Hypothyroidism, Central, With Testicular Enlargement

A number sign (#) is used with this entry because of evidence that central hypothyroidism with or without testicular enlargement (CHTE) is caused by mutation in the IGSF1 gene (300137) on chromosome Xq26.

Description

Central hypothyroidism and testicular enlargement (CHTE) is characterized by central hypothyroidism, delayed pubertal testosterone rise, adult macroorchidism, variable prolactin deficiency, and occasional transient partial GH deficiency. Some carrier females also exhibit central hypothyroidism and mild prolactin deficiency. Inter- and intrafamilial variability has been observed (Joustra et al., 2016).

Clinical Features

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 was also found to have central hypothyroidism, as well as partial growth hormone (GH; 139250) deficiency and low prolactin (PRL; 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 with mutation in the IGSF1 gene. 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. The authors noted that central hypothyroidism was also present in 5 of 20 heterozygous female carriers.

Joustra et al. (2013) reported follow-up evaluation of 24 male patients from 10 families with IGSF1-associated central hypothyroidism previously studied by Sun et al. (2012), as well as 18 heterozygous female relatives. All male patients had central hypothyroidism and macroorchidism, 16 (67%) had hypoprolactinemia, and 3 (13%) had transient partial GH deficiency. Disharmonious pubertal delay was observed in all 8 male patients who were diagnosed in childhood, with delay of pubertal testosterone production, growth spurt, and pubic hair development, whereas testicular enlargement began at a normal age and continued into adulthood. Among the heterozygous female carriers, 6 (33%) had central hypothyroidism and 2 (11%) had hypoprolactinemia; none had GH deficiency. Body mass index (BMI), percent fat, and waist circumference tended to be elevated in male patients as well as in female carriers. The authors designated this disorder 'IGFS1 deficiency syndrome.'

Joustra et al. (2016) reviewed the clinical and biochemical characteristics of patients and female carriers from the 10 families with IGSF1-associated central hypothyroidism previously reported by Joustra et al. (2013) as well as from 20 newly ascertained unrelated families, for a total of 69 affected males and 56 female carriers. Central hypothyroidism was present in all hemizygous males. Growth velocity was usually decreased and bone age delayed; GH deficiency in childhood was noted in 11 (16%) patients. Transient neonatal hypocortisolism was present in 6 (21%) of 28 male newborns for whom data was available, resolving within a few years in all. Pubertal rise in testosterone was often delayed, in contrast to a normal or even advanced start of testicular growth, with macroorchidism present in 88% of adult males. Prolonged jaundice and sometimes dyslipidemia were observed in untreated children. Waist circumference was increased in 60% of male patients, but blood lipids were normal. In adult males, a marker of liver hypothyroidism, sex hormone-binding globulin (SHBG; 182205), was significantly correlated to FT4 levels after correction for BMI, implying suboptimal thyroid hormone exposure in untreated individuals. Female carriers showed low (18%) or low-normal (60%) FT4; no evident relationship with X-chromosome inactivation was observed. Although delayed age at menarche was present in 31% and mild prolactin deficiency in 22%, there were no reported problems with fertility. Increased waist circumference was also present in 57% of carriers, and there was a negative correlation between FT4 levels and metabolic parameters. The authors observed no clear genotype/phenotype relationship associated with any of the features in these patients, and noted that signs and symptoms varied within families among patients with the same mutation. Joustra et al. (2016) stated that mutation in IGSF1 represents the most common genetic cause of central hypothyroidism.

Tenenbaum-Rakover et al. (2016) reported 3 brothers, born of unrelated Ashkenazi Jewish parents, as well as a maternal uncle, who had central hypothyroidism and a mutation in the IGSF1 gene. Hypoprolactinemia was present in 1 of the brothers and in the uncle. All 4 had normal growth patterns, and the adult male was within the normal range for adult height. The 3 brothers were prepubertal, with normal testicular volumes at ages 8 years, 5 years, and 10 months; their 27-year-old uncle exhibited macroorchidism. All 4 affected males showed subtle neurologic symptoms, including hypotonia, delayed motor development, speech problems, attention-deficit disorder, and clumsiness. Another maternal uncle was diagnosed with hypothyroidism at age 3 months, but never treated. He had significant psychomotor delay in infancy and clumsiness as well as speech problems in adulthood, but he declined to participate in the study. The brothers had 2 sisters with normal psychomotor development and normal thyroid function, and their parents were both healthy and had normal thyroid function tests.

Roche et al. (2018) studied a 3-generation Irish family with IGSF1-associated central hypothyroidism in which there were 10 affected males and 11 carrier females. All hemizygous males had mild or moderate central hypothyroidism. Neonatal jaundice, delayed speech or growth, and obesity were observed in 7 patients in whom diagnosis was delayed. The authors observed variable 'physiologic penetrance,' in which the patient with the lowest FT4 level appeared to be physiologically euthyroid, whereas other patients with biochemically milder disease exhibited features consistent with tissue hypothyroidism, including growth impairment and weight gain. The authors also noted normal or 'exuberant' TSH responses to TRH testing in hemizygotes from the Irish family, in contrast to previous reports of subnormal or low-normal responses in patients with IGSF1-associated hypothyroidism. Low or borderline prolactin was present in 5 patients; 1 patient had growth hormone deficiency, and another had insufficient GH concentrations on stimulation testing, with normal IGF1 and growth velocity. Testicular ultrasound was performed in 1 adult hemizygous male and confirmed macroorchidism. Only 1 of 11 heterozygous females showed central hypothyroidism, although the majority of heterozygotes had FT4 levels in the lower third of the reference range.

Cytogenetics

Hughes et al. (2016) studied a 5-generation family in which 10 males exhibited central hypothyroidism, including 1 in whom it was very mild and not clinically manifest. In the 4 patients for whom measurements were available, testis volumes were normal at ages 16, 20, 21, and 24 years. Prolactin deficiency was present in 6 of 7 patients tested, with the seventh being 'borderline;' fertility was not compromised. Growth hormone deficiency was identified in 4 of 8 patients tested. Pituitary function was normal in 4 of 5 obligate carrier females tested; the fifth showed mild central hypothyroidism as well as very low levels of IGFBP3 (146732) and borderline IGF1 (147440), suggestive of GH deficiency. The authors stated that the absence of macroorchidism in affected males from this family suggested that testis enlargement might be caused by an IGSF1-associated primary defect in the testis rather than abnormal hormone levels. In 7 of the male patients and 2 of the obligate carrier females, Hughes et al. (2016) identified a 42-kb deletion encompassing the entire IGSF1 gene and flanking regions.

Molecular Genetics

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.

In an Ashkenazi Jewish boy with central hypothyroidism who was negative for mutation in the TRH (613879), TRHR (188545), and TSHB (188540) genes, Tenenbaum-Rakover et al. (2016) performed whole-exome sequencing and identified a 1-bp insertion in the IGSF1 gene (300137.0006). Sanger sequencing confirmed hemizygosity for the mutation in his 2 affected brothers and an affected maternal uncle who also exhibited macroorchidism. His mother, maternal grandmother, and a sister were heterozygous for the mutation. Of the 3 carriers, only the maternal grandmother had hypothyroidism, which was acquired after treatment of toxic multinodular goiter by radioactive iodine. The authors noted that the presence of subtle neurologic symptoms in all 4 affected males suggested an association between IGSF1 mutation and neurologic phenotypes.

In 10 males and 11 females from a 3-generation Irish family with central hypothyroidism, Roche et al. (2018) screened the IGSF1 gene and identified hemizygosity or heterozygosity, respectively, for a missense mutation in the IGSF1 gene (L773P; 300137.0007). Only 1 of the 11 heterozygous females showed central hypothyroidism. One of the adult male patients underwent testicular ultrasound, which confirmed macroorchidism.