Showing papers by "Alain Verloes published in 2009"

The mutation spectrum in RECQL4 diseases.

Abstract: Mutations in the RECQL4 gene can lead to three clinical phenotypes with overlapping features. All these syndromes, Rothmund–Thomson (RTS), RAPADILINO and Baller–Gerold (BGS), are characterized by growth retardation and radial defects, but RAPADILINO syndrome lacks the main dermal manifestation, poikiloderma that is a hallmark feature in both RTS and BGS. It has been previously shown that RTS patients with RECQL4 mutations are at increased risk of osteosarcoma, but the precise incidence of cancer in RAPADILINO and BGS has not been determined. Here, we report that RAPADILINO patients identified as carriers of the c.1390+2delT mutation (p.Ala420_Ala463del) are at increased risk to develop lymphoma or osteosarcoma (6 out of 15 patients). We also summarize all the published RECQL4 mutations and their associated cancer cases and provide an update of 14 novel RECQL4 mutations with accompanying clinical data.

Expanding the clinical and neuroradiologic phenotype of primary microcephaly due to ASPM mutations

Abstract: Objective: To determine the spectrum of clinical, neuropsychological, and neuroradiologic features in patients with autosomal recessive primary microcephaly (MCPH) due to ASPM gene mutations. Methods: ASPM was sequenced in 52 unrelated MCPH probands. In patients with ASPM mutations, we evaluated the clinical phenotype, cognition, behavior, brain MRI, and family. Results: We found homozygous or compound heterozygous ASPM loss-of-function mutations in 11 (22%) probands and 5 siblings. The probands harbored 18 different mutations, of which 16 were new. Microcephaly was severe after 1 year of age in all 16 patients, although in 4 patients the occipital-frontal circumference (OFC) at birth was decreased by only 2 SD. The OFC Z score consistently decreased after birth. Late-onset seizures occurred in 3 patients and significant pyramidal tract involvement in 1 patient. Intellectual quotients ranged from borderline-normal to severe mental retardation. Mild motor delay was noted in 7/16 patients. Language development was delayed in all patients older than 3 years. Brain MRI (n = 12) showed a simplified gyral pattern in 9 patients and several malformations including ventricle enlargement (n = 7), partial corpus callosum agenesis (n = 3), mild cerebellar hypoplasia (n = 1), focal cortical dysplasia (n = 1), and unilateral polymicrogyria (n = 1). Non-neurologic abnormalities consisted of short stature (n = 1), idiopathic premature puberty (n = 1), and renal dysplasia (n = 1). Conclusions: We provide a detailed description of features associated with ASPM mutations. Borderline microcephaly at birth, borderline-normal intellectual efficiency, and brain malformations can occur in ASPM -related primary hereditary microcephaly.

Elements of morphology: standard terminology for the lips, mouth, and oral region.

Abstract: An international group of clinicians and scientists working in the field of dysmorphology has initiated the standardization of terms used to describe human morphology. The goals are to standardize these terms and reach consensus regarding their definitions. In this way, we will increase the utility of descriptions of the human phenotype and facilitate reliable comparisons of findings among patients. Discussions with other workers in dysmorphology and related fields, such as developmental biology and molecular genetics, will become more precise. Here we summarize the anatomy of the oral region and define and illustrate the terms that describe the major characteristics of the lips and mouth.

MKS3/TMEM67 Mutations Are a Major Cause of COACH Syndrome, a Joubert Syndrome Related Disorder with Liver Involvement

Abstract: The acronym COACH defines an autosomal recessive condition of Cerebellar vermis hypo/aplasia, Oligophrenia, congenital Ataxia, Coloboma and Hepatic fibrosis. Patients present the "molar tooth sign", a midbrain-hindbrain malformation pathognomonic for Joubert Syndrome (JS) and Related Disorders (JSRDs). The main feature of COACH is congenital hepatic fibrosis (CHF), resulting from malformation of the embryonic ductal plate. CHF is invariably found also in Meckel syndrome (MS), a lethal ciliopathy already found to be allelic with JSRDs at the CEP290 and RPGRIP1L genes. Recently, mutations in the MKS3 gene (approved symbol TMEM67), causative of about 7% MS cases, have been detected in few Meckel-like and pure JS patients. Analysis of MKS3 in 14 COACH families identified mutations in 8 (57%). Features such as colobomas and nephronophthisis were found only in a subset of mutated cases. These data confirm COACH as a distinct JSRD subgroup with core features of JS plus CHF, which major gene is MKS3, and further strengthen gene-phenotype correlates in JSRDs.

BCOR analysis in patients with OFCD and Lenz microphthalmia syndromes, mental retardation with ocular anomalies, and cardiac laterality defects.

Abstract: Oculofaciocardiodental (OFCD) and Lenz microphthalmia syndromes form part of a spectrum of X-linked microphthalmia disorders characterized by ocular, dental, cardiac and skeletal anomalies and mental retardation. The two syndromes are allelic, caused by mutations in the BCL-6 corepressor gene (BCOR). To extend the series of phenotypes associated with pathogenic mutations in BCOR, we sequenced the BCOR gene in patients with (1) OFCD syndrome, (2) putative X-linked ('Lenz') microphthalmia syndrome, (3) isolated ocular defects and (4) laterality phenotypes. We present a new cohort of females with OFCD syndrome and null mutations in BCOR, supporting the hypothesis that BCOR is the sole molecular cause of this syndrome. We identify for the first time mosaic BCOR mutations in two females with OFCD syndrome and one apparently asymptomatic female. We present a female diagnosed with isolated ocular defects and identify minor features of OFCD syndrome, suggesting that OFCD syndrome may be mild and underdiagnosed. We have sequenced a cohort of males diagnosed with putative X-linked microphthalmia and found a mutation, p.P85L, in a single case, suggesting that BCOR mutations are not a major cause of X-linked microphthalmia in males. The absence of BCOR mutations in a panel of patients with non-specific laterality defects suggests that mutations in BCOR are not a major cause of isolated heart and laterality defects. Phenotypic analysis of OFCD and Lenz microphthalmia syndromes shows that in addition to the standard diagnostic criteria of congenital cataract, microphthalmia and radiculomegaly, patients should be examined for skeletal defects, particularly radioulnar synostosis, and cardiac/laterality defects.

Nicolaides–Baraitser syndrome: Delineation of the phenotype

Abstract: Nicolaides-Baraitser syndrome (NBS) is an infrequently described condition, thus far reported in five cases. In order to delineate the phenotype and its natural history in more detail, we gathered data on 18 hitherto unreported patients through a multi-center collaborative study, and follow-up data of the earlier reported patients. A detailed comparison of the 23 patients is provided. NBS is a distinct and recognizable entity, and probably has been underdiagnosed until now. Main clinical features are severe mental retardation with absent or limited speech, seizures, short stature, sparse hair, typical facial characteristics, brachydactyly, prominent finger joints and broad distal phalanges. Some of the features are progressive with time. The main differential diagnosis is Coffin-Siris syndrome. There is no important gender difference in occurrence and frequency of the syndrome, and all cases have been sporadic thus far. Microarray analysis performed in 14 of the patients gave normal results. Except for the progressive nature there are no clues to the cause.

SOS1 and PTPN11 mutations in five cases of Noonan syndrome with multiple giant cell lesions

Abstract: We report five cases of multiple giant cell lesions in patients with typical Noonan syndrome. Such association has frequently been referred to as Noonan-like/multiple giant cell (NL/MGCL) syndrome before the molecular definition of Noonan syndrome. Two patients show mutations in PTPN11 (p.Tyr62Asp and p.Asn308Asp) and three in SOS1 (p.Arg552Ser and p.Arg552Thr). The latter are the first SOS1 mutations reported outside PTPN11 in NL/MGCL syndrome. MGCL lesions were observed in jaws ('cherubism') and joints ('pigmented villonodular synovitis'). We show through those patients that both types of MGCL are not PTPN11-specific, but rather represent a low penetrant (or perhaps overlooked) complication of the dysregulated RAS/MAPK signaling pathway. We recommend discarding NL/MGCL syndrome from the nosology, as this presentation is neither gene-nor allele-specific of Noonan syndrome; these patients should be described as Noonan syndrome with MGCL (of the mandible, the long bone...). The term cherubism should be used only when multiple giant cell lesions occur without any other clinical and molecular evidence of Noonan syndrome, with or without mutations of the SH3BP2 gene.

Autism, language delay and mental retardation in a patient with 7q11 duplication

Abstract: Chromosomal rearrangements are found in a subset of patients with autism. Duplications involving loci associated with behavioural disturbances constitute an especially good candidate mechanism. The Williams–Beuren critical region (WBCR), located at 7q11.23, is commonly deleted in Williams–Beuren microdeletion syndrome (WBS). However, only four patients with a duplication of the WBCR have been reported to date. Here, 206 patients with autism spectrum disorders were screened for the WBCR duplication by quantitative microsatellite analysis and multiple ligation-dependent probe amplification. One male patient with a de novo interstitial duplication of the entire WBCR of paternal origin was identified. The patient had autistic disorder, severe language delay and mental retardation, with mild dysmorphism. The present report concerns the first patient with autistic disorder and a WBCR duplication. This observation indicates that the 7q11.23 duplication could be involved in complex clinical phenotypes, ranging from developmental or language delay to mental retardation and autism.

Binder phenotype: clinical and etiological heterogeneity of the so‐called Binder maxillonasal dysplasia in prenatally diagnosed cases, and review of the literature

Abstract: Objective Prenatal Binder profile is a well known clinical phenotype, defined by a flat profile without nasal eminence, contrasting with nasal bones of normal length. Binder profile results of a hypoplasia of the nasal pyramid (sometimes referred to as maxillonasal dysplasia). We report 8 fetuses prenatally diagnosed as Binder phenotype, and discuss their postnatal diagnoses. Methods Ultrasonographic detailed measurements in 2D and 3D were done on the 8 fetuses with Binder profile, and were compared with postnatal phenotype. Results All fetuses have an association of verticalized nasal bones, abnormal convexity of the maxilla, and some degree of chondrodysplasia punctata. The final diagnoses included fetal warfarin syndrome (one patient), infantile sialic acid storage (one patient), probable Keutel syndrome (one patient), and five unclassifiable types of chondrodysplasia punctata. Conclusion This series demonstrates the heterogeneity of prenatally diagnosed Binder phenotype, and the presence of chondrodysplasia punctata in all cases. An anomaly of vitamin K metabolism, possibly due to environmental factors, is suspected in these mild chondrodysplasia punctata. We recommend considering early prophylactic vitamin K supplementation in every suspected acquired vitamin K deficiency including incoercible vomiting of the pregnancy. Copyright © 2009 John Wiley & Sons, Ltd.

Hartsfield holoprosencephaly-ectrodactyly syndrome in five male patients: further delineation and review.

Abstract: We report on five male subjects with a triad of signs compatible with Hartsfield syndrome: ectrodactyly, holoprosencephaly, and mental retardation. Only six patients with this distinctive association have been reported over the past 20 years, all of them being males. Of the patients described here, some have unreported findings such as vermian hypoplasia in one and prolonged survival into adulthood in two. Two patients developed central diabetes insipidus. All were mentally retarded. No abnormalities were found at the cytogenetic level, including array CGH in two. No known genes for holoprosencephaly or ectrodactyly were found, including GLI2. The cause of Hartsfield syndrome is unknown. An X-linked defect is possible, although no recurrences have been described to date. Our observations almost double the number of cases. They underscore the usefulness of fetal brain imaging in the differential diagnosis of syndromal clefting diagnosed in utero, particularly when ectrodactyly-ectodermal dysplasia-clefting syndrome is suspected.

Giant diencephalic harmartoma and related anomalies: A newly recognized entity distinct from the Pallister–Hall syndrome

Abstract: An hypothalamic hamartoma is an abnormal mass of mature glio-neuronal tissue present in the hypothalamic area It usually measures <2 cm of diameter Most of the time, this hamartoma occurs in Pallister-Hall syndrome (PHS), due to heterozygous GLI3 mutations We report on five fetuses with giant diencephalic hamartoma and other midline brain and facial malformations, without mutation in the GLI3 gene or genomic rearrangements in three of them The fetuses showed facial asymmetry, unilateral ear and eye anomalies, and facial cleft Extracephalic malformations consisted of vertebral anomalies and short nails, without polydactyly and cardiac malformation The diencephalon was replaced by an encephaloid mass protruding into the facial cleft Normal cerebral structures were not detectable In one patient, holoprosencephaly of the syntelencephalic type was noted Arhinencephaly was present in all patients Histologically, the ill-defined, multilobulated lesion was made of neuroblastic and neurocytic cell foci, lying in a fibrillar network, elaborating sometimes perivascular pseudorosettes, with a maturation gradient in accordance with the fetal age Owing to their location, the tumors could be described as diencephalic, rather than hypothalamic hamartomas The striking asymmetry of the facial anomalies and the diencephalic malformations are not in the spectrum observed with PHS and related syndromes, suggesting a distinct entity involving abnormal morphogenetic developmental fields at around 5 weeks of gestation

Abnormal muscle development of the diaphragm in a fetus with 2p14-p16 duplication.

Abstract: Abnormal Muscle Development of the Diaphragm in a Fetus With 2p14–p16 Duplication Romain Guilherme,* Fabien Guimiot, Anne-Claude Tabet, Suonavy Khung-Savatovsky, Evelyne Gauthier, Marc Nouchy, Brigitte Benzacken, Alain Verloes, Jean-François Oury, Anne-Lise Delezoide, and Azzedine Aboura Department of Developmental Biology, AP-HP Robert Debr e University Hospital, Paris Diderot University, Paris, France Cytogenetics Unit, AP-HP Robert Debr e University Hospital, Paris Diderot University, Paris, France Clinical Genetics Unit, Department of Genetics, AP-HP Robert Debr e University Hospital, Paris Diderot University, Paris, France Department of Obstetrics and Gynecology, AP-HP Robert Debr e University Hospital, Paris Diderot University, Paris, France Department of Cytogenetics, American Hospital, Neuilly-sur-Seine, France Pasteur-Cerba Institute, Cergy-Pontoise, France INSERM U676, Robert Debr e University Hospital, Paris, France

Mesomelic dysplasia with acral synostoses Verloes–David–Pfeiffer type: Follow-up study documents progressive clinical course

Abstract: Verloes-David-Pfeiffer mesomelia-synostoses syndrome is an autosomal-dominant form of mesomelic dysplasia comprising typical acral synostoses combined with ptosis, hypertelorism, palatal abnormality, CHD, and ureteral anomalies. Since the original reports in 1995, two other patients have been described with this syndrome, one of them the patient reported in 1998 by Day-Salvatore. In this article, we report on the follow-up of some of the original cases and review the literature. We confirm that the Verloes-David-Pfeiffer syndrome (VDPS) is a progressive skeletal disorder that despite repeated corrective surgical intervention leads to severe limb deformities. No mutations were detected in the FLNB gene. To date, the cause and the pathogenesis of VDPS remain unknown. The latter is characterized in this study as a syndromic type of skeletal dysplasia because besides congenital malformations and multiple acromelic synostoses arising prenatally, VDPS manifests in postnatal life as a severe osteochondrodysplasia.

Etude des manifestations cardiovasculaires chez les patients présentant un syndrome de Noonan porteurs de mutation au sein du gène PTPN11: rôles des gènes de la voie de signalisation des MAP kinases pour les syndromes apparentés

Abstract: Les patients decrits initialement par J. Noonan se ressemblent et ont une cardiopathie congenitale : soit une stenose valvulaire pulmonaire (SVP), soit une persistance du canal arteriel. Avant la decouverte du premier gene responsable de ce qui est devenu le syndrome de Noonan, cinq etudes de cohortes decrivant ces patients ont repertorie la prevalence de SVP mais le spectre des cardiopathies semble large, n’a pas ete decrit de maniere exhautive et aucune hypothese n’est emise ou ne fait de lien entre ces differentes manifestations cardiaques et une comprehension integree du developpement embryonnaire. Le gene PTPN11 est le premier gene identifie chez 40% de ces patients. Une correlation existe entre la presence d’une mutation et la survenue de SVP de meme qu’entre l’absence de mutation et la presence d’une cardiomyopathie hypertrophique. Six etudes de cohortes ont repris la description des mutations identifiees au sein du gene PTPN11 et les phenotypes associes, mais les cardiopathies n’ont pas ete systematiquement ou specifiquement analysees (tant au sein des groupes de patients porteurs de mutation que de ceux sans mutation). Le syndrome LEOPARD est allelique du syndrome de Noonan depuis que des mutations specifiques au sein des exons 7,12 et 13 du gene PTPN11 ont ete identifiees chez 95% des patients. Afin d’apprehender les implications possibles du gene PTPN11 dans la survenue des cardiopathies chez les patients porteurs de ces deux syndromes, nous avons conduit une etude chez 272 patients au syndrome de Noonan et une etude chez 19 patients porteurs du syndrome LEOPARD. Parmi la cohorte de patients atteints du syndrome de Noonan, 104 ont ete diagnostiques porteurs d’une mutation du gene (38%). Une prevalence de survenue de cardiopathies affectant les structures droites du cœur se degage chez les patients identifies porteurs d’une mutation avec une difference significative pour la SVP, une tendance est relevee pour le canal atrio-ventriculaire et la communication inter-auriculaire de type Ostium Secundum. L’absence de mutation est correlee avec la survenue de cardiomyopathie hypertrophique et de cardiopathies du cœur gauche. Parmi les patients atteints du syndrome LEOPARD, il n’existe pas de difference statistiquement significative pour les patients porteurs d’une mutation ou non et/ou pour une cardiopathie particuliere. Toutes les mutations identifiees du gene PTPN11 sont des mutations ‘faux-sens’. Ce gene appartient a la famille des genes codant pour une proteine tyrosyl phosphatase, SHP-2, ne possedant pas de recepteur trans-membranaire. Cette phosphatase est impliquee dans la voie de signalisation cellulaire des MAP (‘Mitogen-activated protein’) kinases dont l’expression est ubiquitaire et inclut le coeur. Depuis nos travaux, le concept de syndrome « neuro-cardio-facio-cutane » est etabli puisque, a ce jour, 9 genes (SOS1, RAF1, BRAF, KRAS, NRAS, HRAS, NF1, SPRED1 et SHOC2), tous impliques dans la voie de signalisation RAS (voie des MAP kinases) sont identifies. Un spectre phenotypique existe avec des signes communs mais aussi distinctifs chez les patients presentant le syndrome de Noonan, le syndrome LEOPARD, le syndrome de Costello, le syndrome Cardio-Facio-Cutane (CFC), le syndrome « Noonan-NF1 », le syndrome de Legius et le syndrome « Noonan/Multiple Giant Cell Lesion ». Nous rapportons enfin l’observation d’une patiente atteinte du syndrome CFC et porteuse d’une mutation (p.R257Q) au sein du gene BRAF ayant developpe une cardiomyopathie hypertrophique. Ces travaux de cohortes de patients au phenotype du syndrome de Noonan, du syndrome LEOPARD et cette derniere description d’une patiente au syndrome CFC ont permis de participer a la decouverte de l’implication d’une voie de signalisation cellulaire dont l’origine genetique est maintenant demontree. Les resultats de nos travaux realises depuis 2002 auront permis, avec les equipes travaillant sur le meme sujet, d’orienter les investigations et les nouveaux projets de recherche qui etudient specifiquement le role du gene PTPN11 dans l’embryologie du cœur. Les etudes des orthologues (zebrafish, murin et Drosophila) porteurs a l’etat heterozygote d’une mutation du gene PTPN11 permettent d’integrer les anomalies phenotypiques et cardiaques observees. Ces etudes permettent de postuler les effets cellulaires produits par les mutations chez les patients atteints du syndrome de Noonan et chez les patients atteints du syndrome LEOPARD engendrant in vitro une activation de la phosphatase (effet « gain de fonction ») pour les premiers ou une reduction de l’activite phosphatase (« dominant negatif ») mais engendrant un effet gain de fonction in vivo. Nous discutons les connaissances acquises, les comprehensions obtenues et integrees et tracons enfin les perspectives offertes par ces travaux.

CEMARA: une plate-forme Web pour les maladies rares

Abstract: A rare disease is a condition the prevalence of which is lower than 5 cases per 10,000 inhabitants. At least 7000 rare disease have been discovered. in France, rare diseases affect nearly 30,000 patients and often only few cases for a given disease. Three to 4% of children and 6% of the population in Europe present with a rare disease. Most of these diseases do not have any curative treatment yet. It is thus a true public health stake. In France, a National Rare Diseases Plan was initiated in 2004. Thirty three out of 132 labelled Reference Centres (RC) share a common Information System called CEMARA. It is dedicated to collect continuous and complete records of patients presenting with a rare disease, and their follow-up. The main objective of CEMARA is to analyze the epidemiological patterns of rare diseases. It is also to contribute to the missions of the RC regarding the registration and description of their activities, coordination of the network of their correspondents, organization of the follow-up of rare diseases. A description of CEMARA is provided as well as its cooperation with Orphanet and GenAtlas, and a presentation of the 30,119 current records collected by more than 400 health care professionals belonging to more than 100 specialized sites.