Pseudohypoparathyroidism type 1B associated with assisted reproductive technology

Area of Science:

• Endocrinology
• Genetics
• Reproductive Medicine

Background:

• Assisted reproductive technologies (ART) are associated with an increased incidence of imprinting disorders.
• Pseudohypoparathyroidism (PHP) is a group of disorders characterized by resistance to parathyroid hormone (PTH) and is caused by imprinting abnormalities in the GNAS gene.
• Maternal loss-of-methylation at GNAS exon A/B leads to decreased expression of the stimulatory Gsα subunit, a hallmark of pseudohypoparathyroidism type 1b (PHP1B).

Observation:

• A 4-year-old patient conceived via ART presented with delayed neurocognitive development and elevated creatine kinase (CK).
• At age 6, the patient exhibited elevated PTH with normal calcium and low vitamin D, along with physical features including a narrow forehead, hypoplastic nasal bridge, and micropenis.
• Despite vitamin D normalization, PTH remained elevated, prompting investigation for PHP1B.

Findings:

• Genetic analysis revealed a near-complete loss-of-methylation at GNAS exons A/B and AS, and a gain-of-methylation at exon NESP, consistent with PHP1B.
• No microdeletions in the GNAS/STX16 region or paternal uniparental disomy of chromosome 20q were detected.
• This is the first report suggesting a potential association between methylation defects causing PHP1B and assisted conception.

Implications:

• This case highlights a potential link between ART and imprinting defects leading to PHP1B.
• Elevated creatine kinase levels may be an early indicator associated with increased PTH concentration in such cases.
• Further research is needed to understand the mechanisms linking ART to imprinting disorders and their clinical manifestations.