, and -Ic are associated with reduced or absent expression/function of the protein Gsα (encoded by the maternal GNAS complex locus) due to one of the following:

1. An inactivating GNAS pathogenic variant

2. A genetic alteration in the imprinting regulatory elements in the GNAS complex locus or the nearby gene, STX16, that prevents proper maternal imprint of the GNAS complex locus

3. Isolated epimutations

4. Paternal 20q disomy

PPHP and POH/OC phenotypes are associated with lack of expression/function of Gsα encoded by the paternal GNAS allele due to an inactivating GNAS pathogenic variant; the POH/OC phenotypes are also associated with lack of expression/function of Gsα (encoded by the maternal GNAS allele) as a result of an inactivating GNAS pathogenic variant.

Management: Treatment of manifestations: Deficiencies of parathyroid hormone, thyroid hormone, and gonadotropins due to hormone resistance are treated in a standard manner. Growth hormone replacement therapy should be considered if screening for growth hormone deficiency with appropriate provocative testing is abnormal. Subcutaneous ossifications that are superficial and well circumscribed may be surgically removed when they are large or cause local irritation, although they may recur. Obesity tends to be the most difficult manifestation to treat as individuals with PHP-Ia and PHP-Ic have decreased resting energy expenditure and hyperphagia; thus, the usual recommendation of reduced caloric intake and increased physical activity may be less successful than in persons with obesity from other causes.

Surveillance: Routine monitoring of:

1. Endocrine function: measurement of serum concentration of PTH, calcium and phosphate, TSH and free T4, and urinary calcium excretion;

2. Growth velocity and growth hormone status (serum IGF1 and/or stimulated growth hormone testing);

3. New and/or enlarging ectopic ossifications;

4. Development of and/or progression of cataracts; and

5. Psychoeducational needs regarding school assistance / educational support and developmental therapies (e.g., physical, occupational, and speech therapy).

Agents/circumstances to avoid: Limit dietary intake of phosphorus (dairy products and meats) in persons with persistently elevated serum levels of phosphate.

Evaluation of relatives at risk: It is appropriate to evaluate apparently asymptomatic first-degree relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment.

Pregnancy management: For women with a disorder of GNAS inactivation that affects the maternal allele: Monitoring of serum concentration of calcium and thyroid studies (TSH, free T4) throughout pregnancy, labor, and the postpartum period and supplementation of calcium, vitamin D, and thyroid hormone as needed.

Genetic counseling: Disorders of GNAS inactivation are inherited in an autosomal dominant manner with the specific phenotype determined by the parental origin of the defective allele. Of individuals with a disorder of GNAS inactivation, approximately 38% have an affected parent and 38% have a de novo GNAS pathogenic variant; in the remaining approximately 25% the cause is unknown.

Each child of an individual with a disorder of GNAS inactivation has a 50% chance of inheriting the parent's genetic alteration (except for simplex cases with PHP-1b for whom the mode of inheritance is not well established). If the maternal GNAS complex locus is affected, her offspring are at risk for PHP-Ia, PHP-Ib (when associated with deletions at the imprinting regulatory elements), or PHP-Ic; if the paternal allele has an inactivating GNAS pathogenic variant, his offspring are at risk for PPHP or POH/OC. If the genetic alteration in the GNAS complex locus or the GNAS pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are technically possible.