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 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 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.
Acknowledgments
We are grateful to the patient and his parents who participated in this study.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), grant R01DK46718-20 (to Harald Jueppner).
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
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