A novel mutation in pseudohypoparathyroidism type 1a in a Chinese woman and her son with hypocalcaemia

Tam, Vicki H K; Chen, Sammy P L; Mak, Chole M; Fung, L M; Lee, C Y; Chan, Andrew

doi:10.12809/hkmj134025

Cited by 9 publications

(8 citation statements)

References 10 publications

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“…The different clinical features in the daughter (PHP1A) and mother (PPHP), who shared the same mutation, indicates that the mother either has a de novo mutation involving the paternal allele or inherited this mutation from her father. To date, only four other GNAS mutations in exon 9 have been reported, including three missense mutations [ 31 – 34 ] and one insertion [ 35 ]. Therefore, the presented case involved a novel missense mutation in exon 9, which expands the spectrum of known GNAS mutations related to this disorder.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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BackgroundPseudohypoparathyroidism type 1A (PHP1A) is a rare genetic disease primarily characterized by resistance to parathyroid hormone along with hormonal resistance and other features of Albright hereditary osteodystrophy (AHO). It is caused by heterozygous inactivating mutations in the maternal allele of the GNAS gene, which encodes the stimulatory G-protein alpha subunit (Gsα) and regulates production of the second messenger cyclic AMP (cAMP). Herein, we report a case of of PHP1A with atypical clinical manifestations (oligomenorrhea, subclinical hypothyroidism, and normocalcemia) and explore the underlying genetic cause in this patient.MethodsBlood samples were collected from the patient, her family members, and 100 healthy controls. The 13 exons and flanking splice sites of the GNAS gene were amplified by PCR and sequenced. To further assess whether the novel mutation resulted in gain or loss of function of Gsα, we examined the level of cAMP activity associated with this mutation through in vitro functional studies by introducing the target mutation into a human GNAS plasmid.ResultsA novel heterozygous c.715A > G (p.N239D) mutation in exon 9 of the GNAS gene was identified in the patient. This mutation was also found in her mother, who was diagnosed with pseudopseudohypoparathyroidism. An in vitro cAMP assay showed a significant decrease in PTH-induced cAMP production in cells transfected with the mutant plasmid, compared to that in the wild-type control cells (P < 0.01), which was consistent with loss of Gsa activity.ConclusionWe identified a novel GNAS mutation that altered Gsα function, which furthers our understanding of the pathogenesis of this disease. Screening for GNAS mutations should be considered in suspected cases of PHP1A even if the classical signs are not present.Electronic supplementary materialThe online version of this article (10.1186/s12881-018-0648-z) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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“…A total of 23 different mutations in 32 PHP1A and 4 pseudo‐pseudohypoparathyroidism (PPHP) Asian patients have been reported . Our study added 4 new mutations to this list.…”

Section: Discussionmentioning

confidence: 99%

Clinical and genetic characteristics of Pseudohypoparathyroidism in the Chinese population

Chu

Zhu

Wang

et al. 2017

Clinical Endocrinology

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“…Additional skeletal features have been described in different disorders of the PTH–PTHrP pathway, such as Madelung deformity 72,128 , spinal stenosis 203,254–257 , acro-osteolysis, cortical irregularity of long bones and metadiaphyseal enchondromata or short humerus and curved radius 258 , as well as other craniofacial peculiarities (typical pear-shaped nose, long and flat philtrum, thin upper lip and receding chin) and phalangeal cone-shaped epiphyses, resulting in clinodactyly 259 . Depending on the functional consequences, the patient might require corrective orthopaedic surgery.…”

Section: Managementmentioning

confidence: 99%

Diagnosis and management of pseudohypoparathyroidism and related disorders: first international Consensus Statement

et al. 2018

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This Consensus Statement covers recommendations for the diagnosis and management of patients with pseudohypoparathyroidism (PHP) and related disorders, which comprise metabolic disorders characterized by physical findings that variably include short bones, short stature, a stocky build, early-onset obesity and ectopic ossifications, as well as endocrine defects that often include resistance to parathyroid hormone (PTH) and TSH. The presentation and severity of PHP and its related disorders vary between affected individuals with considerable clinical and molecular overlap between the different types. A specific diagnosis is often delayed owing to lack of recognition of the syndrome and associated features. The participants in this Consensus Statement agreed that the diagnosis of PHP should be based on major criteria, including resistance to PTH, ectopic ossifications, brachydactyly and early-onset obesity. The clinical and laboratory diagnosis should be confirmed by a molecular genetic analysis. Patients should be screened at diagnosis and during follow-up for specific features, such as PTH resistance, TSH resistance, growth hormone deficiency, hypogonadism, skeletal deformities, oral health, weight gain, glucose intolerance or type 2 diabetes mellitus, and hypertension, as well as subcutaneous and/or deeper ectopic ossifications and neurocognitive impairment. Overall, a coordinated and multidisciplinary approach from infancy through adulthood, including a transition programme, should help us to improve the care of patients affected by these disorders.

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A novel mutation in pseudohypoparathyroidism type 1a in a Chinese woman and her son with hypocalcaemia

Cited by 9 publications

References 10 publications

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

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

Clinical and genetic characteristics of Pseudohypoparathyroidism in the Chinese population

Diagnosis and management of pseudohypoparathyroidism and related disorders: first international Consensus Statement

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