Eduardo Fernández-Rebollo, Olga Pérez, Cristina Martinez-Bouzas, Maria Carmen Cotarelo-Pérez, Intza Garin, Jose Luis Ruibal, Gustavo Pérez-Nanclares, Luis Castaño and Guiomar Pérez de Nanclares
The phenotypic variability of patients with syndromes presenting with dysmorphism makes clinical diagnosis difficult, leading to an exhaustive genetic study to determine the underlying mechanism so that a proper diagnosis could be established.
To genetically characterize siblings, the older sister diagnosed with Albright hereditary osteodystrophy and the younger one with CHARGE syndrome.
Clinical case report.
Clinical, biochemical, and radiological studies were performed on the family. In addition, molecular genetic studies including sequencing of GNAS, typing of microsatellites on 2q and 21q, and multiplex ligation-dependent probe amplification of subtelomeric regions were performed, as well as confirmatory fluorescent in situ hybridization analysis.
The genetic analysis revealed that both sisters presented a 2q37 deletion due to the maternal unbalanced segregation of a 2;21 translocation.
This is the first report of a 2q37 deletion where differential diagnosis of CHARGE syndrome is needed due to the appearance of choanal atresia.
Alejandro García-Castaño, Leire Madariaga, Gustavo Pérez de Nanclares, Gema Ariceta, Sonia Gaztambide, Luis Castaño and Spanish Endocrinology Group and Renal Tube Group
Molecular diagnosis is a useful diagnostic tool in calcium metabolism disorders. The calcium-sensing receptor (CaSR) is known to play a central role in the regulation of extracellular calcium homeostasis. We performed clinical, biochemical and genetic characterization of sequence anomalies in this receptor in a cohort of 130 individuals from 82 families with suspected alterations in the CASR gene, one of the largest series described.
The CASR gene was screened for mutations by polymerase chain reaction followed by direct Sanger sequencing.
Presumed CaSR-inactivating mutations were found in 65 patients from 26 families. These patients had hypercalcemia (median: 11.3 mg/dL) but normal or abnormally high parathyroid hormone (PTH) levels (median: 52 pg/mL). On the other hand, presumed CaSR-activating mutations were detected in 17 patients from eight families. These patients had a median serum calcium level of 7.4 mg/dL and hypoparathyroidism (median: PTH 13 pg/mL). Further, common polymorphisms previously associated with high blood ionized calcium levels were found in 27 patients (median calcium: 10.6 mg/dL; median PTH: 65 pg/mL) with no other alterations in CASR. Overall, we found 30 different mutations, of which, 14 have not been previously reported (p.Ala26Ser, p.Cys60Arg, p.Lys119Ile, p.Leu123Met, p.Glu133Val, p.Gly222Glu, p.Phe351Ile, p.Cys542Tyr, p.Cys546Gly, p.Cys677Tyr, p.Ile816Val, p.Ala887Asp, p.Glu934*, p.Pro935_Gln945dup).
Patients with CASR mutations may not fit the classic clinical pictures of hypercalcemia with hypocalciuria or hypocalcemia with hypercalciuria. Molecular studies are important for confirming the diagnosis and distinguishing it from other entities. Our genetic analysis confirmed CaSR disorders in 82 patients in the study cohort.