An Argument for Application of Whole Exome Sequencing in Puzzling Endocrine Cases

Presentation Number: SAT-0759
Date of Presentation: June 21st, 2014

Hebatullah M Ismail*1, Fernanda Delgado2, Catherine Pihoker1 and Anita E Beck1
1Department of Pediatrics, University of Washington, Seattle, WA, 2University of Washington School of Medicine, Seattle, WA


Background: Congenital isolated adrenocorticotrophic hormone deficiency (IAD) is a rare disorder that can be difficult to diagnose, and missed diagnosis may result in infant mortality. IAD is caused by homozygous or compound heterozygous TBX19 gene mutations. TBX19 mutations can be uncovered by whole exome sequencing (WES), a relatively new diagnostic tool, even if the diagnosis is not suspected in advance.
Clinical Case: We present a 24-month-old Hispanic child with a lifelong history of multiple endocrine abnormalities without a unifying diagnosis. He was a full term infant with a history of feeding difficulties and hyperbilirubinemia, referred to endocrinology for congenital hypothyroidism identified on the newborn screen. He had been started on levothyroxine at 1 week of age, and was seen at 4 weeks. Physical exam was notable for icteric sclera, and he was found to have conjugated hyperbilirubinemia. Subsequent evaluation revealed low cortisol, and he was started on hydrocortisone. During an acute illness he was hypoglycemic, at which time stress doses of hydrocortisone were administered. He also had low serum growth hormone and elevated insulin levels, therefore growth hormone and diazoxide were prescribed. A comprehensive clinical evaluation was insufficient to explain his clinical findings. However, a single nucleotide polymorphism (SNP) microarray demonstrated long stretches of homozygosity representing about 23% of his genome and raised concern for possible consanguinity with recessive disorders. Subsequent WES revealed a homozygous TBX19 mutation that partially explains his presentation and conditions. The hypothyroidism appears to be transient, and his levothyroxine has been since stopped; growth hormone therapy and diazoxide are gradually being discontinued.
Conclusions: We report on a perplexing case of congenital IAD and highlight the utility of WES to establish a molecular diagnosis in endocrine practice. The use of WES in endocrinology has led to other major advances and discoveries: germline mutations in patients with pheochromocytomas, a de novo heterozygous nonsense mutation in a gene encoding thyroid hormone receptor alpha, an inactivating mutation in KISS1, as well as novel mutations in the imprinted gene MKRN3 that causes central precocious puberty in humans. With more widespread availability and advances in technology, WES will continue to serve as a valuable tool in endocrine research and clinical practice.


Nothing to Disclose: HMI, FD, CP, AEB