Recent advances in research on isolated congenital central hypothyroidism

Congenital central hypothyroidism (C-CH) is defined as hypothyroidism due to a lack of stimulation of the normal thyroid gland (1, 2). C-CH is caused by anatomical or functional impairments in neurons that secrete hypothalamic-thyrotropin releasing hormone (TRH) and/or pituitary thyrotropes that secrete TSH. C-CH is more frequently recognized as a part of a combined pituitary hormone deficiency (CPHD), but a small proportion of C-CH cases demonstrate isolated C-CH where mainly TSH secretion is impaired. The frequency of C-CH among the general population has been reported as 1/16,000 to 1/30,000 (2–4). In Japan, newborn screening for congenital hypothyroidism has been performed since 1979. While the main purpose of such screening is to detect primary hypothyroidism (thyroid origin), some regions in the country employ simultaneous determination of blood TSH and free T4 (FT4) levels to diagnose C-CH in addition to primary hypothyroidism (2,3,4). Nagasaki et al. reported that C-CH occurs in about 10% of patients with congenital hypothyroidism in Japan (5). In 1971, Miyai et al. (6) first reported a family with isolated TSH deficiency, and in 1989, a mutation in the TSH gene (TSHB) encoding the β-subunit of the protein was eventually discovered (7). Thereafter, over the following three decades, several genetic defects associated with isolated C-CH have been identified (Table 1) (1, 2, 8, 9). This review summarizes the current knowledge regarding the genetic causes and clinical features of isolated C-CH. Table 1. Genetic causes, severity of hypothyroidism, and endocrine findings of isolated-Cent-H Open in a separate window TSHB Deficiency As mentioned, a family in Japan showing TSH deficiency was first reported by Miyai et al. (6), and eventually a mutation in TSHB was discovered in 1989 (7). In the first report, patients showed symptoms of severe congenital hypothyroidism, such as failure to thrive, prolonged jaundice, and developmental delay. Despite very low levels of serum T4 and T3, TSH was not measurable, indicating C-CH. A TRH stimulation test did not increase TSH level at all, but showed a normal PRL response. Finally, their group identified a homozygous mutation p.Gly29Arg in TSHB. Miyai et al. (1) further found several Japanese patients with TSHB deficiency. Genetic analysis showed that all patients had p.Gly29Arg, suggesting a founder effect (1). Since the first report, several patients with TSHB mutations have been reported worldwide (10,11,12,13,14,15,16,17,18,19,20). In all cases, the inheritance of TSHB defects is autosomal recessive. Almost all patients with a TSHB defect develop severe symptoms of congenital hypothyroidism after birth. A delay in diagnosis and thyroid hormone replacement therapy results in poorer psychomotor development. Regarding mutations, nonsense mutations (p.Glu32Ter and p.Gln69Ter), frameshift mutations (p.Cys125ValfsTer10), missense mutations (p.Met1?, p.Glu32Lys, p.Gly49Arg, p.Cys108Tyr, and p.Cys105Arg), and a splice site mutation (c.1625+5G>A) have been identified. One mutation (c.162G>A) did not cause an amino acid change, but it was located at the 5′ donor splice site of exon/intron2, leading to the skipping of exon 2. In addition, a homozygous deletion of TSHB was also reported (16). Among these mutations and deletions, p.Cys125ValfsTer10 has been most frequently reported in Europe, Argentina, and the USA (10, 12, 18,19,20). This mutation has been found in various unrelated families, but several studies using haplotype analysis in Germany, the UK, and Ireland showed that this mutation was derived from common ancestors (18,19,20).