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Gen Nishimura - One of the best experts on this subject based on the ideXlab platform.
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a novel nkx3 2 mutation associated with perinatal lethal phenotype of spondylo megaepiphyseal Metaphyseal Dysplasia in a neonate
European Journal of Medical Genetics, 2019Co-Authors: Pelin Ozlem Simsekkiper, Gen Nishimura, Can Kosukcu, Ozlem Akgundogan, Rahsan Gocmen, Gulen Eda Utine, Tutku Soyer, Ayse Korkmaztoygar, Mehmet Alikasifoglu, Koray BodurogluAbstract:Spondylo-megaepiphyseal-Metaphyseal Dysplasia (SMMD) is an autosomal recessive skeletal Dysplasia, characterized by disproportionate short stature with a short and stiff neck and trunk. SMMD is caused by inactivating mutations in NKX3-2, which encodes a homeobox-containing protein. Because of the rarity of the disorder, the diagnostic feature has not been fully established yet. We describe an affected newborn with dysmorphic facial features and severe short trunk. The patient required immediate intubation at the delivery room and duodenal atresia was detected during his course in neonatal intensive care unit. Skeletal survey revealed total absence of the ossification of the vertebral bodies, pubis, and ischia. Mainly the femora was short and broad with mild flaring of the metaphyses. The downward sloping or tented appearance of the ribs was distinctive. A diagnosis of SMMD was made on clinical and radiological grounds. Molecular analysis revealed homozygosity for a novel mutation, c.507-508delCA (p.Gly171Cysfs*55) in exon 2 of NKX3-2. The patient was operated on postnatal day 7 for duodenal atresia. In the post-operative period he developed sepsis and respiratory failure and he died on postnatal day 14. Although no neuroradiologic imaging could be performed, the findings of clubfoot, neuromuscular respiratory insufficiency requiring invasive mechanical ventilation and downward sloping or tented appearance of the ribs were suggestive of very early cervical cord compression leading to perinatal mortality. To our knowledge this patient yet represents one of the most severe postnatal phenotypes of SMMD.
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Identification of biallelic EXTL3 mutations in a novel type of spondylo-epi-Metaphyseal Dysplasia
Journal of Human Genetics, 2017Co-Authors: Long Guo, Zheng Wang, Naomichi Matsumoto, Noriko Miyake, Nursel H Elcioglu, Shuji Mizumoto, Bilge Noyan, Hatice M Albayrak, Shuhei Yamada, Gen NishimuraAbstract:Spondylo-epi-Metaphyseal Dysplasia (SEMD) is a group of inherited skeletal diseases characterized by the anomalies in spine, epiphyses and metaphyses. SEMD is highly heterogeneous and >20 distinct entities have been identified. Here we describe a novel type of SEMD in two unrelated Turkish patients who presented with severe platyspondyly, kyphoscoliosis, pelvic distortion, constriction of the proximal femora and brachydactyly. Although these phenotypes overlap considerably with some known SEMDs, they had a novel causal gene, exostosin-like glycosyltransferase 3 ( EXTL3 ), that encodes a glycosyltransferase involved in the synthesis of heparin and heparan sulfate. The EXTL3 mutation identified in the patients was a homozygous missense mutation (c.953C>T) that caused a substitution in a highly conserved amino acid (p.P318L). The enzyme activity of the mutant EXTL3 protein was significantly decreased compared to the wild-type protein. Both patients had spinal cord compression at the cranio-vertebral junction and multiple liver cysts since early infancy. One of the patients showed severe immunodeficiency, which is considered non-fortuitous association. Our findings would help define a novel type of SEMD caused by EXTL3 mutations.
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Identification of a novel LRRK1 mutation in a family with osteosclerotic Metaphyseal Dysplasia
Journal of Human Genetics, 2017Co-Authors: Long Guo, Anju Shukla, Aritoshi Iida, Gen Nishimura, Katta M Girisha, Malavika Hebbar, Hitesh Shah, Naomichi Matsumoto, Shifa Nismath, Noriko MiyakeAbstract:Osteosclerotic Metaphyseal Dysplasia (OSMD) is a rare skeletal Dysplasia characterized by osteosclerotic metaphyses with osteopenic diaphyses of the long tubular bones. Our previous study identified a homozygous elongation mutation in leucine-rich repeat kinase 1 gene ( LRRK1 ) in a patient with OSMD and showed that Lrrk1 knockout mice exhibited phenotypic similarity with OSMD. Here we report a second LRRK1 mutation in Indian sibs with OSMD. They had homozygous mutation (c.5971_5972insG) that produces an elongated mutant protein (p.A1991Gfs*31) similar to the first case. The sibs had normal stature, normal intelligence and recurrent fractures. The common radiographic feature was asymmetric and variable sclerosis of vertebral end plates, pelvic margin and metaphyses of tubular bones. One of the sibs had facial dysmorphisms, dentine abnormalities and acro-osteolysis. A comparison between the three OSMD cases with LRRK1 mutations with different ages suggested that the sclerotic lesions resolved with age. Our findings further support that LRRK1 would cause a subset of OSMD cases.
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acroscyphoDysplasia as a phenotypic variation of pseudohypoparathyroidism and acrodysostosis type 2
American Journal of Medical Genetics Part A, 2014Co-Authors: Toshikatsu Mitsui, Gen Nishimura, Christine Hall, A C Offiah, D Johnson, Shun Soneda, Dai Keino, Shohei Matsubayashi, Tomohiro Ishii, Tomonobu HasegawaAbstract:AcroscyphoDysplasia (OMIM250215) is a distinctive form of Metaphyseal Dysplasia characterized by the distal femoral and proximal tibial epiphyses embedded in cup-shaped, large metaphyses known as Metaphyseal scypho (“scypho” = cup) deformity. It is also associated with severe growth retardation and brachydactyly. The underlying molecular mechanism of acroscyphoDysplasia has not yet been elucidated, although scypho-deformity of the knee has been reported in three patients with acrodysostosis due to a mutation in the PDE4D gene. We report on the clinical, radiological, and molecular findings of five female patients with acroscyphoDysplasia; two were diagnosed as pseudohypoparathyroidism (PHP) or Albright hereditary osteodystropy, and the other three as acrodysostosis. They all had radiological findings consistent with severe Metaphyseal scypho-deformity and brachydactyly. Heterozygous mutations were identified in the PHP patients consisting of one novel (p.Q19X) and one recurrent (p.R231C) mutation of the GNAS gene, as well as, in the acrodysostosis patients consisting of two novel mutations (p.T224I and p.I333T) of the PDE4D gene. We conclude that Metaphyseal acroscyphoDysplasia is a phenotypic variation of PHP or acrodysostosis caused by either a GNAS or PDE4D mutation, respectively. © 2014 Wiley Periodicals, Inc.
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genetic deficiency of tartrate resistant acid phosphatase associated with skeletal Dysplasia cerebral calcifications and autoimmunity
Nature Genetics, 2011Co-Authors: Ekkehart Lausch, Yasemin Alanay, Gen Nishimura, Andreas R Janecke, Matthias Bros, Stefanie Trojandt, Corinne De Laet, Christian A Hubner, Peter Meinecke, Mari MatsuoAbstract:Vertebral and Metaphyseal Dysplasia, spasticity with cerebral calcifications, and strong predisposition to autoimmune diseases are the hallmarks of the genetic disorder spondyloenchondroDysplasia. We mapped a locus in five consanguineous families to chromosome 19p13 and identified mutations in ACP5, which encodes tartrate-resistant phosphatase (TRAP), in 14 affected individuals and showed that these mutations abolish enzyme function in the serum and cells of affected individuals. Phosphorylated osteopontin, a protein involved in bone reabsorption and in immune regulation, accumulates in serum, urine and cells cultured from TRAP-deficient individuals. Case-derived dendritic cells exhibit an altered cytokine profile and are more potent than matched control cells in stimulating allogeneic T cell proliferation in mixed lymphocyte reactions. These findings shed new light on the role of osteopontin and its regulation by TRAP in the pathogenesis of common autoimmune disorders.
Yolande Van Bever - One of the best experts on this subject based on the ideXlab platform.
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severe neurologic manifestations from cervical spine instability in spondylo megaepiphyseal Metaphyseal Dysplasia
American Journal of Medical Genetics Part C-seminars in Medical Genetics, 2012Co-Authors: Marleen Simon, Ana Belinda Camposxavier, Laureane Mittazcrettol, Carlos Eduardo Speckmartins, Daniel R Carvalho, Eugenia Ribeiro Valadares, Sheela Nampoothiri, Ercan Mihci, Yasemin Alanay, Yolande Van BeverAbstract:Spondylo-megaepiphyseal-Metaphyseal Dysplasia (SMMD; OMIM 613330) is a dysostosis/Dysplasia caused by recessive mutations in the homeobox-containing gene, NKX3-2 (formerly known as BAPX1). Because of the rarity of the condition, its diagnostic features and natural course are not well known. We describe clinical and radiographic findings in six patients (five of which with homozygous mutations in the NKX3-2 gene) and highlight the unusual and severe changes in the cervical spine and the neurologic complications. In individuals with SMMD, the trunk and the neck are short, while the limbs, fingers and toes are disproportionately long. Radiographs show a severe ossification delay of the vertebral bodies with sagittal and coronal clefts, missing ossification of the pubic bones, large round "balloon-like" epiphyses of the long bones, and presence of multiple pseudoepiphyses at all metacarpals and phalanges. Reduced or absent ossification of the cervical vertebrae leads to cervical instability with anterior or posterior kinking of the cervical spine (swan neck-like deformity, kyknodysostosis). As a result of the cervical spine instability or deformation, five of six patients in our series suffered cervical cord injury that manifested clinically as limb spasticity. Although the number of individuals observed is small, the high incidence of cervical spine deformation in SMMD is unique among skeletal Dysplasias. Early diagnosis of SMMD by recognition of the radiographic pattern might prevent of the neurologic complications via prophylactic cervical spine stabilization.
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severe neurologic manifestations from cervical spine instability in spondylo megaepiphyseal Metaphyseal Dysplasia
American Journal of Medical Genetics Part C-seminars in Medical Genetics, 2012Co-Authors: Marleen Simon, Ana Belinda Camposxavier, Laureane Mittazcrettol, Carlos Eduardo Speckmartins, Daniel R Carvalho, Eugenia Ribeiro Valadares, Sheela Nampoothiri, Ercan Mihci, Yasemin Alanay, Yolande Van BeverAbstract:Spondylo-megaepiphyseal-Metaphyseal Dysplasia (SMMD; OMIM 613330) is a dysostosis/Dysplasia caused by recessive mutations in the homeobox-containing gene, NKX3-2 (formerly known as BAPX1). Because of the rarity of the condition, its diagnostic features and natural course are not well known. We describe clinical and radiographic findings in six patients (five of which with homozygous mutations in the NKX3-2 gene) and highlight the unusual and severe changes in the cervical spine and the neurologic complications. In individuals with SMMD, the trunk and the neck are short, while the limbs, fingers and toes are disproportionately long. Radiographs show a severe ossification delay of the vertebral bodies with sagittal and coronal clefts, missing ossification of the pubic bones, large round "balloon-like" epiphyses of the long bones, and presence of multiple pseudoepiphyses at all metacarpals and phalanges. Reduced or absent ossification of the cervical vertebrae leads to cervical instability with anterior or posterior kinking of the cervical spine (swan neck-like deformity, kyknodysostosis). As a result of the cervical spine instability or deformation, five of six patients in our series suffered cervical cord injury that manifested clinically as limb spasticity. Although the number of individuals observed is small, the high incidence of cervical spine deformation in SMMD is unique among skeletal Dysplasias. Early diagnosis of SMMD by recognition of the radiographic pattern might prevent of the neurologic complications via prophylactic cervical spine stabilization.
Suijlekom-smit, L.w.a. Van - One of the best experts on this subject based on the ideXlab platform.
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Ichthyosis, exocrine pancreatic insufficiency, impaired neutrophil chemotaxis, growth retardation, and Metaphyseal Dysplasia (Shwachman syndrome).
'American Medical Association (AMA)', 1991Co-Authors: Goeteyn M., Ronald De Groot, Oranje A.p., Vuzevski V.d., Suijlekom-smit, L.w.a. VanAbstract:The Shwachman syndrome comprises exocrine pancreatic insufficiency, growth retardation, and bone marrow hypoplasia resulting in neutropenia. Clinical, morphological, and ultrastructural studies, as well as hair analysis, were performed in a patient with Shwachman's syndrome and severe ichthyosis. Clinical findings were lamellar ichthyosiform desquamation on the extremities. The hair was scanty and short on the scalp, in the eyelashes, and in the eyebrows. The nails were hyperkeratotic. Morphologic findings were slight, regular acanthosis and severe diffuse hyperkeratosis with variable parakeratosis. The granular layer was thickened. The papillary dermis showed very slight perivascular lymphocyte infiltration. The most prominent ultrastructural finding was the presence of solitary or multiple droplets of varying size in the cytoplasm of the keratinocytes. Hair analysis revealed no abnormalities; the cystine concentration in hair specimens was normal
Marleen Simon - One of the best experts on this subject based on the ideXlab platform.
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severe neurologic manifestations from cervical spine instability in spondylo megaepiphyseal Metaphyseal Dysplasia
American Journal of Medical Genetics Part C-seminars in Medical Genetics, 2012Co-Authors: Marleen Simon, Ana Belinda Camposxavier, Laureane Mittazcrettol, Carlos Eduardo Speckmartins, Daniel R Carvalho, Eugenia Ribeiro Valadares, Sheela Nampoothiri, Ercan Mihci, Yasemin Alanay, Yolande Van BeverAbstract:Spondylo-megaepiphyseal-Metaphyseal Dysplasia (SMMD; OMIM 613330) is a dysostosis/Dysplasia caused by recessive mutations in the homeobox-containing gene, NKX3-2 (formerly known as BAPX1). Because of the rarity of the condition, its diagnostic features and natural course are not well known. We describe clinical and radiographic findings in six patients (five of which with homozygous mutations in the NKX3-2 gene) and highlight the unusual and severe changes in the cervical spine and the neurologic complications. In individuals with SMMD, the trunk and the neck are short, while the limbs, fingers and toes are disproportionately long. Radiographs show a severe ossification delay of the vertebral bodies with sagittal and coronal clefts, missing ossification of the pubic bones, large round "balloon-like" epiphyses of the long bones, and presence of multiple pseudoepiphyses at all metacarpals and phalanges. Reduced or absent ossification of the cervical vertebrae leads to cervical instability with anterior or posterior kinking of the cervical spine (swan neck-like deformity, kyknodysostosis). As a result of the cervical spine instability or deformation, five of six patients in our series suffered cervical cord injury that manifested clinically as limb spasticity. Although the number of individuals observed is small, the high incidence of cervical spine deformation in SMMD is unique among skeletal Dysplasias. Early diagnosis of SMMD by recognition of the radiographic pattern might prevent of the neurologic complications via prophylactic cervical spine stabilization.
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severe neurologic manifestations from cervical spine instability in spondylo megaepiphyseal Metaphyseal Dysplasia
American Journal of Medical Genetics Part C-seminars in Medical Genetics, 2012Co-Authors: Marleen Simon, Ana Belinda Camposxavier, Laureane Mittazcrettol, Carlos Eduardo Speckmartins, Daniel R Carvalho, Eugenia Ribeiro Valadares, Sheela Nampoothiri, Ercan Mihci, Yasemin Alanay, Yolande Van BeverAbstract:Spondylo-megaepiphyseal-Metaphyseal Dysplasia (SMMD; OMIM 613330) is a dysostosis/Dysplasia caused by recessive mutations in the homeobox-containing gene, NKX3-2 (formerly known as BAPX1). Because of the rarity of the condition, its diagnostic features and natural course are not well known. We describe clinical and radiographic findings in six patients (five of which with homozygous mutations in the NKX3-2 gene) and highlight the unusual and severe changes in the cervical spine and the neurologic complications. In individuals with SMMD, the trunk and the neck are short, while the limbs, fingers and toes are disproportionately long. Radiographs show a severe ossification delay of the vertebral bodies with sagittal and coronal clefts, missing ossification of the pubic bones, large round "balloon-like" epiphyses of the long bones, and presence of multiple pseudoepiphyses at all metacarpals and phalanges. Reduced or absent ossification of the cervical vertebrae leads to cervical instability with anterior or posterior kinking of the cervical spine (swan neck-like deformity, kyknodysostosis). As a result of the cervical spine instability or deformation, five of six patients in our series suffered cervical cord injury that manifested clinically as limb spasticity. Although the number of individuals observed is small, the high incidence of cervical spine deformation in SMMD is unique among skeletal Dysplasias. Early diagnosis of SMMD by recognition of the radiographic pattern might prevent of the neurologic complications via prophylactic cervical spine stabilization.
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homozygous inactivating mutations in the nkx3 2 gene result in spondylo megaepiphyseal Metaphyseal Dysplasia
American Journal of Human Genetics, 2009Co-Authors: Jan Hellemans, Marleen Simon, Ercan Mihci, Yasemin Alanay, Annelies Dheedene, Laila Rifai, Abdelaziz Sefiani, Yolande Van Bever, Morteza Meradji, Andrea SupertifurgaAbstract:Spondylo-megaepiphyseal-Metaphyseal Dysplasia (SMMD) is a rare skeletal Dysplasia with only a few cases reported in the literature. Affected individuals have a disproportionate short stature with a short and stiff neck and trunk. The limbs appear relatively long and may show flexion contractures of the distal joints. The most remarkable radiographic features are the delayed and impaired ossification of the vertebral bodies as well as the presence of large epiphyseal ossification centers and wide growth plates in the long tubular bones. Numerous pseudoepiphyses of the short tubular bones in hands and feet are another remarkable feature of the disorder. Genome wide homozygosity mapping followed by a candidate gene approach resulted in the elucidation of the genetic cause in three new consanguineous families with SMMD. Each proband was homozygous for a different inactivating mutation in NKX3-2, a homeobox-containing gene located on chromosome 4p15.33. Striking similarities were found when comparing the vertebral ossification defects in SMMD patients with those observed in the Nkx3-2 null mice. Distinguishing features were the asplenia found in the mutant mice and the radiographic abnormalities in the limbs only observed in SMMD patients. The absence of the latter anomalies in the murine model may be due to the perinatal death of the affected animals. This study illustrates that NKX3-2 plays an important role in endochondral ossification of both the axial and appendicular skeleton in humans. In addition, it defines SMMD as yet another skeletal Dysplasia with autosomal-recessive inheritance and a distinct phenotype.
K. Kozlowski - One of the best experts on this subject based on the ideXlab platform.
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the manifestations and natural history of spondylo epi Metaphyseal Dysplasia with joint laxity
Clinical Genetics, 2008Co-Authors: Peter Beighton, K. Kozlowski, G S Gericke, L GroblerAbstract:Spondylo-epi-Metaphyseal Dysplasia with joint laxity (SEMDJL) is characterized by severe dwarfism, articular hypermobility and progressive spinal malalignment. The clinical manifestations of 18 affected persons in 13 families of the Afrikans-speaking community of South Africa have been analysed and it has become evident that survival into adulthood is unusual. SEMDJL is inherited as an autosomal recessive trait.
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distinctive new form of spondyloepiMetaphyseal Dysplasia with severe Metaphyseal changes similar to jansen Metaphyseal chondroDysplasia
Journal of Medical Imaging and Radiation Oncology, 2005Co-Authors: Ali Al Kaissi, Maher Ben Ghachem, N Nessib, Farid Ben Chehida, A Hammou, K. KozlowskiAbstract:Summary We report a boy with a unique, ‘new’ form of spondyloepiMetaphyseal Dysplasia. The conspicuous features of the spinal changes were the delay in ossification of the cervical spine and posterior elements of the thoraco-lumbar spine. The vertebral bodies were of abnormal shape but of normal size and well ossified. The hallmark of epiphyseal changes was markedly delayed ossification (bone age). The severely disturbed Metaphyseal ossification was similar to Jansen Metaphyseal Dysplasia. This pattern of changes has not yet been described in spondyloepiMetaphyseal Dysplasia.
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dutch variant of bellini Metaphyseal Dysplasia report of two siblings
Journal of Medical Imaging and Radiation Oncology, 1995Co-Authors: K. Kozlowski, M Meradji, F A BeemerAbstract:SUMMARY Two sibling girls with cone-shaped knee epiphyses and metaphyses are described. Bone Dysplasia with this rare, distinctive, radiographic finding, was first reported by Bellini and Bardare with only few cases reported thereafter. Velores et al. divided bone Dysplasias with cone-shaped epiphyses and metaphyses of the knee in two entities which they named trichoscyphoDysplasia and Metaphyseal acroscyphoDysplasia. Although the authors agree that there is more than one bone Dysplasia that presents with these distinctive radiographic knee appearances, they consider that too few cases have been reported to satisfactorily classify this group of disorders.
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japanese type of spondylo Metaphyseal Dysplasia
Pediatric Radiology, 1994Co-Authors: Tomonobu Hasegawa, K. Kozlowski, Gen Nishimura, H Hara, Y Hasegawa, Taiji Aso, Shinobu Koto, Toshiro Nagai, Yutaka TsuchiyaAbstract:Five members of a Japanese family with a new form of spondylo-Metaphyseal Dysplasia (SMD) are reported. Another member was also probably affected. The disease was characterised by severe coxa vara, moderately severe Metaphyseal changes of the long bones of the lower limbs, mild changes in the long bones of the upper limbs and grossly normal short tubular bones. Platyspondyly, present in the boys, was less marked in their father, whereas two affected aunts had normally shaped vertebral bodies.
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spondylo Metaphyseal Dysplasia report of two cases of common type and delineation of a new variety with rectangular vertebral bodies
European Radiology, 1993Co-Authors: K. Kozlowski, L Brahimi, H Ilyina, I W Lurie, R MassenAbstract:Spondylo-Metaphyseal Dysplasia is a group of bone Dysplasia characterised by spinal and Metaphyseal involvement. Two patients with common type and two with a “new” variety of spondylo-Metaphyseal Dysplasia are reported. The latter is characterised by rectangular shape of the vertebral bodies and small carpal/tsrsal ossification centres without severe bone age retardation which characterists the common type. We propose to call it spondylo-Metaphyseal Dysplasia common type II.