Kenichi Miyako

SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7

Adrenal hypoplasia is a rare, life-threatening congenital disorder. Here we define a new form of syndromic adrenal hypoplasia, which we propose to term MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy) syndrome. By exome sequencing and follow-up studies, we identified 11 patients with adrenal hypoplasia and common extra-adrenal features harboring mutations in SAMD9. Expression of the wild-type SAMD9 protein, a facilitator of endosome fusion, caused mild growth restriction in cultured cells, whereas expression of mutants caused profound growth inhibition. Patient-derived fibroblasts had restricted growth, decreased plasma membrane EGFR expression, increased size of early endosomes, and intracellular accumulation of giant vesicles carrying a late endosome marker. Of interest, two patients developed myelodysplasitc syndrome (MDS) that was accompanied by loss of the chromosome 7 carrying the SAMD9 mutation. Considering the potent growth-restricting activity of the SAMD9 mutants, the loss of chromosome 7 presumably occurred as an adaptation to the growth-restricting condition.

Vitamin D deficiency rickets caused by improper lifestyle in Japanese children

Abstract  Background : Nutritional rickets is considered rare in developed countries. However, reports on vitamin D deficiency rickets caused by improper lifestyle have recently increased. The clinical and laboratory characteristics of patients with vitamin D deficiency rickets treated at Fukuoka Childrens Hospital, Fukuoka, Japan, were evaluated to clarify current causes and ways to prevent this disease.

Rare pseudoautosomal copy-number variations involving SHOX and/or its flanking regions in individuals with and without short stature

Pseudoautosomal region 1 (PAR1) contains SHOX, in addition to seven highly conserved non-coding DNA elements (CNEs) with cis-regulatory activity. Microdeletions involving SHOX exons 1–6a and/or the CNEs result in idiopathic short stature (ISS) and Leri–Weill dyschondrosteosis (LWD). Here, we report six rare copy-number variations (CNVs) in PAR1 identified through copy-number analyzes of 245 ISS/LWD patients and 15 unaffected individuals. The six CNVs consisted of three microduplications encompassing SHOX and some of the CNEs, two microduplications in the SHOX 3′-region affecting one or four of the downstream CNEs, and a microdeletion involving SHOX exon 6b and its neighboring CNE. The amplified DNA fragments of two SHOX-containing duplications were detected at chromosomal regions adjacent to the original positions. The breakpoints of a SHOX-containing duplication resided within Alu repeats. A microduplication encompassing four downstream CNEs was identified in an unaffected father–daughter pair, whereas the other five CNVs were detected in ISS patients. These results suggest that microduplications involving SHOX cause ISS by disrupting the cis-regulatory machinery of this gene and that at least some of microduplications in PAR1 arise from Alu-mediated non-allelic homologous recombination. The pathogenicity of other rare PAR1-linked CNVs, such as CNE-containing microduplications and exon 6b-flanking microdeletions, merits further investigation.

Improved diabetes control by using 'close adjustment algorithms'.

Background : Intensive insulin therapy increases the frequency of severe hypoglycemia despite markedly improved glycemic control in patients with type 1 diabetes mellitus. To determine the optimal dose of insulin, the authors designed algorithms based on self‐monitored blood glucose levels.

Association study between CD30 and CD30 ligand genes and type 1 diabetes in the Japanese population

CD30-CD30 ligand (CD30L) signal transduction appears to protect against autoimmune diabetes by preventing expansion of autoreactive T cells and suppressing Th1-cytokine response. The purpose of this study was to determine whether CD30 or CD30L genes serve as a novel susceptibility gene for type 1 diabetes in humans. We screened CD30 and CD30L genes for polymorphisms in Japanese patients with type 1 diabetes and control subjects. Then, association studies were performed between each of the identified polymorphisms and type 1 diabetes. Direct-sequencing analysis of the CD30 and CD30L genes revealed four polymorphisms: one in the CD30 gene (−201G/A from the transcription start site), and three in the CD30L gene [CA repeat in the promoter, 276G/A in the exon 3, −73T/C in the intron 3 (IVS3 −73T/C)]. Association studies revealed no association between the CD30 and CD30L genes and type 1 diabetes in the whole population. In the female and male subpopulations, however, the frequency of (CA)9 allele of the CD30L gene promoter or T allele of IVS3 −73T/C polymorphism in the CD30L gene was slightly higher in female patients with type 1 diabetes than that in control females. In conclusion, we could not find significant association between CD30 or CD30L genes and type 1 diabetes, but (CA)9 allele in the promotor or T allele of −73T/C in intron 3 in CD30L gene might play a minor role in the pathogenesis of type 1 diabetes, only in the Japanese female population.

A Retrospective Analysis of the Growth Pattern in Patients with Salt-wasting 21-Hydroxylase Deficiency

Abstract The objective of this study was to investigate the growth pattern of children with the salt-wasting form of congenital adrenal hyperplasia caused by 21-hydroxylase deficiency (21-OHD). We reviewed the medical records of 13 patients in whom salt-wasting 21-OHD was diagnosed during the first 2 mo of life at our hospital from 1980 through 2008. Six reached adult height. Growth patterns, bone age, biochemical data, and the hydrocortisone dose at each growth stage were analyzed retrospectively. The mean adult height was 155.1 ± 6.5 cm (mean ± SD) in females and 158.1 ± 7.1 cm in males. Although length at birth was normal or longer than the national mean in almost all patients, the mean height SD score of both boys and girls decreased to below 0 SD during infancy. Subsequently, both boys and girls transiently showed growth acceleration and reached their peak growth velocity at 3–10 yr of age. In conclusion, in addition to suppression of growth during infancy, there was inappropriate growth acceleration during childhood. Especially from 3 mo to 3 yr of age, decreasing the hydrocortisone dose in patients who exhibit slower growth may lead to satisfactory height outcomes. Also, strict adjustment of the hydrocortisone dose to avoid accelerated growth from childhood to adolescence might improve adult height outcomes of patients with 21-OHD.

Improving Circulatory Disturbance in Transient Abnormal Myelopoiesis

Transient abnormal myelopoiesis (TAM) in neonates with Down syndrome (DS) is characterized by circulating blast cells in the blood. TAM usually resolves spontaneously, but several studies have associated this condition with early death, focusing on the development of effective treatments. We report the case of a neonate with DS who had TAM and novel GATA1 mutation. Although the patient eventually died of hepatic failure, exchange blood transfusion and low-dose cytarabine treatment dramatically improved pulmonary hypertension and acute renal failure refractory to conventional therapy. Such a blast-reducing approach might be useful for improving circulatory disturbances in neonates with DS and TAM.

Molecular and cytogenetic analyses of a patient with Prader-Willi syndrome who also had the phenotype of Angelman syndrome

Most cases of Prader-Willi syndrome are caused by partial deletion of the paternally derived chromosome 15, while maternally derived chromosome 15 is responsible for Angelman syndrome. We report the results of molecular and cytogenetic analyses of a patient who was given a final diagnosis of Prader-Willi syndrome, but also had manifestations consistent with Angelman syndrome. The patient was a 15-year-old boy. After birth, PraderWilli syndrome was diagnosedon fluorescence in situ hybridization (FISH), performed because of muscular hypotonia, failure to thrive, and bilateral cryptorchidism. However, at the age of 2 years, the diagnosis was revised to Angelman syndrome because of atypical absence, characteristic electroencephalographic discharges, mental retardation, and excessive laughter. At the age of 14 years, type 2 diabetes developed, and he is now receivinginsulin glargine and voglibose. The height is 147.0 cm (-3.68 SD), and the body weight is 55.0 kg (body mass index, 25.5 kg/m 2 ). He cannot speak any meaningful words or walk. He has hyperphagia, hypopigmentation, almond-shaped eyes, small hands and feet, and a large mouth and jaw. Chromosomal examination by G-banding stain revealed that the karyotype was a mosaic composed of 45, XY, der(1) t(1;15)(p36.3; q13), -15 and 46, XY, der(1) t(1;15) (p36.3; q13),-15 ,+mar. FISH did not detect signals of UBE3A/D15S10 with the probe for Angelman syndrome or SNRPN for Prader-Willi syndrome on the der(1) chromosome. The marker chromosome was derived from the short arm of chromosome 15. Methylation-specific PCR amplified the SNRPN gene using only primers specific for methylated gene. FISH for 1p36 deletion syndrome did not detect the deletion on the der(1) chromosome. We concluded that his diagnosis was Prader-Willi syndrome caused by the partial deletion of the long arm of chromosome 15, which had translocated onto chromosome 1. The clinical manifestations might have beenmodified by the complicatedstructural changes in chromosomesas well as by possible terminal deletion of the short arm of chromosome 1, which could not be detected on FISH.

Vitamin D deficiency presenting in an infant with neonatal lupus erythematosus

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Predisposition to Subdural Hemorrhage in X-Linked Myotubular Myopathy

X-linked myotubular myopathy is a severe congenital myopathy that can involve multiple organs. We report on a 10-month-old boy who manifested X-linked myotubular myopathy with subdural hemorrhage. The diagnosis of X-linked myotubular myopathy was based on typical muscle pathology and MTM1 missense mutation. The patient had undergone no traumatic episodes or bleeding diathesis. Axial growth acceleration is known to occur in X-linked myotubular myopathy, potentially leading to dolichocephaly. In our patient, an enlarged subdural space apparently stretched the bridging veins, increasing susceptibility to subdural hemorrhage. Patients who manifest X-linked myotubular myopathy with typical dolichocephaly are at increased risk for subdural hemorrhage.