RESUMEN
BACKGROUND: Cervical spine deformity in rhizomelic chondrodysplasia punctata (RCDP) has been described with different findings reported in the literature. However, available literature provides limited data from a few cases with magnetic resonance imaging (MRI) of the cervical spine. Our report describes the MRI findings in a group of children with RCDP, aiming to reach a better understanding of this pathology. METHODS: An Institutional Review Board-approved RCDP Registry was created at our institution with the goal of identifying pertinent medical issues over the lifespan of individuals with RCDP. Records of children within the registry were evaluated, and magnetic resonance images obtained between 2004 and 2015, were available for review. The levels of spinal canal stenosis were recorded and the severity of the stenosis was decided based on adults' parameters. Cord compression and myelomalacia were confirmed on the axial images. Sagittal lumbar spine magnetic resonance images were also evaluated when available, and the presence of tethered cord and fatty filum was recorded. RESULTS: Twenty-six children (15 boys and 11 girls) were identified in the RCDP Registry. Eleven children (6 boys and 5 girls) had sagittal MRI of the cervical spine available for review. Age at the time of MRI study was variable (1 wk to 32 mo). All patients except 1 had stenosis of the cervical spinal canal. Myelomalacia of the cord was noted only in this patient. CONCLUSIONS: This study suggests that, in children with RCDP, cervical spinal stenosis and cord compression are a real risk, and children with this diagnosis should have monitoring for these issues. Tethered cord is also a possible finding that needs to be evaluated. Full sagittal spine MRI is necessary to detect the possible deformities at the cervical and lumbar levels.
Asunto(s)
Vértebras Cervicales/patología , Condrodisplasia Punctata Rizomélica/complicaciones , Compresión de la Médula Espinal/etiología , Estenosis Espinal/etiología , Vértebras Cervicales/diagnóstico por imagen , Preescolar , Condrodisplasia Punctata Rizomélica/diagnóstico por imagen , Condrodisplasia Punctata Rizomélica/patología , Constricción Patológica , Femenino , Humanos , Lactante , Vértebras Lumbares/diagnóstico por imagen , Vértebras Lumbares/patología , Imagen por Resonancia Magnética , Masculino , Canal Medular/diagnóstico por imagen , Canal Medular/patología , Compresión de la Médula Espinal/diagnóstico por imagen , Compresión de la Médula Espinal/patología , Enfermedades de la Médula Espinal , Estenosis Espinal/diagnóstico por imagen , Estenosis Espinal/patologíaRESUMEN
BACKGROUND: Rhizomelic chondrodysplasia punctata (RCDP) is an autosomal recessive peroxisomal disorder characterised by rhizomelia, contractures, congenital cataracts, facial dysmorphia, severe psychomotor defects and growth retardation. Biochemically, the levels of plasmalogens (major constituents of cellular membranes) are low due to a genetic defect in their biosynthesis. Cardiac muscle contains high concentrations of plasmalogens. Recently cardiac dysfunction was found in a mouse model for RCDP with undetectable plasmalogen levels in all tissues including the heart. This suggests the importance of plasmalogens in normal cardiac development and function. Congenital heart disease (CHD), however, has not been recognised as a major characteristic of RCDP. AIMS: We aimed to determine the prevalence of CHD found in RCDP patients as well as to describe genetic, biochemical and cardiac correlations. METHODS: We included 23 patients with genetically proven RCDP. The genetic, biochemical and physical data were evaluated. Echocardiograms were reviewed. RESULTS: Cardiac data were available for 18 patients. 12 (52%) had CHD. All twelve had type 1 RCDP and 11 (92%) had the PEX 7:c.875T>A mutation, of whom seven were homozygous (58%). Plasmalogen levels were significantly lower in the patients with CHD. Cardiac lesions included: septal defects (80% atrial), patent ductus arteriosus, pulmonary artery hypoplasia, tetralogy of Fallot and mitral valve prolapse (mostly older patients). CONCLUSIONS: The CHD prevalence among RCDP patients was at least 52%, significantly higher than among the normal population. Plasmalogen levels were significantly lower in patients with CHD. Routine cardiac evaluation should be included in the clinical management of RCDP patients.
Asunto(s)
Condrodisplasia Punctata Rizomélica/patología , Cardiopatías Congénitas/epidemiología , Miocardio/patología , Adolescente , Adulto , Niño , Preescolar , Condrodisplasia Punctata Rizomélica/complicaciones , Femenino , Cardiopatías Congénitas/complicaciones , Cardiopatías Congénitas/patología , Homocigoto , Humanos , Lactante , Masculino , Mutación , Plasmalógenos/biosíntesis , PrevalenciaAsunto(s)
Calcinosis/diagnóstico , Condrodisplasia Punctata Rizomélica/complicaciones , Epífisis/diagnóstico por imagen , Húmero/diagnóstico por imagen , Calcinosis/etiología , Condrodisplasia Punctata Rizomélica/diagnóstico , Diagnóstico Diferencial , Femenino , Pruebas Genéticas , Humanos , Recién Nacido , Receptor de la Señal 2 de Direccionamiento al Peroxisoma/deficiencia , RadiografíaRESUMEN
Rhizomelic chondrodysplasia punctata (RCDP) is an autosomal-recessive disorder resulting from mutations in one of three peroxisomal genes essential for ether lipid biosynthesis, PEX7 (RCDP1), GNPAT (RCDP2), and AGPS (RCDP3). Affected patients have characteristic features including shortening of the proximal long bones, epiphyseal stippling, bilateral cataracts, growth and developmental delays. Whereas the majority of patients have RCDP type 1, around 5% have RCDP type 2 or 3. We identified a patient with RCDP type 2 and an apparent homozygous deletion, c.1428delC, after full sequencing of his GNPAT genes. The father was heterozygous for this mutation, while sequencing of the maternal GNPAT genes revealed only wild-type sequence. Southern analyses performed on parental gDNA did not show evidence of a maternal gene deletion. Amplification and fragment analysis of dinucleotide repeat markers spanning chromosome 1 in the patient and both parents revealed paternal uniparental inheritance. We discuss the potential mechanisms causing uniparental disomy (UPD) in this patient and review the literature on chromosome 1 UPD. The absence of non-RCDP clinical features in this patient was consistent with previous literature supporting the absence of imprinted genes on chromosome 1. This first description of RCDP caused by UPD dramatically changes the parental recurrence risk, highlighting the value of obtaining parental genotypes when the proband has a putative homozygous mutation by sequence analysis.
Asunto(s)
Condrodisplasia Punctata Rizomélica/genética , Cromosomas Humanos Par 1/genética , Padre , Disomía Uniparental/genética , Secuencia de Bases , Condrodisplasia Punctata Rizomélica/complicaciones , Análisis Mutacional de ADN , Femenino , Deformidades Congénitas de la Mano/complicaciones , Deformidades Congénitas de la Mano/diagnóstico por imagen , Humanos , Lactante , Recién Nacido , Deformidades Congénitas de las Extremidades/complicaciones , Deformidades Congénitas de las Extremidades/diagnóstico por imagen , Masculino , Datos de Secuencia Molecular , Linaje , Embarazo , RadiografíaRESUMEN
In three young patients who presented with bilateral cataracts the cause proved to be an inherited metabolic disease. The first patient was a newborn aged 7 weeks, in whom galactokinase deficiency was diagnosed. The second patient was a boy aged 8 years with cerebrotendinous xanthomatosis. The third patient was a girl who was diagnosed with cataracts at the age of 3 months. At the age of 4 years the diagnosis 'rhizomelic chondrodysplasia punctata' was established. Screening for metabolic disorders in all children with bilateral cataracts is essential, as in some disorders progressive and severe symptoms can be avoided with timely initiation of treatment. In addition, diagnosis allows for family studies and genetic counselling to take place. This may result in prevention of disease by early therapeutic intervention and prenatal screening.
Asunto(s)
Catarata/etiología , Condrodisplasia Punctata Rizomélica/diagnóstico , Galactosemias/diagnóstico , Xantomatosis/diagnóstico , Catarata/prevención & control , Niño , Condrodisplasia Punctata Rizomélica/complicaciones , Femenino , Galactosemias/complicaciones , Asesoramiento Genético , Humanos , Lactante , Masculino , Xantomatosis/complicacionesAsunto(s)
Condrodisplasia Punctata Rizomélica/complicaciones , Condrodisplasia Punctata Rizomélica/diagnóstico , Insuficiencia Respiratoria/complicaciones , Insuficiencia Respiratoria/diagnóstico , Condrodisplasia Punctata Rizomélica/genética , Resultado Fatal , Homocigoto , Humanos , Recién Nacido , Mutación , Receptor de la Señal 2 de Direccionamiento al Peroxisoma , Receptores Citoplasmáticos y Nucleares/genética , Insuficiencia Respiratoria/genéticaRESUMEN
Rhizomelic chondrodysplasia punctata (RCDP) is a rare peroxisomal disorder leading to multiple developmental malformations, including skeletal deformity. Specifically, involvement of the vertebral bodies has been described. Presented here is a case of a two-year-old female child with RCDP leading to advanced cervical stenosis as detected on magnetic resonance imaging (MRI) studies of the cervical spine. The practicing clinician should be aware of the possibility of cervical stenosis secondary to RCDP and its impact on the management of the patient with this rare disease process.
Asunto(s)
Condrodisplasia Punctata Rizomélica/complicaciones , Estenosis Espinal/etiología , Vértebras Cervicales/patología , Preescolar , Condrodisplasia Punctata Rizomélica/patología , Femenino , Humanos , Imagen por Resonancia Magnética , Canal Medular/patología , Estenosis Espinal/patologíaRESUMEN
A newborn male with the characteristic phenotype of classic rhizomelic chondrodysplasia punctata (RCDP) and with the usual and severe radiographic skeletal abnormalities is described. The parents were young, healthy, and not consanguineous; the mother had not used licit or illicit drugs, alcohol, or tobacco during pregnancy and had not been exposed to radiation or teratogenic chemicals. The clinical phenotype led us to study peroxisomal function. Plasmalogen content in erythrocytes, membrane, and fibroblasts; dihydroxyacetone phosphate acyltransferase (DHAP-AT), alkyldehydroxyaceton phosphate synthetase (a gift from Professor Henk van der Boch, Utrech) in fibroblasts; and phytanic and pristanic acids in plasma showed normal values. Immunocytofluorescence study with antibodies against peroxisomal membrane showed normal organelles. We found no reference in the literature of a case of RCDP with normal peroxisomal functions, but non-CDP has been described with peroxisomal dysfunction. This phenotype (RCDP) may be due to other metabolic error.
Asunto(s)
Condrodisplasia Punctata Rizomélica/diagnóstico por imagen , Enanismo/diagnóstico por imagen , Aciltransferasas/sangre , Condrodisplasia Punctata Rizomélica/sangre , Condrodisplasia Punctata Rizomélica/complicaciones , Dihidroxiacetona Fosfato/sangre , Resultado Fatal , Ácidos Grasos/sangre , Humanos , Recién Nacido , Masculino , Fenotipo , Ácido Fitánico/sangre , Plasmalógenos/sangre , Radiografía , Insuficiencia Respiratoria/etiologíaRESUMEN
Chondrodysplasia punctata (CDP) is a rare skeletal dysplasia characterized by stippled epiphyses during infancy. The frequency is probably underdiagnosed because of the large heterogeneity in this group. Many genotypic variations exist. Although cervical instability is commonly seen in many skeletal dysplasias, cervical spine stenosis associated with CDP is very rare. We report a boy with phenotypic features of brachytelephalangic chondrodysplasia punctata (BCDP) who had severe cervical spine stenosis successfully corrected by vertebrectomies of C6 and C7 with a fibular strut graft. We discuss the significance of this association.
Asunto(s)
Vértebras Cervicales/patología , Condrodisplasia Punctata Rizomélica/patología , Médula Espinal/patología , Estenosis Espinal/patología , Vértebras Cervicales/cirugía , Preescolar , Condrodisplasia Punctata Rizomélica/complicaciones , Condrodisplasia Punctata Rizomélica/genética , Descompresión Quirúrgica/métodos , Genes Recesivos , Humanos , Laminectomía , Imagen por Resonancia Magnética , Masculino , Compresión de la Médula Espinal/etiología , Compresión de la Médula Espinal/patología , Compresión de la Médula Espinal/cirugía , Estenosis Espinal/etiología , Estenosis Espinal/cirugíaRESUMEN
Rhizomelic chondrodysplasia punctata (RCP), a rare autosomal recessive disease characterized by a disorder of peroxisome metabolism, has been shown to affect multiple organ systems. A neonate presenting with a colonic perforation in the first few hours of life was subsequently diagnosed with RCP. A literature search revealed no previous reports of intestinal perforation associated with RCP. Intestinal perforation should be added to the list of medical complications associated with RCP.
Asunto(s)
Condrodisplasia Punctata Rizomélica/complicaciones , Enfermedades del Colon/etiología , Perforación Intestinal/etiología , Condrodisplasia Punctata Rizomélica/diagnóstico , Enfermedades del Colon/diagnóstico , Diagnóstico Diferencial , Resultado Fatal , Humanos , Recién Nacido , Perforación Intestinal/diagnóstico , MasculinoRESUMEN
Rhizomelic chondrodysplasia punctata (RCP) is a rare autosomal recessive disorder with many associated medical complications. Prior to this study, natural history information about RCP was limited and based on experiences with small populations of affected individuals. We delineate the natural history of RCP through systematic analysis of 35 previously unreported individuals (as well as review of 62 literature cases with respect to survival and cause of death). Survival, growth, and developmental expectations and medical needs are summarized based upon experience with this population. Survival is greater among this population than previously reported, with 90% surviving up to 1 year and 50% surviving up to 6 years. Cause of death is most often respiratory problem. All infants with RCP have joint contractures, bilateral cataracts, and severe growth and psychomotor delays. Recommendations for health supervision of children with RCP and for parental counseling are presented.
Asunto(s)
Condrodisplasia Punctata Rizomélica/complicaciones , Condrodisplasia Punctata Rizomélica/mortalidad , Adolescente , Niño , Preescolar , Progresión de la Enfermedad , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Encuestas y CuestionariosRESUMEN
Although known for almost 80 years, the physiological role of plasmalogens (PLs), the major mammalian ether lipids (ELs), is still enigmatic. Humans that lack ELs suffer from rhizomelic chondrodysplasia punctata (RCDP), a peroxisomal disorder usually resulting in death in early childhood. In order to learn more about the functions of ELs, we generated a mouse model for RCDP by a targeted disruption of the dihydroxyacetonephosphate acyltransferase gene. The mutant mice revealed multiple abnormalities, such as male infertility, defects in eye development, cataract and optic nerve hypoplasia, some of which were also observed in RCDP. Mass spectroscopic analysis demonstrated the presence of highly unsaturated fatty acids including docosahexaenoic acid (DHA) in brain PLs and the occurrence of PLs in lipid raft microdomains (LRMs) isolated from brain myelin. In mutants, PLs were completely absent and the concentration of brain DHA was reduced. The marker proteins flotillin-1 and F3/contactin were found in brain LRMs in reduced concentrations. In addition, the gap junctional protein connexin 43, known to be recruited to LRMs and essential for lens development and spermatogenesis, was down-regulated in embryonic fibroblasts of the EL-deficient mice. Free cholesterol, an important constituent of LRMs, was found in these fibroblasts to be accumulated in a perinuclear compartment. These data suggest that the EL-deficient mice allow the identification of new phenotypes not related so far to EL-deficiency (male sterility, defects in myelination and optic nerve hypoplasia) and indicate that PLs are required for the correct assembly and function of LRMs.
Asunto(s)
Aciltransferasas/genética , Condrodisplasia Punctata Rizomélica/genética , Silenciador del Gen , Plasmalógenos/biosíntesis , Animales , Encéfalo/anatomía & histología , Encéfalo/metabolismo , Condrodisplasia Punctata Rizomélica/complicaciones , Condrodisplasia Punctata Rizomélica/metabolismo , Conexina 43/metabolismo , Cartilla de ADN , Modelos Animales de Enfermedad , Ácidos Docosahexaenoicos/metabolismo , Técnica del Anticuerpo Fluorescente , Técnicas Histológicas , Humanos , Infertilidad Masculina/complicaciones , Masculino , Espectrometría de Masas , Microdominios de Membrana/metabolismo , Ratones , Enfermedades del Nervio Óptico/complicaciones , Reacción en Cadena de la PolimerasaRESUMEN
La condrodisplasia punctata rizomélica clásica (RCDP) es una rara enfermedad multisistémica autosómica recesiva, debida a una alteración del metabolismo peroxisomal que determina una deficiencia de la biosíntesis de plasmalógenos y de la alfaoxidación del ácido fitánico. Se caracteriza por la presencia desde el nacimiento de un acortamiento proximal de las extremidades, calcificaciones periarticulares, dismorfia facial, retraso del desarrollo y mortalidad precoz. Se presentan dos casos de RCDP clásica, o tipo I, con las dos formas clínicas de presentación, grave o mortal y leve o benigna, en relación con la existencia de actividad enzimática residual, y se revisan sus principales aspectos clínicos(AU)
Classic rhizomelic chondrodysplasia punctata (CRCP) is a rare multisystem disease, autosomal recessive disorder. It is due because a peroxisomal metabolism alteration that determine deficiency of the plasmalogen biosynthesis and the alpha oxidation of phytanic acid. It is characterized by proximal shortening of the limbs, punctuate calcifications of the epiphyses, facial dysmorphia, developmental delay and early lethality. We present two cases of CRCP type I with two different forms of presentation, one severe and another one mild or bening, in relation with the residual enzyme activity and we revise the main clinical aspects(AU)