Hypothyroidism, Congenital, Nongoitrous, 4

A number sign (#) is used with this entry because of evidence that congenital nongoitrous hypothyroidism-4 (CHNG4) is caused by homozygous mutation in the TSHB gene (188540) on chromosome 1p13.

For a general phenotypic description and a discussion of genetic heterogeneity of congenital nongoitrous hypothyroidism, see 275200.

Clinical Features

The first familial incidence of isolated thyrotropin deficiency was reported by Miyai et al. (1971), who observed 2 affected sisters. Synthetic thyrotropin-releasing hormone (TRH) resulted in no rise in serum TSH levels. (Thyrotropin is more generally known as TSH (thyroid-stimulating hormone).) The parents were second cousins. A male sib, who died at age 3 years, may also have been affected.

TSH deficiency has been described (Zisman et al., 1969) in patients with pseudohypoparathyroidism (see 103580), but the defect resides in the receptor or response mechanism. The use of TRH produced by the hypothalamus reveals the existence of isolated hypothalamic hypothyroidism (275120) otherwise indistinguishable from TSH deficiency (Pittman et al., 1971).

Kohno et al. (1980) reported a family in which 2 sisters had pituitary hypothyroidism. Similarities to the cases of Miyai et al. (1971) included Japanese race, female sex, second-cousin parentage, and severe hypothyroidism in the neonatal period. Serum TSH did not increase with administration of TRH.

Nygren and Rojdmark (1982) described a patient with isolated thyrotropin deficiency unresponsive to prolonged treatment with thyrotropin-releasing hormone. The patient had narcolepsy. They granted that the defect might be in the responsiveness of pituitary cells rather than in the production of TSH.

Molecular Genetics

In 2 sisters with isolated TSH deficiency, born of consanguineous parents, Hayashizaki et al. (1989) found homozygosity for a missense mutation (G29R; 188540.0001) in the TSHB gene.

In affected members of 2 related Greek families with congenital TSH-deficient hypothyroidism, Dacou-Voutetakis et al. (1990) demonstrated homozygosity for a nonsense mutation (E12X; 188540.0002) in the TSHB gene. The 4 parents and 2 unaffected children were heterozygous for the mutation.

Medeiros-Neto et al. (1996) described 2 related consanguineous Brazilian sibships in which 4 children had congenital nongoitrous hypothyroidism due to homozygosity for a 1-bp deletion (313delT; 188540.0003) in the TSHB gene, resulting in a circulating form of biologically inactive TSH. Five unaffected family members were heterozygous for the deletion.

In a 5-month-old female infant with severe congenital nongoitrous hypothyroidism and undetectable TSH levels, born of unrelated parents of German ancestry, Doeker et al. (1998) identified homozygosity for the 313delT mutation in the TSHB gene.

Brumm et al. (2002) stated that the most frequent mutation in the TSHB gene, 313delT, had been described in 6 apparently unrelated families. To investigate the frequency and possible monophyletic origin of 313delT alleles, they performed haplotype analysis in 3 German families with the mutation; their results suggested a monophyletic origin of the mutation from a common ancestor, with no significant population prevalence.

In an Egyptian girl with congenital hypothyroidism and a hypoplastic thyroid, who was born of first-cousin parents, Bonomi et al. (2001) identified homozygosity for a nonsense mutation (Q49X; 188540.0004) in the TSHB gene. The patient had a hyperplastic-appearing pituitary gland on MRI in infancy, but a CT scan at age 7 showed complete normalization. The authors noted that in this patient TSH values were highly variable depending on the measurement method used, because although the mutant Q49X TSHB is completely devoid of bioactivity, it forms with the alpha-subunit a heterodimer with preserved immunoreactivity in some TSH measurement methods. Bonomi et al. (2001) concluded that high circulating free glycoprotein alpha-subunit levels, variable TSH levels, and possibly hyperplastic pituitary gland are hallmarks of isolated central hypothyroidism due to mutations of the TSHB gene.

Vuissoz et al. (2001) reported a brother and sister from a consanguineous Turkish kindred with congenital nongoitrous hypothyroidism who were homozygous for the Q49X mutation in the TSHB gene.

In a 4-month-old girl with congenital nongoitrous hypothyroidism, born of consanguineous parents, Pohlenz et al. (2002) identified homozygosity for a splice site mutation (IVS2+5G-A; 188540.0005) in the TSHB gene. Her parents and an unaffected older brother were heterozygous for the mutation.

Borck et al. (2004) identified homozygosity for the IVS2+5G-A splice site mutation in 4 children with congenital hypothyroidism from 2 consanguineous Turkish families. By genotyping members of their 2 families and the family reported by Pohlenz et al. (2002) for polymorphic markers at the TSHB locus, Borck et al. (2004) demonstrated that the mutation arose on a common ancestral haplotype in these 3 unrelated Turkish families, indicating a founder mutation.