Hypothyroidism, Congenital, Nongoitrous, 7

A number sign (#) is used with this entry because of evidence that nongoitrous congenital hypothyroidism-7 (CHNG7) is caused by homozygous or compound heterozygous mutation in the TRHR gene (188545) on chromosome 8q23.

Description

Nongoitrous congenital hypothyroidism-7 (CHNG7) is characterized by normal-to-low T4 and normal-to-high thyrotropin (TSH; see 188540) levels, with reduced or absent pituitary responsiveness to thyrotropin-releasing hormone (TRH; 613879). Patients may exhibit short stature, growth retardation, and delayed bone age, as well as lethargy or fatigue (Collu et al., 1997; Bonomi et al., 2009).

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

Clinical Features

Collu et al. (1997) studied a 12.5-year-old boy who presented at age 9 years with short stature. He had low heart rate and delayed bone age, and laboratory evaluation showed low T4 with normal TSH level. Neonatal screening had also shown a low T4 level, but because of a normal TSH value, he was not recalled for further study at that time. Intravenous TRH failed to elicit a rise in TSH and prolactin (PRL; 176760) levels, and brain CT showed a normal pituitary. He was diagnosed with central hypothyroidism and treated with replacement therapy; reevaluation at age 12 confirmed the pituitary unresponsiveness to TRH.

Bonomi et al. (2009) reported a brother and sister with hypothyroidism and complete resistance to TRH, who were homozygous for a nonsense mutation in the TRHR gene. The 30-year-old brother presented at age 11 years with short stature, delayed bone age, lethargy, and fatigue, and he was diagnosed with idiopathic isolated hypothyroidism. His 33-year-old sister, who reported no symptoms and had been considered unaffected, noted substantial improvement in physical and mental activities after receiving thyroxine-replacement therapy. The authors observed that during thyroxine withdrawal, the proband's endogenous thyroid hormone levels had increased at 60 days, indicating some circulating thyrotropin bioactivity; this, coupled with conserved rhythmic pituitary secretions in the proband, suggested that non-TRH signals influencing pituitary function might contribute to this condition. Furthermore, the proband's sister had delivered 2 sons to term and breast-fed both of them, suggesting that TRHR is not essential for female fertility and lactation. Bonomi et al. (2009) concluded that TRH action is not required for breast and pituitary development in humans, nor is it required for expression of the TSH-beta gene (188540) or the PRL gene.

Koulouri et al. (2016) described a 4-year-old Pakistani girl, born of first-cousin parents, who presented with neonatal jaundice that resolved spontaneously. Endocrine evaluation showed normal TSH but low T4, with otherwise normal basal pituitary function and unremarkable pituitary structure on MRI. She had normal growth and neurologic development on replacement therapy. Her mother and brother were euthyroid; her father declined investigation. The authors suggested that T4 measurement should be added to neonatal screening programs for congenital hypothyroidism.

Garcia et al. (2017) reported a consanguineous Spanish Roma family in which the 10-year-old male proband was initially referred for evaluation at age 8 years due to abnormal thyroid function tests in a routine check-up. Although he was asymptomatic, T4 levels were consistently low and TSH was normal or elevated over 4 years of laboratory evaluation. He had a normal TSH response to TRH, and imaging showed normal size and structure of the pituitary and thyroid glands. Reevaluation at age 10 years confirmed normal TSH and PRL responses to TRH stimulation. Evaluation of family members over time showed intermittent elevation of TSH in 2 brothers and the paternal grandmother; the mother was treated with levothyroxine during pregnancy for a slightly elevated TSH, and the maternal grandmother was reported to have had hypothyroidism in her youth.

Molecular Genetics

In a 12.5-year-old boy with isolated central hypothyroidism, Collu et al. (1997) identified compound heterozygosity for mutations in the TRHR gene (188545.0001 and 188545.0002). Mutated receptors were unable to bind TRH or to activate total inositol phosphate accumulation.

In a brother and sister with hypothyroidism and complete resistance to TRH, Bonomi et al. (2009) identified homozygosity for a nonsense mutation in the TRHR gene (R17X; 188545.0003). Their unaffected parents, who were not known to be consanguineous but whose families originated from the same Alpine village, were heterozygous for the mutation.

In a 4-year-old Pakistani girl with congenital hypothyroidism, Koulouri et al. (2016) identified homozygosity for a missense mutation in the TRHR gene (P81R; 188545.0004). Her unaffected mother was heterozygous for the mutation; her father declined evaluation.

In the 10-year-old proband from a consanguineous Spanish Roma family with central hypothyroidism, Garcia et al. (2017) directly sequenced 4 central hypothyroidism-associated genes and identified homozygosity for a missense mutation in the TRHR gene (I131T; 188545.0005). A younger brother, who showed elevated TSH with normal T4 at age 5 years, and normal TSH and T4 on evaluations at ages 7 and 7.5 years, was also homozygous for the variant. Six family members, including their parents, the paternal grandmother, a sister, and 2 brothers were heterozygous for I131T; the paternal grandmother and the 2 brothers showed intermittently elevated TSH with normal T4, whereas the father and sister showed normal TSH and T4 on 2 and 3 evaluations, respectively, and the mother showed an elevated TSH during pregnancy that resolved postpartum. Functional analysis revealed that the I131T mutant receptor has reduced TRH affinity and an increased half-maximal effective concentration for signaling compared to wildtype, but normal responses to high concentrations of TRH. The authors suggested that this might account for the milder phenotype of hypothyroidism in the family compared to previously reported patients.