Increased Prevalence of Renal and Urinary Tract Anomalies in Children with Congenital Hypothyroidism

Congenital malformations are the leading cause of infant mortality in the United States.1 Congenital hypothyroidism is the most common congenital endocrine disorder, affecting 1 in 3000 to 4000 newborns.2 Its incidence has increased 138% from 1978 to 2005 in New York State and 73% in the US from 1987 to 2002.3 Nearly all newborns are routinely screened for congenital hypothyroidism at birth in the United States.4 Thyroid dysgenesis is responsible for about 85% of cases of congenital hypothyroidism; dyshormonogenesis accounts for the remaining cases.5 Congenital hypothyroidism is associated with increased prevalence of congenital malformations.6-11 There are case reports of children with congenital hypothyroidism having defects in the development of the renal and urogenital systems.12-14 However, there are no studies specifically examining prevalence of congenital renal and urologic anomalies in the congenital hypothyroidism population. Congenital renal and urologic anomalies are the most common cause of end-stage kidney disease in children, accounting for almost 50% of the cases.15 Most children with congenital hypothyroidism are not routinely screened for the presence of congenital renal and urologic malformations. Recently, mutations in PAX 8, TITF1, or FOXE1 genes have been associated with congenital hypothyroidism in patients with either isolated thyroid dysplasia or thyroid dysplasia with associated malformations involving kidney, lung, forebrain, and palate.16-20 PAX 8 is expressed in the developing central nervous system and kidney, including the ureteric bud, mesonephric ducts, and the main collecting ducts.17 PAX 2 and PAX 8 transcription factors are central regulators of kidney development. In mouse pronephros and mesonephros, they are found in both the mesenchymal primordium and the epithelial components. PAX 8 expression starts at the renal vesicle stage and is maintained until the end of nephron differentiation. PAX 2 and PAX 8 genes are necessary and sufficient to induce the nephric lineage. Embryos that are mutant for both genes fail to generate the nephric (Wolffian) duct and subsequently all 3 embryonic kidneys are defective.20,21 We hypothesized that children with congenital hypothyroidism have an increased prevalence of congenital renal and urologic anomalies. Our objective was to compare the prevalence of renal and urinary tract anomalies in children with and without congenital hypothyroidism and to determine whether renal ultrasound scanning would be beneficial in management of children with congenital hypothyroidism.