Abstract. About 90% of patients with congenital nephrogenic diabetes insipidus (NDI) have vasopressin type 2 receptor (V2R) gene mutations that are inherited in an X-linked recessive manner. Although most female carriers are asymptomatic, some female carriers show polydipsia and polyuria. The reason why female carriers show NDI symptoms is explained by skewed X-inactivation. We studied X-inactivation patterns of six female carriers with heterozygote V2R gene mutations. The X-inactivation pattern in peripheral blood leukocytes was examined using methylation analysis of the polymorphic CAG repeat in the androgen receptor gene. Two asymptomatic female carriers showed random Xinactivation (61.9% and 60.7%). Skewed X-inactivation patterns (71.6%, 79.4%, and 91.2%) occurring preferentially to normal X alleles were recognized in three female carriers who showed clinical NDI symptoms. However, in one female carrier who showed clinical NDI symptoms, random X-inactivation (55.4%) was recognized. In conclusion, the clinical NDI phenotypes may correlate with the X-inactivation patterns in female carriers with heterozygote V2R gene mutations. However, in some female carriers, we cannot predict the clinical phenotypes by the evaluation of the X-inactivation patterns in peripheral blood leukocytes, because X-inactivation ratios within an individual are sometimes different between tissues.
Subjects who are heterozygous for thyroid stimulating hormone receptor (TSHR) gene mutations present various phenotypes that range from euthyroid to hyperthyrotropinemia. Similarly, heterozygous dual oxidase 2 (DUOX2) gene mutations result in variable phenotypes, such as transient congenital hypothyroidism, subclinical hyperthyrotropinemia, and euthyroid in children. Here, we describe an 8-year-old boy who had normal newborn screening results, but who developed nonautoimmune hypothyroidism at the age of 1 year and 8 months of age. He was heterozygous for previously reported R450H-TSHR mutation and heterozygous for a novel double mutant allele A1323T-DUOX2 and L1343F-DUOX2. He needed levothyroxine (l-T4) replacement therapy to keep serum TSH levels within normal limits; l-T4 dose of 2.01-2.65 μg/kg/day corresponded to the dose taken by children homozygous for R450H-TSHR and by children with permanent congenital hypothyroidism. Therefore, the coexistence of a heterozygous TSHR mutation and a heterozygous DUOX2 mutation may have affected the severity of his hypothyroid condition.
The dual oxidase 2 (DUOX2) mutation results in an impairment of the hydrogen peroxidase-generating system and is identified as a dyshormonogenic cause of congenital hypothyroidism (CH). Here, we describe two unrelated Japanese girls with CH due to a novel DUOX2 mutation. They had high serum thyrotropin levels and low free thyroxine/thyroxine concentrations during the neonatal period. A novel missense mutation with a transversion of G to A at position 1462 in exon 12 of the DUOX2 gene that caused a replacement of glycine (G) with arginine (R) at codon 488 of the protein (c.1462G>A, p.[G488R]) was identified. One patient was a compound heterozygote for p.[L479SfsX3]+[G488R]. The other was homozygous for p.[G488R]. This p.G488R substitution occurred in a highly conserved glycine residue of the mammalian DUOX2 protein. The two patients had different haplotypes, suggesting that the p.G488R alleles were the result of independent, recurrent mutations. Later in life, both patients were still euthyroid even after discontinuing thyroid hormone therapy. We conclude that this p.G488R missense mutation in the DUOX2 gene of the patients is associated with thyroid dysfunction that presents during the neonatal period.
Here, we describe three cases of loss-of-function mutations in the nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase (NOX) domain of dual oxidase 2 (DUOX2) occurring along with concurrent missense mutations in thyroid peroxidase (TPO), leading to transient congenital hypothyroidism (CH). Three Japanese boys with nonconsanguineous parents were diagnosed with CH during their neonatal screenings. All patients presented with moderate-to-severe neonatal hypothyroidism and were diagnosed with transient CH after re-evaluation of thyroid function. Two siblings were compound heterozygous for p.[R1110Q]+[Y1180X] in DUOX2; one of them was also heterozygous for p.[R361L] in TPO. The third patient was compound heterozygous for p.[L1160del]+[R1334W] in DUOX2 and heterozygous for p.[P883S] in TPO. This is the first report of a de novo L1160del mutation affecting the DUOX2 gene and of the novel mutations Y1180X in DUOX2 and R361L in TPO. R1110Q and L1160del were found to reduce H2O2 production (5%-9%, p<0.01), while Y1180X, which introduces a premature stop codon, did not confer detectable H2O2 production (-0.7%±0.6%, p<0.01). Moreover, R1334W, a missense mutation possibly affecting electron transfer, led to reduced H2O2 production (24%±0.9%, p<0.01) in vitro, and R1110Q and R1334W resulted in reduced protein expression. Y1180X was detected in a 120 kDa truncated form, whereas L1160del expression was maintained. Further, R361L, a novel missense mutation in TPO, caused partial reduction in peroxidase activity (20.6%±0.8%, p=0.01), whereas P883S, a missense variant, increased it (133.7%±2.8%, p=0.02). The protein expression levels in the case of R361L and P883S were maintained. In conclusion, we provide clinical and in vitro demonstrations of different functional defects and phenotypic heterogeneity in the same thyroid hormonogenesis pathway.
In this study, we report a Japanese boy with testotoxicosis due to a heterozygous mutation [p. A572V] in the LH/CGR gene, who was the first boy treated with a third-generation aromatase inhibitor (AI) and reached his adult height in Japan. He showed accelerated growth and rapid penile growth from 3 yr of age and was diagnosed as having testotoxicosis. Combined treatment with anastrozole and spironolactone was started when he was 7 yr old and 145.8 cm (+4.45 SD) tall, at which point his bone age (BA) was 13.5 yr. His predicted adult height (PAH) was estimated to be 158.3 cm. The combined treatment was continued until he was 13 yr old and 166.5 cm tall, with his BA being 15.5 yr. He reached his adult height of 166.9 cm at 15 yr of age. Combined treatment with anastrozole and spironolactone successfully decelerated BA advancement, prolonged pubertal period and improved adult height.
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