Hypopituitarism in a Patient With Beckwith-Wiedemann Syndrome Due to Hypomethylation of KvDMR1

Abstract

Beckwith-Wiedemann syndrome (BWS) is caused by dysregulation of imprinted genes on chromosome 11.p15.5. The syndrome includes overgrowth, macroglossia, organomegaly, abdominal wall defects, hypoglycemia, and long-term malignancy risk. No patient who has BWS has been reported with hypopituitarism. We describe a patient who presented at birth with macrosomia, macroglossia, respiratory distress, jaundice, and hypoglycemia, and who was followed for 4.5 years. Genetic test for BWS was performed, which detected loss of maternal methylation on region KvDMR1 (11p15.5). The hypoglycemia was attributable to hyperinsulinism and was treated with diazoxide and chlorothiazide. She responded well, but the hypoglycemia returned after reducing the diazoxide. It was possible to stop the diazoxide after 2.5 years. On routine follow-up she was noted to be developing short stature. Baseline pituitary and growth hormone (GH) stimulation tests detected GH deficiency and secondary hypothyroidism. A brain MRI showed a small anterior pituitary gland. Thereafter, thyroxine and replacement therapy with GH were started, which resulted in a remarkable improvement in growth velocity. This is the first patient to be reported as having hypopituitarism and BWS. It is unclear if the BWS and the hypopituitarism are somehow connected; however, further investigations are necessary. Hypopituitarism explains the protracted hypoglycemia and the short stature. In our patient, GH therapy seems to be safe, but strict follow-up is required given the increased cancer risk related to BWS.

(Epi)genotype–phenotype correlations in Beckwith–Wiedemann syndrome: a paradigm for genomic medicine

“…A variety of minor findings have been described in BWS: polydactyly, genital abnormalities, supernumerary nipples, and cleft palate are more frequently observed in CDKN1C ‐mutated cases . Congenital hypothyroidism of variable etiology and hypopituitarism were also reported: recognition of these coexisting endocrine diseases may be difficult and overlooked as signs and symptoms may overlap with some BWS features. The rare occurrence of diaphragmatic hernia or major cardiac anomalies has relevant implications for prognosis and is important for perinatal management.…”

Severe hypothyroidism developing in an infant with hepatoblastoma and Beckwith-Wiedemann syndrome: could there be a link?

“…• Incidence of congenital hypothyroidism 1:3000 • Incidence of BWS 1:12000 to 1:13700 of live births 2 …”