In Sapporo, Japan, a neonatal screening program for congenital hypothyroidism (CH) has employed measurement of free thyroxine (T4) and TSH in the same filter-paper blood spot. This system has enabled us to identify primary CH and central CH during the neonatal period. The aim of this study was to clarify the prevalence and clinical characteristics of central CH. For this purpose, the screening program requested serum from infants with free T4 concentrations below the cut off value regardless of the TSH levels. Between January 2000 and December 2004, 83,232 newborns were screened and six central CH patients were detected as a result of follow-up of low free T4 and non-elevated TSH screening (1:13,872). This frequency is higher than in other studies. Four patients showed multiple pituitary hormone deficiency with pituitary malformations on magnetic resonance imaging. One patient was diagnosed as having Prader-Willie syndrome. The remaining patient was considered to have isolated central CH. Our study demonstrated that the frequency of central CH is 1:13,872. Free T4 measurement would also be advantageous in early recognition of multiple pituitary hormone deficiency.

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(NR5A1) were identified in two 46, XY female patients with adrenal insufficiency and gonadal dysgenesis [6,7]. The first mutation (G35E) was a heterozygous mutation, which occurred in the P-box of the first zinc finger domain required for the DNA-binding [6,8]. The second mutation was a homozygous missense mutation (R92Q) that disrupts the A-box secondary DNA binding domain [7]. However, recent several studies have demonstrated that heterozygous mutations are more frequently identified in 46, XY disorders of sex development (DSD) patients without adrenal failure rather than in 46, XY DSD patients with adrenal failure [3,[9][10][11][12][13][14][15][16][17]. Therefore, the testis is likely to be more sensitive to partial loss of SF-1/Ad4BP function than the adrenal gland in human. In regard to females with heterozygous NR5A1 mutations, so far seven individuals have been reported [13][14][15][16][17][18]. Among them, only one patient developed adrenal failure, but she had apparently normal ovarian function [18]. The remaining individuals were mothers of 46, XY DSD patients and they did not show any symptoms of adrenal and ovarian failure [13][14][15][16][17]. Indeed, ovarian development during development and at birth is relatively Abstract. Steroidogenic factor-1 [(SF-1/Ad4BP) (mIm184757)] is a nuclear receptor that regulates multiple genes involved in adrenal and gonadal development, steroidogenesis, reproduction, and other metabolic functions. Initially, mutations of SF-1/Ad4BP gene (NR5A1) in humans were identified in two 46, XY female patients with adrenal insufficiency and gonadal dysgenesis. However, recent studies have revealed that heterozygous mutations are more frequently found in 46, XY disorders of sex development (DSD) patients without adrenal failure than in 46, XY DSD patients with adrenal failure. We encountered a japanese female patient of 46, XY DSD without adrenal failure and identified a novel mutation (V41G) of NR5A1. Functional analysis revealed that this mutant protein could not activate CYP19 promoter, indicating loss of function. In conclusion, we add a novel mutation of NR5A1 in 46, XY DSD patient without adrenal failure.

Abstract. We encountered a Japanese patient of congenital hypothyroidism with severe cerebellum atrophy. The boy was born after 40 weeks of gestation by normal vaginal delivery from nonconsanguineous parents. There were no abnormal physical findings; however neonatal mass screening for congenital hypothyroidism at 5 days of age demonstrated elevated thyrotropin (TSH) level (15.5 µU/ml, normal range 0.54-10.0 µU/ml). He was suspected to have subclinical or mild congenital hypothyroidism (CH). Thus he was treated with L-thyroxine using a regimen that rendered his serum TSH concentration within normal range from 27 days of age. Despite early and adequate treatment, he showed signs of global developmental delay and became gradually hypotonic and exhibited a staggering gait at 3 years of age. Brain magnetic resonance imaging (MRI) demonstrated marked cerebellar atrophy with an intact brainstem. Thyroidal uptake of radioiodide and thyroid gland size were normal, indicating a functional defect only. The relation between congenital hypothyroidism and severe cerebellar atrophy in our patient is not clear. As only a few cases of the combination of CH and cerebellar anomalies have been described previously, cerebellar symptoms in CH should be examined carefully. THE occurrence of neurological symptoms and developmental delay in patients with congenital hypothyroidism (CH) has been caused by the lack of thyroid hormone in the developing central nervous system [1]. Untreated CH results in neurological deficits, including mental retardation, disturbance of gait and coordination. As the introduction of neonatal screening for CH enables prompt diagnosis and early initiation of thyroid hormone replacement treatment, most CH patients develop normally [1]. Here, we describe a Japanese patient of CH, who showed developmental delay and ataxic gait, in whom severe cerebellar atrophy was observed by brain magnetic resonance imaging (MRI) despite early and adequate treatment. A Report of CaseThe patient was born after 40 weeks of gestation by normal vaginal delivery from nonconsanguineous parents. His birth weight was 2250 g (small for date) and length was 44.5 cm. There was no abnormal physical findings including goiter; however, neonatal mass screening using filter paper for CH at 5 days of age demonstrated mildly elevated thyrotropin (TSH) level (15.5 µU/ml, normal range 0.54-10.0 µU/ml). For further evaluation, he was referred to our hospital at 27 days of age. His body weight was 2945 g and no symptom of hypothyroidism was seen. At this time, his serum TSH was 12.07 µU/ml, free T4 1.16 ng/dl, free T3 3.75 pg/ml, and thyroid autoantibodies were negative. He was suspected to have subclinical or mild CH and thus L-thyroxine (L-T4, 20 µg/day) therapy was started. He was treated with L-thyroxine using a regime that rendered his serum TSH concentration within normal range. His dose was subsequently increased as he grew, and at 3 years of age, he was

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