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Pseudohypoparathyroidism type 1B associated with assisted reproductive technology.

ABSTRACT: Evidence suggests an increased incidence of imprinting disorders in children conceived by assisted reproductive technologies (ART). Maternal loss-of-methylation at GNAS exon A/B, observed in pseudohypoparathyroidism type 1b (PHP1B), leads to decreased expression of the stimulatory Gs?. We present a patient conceived by ART, who presented at age 4 years with delayed neurocognitive development and persistently increased creatine kinase (CK). At 6 years an elevated PTH was detected with normal calcium and a low 25(OH) vitamin D level (25OHD). Physical exam showed a narrow forehead, nasal bridge hypoplasia and micropenis. After normalizing vitamin D, PTH remained elevated and PHP1B was therefore considered as the underlying diagnosis. An almost complete loss-of-methylation was observed at GNAS exons A/B and AS, but not at exon XL, which was associated with a gain-of-methylation at exon NESP. There was no evidence of a microdeletion within the GNAS/STX16 region and analysis of several microsatellite markers for the GNAS region on Chr.20q revealed no evidence for paternal uniparental disomy (patUPD20q). Established facts Increased incidence of imprinting disorders in children conceived by assisted reproductive technologies (ART) Pseudohypoparathyroidism is caused by imprinting abnormalities. Novel Insights First report of a possible association between a methylation defects that causes PHP1B and assisted conception Increased creatine kinase level was associated with an increase in PTH concentration.

SUBMITTER: Fernandez M

PROVIDER: S-EPMC5938740 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Pseudohypoparathyroidism type 1B associated with assisted reproductive technology.

Fernandez Monica M Zambrano Maria Jose MJ Riquelme Joel J Castiglioni Claudia C Kottler Marie-Laure ML Jüppner Harald H Mericq Veronica V

Journal of pediatric endocrinology & metabolism : JPEM 20171001 10

Evidence suggests an increased incidence of imprinting disorders in children conceived by assisted reproductive technologies (ART). Maternal loss-of-methylation at GNAS exon A/B, observed in pseudohypoparathyroidism type 1b (PHP1B), leads to decreased expression of the stimulatory Gsα. We present a patient conceived by ART, who presented at age 4 years with delayed neurocognitive development and persistently increased creatine kinase (CK). At 6 years an elevated PTH was detected with normal calc ...[more]

PMID: 28902630

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Project description:Background:Pseudohypoparathyroidism type 1B (PHP1B; MIM#603233) is a rare imprinting disorder (ID), associated with the GNAS locus, characterized by parathyroid hormone (PTH) resistance in the absence of other endocrine or physical abnormalities. Sporadic PHP1B cases, with no known underlying primary genetic lesions, could represent true stochastic errors in early embryonic maintenance of methylation. Previous data confirmed the existence of different degrees of methylation defects associated with PHP1B and suggested the presence of mosaicism, a phenomenon already described in the context of other IDs. Results:With respect to mosaic conditions, the study of multiple tissues is a necessary approach; thus, we investigated somatic cell lines (peripheral blood and buccal epithelium and cells from the urine sediment) descending from different germ layers from 19 PHP patients (11 spor-PHP1B, 4 GNAS mutated PHP1A, and 4 PHP with no GNAS (epi)genetic defects) and 5 healthy controls. We identified 11 patients with epigenetic defects, further subdivided in groups with complete or partial methylation defects. The recurrence of specific patterns of partial methylation defects limited to specific CpGs was confirmed by checking methylation profiles of spor-PHP1B patients diagnosed in our lab (n = 56). Underlying primary genetic defects, such as uniparental disomy or deletion, potentially causative for the detected partial methylation were excluded in all samples. Conclusions:Our data showed no differences of methylation levels between organs and tissues from the same patient, so we concluded that the epimutation occurred in early post-zygotic phases and that the partial defects were mosaics. The number of patients with no detectable (epi)genetic GNAS defects was too small to exclude epimutations occurring in later post-zygotic phases, affecting only selected tissues different from blood, thus leading to underdiagnosis during routine molecular diagnosis. Finally, we found no correlation between methylation ratios, representing the proportion of epimutated cells, and the clinical presentation, further confirming the hypothesis of a threshold effect of the GNAS loss of imprinting leading to an "all-or-none" phenotype.

Project description:ImportanceThe number of children born through the use of assisted reproductive technology (ART) has been increasing. These children may have higher risks for epigenetic alteration and adverse perinatal outcomes, which may be associated with childhood cancers.ObjectiveTo determine the associations between different modes of conception and childhood cancers and potential mediation by preterm birth and low birth weight.Design, setting, and participantsThis nationwide, population-based cohort study included registry data from 2 308 016 eligible parents-child triads in Taiwan from January 1, 2004, to December 31, 2017. A total of 1880 children with incident childhood cancer were identified. Data were analyzed between September 1, 2020, and June 30, 2022.ExposureMode of conception, defined as (1) natural conception, (2) subfertility and non-ART (ie, infertility diagnosis but no ART-facilitated conception), or (3) ART (ie, infertility diagnosis and ART-facilitated conception).Main outcomes and measuresDiagnosis of childhood cancer according to the International Classification of Childhood Cancers, Third Edition.ResultsThe mean (SD) paternal and maternal ages were 33.28 (5.07) and 30.83 (4.56) years, respectively. Of the 2 308 016 children, 52.06% were boys, 8.16% were born preterm, and 7.38% had low birth weight. During 14.9 million person-years of follow-up (median, 6 years [IQR, 3-10 years]), ART conception was associated with an increased risk of any type of childhood cancers compared with natural conception (hazard ratio, 1.58; 95% CI, 1.17-2.12) and subfertility with non-ART conception (hazard ratio, 1.42; 95% CI, 1.04-1.95). The increased cancer risk of children conceived with ART was mainly owing to leukemia and hepatic tumor. The increased cancer risk associated with ART conception was not mediated by preterm birth or low birth weight.Conclusions and relevanceIn this cohort study, children conceived via ART had a higher risk of childhood cancers than those conceived naturally and those born to parents with an infertility diagnosis did not use ART. The increased risk could not be explained by preterm birth or low birth weight.

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Pseudohypoparathyroidism type 1B associated with assisted reproductive technology.

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Pseudohypoparathyroidism type 1B associated with assisted reproductive technology.

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