RESUMEN

Three overlapping conditions, namely Rothmund-Thomson (RTS), Baller-Gerold (BGS) and RAPADILINO syndromes, have been attributed to RECQL4 mutations. Differential diagnoses depend on the clinical presentation, but the numbers of known genes remain low, leading to the widespread prescription of RECQL4 sequencing. The aim of our study was therefore to determine the best clinical indicators for the presence of RECQL4 mutations in a series of 39 patients referred for RECQL4 molecular analysis and belonging to the RTS (27 cases) and BGS (12 cases) spectrum. One or two deleterious RECQL4 mutations were found in 10/27 patients referred for RTS diagnosis. Clinical and molecular reevaluation led to a different diagnosis in 7/17 negative cases, including Clericuzio-type poikiloderma with neutropenia, hereditary sclerosing poikiloderma, and craniosynostosis/anal anomalies/porokeratosis. No RECQL4 mutations were found in the BGS group without poikiloderma, confirming that RECQL4 sequencing was not indicated in this phenotype. One chromosomal abnormality and one TWIST mutation was found in this cohort. This study highlights the search for differential diagnoses before the prescription of RECQL4 sequencing in this clinically heterogeneous group. The combination of clinically defined subgroups and next-generation sequencing will hopefully bring to light new molecular bases of syndromes with poikiloderma, as well as BGS without poikiloderma.

Asunto(s)

Craneosinostosis/diagnóstico , Craneosinostosis/genética , Genotipo , Radio (Anatomía)/anomalías , RecQ Helicasas/genética , Adolescente , Adulto , Niño , Preescolar , Hibridación Genómica Comparativa , Consanguinidad , Facies , Femenino , Humanos , Lactante , Masculino , Mutación , Fenotipo , Adulto Joven

RESUMEN

Anophthalmia and microphthalmia (AM) are the most severe malformations of the eye, corresponding respectively to reduced size or absent ocular globe. Wide genetic heterogeneity has been reported and different genes have been demonstrated to be causative of syndromic and non-syndromic forms of AM. We screened seven AM genes [GDF6 (growth differentiation factor 6), FOXE3 (forkhead box E3), OTX2 (orthodenticle protein homolog 2), PAX6 (paired box 6), RAX (retina and anterior neural fold homeobox), SOX2 (SRY sex determining region Y-box 2), and VSX2 (visual system homeobox 2 gene)] in a cohort of 150 patients with isolated or syndromic AM. The causative genetic defect was identified in 21% of the patients (32/150). Point mutations were identified by direct sequencing of these genes in 25 patients (13 in SOX2, 4 in RAX, 3 in OTX2, 2 in FOXE3, 1 in VSX2, 1 in PAX6, and 1 in GDF6). In addition eight gene deletions (five SOX2, two OTX2 and one RAX) were identified using a semi-quantitative multiplex polymerase chain reaction (PCR) [quantitative multiplex PCR amplification of short fluorescent fragments (QMPSF)]. The causative genetic defect was identified in 21% of the patients. This result contributes to our knowledge of the molecular basis of AM, and will facilitate accurate genetic counselling.

Asunto(s)

Anoftalmos/genética , Heterogeneidad Genética , Microftalmía/genética , Mutación Puntual/genética , Adolescente , Adulto , Anoftalmos/diagnóstico , Anoftalmos/patología , Niño , Preescolar , Proteínas del Ojo/genética , Femenino , Factores de Transcripción Forkhead/genética , Factor 6 de Diferenciación de Crecimiento/genética , Proteínas de Homeodominio/genética , Humanos , Lactante , Masculino , Microftalmía/diagnóstico , Microftalmía/patología , Factores de Transcripción Otx/genética , Factor de Transcripción PAX6 , Factores de Transcripción Paired Box/genética , Proteínas Represoras/genética , Factores de Transcripción SOXB1/genética , Factores de Transcripción/genética

RESUMEN

Split hand/foot malformation (SHFM) with long-bone deficiency (SHFLD, MIM#119100) is a rare condition characterized by SHFM associated with long-bone malformation usually involving the tibia. Previous published data reported several unrelated patients with 17p13.3 duplication and SHFLD. Recently, the minimal critical region had been reduced, suggesting that BHLHA9 copy number gains are associated with this limb defect. Here, we report on 13 new families presenting with ectrodactyly and harboring a BHLHA9 duplication.

Asunto(s)

Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Genes Duplicados , Deformidades Congénitas de las Extremidades/genética , Tibia/anomalías , Cromosomas Humanos Par 17/genética , Femenino , Humanos , Deformidades Congénitas de las Extremidades/fisiopatología , Masculino , Linaje , Fenotipo , Tibia/fisiopatología

RESUMEN

Nager syndrome belongs to the group of acrofacial dysostosis, which are characterized by the association of craniofacial and limb malformations. Recently, exome sequencing studies identified the SF3B4 gene as the cause of this condition in most patients. SF3B4 encodes a highly conserved protein implicated in mRNA splicing and bone morphogenic protein (BMP) signaling. We performed SF3B4 sequencing in 14 families (18 patients) whose features were suggestive of Nager syndrome and found nine mutations predicted to result in loss-of-function. SF3B4 is the major gene responsible for autosomal dominant Nager syndrome. All mutations reported predict null alleles, therefore precluding genotype-phenotype correlations. Most mutation-negative patients were phenotypically indistinguishable from patients with mutations, suggesting genetic heterogeneity.

Asunto(s)

Predisposición Genética a la Enfermedad/genética , Haploinsuficiencia/genética , Disostosis Mandibulofacial/genética , Fenotipo , Proteínas de Unión al ARN/genética , Secuencia de Bases , Femenino , Genes Dominantes/genética , Humanos , Masculino , Disostosis Mandibulofacial/patología , Datos de Secuencia Molecular , Mutación/genética , Factores de Empalme de ARN , Análisis de Secuencia de ADN

RESUMEN

We report on a boy, born on term, presenting with a weight loss and a persistent failure to thrive after 10 days despite a normal behavior under bottle-feeding. The clinical examination was normal and biological assessment revealed hyponatremia with hyponatriuria, normal kaliemia and elevated aldosterone values, leading to type I pseudohypoaldosteronism diagnosis. Treatment with salt supplementation allowed growth improvement. The diagnosis was confirmed by the identification of a mutation in the mineralocorticoid receptor. This change was also found in several family members.

Asunto(s)

Insuficiencia de Crecimiento/etiología , Insuficiencia de Crecimiento/genética , Seudohipoaldosteronismo/complicaciones , Seudohipoaldosteronismo/genética , Humanos , Recién Nacido , Masculino , Linaje

RESUMEN

Most microdeletion syndromes identified before the implementation of array-comparative genomic hybridization (array-CGH) were presumed to be well-defined clinical entities. However, the introduction of whole-genome screening led not only to the description of new syndromes but also to the recognition of a broader spectrum of features for well-known syndromes. Here, we report on 10 patients presenting with mental retardation associated with atypical features not suggestive of a known microdeletion and a normal standard karyotype. Array-CGH analyses revealed five microdeletions in the DiGeorge region, three microdeletions in the Williams-Beuren region and two microdeletions in the Smith-Magenis region. Reevaluation in these patients confirmed that the diagnosis remained difficult on clinical grounds and emphasized that well-known genomic disorders can have a phenotype that is heterogeneous and more variable than originally thought. The widespread use of array-CGH shows that such patients may be more readily achieved on the basis of genotype rather than phenotype.

Asunto(s)

Anomalías Múltiples/diagnóstico , Deleción Cromosómica , Cromosomas Humanos Par 22/genética , Cromosomas Humanos Par 7/genética , Discapacidad Intelectual/diagnóstico , Anomalías Múltiples/genética , Adolescente , Adulto , Preescolar , Hibridación Genómica Comparativa , Genotipo , Humanos , Discapacidad Intelectual/genética , Cariotipo , Fenotipo

RESUMEN

Prenatal diagnosis of true mosaic trisomy 7 is rare in amniotic fluid and can be misinterpreted as pseudomosaic. The phenotype is highly variable and may be modified by a maternal uniparental disomy of chromosome 7 leading to mild Russell-Silver syndrome (RSS). We report here the third postnatal case of mosaic trisomy 7 with maternal uniparental disomy of chromosome 7 in a boy presenting a mild RSS. Fetal karyotype performed in amniocentesis for intrauterine growth retardation was considered normal. Mosaic trisomy 7 was diagnosed after birth, on fibroblasts karyotype performed for blaschkolinear pigmentary skin anomalies and failure to thrive. Maternal uniparental disomy of chromosome 7 was observed in blood sample. Retrospectively, trisomic 7 cells were identified in one prenatal long-term flask culture revealing a prenatal diagnosis failure. This report emphasizes the difficulty of assessing fetal mosaicism and distinguishing it from pseudomosaicism in cultured amniocytes. It is important to search for uniparental disomy as an indirect clue of trisomy 7 mosaicism and a major prognosis element. Although there are only few prenatal informative cases, detection of trisomy 7 in amniocentesis appears to be associated with a relatively good outcome when maternal uniparental disomy has been ruled out.

Asunto(s)

Síndrome de Silver-Russell/diagnóstico , Trisomía/diagnóstico , Disomía Uniparental/diagnóstico , Amniocentesis , Cromosomas Humanos Par 7/genética , Diagnóstico Diferencial , Errores Diagnósticos , Femenino , Retardo del Crecimiento Fetal , Humanos , Cariotipo , Masculino , Mosaicismo , Embarazo , Diagnóstico Prenatal , Síndrome de Silver-Russell/genética , Trisomía/genética , Disomía Uniparental/genética

Asunto(s)

Proteínas Portadoras/genética , Proteínas de la Membrana/genética , Errores Innatos del Metabolismo de los Metales/genética , Mutación Puntual , Secuencia de Aminoácidos , Femenino , Humanos , Recién Nacido , Errores Innatos del Metabolismo de los Metales/diagnóstico , Datos de Secuencia Molecular , Molibdoferredoxina/genética , Alineación de Secuencia

RESUMEN

The Bardet-Biedl syndrome (BBS) is a rare ciliopathy clinically defined by the association of retinitis pigmentosa, polydactyly, obesity, kidney disease and cognitive impairment. The cognitive functioning, behavioral phenotype, prevalence of psychiatric diseases and memory performances of a cohort of 34 patients with BBS were evaluated and a systemic brain magnetic resonance imaging (MRI) was performed. The patients' cognitive functioning was of marked variable efficiency ranging from normal to disabling performances. Neuropsychological disorders such as slow thought process, attention difficulties and obsessive-compulsive traits were observed. Our main finding was hippocampal dysgenesis, diagnosed by MRI, found in 42.31% of the patients in this cohort. Moreover, we show that BBS proteins are expressed in the human hippocampus and in the human brain in the normal subject. Recent literature in the murine model shows that hippocampal neurogenesis, in particular in the adult mouse, requires an intact primary cilia. These results encourage us to further investigate the possible role of BBS proteins in the hippocampus and related central nervous system structures.

Asunto(s)

Síndrome de Bardet-Biedl/patología , Cilios/patología , Hipocampo/patología , Factores de Ribosilacion-ADP/genética , Factores de Ribosilacion-ADP/metabolismo , Adolescente , Adulto , Síndrome de Bardet-Biedl/genética , Síndrome de Bardet-Biedl/metabolismo , Chaperoninas , Cilios/genética , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/patología , Estudios de Cohortes , Femenino , Expresión Génica , Chaperoninas del Grupo II/genética , Chaperoninas del Grupo II/metabolismo , Hipocampo/metabolismo , Humanos , Imagen por Resonancia Magnética , Masculino , Memoria , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Persona de Mediana Edad , Neurogénesis , Fenotipo , ARN Mensajero/análisis , ARN Mensajero/genética , Adulto Joven

RESUMEN

Van der Woude syndrome (VWS), caused by dominant IRF6 mutation, is the most common cleft syndrome. In 15% of the patients, lip pits are absent and the phenotype mimics isolated clefts. Therefore, we hypothesized that some of the families classified as having non-syndromic inherited cleft lip and palate could have an IRF6 mutation. We screened in total 170 patients with cleft lip with or without cleft palate (CL/P): 75 were syndromic and 95 were a priori part of multiplex non-syndromic families. A mutation was identified in 62.7 and 3.3% of the patients, respectively. In one of the 95 a priori non-syndromic families with an autosomal dominant inheritance (family B), new insights into the family history revealed the presence, at birth, of lower lip pits in two members and the diagnosis was revised as VWS. A novel lower lip sign was observed in one individual in this family. Interestingly, a similar lower lip sign was also observed in one individual from a 2nd family (family A). This consists of 2 nodules below the lower lip on the external side. In a 3rd multiplex family (family C), a de novo mutation was identified in an a priori non-syndromic CL/P patient. Re-examination after mutation screening revealed the presence of a tiny pit-looking lesion on the inner side of the lower lip leading to a revised diagnosis of VWS. On the basis of this data, we conclude that IRF6 should be screened when any doubt rises about the normality of the lower lip and also if a non-syndromic cleft lip patient (with or without cleft palate) has a family history suggestive of autosomal dominant inheritance.

RESUMEN

OBJECTIVES: To evaluate the prenatal diagnosis and the prognostic value of ultrasound in case of fetal hyperechogenic kidneys. PATIENTS AND METHODS: Seventeen prenatally diagnosed cases of hyperechogenic kidneys were retrospectively reviewed at the University Hospital of Lille from 1997 to 2008. The clinical and ultrasound data were compared to the postnatal follow-up and the long-term prognosis. RESULTS: The aetiologies are nine recessive polycystic kidney diseases, three dominant, two Bardet-Biedl syndromes and three cases of transient renal hyperechogenicity. No renal ultrasonographic criterion is specific of aetiology. Five pregnancies were terminated. We observed one neonatal death and 11 survivors (median follow-up: 30months) including two infants with hypertension. All oligohydramnios (n=8) were associated with poor prenatal outcomes (terminations of pregnancy, neonatal death or hypertension) compared to the other nine with normal amniotic fluid volume (nine children symptom-free). Kidneys less or equal to +4 S.D. and a normal amniotic fluid volume were associated with a good prognosis (n=7, seven symptom-free). CONCLUSION: The fetal kidneys characteristics on prenatal ultrasound fail to provide an accurate etiological diagnosis. Only congenital defects and family history adjust the aetiology. Amniotic fluid volume and fetal kidney size are the best prenatal predictors of outcome.

Asunto(s)

Enfermedades Renales/diagnóstico por imagen , Enfermedades Renales/embriología , Riñón/diagnóstico por imagen , Riñón/embriología , Ultrasonografía Prenatal , Síndrome de Bardet-Biedl/diagnóstico por imagen , Síndrome de Bardet-Biedl/embriología , Femenino , Edad Gestacional , Humanos , Oligohidramnios , Enfermedades Renales Poliquísticas/diagnóstico por imagen , Enfermedades Renales Poliquísticas/embriología , Enfermedades Renales Poliquísticas/genética , Embarazo , Resultado del Embarazo , Pronóstico

RESUMEN

Obesity has become a major worldwide challenge to public health, owing to an interaction between the Western 'obesogenic' environment and a strong genetic contribution. Recent extensive genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms associated with obesity, but these loci together account for only a small fraction of the known heritable component. Thus, the 'common disease, common variant' hypothesis is increasingly coming under challenge. Here we report a highly penetrant form of obesity, initially observed in 31 subjects who were heterozygous for deletions of at least 593 kilobases at 16p11.2 and whose ascertainment included cognitive deficits. Nineteen similar deletions were identified from GWAS data in 16,053 individuals from eight European cohorts. These deletions were absent from healthy non-obese controls and accounted for 0.7% of our morbid obesity cases (body mass index (BMI) >or= 40 kg m(-2) or BMI standard deviation score >or= 4; P = 6.4 x 10(-8), odds ratio 43.0), demonstrating the potential importance in common disease of rare variants with strong effects. This highlights a promising strategy for identifying missing heritability in obesity and other complex traits: cohorts with extreme phenotypes are likely to be enriched for rare variants, thereby improving power for their discovery. Subsequent analysis of the loci so identified may well reveal additional rare variants that further contribute to the missing heritability, as recently reported for SIM1 (ref. 3). The most productive approach may therefore be to combine the 'power of the extreme' in small, well-phenotyped cohorts, with targeted follow-up in case-control and population cohorts.

Asunto(s)

Deleción Cromosómica , Cromosomas Humanos Par 16/genética , Obesidad/genética , Obesidad/fisiopatología , Penetrancia , Adolescente , Adulto , Edad de Inicio , Envejecimiento , Índice de Masa Corporal , Estudios de Casos y Controles , Niño , Trastornos del Conocimiento/complicaciones , Trastornos del Conocimiento/genética , Estudios de Cohortes , Europa (Continente) , Femenino , Estudio de Asociación del Genoma Completo , Heterocigoto , Humanos , Patrón de Herencia/genética , Masculino , Mutación/genética , Obesidad/complicaciones , Reproducibilidad de los Resultados , Caracteres Sexuales , Adulto Joven

RESUMEN

BACKGROUND: Over the last few years, array-comparative genomic hybridisation (CGH) has considerably improved our ability to detect cryptic unbalanced rearrangements in patients with syndromic mental retardation. METHOD: Molecular karyotyping of six patients with syndromic mental retardation was carried out using whole-genome oligonucleotide array-CGH. RESULTS: 5q14.3 microdeletions ranging from 216 kb to 8.8 Mb were detected in five unrelated patients with the following phenotypic similarities: severe mental retardation with absent speech, hypotonia and stereotypic movements. Facial dysmorphic features, epilepsy and/or cerebral malformations were also present in most of these patients. The minimal common deleted region of these 5q14 microdeletions encompassed only MEF2C, the gene for a protein known to act in brain as a neurogenesis effector, which regulates excitatory synapse number. In a patient with a similar phenotype, an MEF2C nonsense mutation was subsequently identified. CONCLUSION: Taken together, these results strongly suggest that haploinsufficiency of MEF2C is responsible for severe mental retardation with stereotypic movements, seizures and/or cerebral malformations.

Asunto(s)

Cerebro/anomalías , Deleción Cromosómica , Cromosomas Humanos Par 5/genética , Epilepsia/genética , Discapacidad Intelectual/genética , Proteínas de Dominio MADS/genética , Factores Reguladores Miogénicos/genética , Trastorno de Movimiento Estereotipado/genética , Cerebro/metabolismo , Niño , Preescolar , Haploidia , Humanos , Lactante , Factores de Transcripción MEF2

RESUMEN

Oculo-dento-digital dysplasia (ODDD) is an autosomal dominant disorder with complete penetrance and high intra- and interfamilial phenotypic variability. The key features in this syndrome are microphthalmia, enamel hypoplasia and syndactyly of the 4th-5th fingers. ODDD is caused by mutations in the connexin 43 gene (GJA1). We report here four patients from three families with GJA1 mutations, one of them diagnosed prenatally. The three mutations (c.52T > C/p.Ser18Pro, c.689_690delTA/p.Tyr230CysfsX6, c.442C > G/p.Arg148Gly) have been reported once before. Two patients had white matter hypersignal anomalies, associated in one case with mental retardation, but asymptomatic in the other one, an observation that leads us to discuss systematic neuroradiological imaging for ODDD. One case has optic atrophy, another has hypospadias. The patient carrying a truncating mutation of Cx43 did not have palmoplantar keratoderma, in contradiction with the previously suggested genotype-phenotype correlation between truncating mutation and skin involvement.

Asunto(s)

Conexina 43/genética , Diagnóstico por Imagen , Anomalías del Ojo/genética , Sindactilia/genética , Anomalías Dentarias/genética , Adulto , Secuencia de Aminoácidos , Preescolar , Hipoplasia del Esmalte Dental/genética , Femenino , Dedos/anomalías , Genotipo , Humanos , Hipospadias/genética , Discapacidad Intelectual/genética , Masculino , Mutación , Linaje , Fenotipo , Análisis de Secuencia de ADN , Adulto Joven

RESUMEN

Cohen syndrome (CS) is an autosomal recessive disorder with variability in the clinical manifestations, characterised by mental retardation, postnatal microcephaly, facial dysmorphism, pigmentary retinopathy, myopia, and intermittent neutropenia. Mutations in the gene COH1 have been found in an ethnically diverse series of patients. Brief clinical descriptions of 24 patients with CS are provided. The patients were from 16 families of different ethnic backgrounds and between 2.5 and 60 years of age at assessment. DNA samples from all patients were analysed for mutations in COH1 by direct sequencing. Splice site mutations were characterised using reverse transcriptase PCR analysis from total RNA samples. In this series, we detected 25 different COH1 mutations; 19 of these were novel, including 9 nonsense mutations, 8 frameshift mutations, 4 verified splice site mutations, 3 larger in frame deletions, and 1 missense mutation. We observed marked variability of developmental and growth parameters. The typical facial gestalt was seen in 23/24 patients. Early onset progressive myopia was present in all the patients older than 5 years. Widespread pigmentary retinopathy was found in 12/14 patients assessed over 5 years of age. We present evidence for extended allelic heterogeneity of CS, with the vast majority of mutations leading to premature termination codons in COH1. Our data confirm the broad clinical spectrum of CS with some patients lacking even the characteristic facial gestalt and pigmentary retinopathy at school age.

Asunto(s)

Anomalías Múltiples/diagnóstico , Discapacidad Intelectual/diagnóstico , Proteínas de la Membrana/genética , Miopía/diagnóstico , Retinitis Pigmentosa/diagnóstico , Anomalías Múltiples/genética , Adolescente , Adulto , Niño , Preescolar , Análisis Mutacional de ADN , Cara/anomalías , Femenino , Heterogeneidad Genética , Humanos , Discapacidad Intelectual/genética , Masculino , Persona de Mediana Edad , Mutación , Miopía/genética , Fenotipo , Polimorfismo de Nucleótido Simple , Retinitis Pigmentosa/genética , Síndrome , Proteínas de Transporte Vesicular

RESUMEN

Limb malformations are frequent. These malformations are isolated or associated with anomalies of other developmental fields and accurate diagnostic is essential for prognosis evaluation, treatment and genetic counseling. Animal embryology and molecular biology techniques, have given us a better understanding of the processes of growth and patterning of the limb buds. The key genes that are involved in these processes have been identified and their interactions recognized. Human genetics has been able to identify, or at least localize, several genes implicated in limb development. We here review the present knowledge on these genes and their mutations responsible for limb anomalies.

Asunto(s)

Regulación del Desarrollo de la Expresión Génica , Deformidades Congénitas de las Extremidades/genética , Deformidades Congénitas de las Extremidades/cirugía , Ortopedia , Extremidades/embriología , Asesoramiento Genético , Pruebas Genéticas , Humanos , Pronóstico

RESUMEN

We present a Belgian Adams-Oliver syndrome (AOS) family with 10 affected individuals over four generations, of which six were available for this study. Clinical symptoms observed in these patients were very variable as previously reported in other families and included large areas of alopecia on the vertex of the skull and serious limb reduction defects with agenesis of all toes of one foot. To identify the disease-causing gene, we sequenced the MSX1, CART1, P63 (P73L), RUNX2, and HOXD13 genes in this family and nine previously reported families, but no disease-causing mutations were found. Further investigation is ongoing in these families in order to identify the genetic cause of AOS.

Asunto(s)

Displasia Ectodérmica/genética , Genes Dominantes , Deformidades Congénitas de las Extremidades/genética , Análisis Mutacional de ADN , Salud de la Familia , Femenino , Humanos , Masculino , Linaje , Fenotipo , Síndrome

Asunto(s)

Anomalías Múltiples/genética , Proteínas Morfogenéticas Óseas/genética , Dedos/anomalías , Cadera/anomalías , Mutación , Anomalías Dentarias/patología , Anomalías Múltiples/patología , Niño , Análisis Mutacional de ADN , Salud de la Familia , Femenino , Factor 5 de Diferenciación de Crecimiento , Deformidades Congénitas de la Mano/patología , Humanos , Masculino , Linaje

RESUMEN

Familial duodenal atresia occurs as part of Feingold syndrome. Other features of this variable autosomal dominant condition include tracheo-oesophageal fistula and oesophageal atresia, microcephaly, hand and foot anomalies, facial dysmorphism, and developmental delay. We report a father and two sons with Feingold syndrome. One has bilateral dysplastic kidneys which have not been reported previously.

Asunto(s)

Anomalías Múltiples/patología , Obstrucción Duodenal/congénito , Atresia Intestinal , Anomalías Múltiples/genética , Salud de la Familia , Humanos , Fístula Intestinal , Masculino , Riñón Displástico Multiquístico , Síndrome

Asunto(s)

Adenilosuccinato Liasa/deficiencia , Anomalías Maxilofaciales/patología , Preescolar , Facies , Femenino , Humanos , Discapacidad Intelectual/diagnóstico , Modelos Biológicos , Purinas/metabolismo , Convulsiones/diagnóstico