Background: Although multiple imprinting defects have been found by genetic analysis in a subset of patients with BeckwithWiedemann Syndrome (BWS), very few patients have been described with both genetic and clinical signs and symptoms of multiple diseases caused by imprinting defects.
Methods: Methylation analysis of the KCNQ1OT1 gene was performed by Southern blot, methylation analysis of the GNAS region was done by MLPA.
Case report: A girl presented at the age of 6 months with morbid obesity (BMI +7.5 SDS) and a large umbilical hernia. Genetic analysis showed hypomethylation of the KCNQ1OT1 gene, consistent with BWS. She had no signs of Albright hereditary osteodystrophy (AHO) and calcium homeostasis was normal (Ca. 2.75 mmol/l, P 1.99 mmol/l, and PTH 5.6 pmol/l).
At the age of 10 years she presented with fatigue. Laboratory analyses showed marked hypocalcemia with signs of PTH resistance (high PTH, high phosphate, low urine phosphate, and normal alkaline phosphatase). The clinical picture of PTH resistance in a patient without AHO and with a known imprinting defect was suggestive of Pseudohypoparathyroidism Type 1B (PHP1B) due to defective imprinting of the GNAS region. Methylation analysis of the GNAS complex revealed hypomethylation (<20%) of the GNAS exon 1A, NESPAS and GNASXL loci and 100% methylation of NESP locus, consistent with the clinical diagnosis of PHP1B.
Conclusion: This unique patient shows that multiple imprinting defects can cause multiple diseases in patients. Furthermore, symptoms of PHP1B may be absent at diagnosis. As prolonged subclinical hypocalcemia can have negative consequences (intracerebral calcifications, cardiomyopathy, etc.), on should be aware of multiple imprinting defects, especially PHP1B, in patients with BWS.
20 - 22 Sep 2014
European Society for Paediatric Endocrinology