A number sign (#) is used with this entry because of evidence that abnormal thyroid hormone metabolism-1 (THMA1) is caused by homozygous or compound heterozygous mutation in the SECISBP2 gene (607693) on chromosome 9q22.

Abnormal thyroid hormone metabolism-1 (THMA1) is characterized by multiorgan defects, including abnormal thyroid hormone metabolism, myopathy, hearing loss, and male infertility (summary by Catli et al., 2018).

Genetic Heterogeneity of Abnormal Thyroid Hormone Metabolism

THMA2 (619855) is caused by mutation in the DIO1 gene (147892) on chromosome 1p32. THMA3 (620198) is caused by mutation in the TRU-TCA1-1 gene (165060) on chromosome 19q13.

Dumitrescu et al. (2005) described 2 families with a specific thyroid phenotype associated with a reduction in type II iodothyronine deiodinase (DIO2; 601413) activity. In a Bedouin Saudi family, 3 of 7 sibs had abnormal thyroid function tests. The proband had short stature at 14 years of age and delayed bone age of 9 at 12 years of age, while still prepubertal. During the ensuing 2 years, a pubertal growth spurt brought his height to normal. At neonatal screening his blood thyrotropin (TSH; see 188540) level was high, but no treatment was given because serum thyroxine (T4) was not low. TSH levels remained above normal, but development proceeded normally. Concentrations of total T4, free T4, and total triiodothyronine metabolite (reverse T3) were high, whereas those of total and free T3 were low. The same pattern of thyroid function test abnormalities was observed in the proband's 7-year-old brother and 4-year-old sister, both clinically euthyroid. All other family members had normal thyroid function tests. Fibroblasts from the 3 sibs showed decreased DIO2 enzymatic activity not linked to the DIO2 locus. The single affected child of an Irish family presented at age 6 with transient growth retardation and thyroid abnormalities similar to those observed in affected members of the Bedouin Saudi family.

Catli et al. (2018) reported a 12.75-year-old Turkish boy who presented at age 10 years for evaluation of obesity. He also had leg weakness, easy fatigability, and attention deficit disorder. Examination revealed right eye ptosis, which had been present since infancy, and weakness of proximal lower extremity muscles. Electromyography revealed myogenic involvement of proximal upper and lower extremities, and MRI showed fatty infiltration of the muscles. Laboratory evaluation showed elevated total T4, free T4, and reverse T3, with normal to slightly elevated TSH, whereas free T3 was low, as was serum selenium (Se). Normalization of Se levels by supplementation did not correct the thyroid hormone abnormalities. Examination at age 12.75 showed normal Tanner stage (III) but his growth velocity had slowed, with height going from the 50th centile to the 25th. Although his IGF1 (147440) level was normal, provocative testing showed growth hormone (GH) responses to be insufficient; however, the parents declined GH replacement therapy.

Dumitrescu et al. (2005) performed systematic linkage analysis of genes involved in DIO2 synthesis and degradation and identified mutations in the SECISBP2 gene as the cause of the disorder. The Bedouin family carried a homozygous missense mutation in exon 12 resulting in the amino acid substitution arg540-to-gln (607693.0001). The proband of the Irish family was compound heterozygous for a nonsense mutation in exon 10 and a splice mutation at the intron 8 splice donor site (see 607693.0002). Because SECISBP2 is epistatic to selenoprotein synthesis, these defects had a generalized effect on selenoproteins. Dumitrescu et al. (2005) hypothesized that incomplete loss of SECISBP2 function probably caused the mild phenotype.

In a 12.75-year-old Turkish boy with abnormal thyroid hormone metabolism, Catli et al. (2018) sequenced the SECISBP2 gene and identified homozygosity for a 1-bp insertion (607693.0004) that segregated with disease in the family.

Dumitrescu et al. (2005) noted that affected individuals in the 2 families described by them had a thyroid phenotype similar to that of mice with targeted disruption of both Dio1 (147892) and Dio2, although they had no defects in neither of these loci. Like the subjects described by Dumitrescu et al. (2005), such mice had high serum T4 and TSH concentrations, low T3 concentrations, and markedly elevated rT3 concentrations. Like Dio2-knockout male mice, they had delayed growth between 3 and 8 weeks of age, reminiscent of the probands of both families.