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Submitted on October 19, 2006
Accepted on March 23, 2007
Endocrinology and Diabetes Research Unit, Hospital de Cruces, Barakaldo, E48903, Basque Country, Spain. Pediatric Endocrinology Unit, Severo Ochoa Hospital, Leganés, Madrid, Spain. Departments of Medicine, Nursing and Pediatrics, University of Basque Country, Spain. Endocrinology Service, Hospital de Navarra, Pamplona, Spain. Endocrinology Service, Hospital do Meixoeiro, Vigo, Spain. Pediatric Endocrinology, Growth and Adolescence Unit, Clinical University of Santiago de Compostela, Spain. Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain. Department of Pediatric and Adolescent Medicine, University of Lübeck, Germany. Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, USA
* To whom correspondence should be addressed. E-mail: lcastano{at}hcru.osakidetza.net.
Context: Several endocrine disorders that share resistance to PTH are grouped under the term pseudohypoparathyroidism (PHP). PHP type-I, associated with blunted PTH-induced nephrogenous cAMP formation and phosphate excretion, is subdivided according to the presence or absence of additional endocrine abnormalities, Albright's hereditary osteodystrophy (AHO), and reduced Gs
activity caused by GNAS mutations.
Objective: We sought to identify the molecular defect in four unrelated patients who were thought to have PHP-Ia because of PTH- and TSH-resistance and mild AHO features.
Methods: Gs activity and mutation analysis, and assessment of GNAS haplotype, methylation, and gene expression were performed for probands and family members.
Results: Two patients showed modest decreases in erythrocyte Gs activity. Instead of Gs point mutations, however, all four patients showed methylation defects of the GNAS locus, a feature previously described only for PHP-Ib. Furthermore, one patient with an isolated loss of GNAS exon A/B methylation had the 3-kb STX16 deletion frequently identified in PHP-Ib patients. In all but one of the remaining patients, haplotype analysis excluded large deletions or uniparental disomy as the cause of the observed methylation changes.
Conclusions: Our investigations indicate that an overlap may exist between molecular and clinical features of PHP-Ia and PHP-Ib. No current mechanisms can explain the AHO-like features of our patients, some of which may not be linked to GNAS. Therefore, patients with hormone resistance and AHO-like features in whom coding Gs mutations have been excluded should be evaluated for epigenetic alterations within GNAS.
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