Evaluating the variety of GNAS inactivation disorders and their clinical manifestations in 11 Chinese children.
Adolescent
Bone Diseases, Metabolic
/ diagnosis
Child
Child, Preschool
China
Chromogranins
/ genetics
Female
GTP-Binding Protein alpha Subunits, Gs
/ genetics
Humans
Infant
Male
Ossification, Heterotopic
/ diagnosis
Pseudohypoparathyroidism
/ diagnosis
Pseudopseudohypoparathyroidism
/ diagnosis
Skin Diseases, Genetic
/ diagnosis
Albright’s hereditary osteodystrophy
GNAS
Progressive osseous heteroplasia
Pseudohypoparathyroidism
Pseudopseudohypoparathyroidism
Journal
BMC endocrine disorders
ISSN: 1472-6823
Titre abrégé: BMC Endocr Disord
Pays: England
ID NLM: 101088676
Informations de publication
Date de publication:
16 Mar 2022
16 Mar 2022
Historique:
received:
25
08
2021
accepted:
30
12
2021
entrez:
17
3
2022
pubmed:
18
3
2022
medline:
29
3
2022
Statut:
epublish
Résumé
The GNAS gene on chromosome 20q13.3, encodes the alpha-subunit of the stimulatory G protein, which is expressed in most tissues and regulated through reciprocal genomic imprinting. Disorders of GNAS inactivation produce several different clinical phenotypes including pseudohypoparathyroidism (PHP), pseudopseudohypoparathyroidism (PPHP), progressive osseous heteroplasia (POH), and osteoma cutis (OC). The clinical and biochemical characteristics overlap of PHP subtypes and other related disorders presents challenges for differential diagnosis. We enrolled a total of 11 Chinese children with PHP in our study and analyzed their clinical characteristics, laboratory results, and genetic mutations. Among these 11 patients, nine of them (9/11) presented with resistance to parathyroid hormone (PTH); and nine (9/11) presented with an Albright's hereditary osteodystrophy (AHO) phenotype. GNAS abnormalities were detected in all 11 patients, including nine cases with GNAS gene variations and two cases with GNAS methylation defects. These GNAS variations included an intronic mutation (c.212 + 3_212 + 6delAAGT), three missense mutations (c.314C > T, c.308 T > C, c.1123G > T), two deletion mutations (c.565_568delGACT*2, c.74delA), and two splicing mutations (c.721 + 1G > A, c.432 + 1G > A). Three of these mutations, namely, c.314C > T, c.1123G > T, and c.721 + 1G > A, were found to be novel. This data was then used to assign a GNAS subtype to each of these patients with six cases diagnosed as PHP1a, two cases as PHP1b, one as PPHP, and two as POH. Evaluating patients with PTH resistance and AHO phenotype improved the genetic diagnosis of GNAS mutations significantly. In addition, our results suggest that when GNAS gene sequencing is negative, GNAS methylation study should be performed. Early genetic detection is required for the differential diagnosis of GNAS disorders and is critical to the clinician's ability to distinguish between heterotopic ossification in the POH and AHO phenotype.
Sections du résumé
BACKGROUND
BACKGROUND
The GNAS gene on chromosome 20q13.3, encodes the alpha-subunit of the stimulatory G protein, which is expressed in most tissues and regulated through reciprocal genomic imprinting. Disorders of GNAS inactivation produce several different clinical phenotypes including pseudohypoparathyroidism (PHP), pseudopseudohypoparathyroidism (PPHP), progressive osseous heteroplasia (POH), and osteoma cutis (OC). The clinical and biochemical characteristics overlap of PHP subtypes and other related disorders presents challenges for differential diagnosis.
METHODS
METHODS
We enrolled a total of 11 Chinese children with PHP in our study and analyzed their clinical characteristics, laboratory results, and genetic mutations.
RESULTS
RESULTS
Among these 11 patients, nine of them (9/11) presented with resistance to parathyroid hormone (PTH); and nine (9/11) presented with an Albright's hereditary osteodystrophy (AHO) phenotype. GNAS abnormalities were detected in all 11 patients, including nine cases with GNAS gene variations and two cases with GNAS methylation defects. These GNAS variations included an intronic mutation (c.212 + 3_212 + 6delAAGT), three missense mutations (c.314C > T, c.308 T > C, c.1123G > T), two deletion mutations (c.565_568delGACT*2, c.74delA), and two splicing mutations (c.721 + 1G > A, c.432 + 1G > A). Three of these mutations, namely, c.314C > T, c.1123G > T, and c.721 + 1G > A, were found to be novel. This data was then used to assign a GNAS subtype to each of these patients with six cases diagnosed as PHP1a, two cases as PHP1b, one as PPHP, and two as POH.
CONCLUSIONS
CONCLUSIONS
Evaluating patients with PTH resistance and AHO phenotype improved the genetic diagnosis of GNAS mutations significantly. In addition, our results suggest that when GNAS gene sequencing is negative, GNAS methylation study should be performed. Early genetic detection is required for the differential diagnosis of GNAS disorders and is critical to the clinician's ability to distinguish between heterotopic ossification in the POH and AHO phenotype.
Identifiants
pubmed: 35296306
doi: 10.1186/s12902-022-00941-8
pii: 10.1186/s12902-022-00941-8
pmc: PMC8928694
doi:
Substances chimiques
Chromogranins
0
GNAS protein, human
EC 3.6.1.-
GTP-Binding Protein alpha Subunits, Gs
EC 3.6.5.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
70Subventions
Organisme : National Science Foundation for Young Scientists of China
ID : 81900722
Organisme : the Project of Shanghai Municipal Science and Technology Commission
ID : 20MC1920400
Organisme : the Project of Shanghai Municipal Science and Technology Commission
ID : 20MC1920400
Informations de copyright
© 2022. The Author(s).
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