Diagnostic Criteria

No specific clinical criteria establish the diagnosis of a disorder of GNAS inactivation.

Suggestive Findings

A disorder of GNAS inactivation should be suspected in individuals with the following phenotypes. Pseudohypoparathyroidism Ia (PHP-Ia) and pseudohypoparathyroidism Ic (PHP-Ic). The most readily recognized form of PHP is PHP-Ia, which has clinical and endocrine features similar to PHP-Ic. Note: PHP-Ic differs from PHP-Ia on the basis of normal functional activity of Gs (the protein encoded by GNAS) determined in some biochemical assays based on receptor-independent activation of Gs . PHP-Ia and PHP-Ic should be suspected in individuals with some of the following clinical and endocrine findings (which may emerge over time):

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"

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a disorder of GNAS inactivation, the following evaluations are recommended:

• Assessment of height, weight, body mass index, growth velocity, and pubertal development

• X-ray of hands and feet to classify the type and extent of brachydactyly; bone age study to determine whether skeletal maturation is advanced

• Endocrinology evaluation, with studies that may include the following:

• Serum concentration of calcium and phosphorous

• Serum concentration of 25-hydroxyvitamin D and magnesium to evaluate respectively for severe vitamin D deficiency and hypomagnesemia, either of which can cause decreased responsiveness to PTH or secondary hyperparathyroidism

• Parathyroid hormone (PTH)

• Thyroid-stimulating hormone (TSH) and free T4

• Growth hormone evaluation (IGF1, IGFBP3, stimulated GH testing)

• Urinary calcium excretion and tubular reabsorption of phosphorus

Note: Renal responsiveness to PTH (via measurement of the serum or urinary nephrogenous cyclic AMP response to administered PTH) is rarely indicated.

• Psychoeducational profile/developmental assessment

• Ophthalmologic examination for cataracts

• Consultation with nutritionist when obesity is present

• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Hypocalcemia. Therapy of hypocalcemia is similar to the treatment of other forms of hypoparathyroidism: restoring serum calcium to the normal level ...

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"

Surveillance Guidelines

Surveillance includes the following:

• Once the diagnosis is established, annual monitoring for endocrine abnormalities with measurement of serum concentration of PTH, calcium, and phosphate; TSH and free T4, and urinary calcium excretion (either 24-hour urine collection or random urine collections for determination of the calcium/creatinine ratio). These studies should be begun as soon an individual begins treatment, and may be performed more frequently in growing children who may experience increasing requirements for thyroid hormone and/or activated forms of vitamin D.

• Growth velocity and growth hormone status (serum IGF1 and/or stimulated growth hormone testing) should be evaluated annually. Individuals who receive growth hormone replacement should be monitored every three to four months per customary protocols.

• Routine physical examination including assessment of: (1) height to identify changes in growth velocity; (2) the hands and feet for evidence of brachydactyly; and (3) new and/or enlarging ectopic ossifications

• Annual examination by an ophthalmologist to monitor development of and/or progression of cataracts

• Periodic assessment of psychoeducational needs regarding school assistance/educational support and developmental therapies (e.g., physical, occupational, and speech therapy)

• Monitoring of post-pubertal females for disturbances in hypothalamic-pituitary-ovarian function

Source: GeneReviews — "Disorders of GNAS Inactivation"