A Novel GNAS Mutation in a Patient with Ia Pseudohypoparathyroidism (iPPSD2) Phenotype

Abstract

Pseudohypoparathyroidism (PHP) is a heterogeneous orphan disease characterized by multihormonal resistance and several phenotypic features. In some cases, PHP is caused by a mutation in the GNAS that encodes the alpha subunit of the G protein, one of the key transmitters of intracellular signals. A correlation between the genotype and phenotype of patients with GNAS mutations has not yet been described. This often makes diagnosis, drug prescription, and timely diagnosis difficult. Information about GNAS functioning and the impact of specific mutations on the clinical course of the disease is limited. Establishing of the pathogenicity by newly identified GNAS mutations will expand the understanding of this gene functioning in the cAMP signaling pathway and may become the basis for personalized treatment. This paper provides a clinical description of a patient with the Ia PHP phenotype caused by a previously unknown mutation in GNAS (NC_000020.11(NM_000516.7)): c.719-29_719-13delinsACCAAAGAGAGCAAAGCCAAG in the heterozygous state. Verification of the pathogenicity of the detected mutation is also described.

Pseudohypoparathyroidism versus signaling disorder: A case report

“… 2 The major criteria are more specific, and are comprised of PTH resistance, ectopic ossifications, and brachydactyly. 2 , 10 The minor criteria are less specific, and are comprised of TSH resistance, other hormonal resistance, motor and cognitive retardation or impairment, intrauterine and postnatal growth retardation, obesity/overweight, and a flat nasal bridge and/or maxillary hypoplasia and/or a round face. 2 , 11 The presence of a major criterion of either PTH resistance or ectopic ossifications, or the presence of the major criterion of brachydactyly with at least two minor criteria establishes a diagnosis of iPPSD.…”

Identification of a novel GNAS mutation in a family with pseudohypoparathyroidism type 1A

“…To date, more than 180 different mutations in the GNAS that lead to PHP1A are known [ 19 ]. At the same time, two-thirds of these mutations are found only once time.…”

“…There is no strict correlation between the genotype and phenotype in GNAS variants. The GNAS locus has a complex structure and variable expression that conditions clinical variability [ 2 ], so a wide variability in both phenotype and severity of progression are described [ 19 , 20 ].…”