Hypothyroidism, Congenital, Nongoitrous, 1

A number sign (#) is used with this entry because of evidence that congenital nongoitrous hypothyroidism-1 (CHNG1) is caused by homozygous or compound heterozygous mutation in the gene encoding the thyroid-stimulating hormone receptor (TSHR; 603372) on chromosome 14q31.

Description

Resistance to thyroid-stimulating hormone (TSH; see 188540), a hallmark of congenital nongoitrous hypothyroidism, causes increased levels of plasma TSH and low levels of thyroid hormone. Only a subset of patients develop frank hypothyroidism; the remainder are euthyroid and asymptomatic (so-called compensated hypothyroidism) and are usually detected by neonatal screening programs (Paschke and Ludgate, 1997).

Genetic Heterogeneity of Congenital Nongoitrous Hypothyroidism

Also see CHNG2 (218700), caused by mutation in the PAX8 gene (167415) on chromosome 2q14; CHNG3 (609893), mapped to chromosome 15q25.3; CHNG4 (275100), caused by mutation in the TSHB gene (188540) on chromosome 1p13; CHNG5 (225250), caused by mutation in the NKX2-5 gene (600584) on chromosome 5q35; CHNG6 (614450), caused by mutation in the THRA gene (190120) on chromosome 17q21; and CHNG7 (618573), caused by mutation in the TRHR gene (188545) on chromosome 8q24.

Clinical Features

Stanbury et al. (1968) described an 8-year-old boy with congenital hypothyroidism who was the offspring of parents related as first cousins once removed. He showed high serum levels of biologically active thyrotropin but no response to thyrotropin in vivo or in thyroid tissue slices in vitro. The findings suggested end-organ unresponsiveness.

Medeiros-Neto et al. (1979) reported a 19-year-old man with congenital hypothyroidism with thyroglobulin deficiency and high levels of plasma TSH. No antibodies against thyroid antigens were found. Studies of thyroid biopsy tissue showed no formation of cAMP after stimulation with TSH, although the patient's TSH was biologically active in normal tissue samples.

Codaccioni et al. (1980) described a similar case in a 17-year-old male born of consanguineous parents. Plasma thyroid hormone levels were very low and TSH concentrations very high. Uptake of (131)I by the thyroid was not stimulated by TSH, but was increased by an intravenous injection of dibutyryl cyclic AMP. Codaccioni et al. (1980) found normal binding of TSH to thyroid cell membranes, and concluded that the defect lay somewhere between the receptor binding site and the receptor-cyclase binding protein. The authors noted that resistance to TSH as well as to other pituitary trophic hormones is observed in some cases of pseudohypoparathyroidism (Marx et al., 1971). In some instances, infantile hypothyroidism is the initial manifestation of pseudohypoparathyroidism (Levine et al., 1985).

Saldanha and Toledo (1988) reviewed reported cases of inherited hypothyroidism due to unresponsiveness to thyrotropin; none had goiter, a feature distinguishing this disorder from the inborn errors of thyroxine biosynthesis.

Takamatsu et al. (1993) described congenital hypothyroidism due to unresponsiveness to TSH in a brother and sister, aged 29 and 26 years, respectively. Congenital hypothyroidism was discovered at ages 5 and 2 years. The parents were first cousins. Takamatsu et al. (1993) claimed that unresponsiveness to TSH had been identified and sufficiently studied in only 3 patients and that theirs was the first documentation of familial occurrence.

Sunthornthepvarakul et al. (1995) reported 3 sibs who were euthyroid and had normal concentrations of thyroid hormone, but increased plasma thyrotropin (approximately 20-fold elevation), a situation referred to as partial thyrotropin resistance or compensated hypothyroidism. The proband was ascertained by a neonatal screening program; the abnormality was demonstrated at birth in 2 of the 3 sibs. The persistence of the high serum thyrotropin concentrations was not compatible with transient infantile hyperthyrotropinemia, a normal variant. None of the sibs had symptoms or signs of hypothyroidism at any time. The persistent hyperthyrotropinemia in the 3 sibs suggested that the disorder was inherited, and the parents showed borderline elevation of serum thyrotropin concentrations. There was no parental consanguinity; the parents were of different ethnic extraction. The normal growth and development of the eldest girl, who did not receive thyroid hormone until the age of 5 years, suggested that her increased thyrotropin secretion was not due to primary hypothyroidism. Sunthornthepvarakul et al. (1995) concluded that the elevated TSH levels were required to maintain normal thyroid hormone secretion by cells expressing the mutant TSH receptor.

Kempers et al. (2009) examined the body surface of 242 Dutch patients with congenital hypothyroidism (CH) of thyroidal origin with thyroid agenesis, an ectopic thyroid rudiment, or eutopic thyroid gland, for visually detectable morphologic abnormalities. The percentage of patients with 1 or more major anomalies in the total CH cohort (33%) and in patients with ectopic thyroid (37.2%) was significantly higher than in 1,007 Dutch controls (21.8%; p less than 0.001), and specific major malformations such as bilateral ear pits and oligodontia were more frequent in the group of patients with ectopic thyroid. In addition, the percentage of patients in the congenital hypothyroidism cohort with 1 or more minor anomalies (96.3%) was significantly higher than in the control group (82.5%; p less than 0.001).

Diagnosis

Takeshita et al. (1994) made the diagnosis of TSH unresponsiveness in 3 patients based on the following criteria: (1) congenital primary hypothyroidism with autosomal recessive inheritance; (2) a nongoitrous thyroid gland in a normal position with low thyroidal radioactive iodine uptake; (3) normal in vitro TSH bioactivity or absent in vivo response to exogenous TSH; and (4) absence of thyroid autoantibodies.

Mapping

Genetic Heterogeneity

Some cases of thyrotropin resistance may not be due to mutation in the TSHR gene on chromosome 14. Ahlbom et al. (1997) investigated 10 Swedish families, each with 2 cases of congenital hypothyroidism, 11 affected families from Pakistan, and 1 affected family each from Syria and Egypt. They mapped the TSHR gene on radiation panels and identified 2 flanking DNA markers which were analyzed for linkage analysis. Assuming homogeneity, the 2-point lod score at theta = 0.1 was -4.8 for one marker and -5.8 for the second, thus excluding linkage to TSHR. Even when the data were analyzed with allowance for heterogeneity, there was no evidence of linkage to the TSHR gene. Ahlbom et al. (1997) concluded that if mutation of the TSHR gene causes familial congenital hypothyroidism in humans, it affects only a small proportion of cases.

Associations Pending Confirmation

Carre et al. (2007) analyzed alanine tract length in the FOXE1 gene (602617) in 115 patients with thyroid dysgenesis and 129 controls and found suggestive evidence that FOXE1 alanine tract length modulates genetic susceptibility to thyroid dysgenesis.

Denny et al. (2011) performed a genomewide association study of 1,317 cases of primary hypothyroidism and 5,053 controls that had been identified by electronic selection algorithms of medical records. Four SNPs at chromosome 9q22 near the FOXE1 gene were associated with hypothyroidism at genomewide significance, with the strongest association at rs7850258 (OR, 0.74; p = 3.96 x 10(-9)). A phenomewide association study performed on this locus identified associations with additional thyroid-related phenotypes: thyroiditis (OR, 0.58; p = 1.4 x 10(-5)), nodular goiter (OR, 0.76; p = 3.1 x 10(-5)), multinodular goiter (OR, 0.69; p = 3.9 x 10(-5)), and thyrotoxicosis (OR, 0.76; p = 1.5 x 10(-3)). Graves disease and thyroid cancer, however, were not significantly associated with the locus in the phenomewide study.

Molecular Genetics

In 3 sibs with normal serum thyroid hormone concentrations but high serum thyrotropin concentrations ('compensated hypothyroidism'), Sunthornthepvarakul et al. (1995) identified compound heterozygosity for 2 mutations in the TSHR gene (603372.0005; 603372.0006). Sunthornthepvarakul et al. (1995) concluded that the elevated TSH levels were required to maintain normal thyroid hormone secretion by cells expressing the mutant TSH receptor.

De Roux et al. (1996) studied 4 unrelated French patients with congenital hypothyroidism found on neonatal screening in whom they identified loss-of-function mutations in the TSHR gene. One patient was homozygous, and 3 others were compound heterozygous (see 603372.0006; 603372.0010-603372.0015). The patients showed 'partial thyrotropin resistance' with increased plasma TSH concentration and normal T3 and T4 concentrations. TSH levels were normal in the heterozygous parents.

In a child with congenital hypothyroidism associated found on neonatal screening who had markedly increased serum TSH concentrations and low normal thyroid hormone levels, Clifton-Bligh et al. (1997) identified compound heterozygosity for 2 mutations in the TSHR gene (603372.0009; 603372.0010).

In a brother and sister, born of consanguineous parents, with congenital nonautoimmune hypothyroidism, Abramowicz et al. (1997) identified a homozygous mutation in the TSHR gene (603372.0016). The mutation was heterozygous in both parents and 2 unaffected sibs. The patients were initially diagnosed with thyroid agenesis, but cervical ultrasonography in both patients revealed a very hypoplastic thyroid gland.

In a child with congenital hypothyroidism associated with a reduced gland volume, Biebermann et al. (1997) identified compound heterozygosity for 2 mutations in the TSHR gene (603372.0015; 603372.0018).

De Felice and Di Lauro (2004) reviewed the development of the thyroid gland and the genetic molecular mechanisms leading to thyroid dysgenesis.

Park and Chatterjee (2005) reviewed the genetics of primary congenital hypothyroidism, summarizing the different phenotypes associated with known genetic defects and proposing an algorithm for investigating the genetic basis of the disorder.

Genetic Heterogeneity

Takeshita et al. (1994) analyzed the nucleotide sequence of the entire coding region of the TSHR gene in 3 patients with this disorder. The TSHR cDNA was obtained from RNA of peripheral mononuclear leukocytes with reverse transcription and PCR, and was sequenced directly. Comparison of these nucleotide sequences with the normal TSHR sequence revealed no difference in the predicted amino acid sequence.

Xie et al. (1997) studied 3 unrelated families with resistance to TSH that followed a dominant rather than a recessive pattern of inheritance in 2 families and was not associated with TSHR gene abnormalities. TSHR gene abnormalities were excluded by sequencing all coding sequences, exon/intron junctions, and the promoter region of the gene. In addition, linkage analysis using intragenic polymorphic markers demonstrated that the TSHR gene did not cosegregate with the disease phenotype in 2 families. Xie et al. (1997) excluded defects in the TSH-beta subunit (188540) by DNA sequencing and by showing that circulating TSH in affected subjects from all families had normal bioactivity. Also, no abnormalities were found in the Gs-alpha gene (GNAS1; 139320) of one family analyzed by GC-clamped denaturing gradient gel electrophoresis (DGGE). The authors concluded that resistance to TSH may be a manifestation of several different genetic defects that requires the exploration of other candidate genes involved in the TSH/TSHR/Gs-alpha cascade and genes participating in its regulation.

Animal Model

The 'hyt' mouse is a model for autosomal recessive congenital hypothyroidism (Beamer et al., 1981). The phenotype of the mutant mouse is very similar to that of human congenital hypothyroidism. Stein et al. (1994) demonstrated a mutation in the Tshr gene as the cause of the disease in the hyt mouse.