Clinical and genetic characterization of Portuguese patients with pseudohypoparathyroidism type Ib.
Patients with pseudohypoparathyroidism type Ib (PHP-Ib) present hypocalcemia and hyperphosphatemia, as a consequence of a resistance to PTH action, through its G-protein-coupled receptor, in the renal tubules. This resistance results from tissue-specific silencing of the G-protein alpha-subunit (G(s)α), due to imprinting disruption of its encoding locus--GNAS. In familial PHP-Ib, maternally inherited deletions at the STX16 gene are associated to a regional GNAS methylation defect. In sporadic PHP-Ib, broad methylation changes at GNAS arise from unknown genetic causes. In this study, we describe the clinical presentation of PHP-Ib in four Portuguese patients (two of whom were siblings), and provide further insight for the management of patients with this disease. The diagnosis of PHP-Ib was made after detection of GNAS imprinting defects in each of the cases. In the siblings, a regional GNAS methylation change resulted from a known 3.0 kb STX16 deletion. In the other two patients, the broad methylation defects at GNAS, which were absent in their relatives, resulted from genetic alterations that remain to be identified. We report the first clinical and genetic study of Portuguese patients with PHP-Ib. The genetic identification of a hereditary form of this rare disease allowed an early diagnosis, and may prevent hypocalcemia-related complications.
Cavaco
Branca Maria
BM
Centro de Investigação de Patobiologia Molecular, CIPM, Instituto Português de Oncologia de Lisboa Francisco Gentil, 1099-023 Lisbon, Portugal. bcavaco@ipolisboa.min-saude.pt
Tomaz
Rute Alexandra
RA
Fonseca
Fernando
F
Mascarenhas
Mário Rui
MR
Leite
Valeriano
V
Sobrinho
Luís Gonçalves
LG
D000328:Adult; D002648:Child; D002864:Chromogranins; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D006801:Humans; D011174:Portugal; D011547:Pseudohypoparathyroidism / Q000175:diagnosis* / Q000235:genetics; D051438:Syntaxin 16 / Q000235:genetics; D055815:Young Adult
D002864:Chromogranins; C496118:STX16 protein, human; D051438:Syntaxin 16; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs