RESUMO
BACKGROUND: Primary hereditary microcephaly (MCPH) comprises a large group of autosomal recessive disorders mainly affecting cortical development and resulting in a congenital impairment of brain growth. Despite the identification of >25 causal genes so far, it remains a challenge to distinguish between different MCPH forms at the clinical level. METHODS: 7 patients with newly identified mutations in CDK5RAP2 (MCPH3) were investigated by performing prospective, extensive and systematic clinical, MRI, psychomotor, neurosensory and cognitive examinations under similar conditions. RESULTS: All patients displayed neurosensory defects in addition to microcephaly. Small cochlea with incomplete partition type II was found in all cases and was associated with progressive deafness in 4 of them. Furthermore, the CDK5RAP2 protein was specifically identified in the developing cochlea from human fetal tissues. Microphthalmia was also present in all patients along with retinal pigmentation changes and lipofuscin deposits. Finally, hypothalamic anomalies consisting of interhypothalamic adhesions, a congenital midline defect usually associated with holoprosencephaly, was detected in 5 cases. CONCLUSION: This is the first report indicating that CDK5RAP2 not only governs brain size but also plays a role in ocular and cochlear development and is necessary for hypothalamic nuclear separation at the midline. Our data indicate that CDK5RAP2 should be considered as a potential gene associated with deafness and forme fruste of holoprosencephaly. These children should be given neurosensory follow-up to prevent additional comorbidities and allow them reaching their full educational potential. TRIAL REGISTRATION NUMBER: NCT01565005.
Assuntos
Proteínas de Ciclo Celular/genética , Doenças Cocleares/genética , Microcefalia/genética , Proteínas do Tecido Nervoso/genética , Criança , Pré-Escolar , Cóclea/diagnóstico por imagem , Cóclea/metabolismo , Cóclea/patologia , Doenças Cocleares/diagnóstico por imagem , Doenças Cocleares/patologia , Anemia de Fanconi/genética , Anemia de Fanconi/patologia , Feminino , Humanos , Hipotálamo/diagnóstico por imagem , Hipotálamo/patologia , Lactente , Imageamento por Ressonância Magnética , Masculino , Microcefalia/diagnóstico por imagem , Microcefalia/patologia , Mutação , Neurogênese/genética , Linhagem , Retina/diagnóstico por imagem , Retina/patologiaRESUMO
Autosomal recessive microcephaly or microcephaly primary hereditary (MCPH) is a genetically heterogeneous neurodevelopmental disorder characterized by a reduction in brain volume, indirectly measured by an occipitofrontal circumference (OFC) 2 standard deviations or more below the age- and sex-matched mean (-2SD) at birth and -3SD after 6 months, and leading to intellectual disability of variable severity. The abnormal spindle-like microcephaly gene (ASPM), the human ortholog of the Drosophila melanogaster "abnormal spindle" gene (asp), encodes ASPM, a protein localized at the centrosome of apical neuroprogenitor cells and involved in spindle pole positioning during neurogenesis. Loss-of-function mutations in ASPM cause MCPH5, which affects the majority of all MCPH patients worldwide. Here, we report 47 unpublished patients from 39 families carrying 28 new ASPM mutations, and conduct an exhaustive review of the molecular, clinical, neuroradiological, and neuropsychological features of the 282 families previously reported (with 161 distinct ASPM mutations). Furthermore, we show that ASPM-related microcephaly is not systematically associated with intellectual deficiency and discuss the association between the structural brain defects (strong reduction in cortical volume and surface area) that modify the cortical map of these patients and their cognitive abilities.
Assuntos
Microcefalia/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Pré-Escolar , Cognição , Estudos de Coortes , Família , Feminino , Estudos de Associação Genética , Geografia , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Microcefalia/epidemiologiaRESUMO
Noonan syndrome is a heterogeneous autosomal dominant disorder caused by mutations in at least eight genes involved in the RAS/MAPK signaling pathway. Recently, RIT1 (Ras-like without CAAX 1) has been shown to be involved in the pathogenesis of some patients. We report a series of 44 patients from 30 pedigrees (including nine multiplex families) with mutations in RIT1. These patients display a typical Noonan gestalt and facial phenotype. Among the probands, 8.7% showed postnatal growth retardation, 90% had congenital heart defects, 36% had hypertrophic cardiomyopathy (a lower incidence compared with previous report), 50% displayed speech delay and 52% had learning difficulties, but only 22% required special education. None had major skin anomalies. One child died perinatally of juvenile myelomonocytic leukemia. Compared with the canonical Noonan phenotype linked to PTPN11 mutations, patients with RIT1 mutations appear to be less severely growth retarded and more frequently affected by cardiomyopathy. Based on our experience, we estimate that RIT1 could be the cause of 5% of Noonan syndrome patients. Because mutations found constitutionally in Noonan syndrome are also found in several tumors in adulthood, we evaluated the potential contribution of RIT1 to leukemogenesis in Noonan syndrome. We screened 192 pediatric cases of acute lymphoblastic leukemias (96 B-ALL and 96 T-ALL) and 110 cases of juvenile myelomonocytic leukemias (JMML), but detected no variation in these tumoral samples, suggesting that Noonan patients with germline RIT1 mutations are not at high risk to developing JMML or ALL, and that RIT1 has at most a marginal role in these sporadic malignancies.
Assuntos
Leucemia Mielomonocítica Juvenil/genética , Mutação , Síndrome de Noonan/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas ras/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Leucemia Mielomonocítica Juvenil/patologia , Masculino , Síndrome de Noonan/patologia , Linhagem , Fenótipo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologiaRESUMO
Our study was designed to analyze prenatal manifestations in patients affected with cardio-facio-cutaneous syndrome (CFCS), in order to define indications of DNA testing in utero. Prenatal features were extracted from a national database and additional data were collected from 16 families contacted through the French association of CFC-Costello syndrome. We collected results of ultrasound scan (USS) biometrics, presence of congenital birth defects, and polyhydramnios. From the database, increased nuchal translucency was present in 13% of pregnancies, polyhydramnios in 52%, macrosomia and/or macrocephaly in 16%. Of the 16 pregnancies, 81% were complicated by abnormal USS findings. Polyhydramnios was reported in 67%. Head circumference, biparietal diameter, and abdominal circumference were above the 90th centile in 72%, 83% and, 81% of fetuses, respectively. Contrasting with macrosomia, femur length was below the 10th centile in 38%. Urinary tract abnormalities were found in 47% of fetuses. Most CFCS fetuses showed a combination of macrocephaly, macrosomia, and polyhydramnios, contrasting with relatively short femora. This growth pattern is also seen in Costello syndrome. We suggest that screening for CFCS and Costello gene mutations could be proposed in pregnancies showing this unusual pattern of growth parameters.
Assuntos
Anormalidades Múltiplas/genética , Face/anormalidades , Cardiopatias Congênitas/diagnóstico , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Anormalidades da Pele/diagnóstico , Anormalidades Múltiplas/patologia , Feminino , Feto/anormalidades , Feto/metabolismo , Feto/patologia , Cardiopatias Congênitas/genética , Humanos , Recém-Nascido , Masculino , Fenótipo , Gravidez , Prognóstico , Anormalidades da Pele/genéticaRESUMO
Autosomal recessive primary microcephaly results from abnormal brain development linked to proliferation defects in neural progenitors. The most frequent form, caused by ASPM mutations, is usually defined by a reduced brain volume and is associated with intellectual disability. Although many ASPM cases have now been reported, structural brain abnormalities and their link with cognitive disabilities have rarely been investigated. In this study, we used high resolution T1-weighted magnetic resonance imaging in seven patients with ASPM mutations and 39 healthy age-matched controls to quantify regional volumes, thickness, surface area, gyrification index and white matter volumes of 30 cortical regions. We observed a consistent reduction of 50% or more in the volume and surface area of all cortical regions except for the hippocampus and surrounding medial temporal structures, which were significantly less reduced. Neuropsychologic assessment indicated significant impairments of cognitive abilities. However, these impairments were associated with normal mnesic abilities, in keeping with the relative preservation of the hippocampus and medial temporal structures. These results show that, contrary to current opinion, the cortical volume and surface area of patients with ASPM mutations is reduced depending on a regionally specific fashion and their cognitive profile reflects this heterogeneity. The precise characterization of the cortical map and cognitive abilities of patients with ASPM mutations should allow developing more focused reeducative interventions well-suited to their real abilities.
Assuntos
Hipocampo/patologia , Memória de Longo Prazo/fisiologia , Microcefalia/genética , Mutação , Neocórtex/patologia , Proteínas do Tecido Nervoso/genética , Adolescente , Criança , Cognição/fisiologia , Feminino , Humanos , Masculino , Microcefalia/patologia , Testes Neuropsicológicos , Substância Branca/patologia , Adulto JovemRESUMO
BACKGROUND/AIMS: Transient idiopathic hyperglycaemia (TIH) is partly due to defective processing of proinsulin to insulin in preterm neonates, whereas transient neonatal diabetes mellitus (TNDM) is a rare genetic form of pancreatic ß-cell dysfunction. Distinguishing these two conditions is difficult yet essential to allow personalised management and genetic testing. Here we investigated whether metabolic or therapeutic features contributed to the diagnosis in preterm neonates. METHODS: We prospectively included 13 preterm neonates with TIH between 2008 and 2011, and we identified 2 patients with TNDM in the French neonatal diabetes cohort registry. All of them were born before 32 weeks of gestation. We compared clinical features, glycaemic profiles, insulin dosages, and nutritional intakes. RESULTS: TNDM patients had higher day-1 glycaemia levels before insulin therapy [median 23.5 (20-27) vs. 13.6 (10.7-19.8) mmol/l, p = 0.025] and higher insulin requirements [median 1.2 (0.9-1.5) vs. 0.8 (0.3-0.9) IU/kg/day, p = 0.037] compared to TIH. They also required insulin therapy earlier [median 0.75 (0.5-1) vs. 2 (0.5-7) days, p = 0.036] and for a longer time [median 85 (57-113) vs. 11 (4-15) days, p = 0.036]. CONCLUSION: TNDM and TIH are different clinical and genetic entities with specific pathophysiological mechanisms. Metabolic and therapeutic features may help to detect TNDM in preterm neonates as soon as day-1 of hyperglycaemia.
Assuntos
Diabetes Mellitus , Hiperglicemia , Doenças do Prematuro , Recém-Nascido Prematuro , Insulina/administração & dosagem , Sistema de Registros , Diabetes Mellitus/sangue , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/genética , Feminino , Humanos , Hiperglicemia/sangue , Hiperglicemia/diagnóstico , Hiperglicemia/tratamento farmacológico , Hiperglicemia/genética , Recém-Nascido , Doenças do Prematuro/sangue , Doenças do Prematuro/diagnóstico , Doenças do Prematuro/tratamento farmacológico , Doenças do Prematuro/genética , Masculino , Estudos ProspectivosRESUMO
BACKGROUND: Infants with Noonan syndrome (NS) are predisposed to developing juvenile myelomonocytic leukaemia (JMML) or JMML-like myeloproliferative disorders (MPD). Whereas sporadic JMML is known to be aggressive, JMML occurring in patients with NS is often considered as benign and transitory. However, little information is available regarding the occurrence and characteristics of JMML in NS. METHODS AND RESULTS: Within a large prospective cohort of 641 patients with a germline PTPN11 mutation, we identified MPD features in 36 (5.6%) patients, including 20 patients (3%) who fully met the consensus diagnostic criteria for JMML. Sixty percent of the latter (12/20) had severe neonatal manifestations, and 10/20 died in the first month of life. Almost all (11/12) patients with severe neonatal JMML were males. Two females who survived MPD/JMML subsequently developed another malignancy during childhood. Although the risk of developing MPD/JMML could not be fully predicted by the underlying PTPN11 mutation, some germline PTPN11 mutations were preferentially associated with myeloproliferation: 10/48 patients with NS (20.8%) with a mutation in codon Asp61 developed MPD/JMML in infancy. Patients with a p.Thr73Ile mutation also had more chances of developing MPD/JMML but with a milder clinical course. SNP array and whole exome sequencing in paired tumoral and constitutional samples identified no second acquired somatic mutation to explain the occurrence of myeloproliferation. CONCLUSIONS: JMML represents the first cause of death in PTPN11-associated NS. Few patients have been reported so far, suggesting that JMML may sometimes be overlooked due to early death, comorbidities or lack of confirmatory tests.
Assuntos
Leucemia Mielomonocítica Juvenil/complicações , Leucemia Mielomonocítica Juvenil/genética , Síndrome de Noonan/complicações , Síndrome de Noonan/genética , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Leucemia Mielomonocítica Juvenil/mortalidade , Leucemia Mielomonocítica Juvenil/fisiopatologia , Masculino , Mutação , Síndrome de Noonan/mortalidade , Síndrome de Noonan/fisiopatologia , Estudos Prospectivos , Proteína Tirosina Fosfatase não Receptora Tipo 11/genéticaRESUMO
We report on a 6-year-old child with a de novo 1.6 Mb deletion in the 3q26.31q26.32 region identified by SNP array, involving only one relevant gene: TBL1XR1. The girl shows non-specific, mild to moderate intellectual deficiency but no autistic behavior. Point mutations in TBL1XR1 have recently been implicated in three patients with intellectual disability (ID) and autistic features. Our report supports that haploinsufficiency for TBL1XR1 could be implicated in non-ASD autosomal dominant ID.
Assuntos
Deficiências do Desenvolvimento/genética , Deleção de Genes , Deficiência Intelectual/genética , Proteínas Nucleares/genética , Receptores Citoplasmáticos e Nucleares/genética , Proteínas Repressoras/genética , Criança , Pré-Escolar , Fácies , Feminino , Humanos , Recém-Nascido , Polimorfismo de Nucleotídeo Único/genética , GravidezRESUMO
BACKGROUND: Neonatal diabetes mellitus is a rare genetic form of pancreatic ß-cell dysfunction. We compared phenotypic features and clinical outcomes according to genetic subtypes in a cohort of patients diagnosed with neonatal diabetes mellitus before age 1 year, without ß-cell autoimmunity and with normal pancreas morphology. METHODS: We prospectively investigated patients from 20 countries referred to the French Neonatal Diabetes Mellitus Study Group from 1995 to 2010. Patients with hyperglycaemia requiring treatment with insulin before age 1 year were eligible, provided that they had normal pancreatic morphology as assessed by ultrasonography and negative tests for ß-cell autoimmunity. We assessed changes in the 6q24 locus, KATP-channel subunit genes (ABCC8 and KCNJ11), and preproinsulin gene (INS) and investigated associations between genotype and phenotype, with special attention to extra-pancreatic abnormalities. FINDINGS: We tested 174 index patients, of whom 47 (27%) had no detectable genetic defect. Of the remaining 127 index patients, 40 (31%) had 6q24 abnormalities, 43 (34%) had mutations in KCNJ11, 31 (24%) had mutations in ABCC8, and 13 (10%) had mutations in INS. We reported developmental delay with or without epilepsy in 13 index patients (18% of participants with mutations in genes encoding KATP channel subunits). In-depth neuropsychomotor investigations were done at median age 7 years (IQR 1-15) in 27 index patients with mutations in KATP channel subunit genes who did not have developmental delay or epilepsy. Developmental coordination disorder (particularly visual-spatial dyspraxia) or attention deficits were recorded in all index patients who had this testing. Compared with index patients who had mutations in KATP channel subunit genes, those with 6q24 abnormalities had specific features: developmental defects involving the heart, kidneys, or urinary tract (8/36 [22%] vs 2/71 [3%]; p=0·002), intrauterine growth restriction (34/37 [92%] vs 34/70 [48%]; p<0·0001), and early diagnosis (median age 5·0 days, IQR 1·0-14·5 vs 45·5 days, IQR 27·2-95·0; p<0·0001). Remission of neonatal diabetes mellitus occurred in 89 (51%) index patients at a median age of 17 weeks (IQR 9·5-39·0; median follow-up 4·7 years, IQR 1·5-12·8). Recurrence was common, with no difference between the groups who had 6q24 abnormalities versus mutations in KATP channel subunit genes (82% vs 86%; p=0·36). INTERPRETATION: Neonatal diabetes mellitus is often associated with neuropsychological dysfunction and developmental defects that are specific to the underlying genetic abnormality. A multidisciplinary assessment is therefore essential when patients are diagnosed. Features of neuropsychological dysfunction and developmental defects should be tested for in adults with a history of neonatal diabetes mellitus. FUNDING: Agence Nationale de la Recherche-Maladies Rares Research Program Grant, the Transnational European Research Grant on Rare Diseases, the Société Francophone du Diabète-Association Française du Diabète, the Association Française du Diabète, Aide aux Jeunes Diabétiques, a CIFRE grant from the French Government, HRA-Pharma, the French Ministry of Education and Research, and the Société Française de Pédiatrie.
Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 6/genética , Deficiências do Desenvolvimento/genética , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/genética , Fenótipo , Transtornos Psicomotores/genética , Criança , Estudos de Coortes , Deficiências do Desenvolvimento/patologia , França/epidemiologia , Estudos de Associação Genética , Humanos , Lactente , Recém-Nascido , Insulina/genética , Estimativa de Kaplan-Meier , Mutação/genética , Pâncreas/diagnóstico por imagem , Canais de Potássio Corretores do Fluxo de Internalização/genética , Estudos Prospectivos , Precursores de Proteínas/genética , Transtornos Psicomotores/patologia , Receptores de Sulfonilureias/genética , UltrassonografiaRESUMO
Recently, germline mutations of NRAS have been shown to be associated with Noonan syndrome (NS), a relatively common developmental disorder characterized by short stature, congenital heart disease, and distinctive facial features. We report on the mutational analysis of NRAS in a cohort of 125 French patients with NS and no known mutation for PTPN11, KRAS, SOS1, MEK1, MEK2, RAF1, BRAF, and SHOC2. The c.179G>A (p.G60E) mutation was identified in two patients with typical NS, confirming that NRAS germline mutations are a rare cause of this syndrome. We also screened our cohort of 95 patients with juvenile myelomonocytic leukemia (JMML). Among 17 patients with NRAS-mutated JMML, none had clinical features suggestive of NS. None of the 11 JMML patients for which germline DNA was available had a constitutional NRAS mutation.
Assuntos
Genes ras/genética , Mutação em Linhagem Germinativa , Leucemia Mielomonocítica Juvenil/genética , Síndrome de Noonan/genética , Adolescente , Análise Mutacional de DNA , Feminino , Humanos , Lactente , MasculinoRESUMO
Cardio-facio-cutaneous (CFC) syndrome, Noonan syndrome (NS), and Costello syndrome (CS) are clinically related developmental disorders that have been recently linked to mutations in the RAS/MEK/ERK signalling pathway. This study was a mutation analysis of the KRAS, BRAF, MEK1 and MEK2 genes in a total of 130 patients (40 patients with a clinical diagnosis of CFC, 20 patients without HRAS mutations from the French Costello family support group, and 70 patients with NS without PTPN11 or SOS1 mutations). BRAF mutations were found in 14/40 (35%) patients with CFC and 8/20 (40%) HRAS-negative patients with CS. KRAS mutations were found in 1/40 (2.5%) patients with CFC, 2/20 (10%) HRAS-negative patients with CS and 4/70 patients with NS (5.7%). MEK1 mutations were found in 4/40 patients with CFC (10%), 4/20 (20%) HRAS-negative patients with CS and 3/70 (4.3%) patients with NS, and MEK2 mutations in 4/40 (10%) patients with CFC. Analysis of the major phenotypic features suggests significant clinical overlap between CS and CFC. The phenotype associated with MEK mutations seems less severe, and is compatible with normal mental development. Features considered distinctive for CS were also found to be associated with BRAF or MEK mutations. Because of its particular cancer risk, the term "Costello syndrome" should only be used for patients with proven HRAS mutation. These results confirm that KRAS is a minor contributor to NS and show that MEK is involved in some cases of NS, demonstrating a phenotypic continuum between the clinical entities. Although some associated features appear to be characteristic of a specific gene, no simple rule exists to distinguish NS from CFC easily.
Assuntos
Anormalidades Múltiplas/genética , Face/anormalidades , Genes ras , Cardiopatias Congênitas/genética , Sistema de Sinalização das MAP Quinases/genética , Mutação de Sentido Incorreto , Síndrome de Noonan/genética , Anormalidades da Pele/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/patologia , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Análise Mutacional de DNA , Diagnóstico Diferencial , Feminino , Genótipo , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/patologia , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , MAP Quinase Quinase 1/genética , MAP Quinase Quinase 2/genética , Masculino , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/patologia , Fenótipo , Proteínas Proto-Oncogênicas B-raf/genética , Transdução de Sinais/genética , Anormalidades da Pele/diagnóstico , Anormalidades da Pele/patologia , SíndromeRESUMO
The latency of eye movements is influenced by the fixation task; when the fixation stimulus is switched off before the target presentation (gap paradigm) the latency becomes short and express movements occur. In contrast, when the fixation stimulus remains on when the target appears (overlap paradigm), eye movement latency is longer. Several previous studies have shown increased rates of express saccades in children; however the presence of an express type of latency for vergence and combined movements in children has never been explored. The present study examines the effects of the gap and the overlap paradigms on horizontal saccades at far (150 cm) and at close (20 cm) viewing distances, on vergence along the median plane, and on saccades combined with convergence or divergence in 15 normal seven-year-old children. The results show that the gap paradigm produced shorter latency for all eye movements than the overlap paradigm, but the difference was only significant for saccades at close viewing distances, for divergence (pure and combined), and for saccades combined with vergence. The gap paradigm produced significantly higher rates of express latencies for saccades at close viewing distances, for divergence, and for saccades combined with divergence; in contrast, the frequencies of express latencies for saccades at far viewing distances and for convergence (pure or combined) were similar in the gap and the overlap paradigms. Interestingly, the rate of anticipatory latencies (<80 ms) was particularly high for divergence in the gap paradigm. Our collective findings suggest that the initiation of saccades at close viewing distances and of divergence is more reflexive, particularly in the gap paradigm. The finding of frequent anticipatory divergence that occurs at similar rates for seven-year-old children (this study) and for adults (Coubard et al., 2004, Exp Brain Res 154:368-381) indicates that predictive initiation of divergence is dominant.