Abstract | CONTEXT:
Pseudohypoparathyroidism type Ib (PHP-Ib) is a rare imprinting disorder characterized by end-organ resistance to PTH and, frequently, to thyroid-stimulating hormone. PHP-Ib familial form, with an autosomal dominant pattern of transmission (autosomal dominant pseudohypoparathyroidism type Ib [AD-PHP-Ib]), is typically characterized by an isolated loss of methylation at the guanine nucleotide- binding protein α-stimulating activity polypeptide 1 A/B differentially methylated region (DMR), secondary to genetic deletions disrupting the upstream imprinting control region in the syntaxin-16 (STX16) locus. However, deletions described up to now failed to account some cases of patients with a methylation defect limited to the A/B DMR; thus, it is expected the existence of other still unknown rearrangements, undetectable with conventional molecular diagnostic methods. OBJECTIVE: We investigated a PHP-Ib patient with a methylation defect limited to the A/B DMR and no known STX16 deletions to find the underlying primary genetic defect. PATIENT AND METHODS: A PHP-Ib patient (hypocalcaemia, hyperphosphataemia, raised serum PTH levels, no vitamin D deficiency) and his unaffected relatives were investigated by methylation specific-multiplex ligand-dependent probe amplification to search for novel pathogenetic defects affecting the guanine nucleotide- binding protein α-stimulating activity polypeptide 1 and STX16 loci. RESULTS: We report the clinical, biochemical, and molecular analysis of an AD-PHP-Ib patient with a novel STX16 deletion overlapping with previously identified STX16 deletions but that, unlike these genetic defects associated with AD-PHP-Ib, goes unnoticed with commonly used first-level diagnostic techniques. CONCLUSIONS: Our work highlights the importance of performing accurate investigations in PHP-Ib patients with methylation defects to allow precise genetic counseling because, in case of deletions, the segregation ratio is about 50% and the disease phenotype is transmitted in an autosomal dominant fashion via the mother.
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Authors | Francesca M Elli, Luisa de Sanctis, Erika Peverelli, Paolo Bordogna, Barbara Pivetta, Gianmaria Miolo, Paolo Beck-Peccoz, Anna Spada, Giovanna Mantovani |
Journal | The Journal of clinical endocrinology and metabolism
(J Clin Endocrinol Metab)
Vol. 99
Issue 4
Pg. E724-8
(Apr 2014)
ISSN: 1945-7197 [Electronic] United States |
PMID | 24438374
(Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- STX16 protein, human
- Syntaxin 16
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Topics |
- DNA Methylation
(genetics)
- Gene Deletion
- Genes, Dominant
- Genomic Imprinting
(genetics)
- Humans
- Male
- Pedigree
- Pseudohypoparathyroidism
(genetics)
- Syntaxin 16
(genetics)
- Young Adult
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