Isolated central hypothyroidism in young siblings as a manifestation of PROP1 deficiency: clinical impact of whole exome sequencing.

BACKGROUND/AIMS Central hypothyroidism (CH) in children is rare and may be due to a variety of genetic defects. Most of these defects, but not all, are associated with additional pituitary hormone deficits. In a young child presenting with CH, it is important to determine whether additional pituitary hormone deficiencies are present, but this may be difficult to establish clinically. METHODS We describe the clinical characteristics of two young siblings, aged 6 months and 2 years, presenting with isolated CH. Whole exome sequencing was performed to determine the genetic basis of isolated CH. RESULTS A homozygous frameshift mutation of PROP1 (296delGA) was identified in both probands. Defects in PROP1 cause progressive deficiency of multiple pituitary hormones. Based on this genetic diagnosis, further clinical testing was performed that demonstrated growth hormone deficiency in one sibling. CONCLUSIONS PROP1 deficiency may present as isolated CH at a very young age. In disorders with multiple potential causative genes, whole exome sequencing may facilitate rapid genetic diagnosis and lead to important changes in clinical management.