Sun et al. (2012) studied a Dutch family in which the proband was diagnosed with central hypothyroidism by neonatal screening. A male cousin was referred for growth failure at 7.3 years of age and also found to have ... Sun et al. (2012) studied a Dutch family in which the proband was diagnosed with central hypothyroidism by neonatal screening. A male cousin was referred for growth failure at 7.3 years of age and also found to have central hypothyroidism, as well as partial growth hormone (GH; 139250) deficiency, and low prolactin (176760) concentration. In early adolescence, both boys initially had normal progression of testicular growth, but their testes subsequently grew beyond the reference range for testis volume. However, their serum testosterone concentrations remained inappropriately low for testicular size until ages 15 and 14 years, respectively, causing a late growth spurt and delayed pubic hair development. Their maternal grandfather and another male relative were later also found to have central hypothyroidism and enlarged testicles. Additional families with male-specific central hypothyroidism and testicular enlargement were subsequently identified genetically (see MOLECULAR GENETICS). Sun et al. (2012) observed considerable differences in the extent of hypothyroidism within families, with some older patients diagnosed only after genetic screening. Testicular development showed a characteristic pattern involving normal testicular volume in childhood; increase in testicular volume from approximately 11 years of age onward, while serum testosterone was still low; relatively large testes for serum testosterone levels in adolescence; and macroorchidism in adulthood. In 10 of 11 cases for which data were available, there was delayed testosterone production or delayed pubertal growth spurt. Serum prolactin concentrations were decreased in 18 of 26 cases, and 4 patients showed growth retardation in childhood associated with GH insufficiency. Three of 11 patients who underwent MRI had abnormal findings, showing a frontoparietal hygroma, hypoplasia of the corpus callosum, and a small stalk lesion, respectively; however, in the remaining 8 patients, MRIs were normal. At the most recent evaluation of the cohort, mean height was close to population references, but BMI was increased in 11 of 13 adults and 5 of 13 children. Plasma testosterone levels were normal in most cases.
In 2 Dutch cousins with central hypothyroidism and testicular enlargement, Sun et al. (2012) performed X-chromosome exome sequencing and identified a 27-bp deletion in the IGSF1 gene (300137.0001). The mutation was also identified in their maternal grandfather and ... In 2 Dutch cousins with central hypothyroidism and testicular enlargement, Sun et al. (2012) performed X-chromosome exome sequencing and identified a 27-bp deletion in the IGSF1 gene (300137.0001). The mutation was also identified in their maternal grandfather and another affected male relative. Independent whole-exome sequencing in 2 brothers from a British family with central hypothyroidism revealed a nonsense mutation in IGSF1 (300137.0002); their maternal uncle and a more distant male relative, who both had central hypothyroidism and enlarged testicles, also carried the mutation. Subsequent screening of all male patients with central hypothyroidism of unknown genetic origin in Leiden, Amsterdam, Rotterdam, and Milan identified mutations in the IGSF1 gene in 9 additional families with male-specific central hypothyroidism and testicular enlargement (see, e.g., 300137.0003-300137.0005), including 2 families with complete IGSF1 deletion.