GNAS inactivation disorders / pseudopseudohypoparathyroidism

GNAS inactivation disorders typically present during childhood with metabolic, skeletal, and connective-tissue manifestations. The most prominent endocrine abnormalities are parathyroid hormone (PTH) resistance resulting in hypocalcaemia and hyperphosphataemia, thyroid-stimulating hormone (TSH) resistance leading to primary hypothyroidism, usually without goitre, and growth hormone deficiency secondary to growth hormone–releasing hormone (GHRH) resistance; the latter has been reported in approximately 50–70% of affected individuals. Hormone resistance may additionally involve gonadotropins and, less commonly, calcitonin. Many affected individuals exhibit features of Albright hereditary osteodystrophy, including a round face, short stature, brachydactyly or brachymetacarpia, and heterotopic ossification involving the dermis and subcutaneous tissues. Early-onset obesity and variable degrees of neurocognitive involvement are also recognised. Pseudohypoparathyroidism type Ia is most commonly diagnosed during childhood, although mildly affected individuals may remain undiagnosed until adulthood. Pseudohypoparathyroidism type Ib generally presents later in childhood or adolescence, often after biochemical evidence of PTH resistance becomes apparent. In contrast, disorders characterised predominantly by ectopic ossification, such as osteoma cutis and progressive osseous heteroplasia, may manifest during infancy. Pseudopseudohypoparathyroidism is characterised by the skeletal features of Albright hereditary osteodystrophy in the absence of clinically significant endocrine resistance.

GNAS inactivation disorders are rare, with the prevalence of pseudohypoparathyroidism – the most common clinical presentation – estimated at approximately 0.79 per 100,000 population.

Disorders of GNAS inactivation result from germline pathogenic variants and/or epigenetic imprinting defects affecting the imprinted GNAS locus on chromosome 20q13.32. Owing to the complex tissue-specific imprinting of GNAS, clinical manifestations differ according to the parental origin of the affected allele and can broadly be divided into maternal- and paternal-inheritance phenotypes. Maternal GNAS defects typically lead to pseudohypoparathyroidism type Ia, characterised by multi-hormone resistance and features of Albright hereditary osteodystrophy. In contrast, paternal GNAS defects are associated with pseudopseudohypoparathyroidism, in which Albright hereditary osteodystrophy occurs without hormone resistance, and with progressive osseous heteroplasia, characterised by progressive heterotopic ossification involving deeper connective and soft tissues.

The genetic forms of GNAS inactivation disorders are most commonly inherited in an autosomal dominant manner. Disease manifestations depend strongly on the parental origin of the affected allele, reflecting the complex tissue-specific imprinting pattern of the GNAS locus. Both inherited and de novo pathogenic variants have been reported, while some cases result from epigenetic alterations affecting GNAS methylation and imprinting rather than sequence variants.

• Where a genetic cause is suspected, molecular genetic testing can identify the underlying condition and confirm a clinical suspicion.
• The identified entity guides further clinical management and is a prerequisite for targeted medical care; therapeutic options are evaluated individually by the treating physicians.
• Identification of the underlying pathogenic germline variant enables predictive testing of at-risk family members and provides information relevant to family planning.

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• Underbjerg L, Sikjaer T, Mosekilde L, Rejnmark L. Pseudohypoparathyroidism: epidemiology, mortality and risk of complications. Clin Endocrinol (Oxf). 2016;84(6):904-911. PMID: .
• Mantovani G, Bastepe M, Monk D, de Sanctis L, Thiele S, Usardi A, et al. Diagnosis and management of pseudohypoparathyroidism and related disorders: first international Consensus Statement. Nat Rev Endocrinol. 2018;14(8):476-500. PMID: .