Wiedemann-Steiner syndrome as a major cause of syndromic intellectual disability: A study of 33 French cases.

Wiedemann-Steiner syndrome (WSS) is a rare syndromic condition in which intellectual disability (ID) is associated with hypertrichosis cubiti, short stature, and characteristic facies. Following the identification of the causative gene (KMT2A) in 2012, only 31 cases of WSS have been described precisely in the literature. We report on 33 French individuals with a KMT2A mutation confirmed by targeted gene sequencing, high-throughput sequencing or exome sequencing. Patients' molecular and clinical features were recorded and compared with the literature data. On the molecular level, we found 29 novel mutations. We observed autosomal dominant transmission of WSS in 3 families and mosaicism in one family. Clinically, we observed a broad phenotypic spectrum with regard to ID (mild to severe), the facies (typical or not of WSS) and associated malformations (bone, cerebral, renal, cardiac and ophthalmological anomalies). Hypertrichosis cubiti that was supposed to be pathognomonic in the literature was found only in 61% of our cases. This is the largest series of WSS cases yet described to date. A majority of patients exhibited suggestive features, but others were less characteristic, only identified by molecular diagnosis. The prevalence of WSS was higher than expected in patients with ID, suggesting than KMT2A is a major gene in ID.

Chondrodysplasia with multiple dislocations: comprehensive study of a series of 30 cases.

The group of chondrodysplasia with multiple dislocations includes several entities, characterized by short stature, dislocation of large joints, hand and/or vertebral anomalies. Other features, such as epiphyseal or metaphyseal changes, cleft palate, intellectual disability are also often part of the phenotype. In addition, several conditions with overlapping features are related to this group and broaden the spectrum. The majority of these disorders have been linked to pathogenic variants in genes encoding proteins implicated in the synthesis or sulfation of proteoglycans (PG). In a series of 30 patients with multiple dislocations, we have performed exome sequencing and subsequent targeted analysis of 15 genes, implicated in chondrodysplasia with multiple dislocations, and related conditions. We have identified causative pathogenic variants in 60% of patients (18/30); when a clinical diagnosis was suspected, this was molecularly confirmed in 53% of cases. Forty percent of patients remain without molecular etiology. Pathogenic variants in genes implicated in PG synthesis are of major importance in chondrodysplasia with multiple dislocations and related conditions. The combination of hand features, growth failure severity, radiological aspects of long bones and of vertebrae allowed discrimination among the different conditions. We propose key diagnostic clues to the clinician.

[Hyperechogenic fetal bowel: Which fetal and neonatal outcome? A French study of 149 cases]. / Hyperéchogénicité intestinale fœtale : quel bilan proposer et quel pronostic ? À propos d'une série continue de 149 patientes.

OBJECTIVES: In case of hyperechogenic fetal bowel (HFB), invasive procedures such as amniocentesis are often proposed to detect an underlying cause. Our goal is to study etiologies and prognosis of HFB according to antenatal sonographic findings in order to evaluate the relevance of antenatal assessment. MATERIALS AND METHODS: It is a retrospective monocentric study lead from 2008 to 2012, including all patients with a suspicion of HFB on routine sonography. We analysed the antenatal and neonatal results, distinguishing four situations: isolated HFB, HFB+other digestive anomalies, HFB+vascular pathology, HFB+other associated anomalies. RESULTS: For 149 patients, HBF was confirmed. Sixty-nine were isolated HFB, 24 associated with other digestive anomalies, 16 with vascular pathology and 40 with other anomalies. Pregnancy outcomes were different with 92.8, 41.7, 0 and 45.0% of healthy newborns. In the case of isolated HBF, we noted 2.9% cystic fibrosis and 2.9% congenital infection. CONCLUSION: Isolated HBF seems to have a better prognosis than associated forms. However, prenatal investigations to eliminate cystic fibrosis or congenital infection should be offered and may be initially non-invasive, if a larger series confirmed the absence of dyschromosomy in this population.

Search for ReCQL4 mutations in 39 patients genotyped for suspected Rothmund-Thomson/Baller-Gerold syndromes.

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.

Pilot study of submucosal radiofrequency for epistaxis in hereditary hemorrhagic telangiectasia.

OBJECTIVE: To assess the safety and efficacy of submucosal radiofrequency (RF) treatment for hereditary hemorrhagic telangiectasia (HHT) with mild or moderate epistaxis. METHODOLOGY: We carried out a prospective pilot study of 16 consecutive patients with HHT-related epistaxis from June 2010 to April 2012. Under local anesthesia, RF was applied to one or both sides of the nose from the columella beneath the septal mucosal (50 joules per puncture). Patients were sent a questionnaire at least six months after the procedure. RESULTS: RF under local anesthesia was well tolerated, according to visual analog scale scores. Neither crusting nor pain was reported one week after the intervention. The frequency of epistaxis per day and per month was significantly lower after RF. The duration of bleeding also decreased from more than 10 minutes to less than 5 minutes in two thirds of patients. Thirteen of the 16 patients were satisfied with the technique and would request it for subsequent procedures to treat repeated bleeding. CONCLUSION: Submucosal RF treatment for HHT is a safe, well tolerated procedure with significant efficacy in the short term. It should be considered as an alternative technique for managing HHT-related epistaxis, although long-term results remain to be evaluated.

Intragenic rearrangements in LARGE and POMGNT1 genes in severe dystroglycanopathies.

Dystroglycanopathies are a heterogeneous group of muscular dystrophies with autosomal recessive inheritance characterized by abnormal glycosylation of alpha-dystroglycan. The most severe phenotypes are Walker-Warburg Syndrome (WWS) and muscle-eye-brain disease (MEB) presenting with lissencephaly type II (LIS II) and in which muscular dystrophy is associated with mental retardation and eye abnormalities. To date, six distinct genes, POMT1, POMT2, POMGNT1, FKTN, FKRP, LARGE and recently in one case DPM3, have been shown to be involved in dystroglycanopathies. Genomic sequencing alone is still frequently used for diagnosis purpose, not allowing detection of intragenic rearrangements at the heterozygous state contrarily to RNA analysis, quantitative PCR and CGH array analysis. These latter methods enabled us to identify four new intragenic rearrangements in the LARGE gene in three fetuses with WWS, born to two unrelated families: deletion of exons 9-10 and duplication of introns 1-4 for the first family and deletion of exons 4 and 7 for the second one; and a deletion of the last six exons of the POMGNT1 gene in two unrelated MEB patients. Genomic dosage studies using emerging tools such as CGH array should be included in routine molecular analysis of dystroglycanopathies, not only for the screening of the LARGE gene in which this kind of mutation seems to be more frequent than point mutations, but also for the other involved genes, especially in severe clinical cases.

IRF6 Screening of Syndromic and a priori Non-Syndromic Cleft Lip and Palate Patients: Identification of a New Type of Minor VWS Sign.

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.

Microdeletion at chromosome 4q21 defines a new emerging syndrome with marked growth restriction, mental retardation and absent or severely delayed speech.

BACKGROUND Genome-wide screening of large patient cohorts with mental retardation using microarray-based comparative genomic hybridisation (array-CGH) has recently led to identification several novel microdeletion and microduplication syndromes. METHODS Owing to the national array-CGH network funded by the French Ministry of Health, shared information about patients with rare disease helped to define critical intervals and evaluate their gene content, and finally determine the phenotypic consequences of genomic array findings. RESULTS In this study, nine unrelated patients with overlapping de novo interstitial microdeletions involving 4q21 are reported. Several major features are common to all patients, including neonatal muscular hypotonia, severe psychomotor retardation, marked progressive growth restriction, distinctive facial features and absent or severely delayed speech. The boundaries and the sizes of the nine deletions are different, but an overlapping region of 1.37 Mb is defined; this region contains five RefSeq genes: PRKG2, RASGEF1B, HNRNPD, HNRPDL and ENOPH1. DISCUSSION Adding new individuals with similar clinical features and 4q21 deletion allowed us to reduce the critical genomic region encompassing two genes, PRKG2 and RASGEF1B. PRKG2 encodes cGMP-dependent protein kinase type II, which is expressed in brain and in cartilage. Information from genetically modified animal models is pertinent to the clinical phenotype. RASGEF1B is a guanine nucleotide exchange factor for Ras family proteins, and several members have been reported as key regulators of actin and microtubule dynamics during both dendrite and spine structural plasticity. CONCLUSION Clinical and molecular delineation of 4q21 deletion supports a novel microdeletion syndrome and suggests a major contribution of PRKG2 and RASGEF1B haploinsufficiency to the core phenotype.

Delineation of 15q13.3 microdeletions.

The increasing use of array-comparative genomic hybridization (array-CGH) to identify copy number variations (CNVs) in patients with developmental delay (DD), mental retardation and/or dysmorphic features has allowed the recent recognition of numerous genomic imbalances, including the 15q13.3 microdeletion. Patients with this microdeletion generally present with relatively consistent breakpoints at BP4 and BP5, which include the CHRNA7 gene. About 100 index cases have been reported since the first publication in 2008. This large number of patients ascertained through highly variable samples has been necessary to describe the full phenotypic spectrum of this microdeletion, ranging from mental retardation with dysmorphic features, epilepsy, neuropsychiatric disturbances with or without cognitive impairment to complete absence of anomalies. Here, we describe a collaborative study reporting a new cohort of 12 index patients and 13 relatives carrying a heterozygous BP4-BP5 microdeletion out of a series of 4625 patients screened by array-CGH for DD. We confirm the clinical expressivity of the disease as well as the incomplete penetrance in seven families. We showed through a review of the literature that males are more likely to be symptomatic. Sequence analysis of CHRNA7 yielded no data to support the unmasking of recessive variants as a cause of phenotypic variability. We also report the first patient carrying a 15q13.3 homozygous microdeletion inherited from both parents. He had severe epileptic encephalopathy with retinopathy, autistic features and choreoathetosis. Besides the classical approximately 1.5 Mb BP4-BP5 microdeletion, we also describe three index patients and two relatives with a smaller 500 kb microdeletion, including the CHRNA7 gene.

A new highly penetrant form of obesity due to deletions on chromosome 16p11.2.

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.

Bilateral periventricular nodular heterotopia in France: frequency of mutations in FLNA, phenotypic heterogeneity and spectrum of mutations.

Bilateral periventricular nodular heterotopia (BPNH) is the most common form of periventricular heterotopia. Mutations in FLNA, encoding filamin A, are responsible for the X linked dominant form of BPNH (FLNA-BPNH). Recently, atypical phenotypes including BPNH with Ehlers-Danlos syndrome (BPNH-EDS) have been recognised. A total of 44 FLNA mutations have so far been reported in this phenotype. Most of these mutations lead to a truncated protein, but few missense mutations have also been described. Here, the results of a mutation screening conducted in a series of 32 BPNH patients with the identification of 12 novel point mutations in 15 patients are reported. Nine mutations were truncating, while three were missense. Three additional patients with BPNH-EDS and a mutation in FLNA are described. No phenotype-genotype correlations could be established, but these clinical data sustain the importance of cardiovascular monitoring in FLNA-BPNH patients.

Congenital idiopathic intestinal pseudo-obstruction and hydrocephalus with stenosis of the aqueduct of sylvius.

We present the first report of an association between hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS) and a specific form of congenital idiopathic intestinal pseudo-obstruction (CIIP) in an infant. Diagnosis of HSAS was suspected during the neonatal period because of a severely dilated ventricular system associated with bilateral adducted thumbs, and was confirmed by demonstration of a mutation in the gene encoding L1 cell adhesion molecule (L1CAM). L1CAM mutations cause a variable clinical spectrum. This gene is located at Xq28 and encodes a transmembrane glycoprotein involved in neurite outgrowth and neuronal migration. Hirschprung disease has been reported to involve an L1CAM mutation that manifests as a quantitative defect in the migration of neural crest cells in distal segments of the gut. We report an association that suggests that alterations of L1CAM may cause another type of intestinal pseudo-obstruction distension with a qualitative defect in differentiated Cajal's cells in the anterior part of the gut. This observation suggests that L1CAM has a role in the developmental regulation of multiple systems. Further clinical descriptions of gastroenterological and neuropathological data are required to extend our understanding of the mechanisms underlying L1CAM functions.

Homozygosity mapping of a Dyggve-Melchior-Clausen syndrome gene to chromosome 18q21.1.

Dyggve-Melchior-Clausen syndrome (DMC) is an autosomal recessive condition characterised by short trunk dwarfism, scoliosis, microcephaly, coarse facies, mental retardation, and characteristic radiological features. X rays show platyspondyly with double vertebral hump, epiphyseal dysplasia, irregular metaphyses, and a characteristic lacy appearance of the iliac crests. Electron microscopy of chondrocytes have shown widened cisternae of rough endoplasmic reticulum and biochemical analyses have shown accumulation of glucosaminoglycan in cartilage, but the pathogenesis of DMC remains unexplained. Here, we report on the homozygosity mapping of a DMC gene to chromosome 18q21.1 in seven inbred families (Zmax=9.65 at theta=0 at locus D18S1126) in the genetic interval (1.8 cM) defined by loci D18S455 and D18S363. Despite the various geographical origins of the families reported here (Morocco, Tunisia, Portugal, and Lebanon), this condition was genetically homogeneous in our series. Continuing studies will hopefully lead to the identification of the disease causing gene.

[An ischemic pulmonary malformation of the surviving fetus occurring after selective embryo reduction in bichorionic pregnancy. Report of one case and literature review]. / Une anomalie pulmonaire ischémique inhabituelle du foetus survivant après interruption sélective sur grossesse bichoriale. A propos d'un cas et revue de la littérature.

We describe, to our knowledge, the first case of a pulmonary malformation called acinar dysplasia occurring at a surviving fetus after selective embryo reduction in a bichorionic pregnancy. The chronological and histological observations suggest that this anomaly may be linked with a feticide achieved at 13 week's gestation. Literature review concerning selective embryo reduction shows rare cases of vascular connections in bichorionic pregnancies especially during the first half of gestation, that can explain in part the apparition of survivor's anomalies.

Large-scale deletions and SMADIP1 truncating mutations in syndromic Hirschsprung disease with involvement of midline structures.

Hirschsprung disease (HSCR) is a common malformation of neural-crest-derived enteric neurons that is frequently associated with other congenital abnormalities. The SMADIP1 gene recently has been recognized as disease causing in some patients with 2q22 chromosomal rearrangement, resulting in syndromic HSCR with mental retardation, with microcephaly, and with facial dysmorphism. We screened 19 patients with HSCR and mental retardation and eventually identified large-scale SMADIP1 deletions or truncating mutations in 8 of 19 patients. These results allow further delineation of the spectrum of malformations ascribed to SMADIP1 haploinsufficiency, which includes frequent features such as hypospadias and agenesis of the corpus callosum. Thus, SMADIP1, which encodes a transcriptional corepressor of Smad target genes, may play a role not only in the patterning of neural-crest-derived cells and of CNS but also in the development of midline structures in humans.

Radioulnar synostosis, radial ray abnormalities, and severe malformations in the male: a new X-linked dominant multiple congenital anomalies syndrome?

We describe a multiple congenital anomalies (MCA) syndrome dominantly transmitted through three generations. Radial ray abnormalities with wide variability of expression were observed in four female patients. Moreover, a 14-week-gestation male fetus had severe radial ray malformation, anencephaly, unilateral renal agenesis, and a common dorsal mesentery. Results of high-resolution karyotyping were normal in the malformed fetus and his affected mother. Furthermore, several spontaneous abortions of male fetuses had occurred in this pedigree. To our knowledge, a similar association has not been described previously. It could represent a new X-linked dominant MCA syndrome, or an autosomal dominant condition with severe expression limited to males.

[Trisomy 18: ultrasound aspects. Report of 40 cases]. / Trisomie 18: aspects échographiques. A propos de 40 observations.

OBJECTIVE: We describe the different ultrasound findings suggestive of trisomy 18. PATIENTS AND METHODS: We conducted a retrospective study in 40 cases of trisomy 18 diagnosed in the department of obstetrics at the Lille University Hospital between 1988 and 1998. RESULTS: Eighty percent of the women in this series were multiparous. Mean maternal age at discovery of the trisomy as 33.2 years and the mean gestational age was 20.4 weeks. Fifty-five percent of the cases were discovered during the second trimester of pregnancy, 22.5% during the third trimester and 22.5% during the first trimester. One ultrasound abnormality, at least, was detected in 36/40 cases (90%) a percentage that reached 96.8% taking into consideration the ultrasound examinations performed during the second and third trimesters (30/31 cases). The most frequently detected ultrasound abnormalities were: intra uterine growth retardation (IUGR: 50%), poly-hydramnios (42.5%), limb abnormalities (42.5%), cardiac defects (30%), facial abnormalities (37.5%), meningomyelocele (32.5%), digestive abnormalities (32.5%), urinary tract abnormalities (27.5%), lymphangiectasia and cystic hygroma (15%), and single umbilical artery (12.5%). Medical termination of pregnancy (TOP) was performed in 28 cases. There was one spontaneous miscarriage at 8 weeks and one in utero death (IUD) at 39 weeks in a patient who desired to continue her pregnancy. In 6 cases, the issue of the pregnancy was unknown because the patients were lost to follow-up. In 4 cases (10%), pregnancy was continued to delivery of live babies that only survived a few minutes to 7 days. CONCLUSION: The ultrasound signs suggestive of trisomy 18 change according to the term of pregnancy. At the first trimester, most of the signs are nonspecific, such as cystic hydroma or lymphangiectasia, and do not suggest the need for a karyotype. At the end of the second trimester, an association of various signs that alone would not be highly suspect suggest the need for further exploration in search of other signs: early IUGR, associated or not with poly-hydramnios, limb abnormalities, cardiac defects, omphalocele, diaphragmatic hernia, meningomyelocele, enlarged cisterna magna, choroid plexus cysts, single umbilical artery, facial dysmorphism, facial cleft, hydronephrosis.

Characterization of eleven novel mutations (M45L, R119H, 544delG, G145V, H154Y, C184Y, D289V, 862+5A, 1172delC, R411X, E459K) in the tissue-nonspecific alkaline phosphatase (TNSALP) gene in patients with severe hypophosphatasia. Mutations in brief no. 217. Online.

Hypophosphatasia is a rare inherited disorder characterized by defective bone mineralization and deficiency of serum and tissue liver/ bone/kidney tissue alkaline phosphatase (L/B/K ALP) activity. We report the characterization of tissue-nonspecific alkaline phosphatase (TNSALP) gene mutations in a series of 9 families affected by severe hypophosphatasia. Fourteen distinct mutations were found, 3 of which were previously reported in the North American or Japanese populations. Seven of the 11 new mutations were missense mutations (M45L, R119H, G145V, C184Y and H154Y, D289V, E459K), the four others were 2 single nucleotide deletions (544delG and 1172delC), a mutation affecting donor splice site (862 + 5A) and a nonsense mutation (R411X).