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A 17-year-old woman with a history of childhood leukemia and hematopoietic stem cell transplantation (HSCT), preceded by total body irradiation, developed diabetes, dyslipidemia, fatty liver, and marked insulin resistance. Based on Dunnigan phenotype, HSCT-associated lipodystrophy was suspected. Because of rapid deterioration of diabetes control, metreleptin was introduced at 23 years of age upon receipt of her caregiver's documented consent. This trial was initially planned as a prospective 18 month-long study, with regular assessments of the patient's physical activity, food intake, and body composition analysis. However, because an abrupt and transient attenuation of the metreleptin effect occurred 16 months after the treatment initiation, the entire course of 28 months is reported here. Over the period, her HbA1c decreased from 10.9% to 6.7% despite no significant increase of physical activity and with a stable food intake. Decreased levels of triglyceride and non-HDL cholesterol were found. Her liver function improved, indicating the amelioration of fatty liver. In addition, a 25% reduction in the subcutaneous fat area at umbilical level was found, accompanied by a decrease in fat percentage of both total-body and trunk. The formation of neutralizing antibodies to metreleptin may be responsible for the transient loss of efficacy, considering a sudden elevation in her serum leptin level. In conclusion, metreleptin is useful for the management of HSCT-associated lipodystrophy, supporting the concept that adipose tissue dysfunction is responsible for diverse post-HSCT metabolic aberrations.

In Kanagawa Prefecture, Japan, simultaneous measurements of free T4 (FT4) and TSH levels are performed during newborn screening for congenital hypothyroidism (CH). FT4 measurement enables the detection of CH of central origin (CH-C), the incidence of which is estimated to be 1 in 30,833 live births in Kanagawa Prefecture. In this study, we aimed to evaluate the efficacy of FT4 screening when transient CH-C and thyroidal CH (CH-T) with delayed TSH elevation are included as screening targets. Data collected on CH-C patients using a regional survey, as well as data from a database created by a screening organization, were used. Of the 24 CH-C patients who had been born in Kanagawa Prefecture between 1999 and 2008, a positive screening result for FT4 (

Bartter syndrome (BS) type 1, also referred to antenatal BS, is a genetic tubulopathy with hypokalemic metabolic alkalosis and prenatal onset of polyuria leading to polyhydramnios. It has been shown that BS type 1 is caused by mutations in the SLC12A1 gene encoding bumetanide-sensitive Na-K-2Cl (-) cotransporter (NKCC2). We had the opportunity to care for two unrelated Japanese patients of BS type 1 with typical manifestations including polyhydramnios, prematurity, hypokalemia, alkalosis, and infantile-onset nephrocalcinosis. Analysis of the SLC12A1 gene demonstrated four novel mutations: N117X, G257S, D792fs and N984fs. N117X mutation is expected to abolish most of the NKCC2 protein, whereas G257, which is evolutionary conserved, resides in the third transmembrane domain. The latter two frameshift mutations reside in the intra-cytoplasmic C-terminal domain, which illustrates the importance of this domain for the NKCC2 function. In conclusion, we found four novel SLC12A1 mutations in two BS type 1 patients. Development of effective therapy for hypercalciuria is mandatory to prevent nephrocalcinosis and resultant renal failure.

We report the case of a 17-year-old boy with delayed puberty, who presented a complexity of clinical problems. An analysis of steroid hormones led to a diagnosis of 17alpha-hydroxylase/17,20-lyase deficiency (17OHD). Unlike typical cases of 17OHD, however, the patient had pubertal development without medical intervention. In addition, he never exhibited the symptoms of mineralocorticoid excess, showing instead the symptoms of glucocorticoid deficiency, including fatigability, emaciation, and weight-loss induced by minor infection. He also had dysmorphic features, which comprised marfanoid habitus, arachnodactyly and putative craniosynostosis. The combination of these malformations substantially resembled that of Shprintzen-Goldberg syndrome. Direct sequencing of the CYPl7 gene did not reveal any significant aberrations in the exons or exon-intron boundaries. We speculate that the association of partial combined 17OHD with the Shprintzen-Goldberg phenotype in the present patient may result from an aberration of a hitherto unknown gene that controls both steroid hormone synthesis and skeletal development.