RESUMEN
BACKGROUND: We have previously described an autosomal recessive syndrome of macrocephaly, multiple epiphyseal dysplasia (MED), and distinctive facies in a large, extended Omani family. The MED observed seems to be part of a larger malformation syndrome, since both craniofacial and central nervous system changes were present in the family. We performed a whole genome scan in this family in order to identify the gene locus for this malformation syndrome. METHODS AND RESULTS: Using homozygosity mapping, we show linkage to the telomeric region of the long arm of chromosome 15. The position of both the disease gene and the principal glycoprotein, chondroitin sulphate proteoglycan (aggrecan, AGC1) on chromosome 15q26, suggested that the aggrecan gene is a candidate for the disease in this family. However, three of the four affected children were heterozygous for a polymorphism at position 831 of the coding sequence of AGC1, providing strong evidence against its involvement. CONCLUSION: We have identified a gene locus for a recessive syndrome of macrocephaly, MED, and distinctive facies in a large Omani family. Aggrecan located on chromosome 15q26, within the critical region determined for this syndrome in this family, was excluded as a candidate gene.
Asunto(s)
Anomalías Múltiples/genética , Cromosomas Humanos Par 12 , Anomalías Craneofaciales/genética , Proteínas de la Matriz Extracelular , Facies , Genes Recesivos , Osteocondrodisplasias/genética , Anomalías Múltiples/patología , Agrecanos , Niño , Preescolar , Mapeo Cromosómico , Consanguinidad , Anomalías Craneofaciales/patología , Salud de la Familia , Femenino , Humanos , Lectinas Tipo C , Masculino , Osteocondrodisplasias/diagnóstico por imagen , Linaje , Polimorfismo de Nucleótido Simple , Proteoglicanos/genética , Radiografía , SíndromeRESUMEN
Desbuquois dysplasia is a rare autosomal recessive chondrodysplasia characterised by short stature, joint laxity, facial dysmorphism, a "Swedish key" appearance of the proximal femur, advanced carpal and tarsal bone age, and hand anomalies consisting of phalangeal dislocations and an extra ossification centre distal to the second metacarpal. However, the latter changes are not consistently observed in all Desbuquois patients, defining two distinct groups, based on the presence or absence of hand anomalies. We have performed a genome wide search in four inbred Desbuquois families with typical hand anomalies originating from France, Sri-Lanka, the United Arab Emirates, and Morocco. Here, we report on the mapping of a disease gene to chromosome 17q25.3 (Zmax=4.61 at theta=0 at locus D17S1806) in the 9.5 cM interval defined by loci D17S802 and D17S1822. The present study supports the genetic homogeneity of the clinical subtype with hand anomalies and will hopefully help in identifying the Desbuquois dysplasia gene.
Asunto(s)
Cromosomas Humanos Par 17/genética , Osteocondrodisplasias/genética , Mapeo Cromosómico , Consanguinidad , Salud de la Familia , Femenino , Ligamiento Genético , Predisposición Genética a la Enfermedad/genética , Haplotipos , Homocigoto , Humanos , Escala de Lod , Masculino , Repeticiones de Microsatélite , Osteocondrodisplasias/patología , LinajeRESUMEN
Non-syndromic sensorineural deafness is an extremely genetically heterogeneous condition. We have used autozygosity mapping in a large consanguineous United Arab Emirate family to identify a novel locus for autosomal recessive non-syndromic sensorineural deafness, DFNB27, on chromosome 2q23-q31, with a maximum two-point lod score of 5.18 at theta = 0 for marker D2S2257. The DFNB27 locus extends over a 17 cM region between D2S2157 and D2S2273, and may overlap the DFNA16 locus for dominantly inherited, fluctuating, progressive non-syndromal hearing loss. However, genotype data suggests that the locus is likely to be refined to between D2S326 and D2S2273 and thus distinct from the DFNA16 locus.
Asunto(s)
Cromosomas Humanos Par 2 , Pérdida Auditiva Sensorineural/genética , Mapeo Cromosómico , Consanguinidad , Femenino , Homocigoto , Humanos , Masculino , LinajeRESUMEN
Gerodermia osteodysplastica (GO) is a connective tissue disorder characterized by premature aging, wrinkled, and lax skin with reduced elasticity which is more marked on the dorsum of the hands and feet associated with hyperextensible joints and osteoporosis. The wrinkly skin syndrome (WSS) is characterized by wrinkled skin over the dorsum of the hands, feet, and abdomen; hyperextensible joints, particularly of the hands; intrauterine growth retardation; postnatal failure to thrive; and mental and developmental delay. We report on five children from two consanguineous Arab families with features overlapping both GO and WSS. All five children had similar dysmorphic facial features consisting of broad and prominent forehead, hypotelorism with epicanthal folds, prominent bulbous nose, flat malar region, and large protruding ears. All had wrinkling of the skin more marked on the dorsum of the hands, feet, and abdomen; hyperextensibility of the joints, particularly of the hands; and aged appearance. Intrauterine growth retardation, subsequent failure to thrive, developmental delay, and variable degree of osteoporosis was also present in all of them. The older three children developed progressive prognathism. We suggest that GO and WSS could represent variable manifestation of the same disorder.
Asunto(s)
Anomalías Múltiples/patología , Osteoporosis/patología , Anomalías Cutáneas/patología , Envejecimiento de la Piel/patología , Anomalías Múltiples/genética , Adolescente , Niño , Diagnóstico Diferencial , Salud de la Familia , Femenino , Humanos , Lactante , Articulaciones/anomalías , Masculino , SíndromeRESUMEN
We report on a child with severe midline facial cleft, bilateral cleft lip and palate, telecanthus, S-shaped palpebral fissures, limbic dermoid, midface hypoplasia, hypoplastic corpus callosum, and multiple skin appendages. This case may be an example of severe frontofacionasal "dysplasia" or a newly recognised syndrome.
Asunto(s)
Anomalías Múltiples/patología , Anomalías Craneofaciales , Anomalías Múltiples/genética , Labio Leporino , Cuerpo Calloso , Extremidades , Humanos , Masculino , Enfermedades de la Piel/patología , Síndrome , Tomógrafos Computarizados por Rayos XRESUMEN
The association of neural tube defects (NTDs) with Down syndrome (trisomy 21) and altered folate metabolism in both mother and affected offspring provide a unique opportunity for insight into the etiologic role of folate deficiency in these congenital anomalies. We describe here the case of a male child with trisomy 21, cervical meningomyelocele, agenesis of corpus callosum, hydrocephaly, cerebellar herniation into the foramen magnum, and shallow posterior cranial fossa. Molecular analysis of the methylenetetrahydrofolate (MTHFR) gene revealed homozygosity for the mutant 677C-->T polymorphism in both the mother and child. The plasma homocysteine of the mother was highly elevated at 25.0 micromol/L and was associated with a low methionine level of 22.1 micromol/L. Her S-adenosylhomocysteine (SAH) level was three times that of reference normal women, resulting in a markedly reduced ratio of S-adenosylmethionine (SAM) to SAH and significant DNA hypomethylation in lymphocytes. The child had low plasma levels of both homocysteine and methionine and a reduced SAM/SAH ratio that was also associated with lymphocyte DNA hypomethylation. In addition, the child had a five-fold increase in cystathionine level relative to normal children, consistent with over-expression of the cystathionine beta synthase gene present on chromosome 21. We suggest that altered folate status plus homozygous mutation in the MTHFR gene in the mother could promote chromosomal instability and meiotic non-disjunction resulting in trisomy 21. Altered folate status and homozygous TT mutation in the MTHFR gene in both mother and child would be expected to increase the risk of neural tube defects. The presence of both trisomy 21 and postclosure NTD in the same child supports the need for an extended periconceptional period of maternal folate supplementation to achieve greater preventive effects for both NTD and trisomy 21.
Asunto(s)
Síndrome de Down/patología , Ácido Fólico/metabolismo , Defectos del Tubo Neural/patología , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/genética , Aminoácidos Sulfúricos/sangre , Consanguinidad , ADN/genética , ADN/metabolismo , Metilación de ADN , Síndrome de Down/enzimología , Síndrome de Down/genética , Genotipo , Humanos , Lactante , Masculino , Metilenotetrahidrofolato Reductasa (NADPH2) , Mutación , Defectos del Tubo Neural/enzimología , Defectos del Tubo Neural/genética , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/metabolismo , Polimorfismo GenéticoRESUMEN
Moyamoya syndrome has occasionally been seen in association with Down syndrome. We report a child with moyamoya syndrome and Down syndrome who was admitted with repeated episodes of strokes; his magnetic resonance imaging and magnetic resonance angiography findings confirmed the presence of occlusive cerebrovascular disease with basal collateral vessels. His protein C levels were significantly decreased during the stroke. Complete clinical recovery was seen during follow-up. This raises the possibility of a link between protein C deficiency and Down syndrome with moyamoya syndrome.
Asunto(s)
Síndrome de Down/complicaciones , Enfermedad de Moyamoya/complicaciones , Deficiencia de Proteína C/complicaciones , Accidente Cerebrovascular/etiología , Preescolar , Síndrome de Down/sangre , Síndrome de Down/diagnóstico , Humanos , Angiografía por Resonancia Magnética , Imagen por Resonancia Magnética , Masculino , Enfermedad de Moyamoya/sangre , Enfermedad de Moyamoya/diagnóstico , Deficiencia de Proteína C/sangre , Recuperación de la Función , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/diagnósticoRESUMEN
The authors report on seven patients, six males and one female, with Joubert's syndrome who underwent developmental evaluation, neurologic and ophthalmologic examinations, and magnetic resonance imaging of the brain. All patients had severe developmental delay, hypotonia, impairment of smooth visual pursuit, and saccadic eye movements. Six had jerky eye movements and ptosis was observed in two patients and retinal dystrophy in one. The posterior lobe of the vermis was absent in all patients and the small rudimentary anterior lobe lacked fusion in the midline, with cleft formation in five patients. Malformation of the pontomesencephalic junction, with prominent superior cerebellar peduncles and deep interpeduncular fossa, was observed in all patients. Abnormal cerebellar-brainstem and cerebellocortical connections because of the lack of the posterior vermis and dysplasia of the deep cerebellar nuclei might be responsible for the abnormal eye movements and retarded development in Joubert's syndrome. Correlation between radiologic findings and clinical symptoms and the possible role of abnormal patterning of the midbrain-hindbrain by homeotic genes during embryonic development are reviewed.
Asunto(s)
Anomalías Múltiples/genética , Encefalopatías/diagnóstico , Encefalopatías/genética , Encéfalo/anomalías , Adolescente , Niño , Preescolar , Consanguinidad , Discapacidades del Desarrollo/diagnóstico , Femenino , Genes Homeobox/genética , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Mesencéfalo/embriología , Trastornos de la Motilidad Ocular/genética , Trastornos de la Motilidad Ocular/fisiopatología , Rombencéfalo/embriología , SíndromeRESUMEN
The cranial magnetic resonance imaging findings in three siblings with nonrhizomelic chondrodysplasia punctata due to isolated dihydroxyacetonephosphate acyltransferase (DHAP-AT) deficiency are reported. Areas of high signal intensity in a patchy distribution on the T2-weighted images were detected in the centrum semiovale in the eldest patient (a 6-year-old girl). The white matter of the second child (a 5-year-old boy) was spared, whereas the youngest sibling (a 2-year-old boy) manifested very severe white matter abnormalities. DHAP-AT catalyzes the first step in the synthesis of plasmalogens, which are major constituents of myelin. Defective plasmalogen synthesis may have contributed to abnormal myelin formation in 2 patients. Because the clinical presentation of the child without detectable defect in myelination was similar to that of his siblings, the neurologic signs observed in isolated DHAP-AT deficiency cannot be attributed solely to the disturbances in the myelin formation.
Asunto(s)
Aciltransferasas/deficiencia , Microcuerpos/enzimología , Vaina de Mielina/patología , Encéfalo/patología , Niño , Preescolar , Condrodisplasia Punctata/diagnóstico por imagen , Condrodisplasia Punctata/etiología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , RadiografíaRESUMEN
We report an inbred Arab family from the United Arab Emirates with two children affected with mental retardation, iris coloboma, optic atrophy, nystagmus, and a distinctive facial appearance. This includes a long narrow face, downslanting palpebral fissures, a narrow nose with hypoplasia of the alae nasi, a small philtrum and a thin upper lip. We suggest that the combination of abnormalities in these children represents a previously undescribed autosomal recessive syndrome.
Asunto(s)
Coloboma , Facies , Discapacidad Intelectual , Iris/anomalías , Núcleo Familiar , Atrofia Óptica , Consanguinidad , Femenino , Humanos , Recién Nacido , MasculinoRESUMEN
We report a child from a highly inbred Omani family with hypoparathyroidism, growth failure, developmental delay and a distinctive facial appearance. Thirty cases with this syndrome have been previously reported; 22 came from the Arab Gulf Countries and eight were Arabs living in Israel. These cases are reviewed.
Asunto(s)
Discapacidades del Desarrollo/genética , Cara/anomalías , Trastornos del Crecimiento/genética , Hipoparatiroidismo/genética , Consanguinidad , Femenino , Genes Recesivos , Humanos , Hipoparatiroidismo/congénito , Lactante , Masculino , Fenotipo , SíndromeRESUMEN
We report an inbred Omani family with four children in two sibships affected with a recessive type of multiple epiphyseal dysplasia, associated with macrocephaly frontal lobe atrophy on CT scan of the brain, lymphoedema and a distinctive facial appearance. We suggest that the constellation of abnormalities in these children represents a previously undescribed syndrome.
Asunto(s)
Anomalías Múltiples/genética , Anomalías Craneofaciales , Facies , Genes Recesivos , Osteocondrodisplasias , Anomalías Múltiples/diagnóstico por imagen , Atrofia , Niño , Consanguinidad , Femenino , Lóbulo Frontal/patología , Humanos , Masculino , Linaje , Radiografía , SíndromeRESUMEN
We report a patient of Baluchi origin with an anterior encephalocele, anophthalmia and dilated cerebral ventricles and discuss the possible etiology.
Asunto(s)
Anoftalmos/patología , Cerebelo/anomalías , Encefalocele/patología , Meningocele/patología , Humanos , Recién Nacido , MasculinoRESUMEN
We report two sibs with typical clinical and radiological features of spondylo-meta-epiphyseal dysplasia, short limb abnormal calcification type. In both, the degree of calcification is more extensive than in the previously reported cases and involved all the epiphyses, ligaments and chondral tissues. Intelligence is normal in both children and the eldest is 8 years old with no complications. The literature is reviewed.
Asunto(s)
Brazo/anomalías , Calcinosis/genética , Pierna/anomalías , Osteocondrodisplasias/genética , Adulto , Calcinosis/fisiopatología , Estudios de Seguimiento , Crecimiento , Humanos , Lactante , Recién Nacido , Inteligencia , Masculino , Osteocondrodisplasias/fisiopatologíaRESUMEN
Setleis syndrome is a rare skin disorder characterized by congenital scar-like depressions on the temples and distinctive facial appearance. We report on two cases from a consanguineous Omani family, with typical features of this syndrome. The mother in one case has mild dysmorphic features reminiscent of this syndrome and the father of the other case has bitemporal scars only.
Asunto(s)
Cara/anomalías , Genes Dominantes , Genes Recesivos , Enfermedades de la Piel/genética , Adulto , Consanguinidad , Femenino , Humanos , Recién Nacido , Masculino , Linaje , SíndromeRESUMEN
We report a child with multiple congenital abnormalities which include complex central nervous system malformations, dense bones with wide irregular metaphyses, facial dysmorphic features and lethality. We suggest that the combination of abnormalities in the child could represent a new syndrome.
Asunto(s)
Anomalías Múltiples/genética , Anomalías Múltiples/patología , Huesos/anomalías , Sistema Nervioso Central/anomalías , Anomalías Craneofaciales/genética , Anomalías Craneofaciales/patología , Anomalías Múltiples/diagnóstico por imagen , Huesos/diagnóstico por imagen , Sistema Nervioso Central/diagnóstico por imagen , Consanguinidad , Anomalías Craneofaciales/diagnóstico por imagen , Femenino , Genes Recesivos , Humanos , Recién Nacido , Masculino , Linaje , Síndrome , Tomografía Computarizada por Rayos XRESUMEN
A male child with cherubism, visual impairment due to optic atrophy and short stature is described. This association has not been reported previously.
Asunto(s)
Estatura/genética , Querubismo/genética , Atrofia Óptica/genética , Anomalías Múltiples/genética , Preescolar , Humanos , MasculinoRESUMEN
We report a consanguineous Arab family with four children affected with bifid nose associated with renal agenesis and variable degree of anorectal malformations. We suggest that the combination of abnormalities in these children represent a previously undescribed autosomal recessive syndrome.
Asunto(s)
Anomalías Múltiples/genética , Anomalías Múltiples/patología , Riñón/anomalías , Nariz/anomalías , Recto/anomalías , Niño , Preescolar , Salud de la Familia , Resultado Fatal , Femenino , Genes Recesivos , Humanos , Recién NacidoRESUMEN
We report an Omani child with fibrochondrogenesis. This neonatally lethal bone dysplasia is characterized by a distinctive facial appearance and specific radiological changes. Only seven cases have been reported previously. The clinical and radiological features together with the differential diagnosis is discussed.
Asunto(s)
Osteocondrodisplasias/diagnóstico por imagen , Osteocondrodisplasias/patología , Anomalías Múltiples/diagnóstico por imagen , Anomalías Múltiples/patología , Huesos/anomalías , Consanguinidad , Cara/anomalías , Femenino , Humanos , Recién Nacido , Radiografía , Cráneo/anomalíasRESUMEN
Two sibs with early onset diabetes and epiphysed dysplasia (Wolcott-Rallison syndrome) are described. The epiphyseal changes were radiologically apparent at 6 months of age in one of them, and both developed insulin dependent diabetes in the first few weeks of life. The clinical and radiological features of this syndrome are reviewed.