Double-layered patella in multiple epiphyseal dysplasia is not exclusive to DTDST mutation.
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Anion Transport Proteins↗
Biomedical subjects
Gen Nishimura
Publications and source records attributed to Gen Nishimura.
Novel COL9A3 mutation in a family with multiple epiphyseal dysplasia.
Multiple epiphyseal dysplasia (MED) is a common skeletal dysplasia characterized by mild to moderate short stature, early-onset of osteoarthritis (OA) mainly in the hip and knee joints, and abnormally small and/or irregular epiphyses. MED is clinically and genetically heterogeneous. Six causative genes of MED have been reported, including type IX collagen genes (COL9A1, COL9A2, COL9A3). All the type IX collagen mutations previously reported cause exon skipping that loses the COL3 domain. Here we have identified a novel COL9A3 mutation co-segregating in a three-generation family with MED. The mutation (IVS3 + 5G > A) was speculated to lose the COL3 domain by skipping of exon 3, which was confirmed by in vitro analysis. The patients were of normal height and had minimal complaints with phenotypes being more severe in male patients. The radiographic phenotypes of the patients were relatively milder than those of previously reported cases, and were indistinguishable to common, idiopathic OA.
Adult↗
Novel and recurrent exon 13 mutations of COMP in pseudoachondroplasia.
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Achondroplasia↗
The phenotypic spectrum of COL2A1 mutations.
Heterozygous mutations of COL2A1 create several clinical entities collectively termed type II collagenopathies. These disorders not only impair skeletal growth but also cause ocular and otolaryngological abnormalities. The classical phenotypes include the spondyloepiphyseal dysplasia (SED) spectrum with variable severity, Stickler dysplasia type I (STD-I), and Kniest dysplasia (KND). Most COL2A1 mutations occur in the triple helical region of alpha 1(II) chains: the SED spectrum is mostly attributed to missense mutations that substitute bulky amino acids for glycine residues, STD-I to haploinsufficiency of truncation mutations, and KND to exon skipping due to splice-site mutations. To further elucidate the genotype-phenotype relationship of type II collagenopathies, we examined COL2A1 mutations in 56 families that were suspected of having type II collagenopathies, and found 38 mutations in 41 families. Phenotypes for all 22 missense mutations and one in-frame deletion in the triple helical region fell along the SED spectrum. Glycine to serine substitutions resulted in alternating zones that produce severer and milder skeletal phenotypes. Glycine to nonserine residue substitutions exclusively created more severe phenotypes. The gradient of the SED spectrum did not necessarily correlate with the occurrence of extraskeletal manifestations. All nine truncation or splice-site mutations in the triple helical or N-propeptide region caused STD-I or KND, and extraskeletal changes were inevitable in both phenotypes. All six C-propeptide mutations produced a range of atypical skeletal phenotypes and created ocular, but not otolaryngological, changes.
Adolescent↗
Pachygyria in a girl with microcephalic osteodysplastic primordial short stature type II.
We report a mild form of lissencephaly or a pachygyric brain in a girl with microcephalic osteodysplastic primordial 'dwarfism' (MOPD) type II. She was born with severe intrauterine growth failure. A diagnosis of MOPD type II was warranted by persistent postnatal growth failure, microcephaly with a Seckel-like facial appearance, and distinctive radiological findings, including overtubulation of the long bones, metaphyseal cupping of the distal femora, and brachyphalangy with ivory epiphyses. Brain MRI showed thickened cerebral cortices with few and large gyri, most prominently in the frontal and posterior temporal regions. The Sylvian fissures developed incompletely, and the posterior horns of the lateral ventricle were dilated (colpocephaly). Despite the severe imaging findings, she showed only mild retardation of psychomotor development. To date, only minor brain malformations have attracted attention in MOPD type II. Our experience may suggest a wider spectrum of brain anomalies in this entity.
Abnormalities, Multiple↗
[Management of asymptomatic newborns with periportal hypodensity and high serum IgM who were born from untreated tuberculosis mothers].
OBJECTIVES: We previously reported the presence of periportal hypodensity on CT image in two newborns and an early infant with congenital tuberculosis as an adjunct diagnostic option. The aim of this study was to determine the degree of treatment based on both periportal hypodensity and serum IgM presented in asymptomatic newborns born from tuberculosis mothers. SUBJECTS AND METHODS: Eight newborns born from mothers with untreated tuberculosis between 1996 and 2002 were retrospectively studied. Newborns who presented periportal hypodensity and high serum IgM were treated with anti-tuberculosis medicines, combination of isoniazid and rifampicin for nine to 12 months with streptomycin in the initial two months, and the outcomes of the treatment were followed for at least two years. RESULTS: All eight newborns had gastric aspirates negative for Mycobacterium tuberculosis. Three of eight newborns (38%) demonstrated periportal hypodensity, and they also demonstrate a tendency of high serum IgM. None of these three newborns treated with combination of isoniazid, rifampin, and streptomycin for 9 to 12 months developed tuberculosis during the observation period. CONCLUSIONS: These results suggest that presence of both periportal hypodensity and high serum IgM in asymptomatic newborns born from mothers with untreated tuberculosis may be one of risk factors of developing congenital tuberculosis, and that anti-tuberculosis treatment for nine to 12 months may prevent them from the disease development despite possible criticism of overdiagnosis and overtreatment.
Female↗
Cytochrome P450 oxidoreductase gene mutations and Antley-Bixler syndrome with abnormal genitalia and/or impaired steroidogenesis: molecular and clinical studies in 10 patients.
We report on molecular and clinical findings in 10 Japanese patients (four males and six females) from eight families (two pairs of siblings and six isolated cases) with Antley-Bixler syndrome accompanied by abnormal genitalia and/or impaired steroidogenesis. Direct sequencing was performed for all the 15 exons of cytochrome P450 oxidoreductase gene (POR), showing two missense mutations (R457H and Y578C), a 24-bp deletion mutation resulting in loss of nine amino acids and creation of one amino acid (L612_W620delinsR), a single bp insertion mutation leading to frameshift (I444fsX449), and a silent mutation (G5G). R457H has previously been shown to be a pathologic mutation, and computerized modeling analyses indicated that the 15A>G for G5G could disturb an exonic splicing enhancer motif, and the remaining three mutations should affect protein conformations. Six patients were compound heterozygotes, and three patients were R457H homozygotes; no mutation was identified on one allele of the remaining one patient. Clinical findings included various degrees of skeletal features, such as brachycephaly, radiohumeral synostosis, and digital joint contractures in patients of both sexes, normal-to-poor masculinization during fetal and pubertal periods in male patients, virilization during fetal life and poor pubertal development without worsening of virilization in female patients, and relatively large height gain and delayed bone age from the pubertal period in patients of both sexes, together with maternal virilization during pregnancy. Blood cholesterol was grossly normal, and endocrine studies revealed defective CYP17A1 and CYP21A2 activities. The results suggest that Antley-Bixler syndrome with abnormal genitalia and/or impaired steroidogenesis is caused by POR mutations, and that clinical features are variable and primarily explained by impaired activities of POR-dependent CYP51A1, CYP17A1, CYP21A2, and CYP19A1.
Abnormalities, Multiple↗
Circulating COMP is decreased in pseudoachondroplasia and multiple epiphyseal dysplasia patients carrying COMP mutations.
Mutations in the gene encoding cartilage oligomeric matrix protein (COMP) cause two common skeletal dysplasias, pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED). At present, diagnosis of these diseases is based primarily on clinical and radiographic findings and is sometimes erroneous, particularly in adult patients. However, genetic diagnosis is difficult, because COMP mutations are scattered throughout the gene and five additional disease genes for MED exist. There is evidence that circulating COMP may serve as a molecular indicator of a variety of diseases affecting cartilage. Therefore, we investigated plasma COMP concentrations in 21 patients with PSACH or MED. Of these, six PSACH and seven MED patients carried COMP mutations, and the remaining eight MED patients lacked mutations in COMP. We observed significantly decreased plasma COMP levels in patients with COMP mutations compared with controls (P < 0.0001). In addition, plasma COMP levels were significantly decreased in MED patients carrying mutations in COMP relative to those who lacked COMP mutations (P = 0.001). Our results indicate that circulating COMP levels reflect genetic abnormalities in COMP, providing an easier, more rapid and cost-efficient method for diagnosing PSACH and particularly for MED.
Adolescent↗
Newly recognized syndrome of metaphyseal undermodeling, spondylar dysplasia, and overgrowth: report of two adolescents and a child.
We report on a previously undescribed syndrome characterized by generalized skeletal alterations and overgrowth in three unrelated individuals: a boy who died at age 16 years, a 16-year-old girl, and a 15-month-old boy. The skeletal changes included bony overgrowth of the skull base, spondylar dysplasia, and undermodeling of the tubular bones. Bone age was accelerated in early childhood. Overgrowth, which was independent of GH-IGF axis, was of prenatal onset in the two boys, but postnatal in the girl. In the two adolescents, growth rate did not decline with age, and high-dose estrogen therapy failed to induce physeal fusion. Their adolescent height reached +4 approximately +7 SD of the mean. Delayed puberty in the girl and cryptorchidism and hypospadias in the younger boy raised the possibility that hypogonadism is a syndromic constituent. Molecular analysis of IGF2, GPC3, and FGFR3 in the older boy yielded no abnormalities.
Adolescent↗
Isolated congenital anosmia with morphologically normal olfactory bulb in two Iranian families: a new clinical entity?
Congenital total loss of the sense of smell occurs as a part of a syndrome or isolated anosmia. Kallmann syndrome is the most well known congenital anosmia associated with hypogonadotropic hypogonadism. Isolated congenital anosmia (ICA) is a very rare condition and appears to be due to changes in the olfactory epithelium or to aplasia of the olfactory nerve, bulb, and tract. Here we report two unrelated Iranian families with ICA. One family consisted of nine affected members, and the other family contained three affected members. Clinical history, physical examination, and smell testing by intravenous injection of combined vitamins (Alinamin trade mark, Takeda Pharmaceutical Co. Ltd., Japan) confirmed the disease in each affected member. No signs of hypogonadism or other neurological disorders were observed in any affected members. Family analysis with the complete ascertainment method under assumption of the same condition in the two families suggested that the disease is not inconsistent with an autosomal dominant mode with incomplete penetrance. The inheritance in one family appears unusual, i.e., there were no affected individuals in the third generation. When only two upper generations in the family are concerned, the segregation ratio was 0.39 +/- 0.11. Male-to-male transmissions were observed and both sexes were affected in both families. Magnetic resonance imaging (MRI) of the olfactory bulb and sulcus revealed no evidence of morphological changes in all affected members, suggesting that these patients have either a defect in the olfactory epithelium or a functional defect in the olfactory cortex.
Female↗
TGFB1 mutations in four new families with Camurati-Engelmann disease: confirmation of independently arising LAP-domain-specific mutations.
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Camurati-Engelmann Syndrome↗
Novel SBDS mutations caused by gene conversion in Japanese patients with Shwachman-Diamond syndrome.
Shwachman-Diamond syndrome (SDS; OMIM 260400) is an autosomal recessive disorder characterized by exocrine pancreatic insufficiency, bone marrow dysfunction and metaphyseal chondrodysplasia. SDS is caused by mutations in SBDS, an uncharacterized gene. A previous study in SDS patients largely of European ancestry found that most SBDS mutations occurred within a approximately 240-bp region of exon 2 and resulted from gene conversion due to recombination with a pseudogene, SBDSP. It is unknown, however, whether these findings are applicable to other ethnic groups. To address this question, we examined SBDS mutations in six Japanese families with SDS by direct sequencing. We identified compound heterozygous mutations in four families: two were recurrent (96-97insA, 258+2T>C), and three were novel [292-295delAAAG, (183-184TA>CT +201A>G), (141C>T+183-184TA>CT+201A>G)] mutations. Most of these mutations also appear to result from gene conversion, but the conversion events occurred at various sites between intron 1 and exon 3. Thus, gene conversion mutations in SBDS are common to different ethnic groups, but they are not confined to a limited region of the gene.
Alleles↗
Novel and recurrent mutations clustered in the von Willebrand factor A domain of MATN3 in multiple epiphyseal dysplasia.
Multiple epiphyseal dysplasia (MED) is a common skeletal dysplasia characterized by joint pain and stiffness, delayed and irregular ossification of epiphyses, and early-onset osteoarthritis. Six genes responsible for MED have been identified, including COMP, COL9A1, COL9A2, COL9A3, DSTDT and MATN3. MATN3 encodes matrilin-3, a cartilage-specific extracellular matrix protein. To date, seven different MATN3 mutations have been identified; all are located within the beta-sheet regions of the von Willebrand factor type A (vWFA) domain, which is encoded by exon 2. We examined MATN3 mutations in27 Japanese MED patients who were possibly autosomal dominant inheritance and had been excluded for COMP mutations. Ten of them had a positive family history. We examined all eight exons of MATN3 by PCR and direct sequencing from genomic DNA. We have identified four missense mutations in eight unrelated families; two are novel, and two have been characterized previously. Like previously characterized MATN3 mutations, those identified in this study are clustered within exon 2, specifically in and around the 2nd beta-sheet region of the vWFA domain (aa. 120-127). Contrary to the previous assumption that the MATN3 mutation in MED is confined to the beta-sheet regions, one novel mutation (p.F105S) is located outside the beta-sheet region, within an alpha-helix region.
Adolescent↗
Radiographic and genetic diagnosis of sporadic hypochondroplasia early in the neonatal period.
Hypochondroplasia is an autosomal dominant skeletal dysplasia expressing postnatal onset of short stature with mild rhizomelic shortening of the limbs. This manifestation leads to restricted prenatal diagnosis of the disorder. We report here on a sporadic case of a hypochondroplastic baby, whose prenatal sonographic measurements were serially recorded from 19 weeks of gestation. Mild shortening of the limbs became manifest after 26 weeks of gestation. Biparietal diameter was within the normal range throughout gestation. Both parents were of average stature. A tentative diagnosis of a nonlethal short-limb skeletal dysplasia was made. At birth, the clinical manifestations of the neonate were not characteristic, but the radiographic features raised the possibility of hypochondroplasia. Molecular analyses revealed a C to G mutation at nucleotide 1659 of the fibroblast growth factor receptor 3 (FGFR3) gene, a common mutation in hypochondroplasia.
Adult↗
Postnatal remission of ocular, auditory, and somatic findings in Stickler syndrome.
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Abnormalities, Multiple↗
Large fontanelles are a shared feature of haploinsufficiency of RUNX2 and its co-activator CBFB.
CBFB at 16q22 heterodimerizes with either RUNX2 (also known as CBFA1) or RUNX1 (CBFA2) to activate the transcription of downstream molecules. RUNX2 regulates osteoblast differentiation and chondrocyte maturation and its haploinsufficiency leads to cleidocranial dysplasia, characterized large fontanelles, hypoplasia or aplasia of the clavicles, hypoplasia of the distal phalanges, and a wide pubic symphysis. Complete loss of Runx1 or Cbfb in mice is lethal because of the absence of fetal liver hematopoiesis. Fetal rescue in Cbfb(-/-) mice by providing the Cbfb functions in the hematopoietic progenitors leads to wide fontanelle and delayed chondrocyte maturation, presumably resulting from the incomplete function of the transcriptional pathway mediated by the Cbfb-Runx2 heterodimer. The present report describes a patient with a small deletion of chromosome 16q22.1 encompassing CBFB. Skeletal abnormalities included a widely open fontanelle, multiple wormian bones along the sagittal suture, hypoplasia of the distal phalanges, and mildly shortened clavicles. G-banding analysis revealed a shortening of the 16q22.1 band. A fluorescence in situ hybridization analysis, using the BAC probe spanning the CBFB locus at 16q22.1, revealed that the CBFB probe hybridized to only one of the two homologous chromosome 16 regions. Array-comparative genomic hybridization analysis revealed that the deletion spans 1.2 megabases. In reviewing eight previously reported cases of 16q interstitial deletions involving band q22, large cranial sutures were noted in all but one case. Considering the phenotypic similarity of the 16q22 deletion case and Cbfb(-/-) mice rescued for hematopoiesis and the consistency of the phenotype among 16q22 deletion cases, we suggest that the common phenotypic feature of the 16q22 deletion, large fontanelles, can be attributed to a haploinsufficiency of CBFB.
Animals↗
[CT imaging findings in congenital tuberculosis, Part I: Usefulness of periportal hypodensity in the diagnosis of congenital tuberculosis].
We treated three newborns and early infants with congenital tuberculosis between 1996 and 2001. We reported imaging presentations of the three cases born in and after 1996 when new CT equipment (CT-HAS-SGS, GE-Yokokawa, Tokyo) was introduced in our institute. These three cases of congenital tuberculosis showed periportal hypodensity, in addition to pulmonary infiltrate, mediastinal and abdominal lymphadenopathy on CT images. Early diagnosis of congenital tuberculosis is urgently needed, however, it is very difficult. Our findings suggested that clinical suspicion supplemented by careful imaging examinations may facilitate the early diagnosis of congenital tuberculosis, and the detection of periportal hypodensity may offer a new additive diagnostic option to congenital tuberculosis.
Adult↗
[An infant with tuberculosis who previously contacted an infant with congenital tuberculosis].
We report a case of one-year and three-month old male infant with healed tuberculosis who was found by positive tuberculin skin test prior to scheduled BCG vaccination. Abdominal CT imaging revealed calcification in liver, spleen, and lymphnodes along pancreas and hepato-duodenal ligament, despite of normal chest imaging. A temporary intubated infant with congenital tuberculosis and/or his mother with untreated tuberculosis might infect him during his stay in the same NICU when he had digestive disease at three-month old. This report suggests that periodic contact investigation is needed for infants who had contact with the intubated infant with congenital tuberculosis in the same room, since cell-mediated immunity is not well developed in infants.
Cross Infection↗