Mental health status of individuals with sexual development disorders: A review.

Healthcare recommendations for people with disorders of sexual development (DSDs) include mental health attention and active participation of psychiatrists and psychologists in dedicated multidisciplinary teams. Therefore, it seems crucial for them to improve knowledge about specific difficulties and needs of these patients. The aim of this article is to report in a synthesizing manner the recent works evaluating the mental health and psychological status of individuals with DSDs. After research conducted using PubMed and ScienceDirect, 18 studies were inventoried and qualitatively analyzed in response to three main questions: Do individuals with DSDs suffer more frequently and/or more severely from psychological conditions or mental disorders? From what kind of disorder do they suffer? and What are the determinant factors involved in their development? This work highlights an increased risk of affective disorders in individuals with DSDs, particularly anxiety and depressive disorders and interpersonal difficulties. Studies identified some potentially determining factors implicated in their development, among which are the etiology of DSDs, the life stage, the age at the time of diagnosis, and the lack of conformity of sexual phenotype with sex assignment. Taken together, the etiology of DSDs, the lack of conformity of sexual phenotype with sex assignment, and the feeling of being different from peers seem to be interesting factors to study in the future. Multicentric and longitudinal studies using standardized evaluation and control groups should be the most robust way to improve knowledge about these preoccupations.

SF1 and spleen development: new heterozygous mutation, literature review and consequences for NR5A1-mutated patient's management.

Steroidogenic factor 1 (encoded by SF1/NR5A1) is a transcription factor with multiple target genes involved in the development and function of multiple steroidogenic and non-steroidogenic tissues. NR5A1 mutations lead to several phenotypes, including sex reversal, spermatogenesis failure, premature ovarian failure and adrenocortical insufficiency. The implication of NR5A1 mutations in spleen development anomalies was recently highlighted. We provide new evidence of this involvement, describing a novel heterozygous non-sense NR5A1 mutation in a 46,XY-DSD with polysplenia female proband and her father, who had hypospadias and asplenia.

Clinical reappraisal of SHORT syndrome with PIK3R1 mutations: toward recommendation for molecular testing and management.

SHORT syndrome has historically been defined by its acronym: short stature (S), hyperextensibility of joints and/or inguinal hernia (H), ocular depression (O), Rieger abnormality (R) and teething delay (T). More recently several research groups have identified PIK3R1 mutations as responsible for SHORT syndrome. Knowledge of the molecular etiology of SHORT syndrome has permitted a reassessment of the clinical phenotype. The detailed phenotypes of 32 individuals with SHORT syndrome and PIK3R1 mutation, including eight newly ascertained individuals, were studied to fully define the syndrome and the indications for PIK3R1 testing. The major features described in the SHORT acronym were not universally seen and only half (52%) had four or more of the classic features. The commonly observed clinical features of SHORT syndrome seen in the cohort included intrauterine growth restriction (IUGR) <10th percentile, postnatal growth restriction, lipoatrophy and the characteristic facial gestalt. Anterior chamber defects and insulin resistance or diabetes were also observed but were not as prevalent. The less specific, or minor features of SHORT syndrome include teething delay, thin wrinkled skin, speech delay, sensorineural deafness, hyperextensibility of joints and inguinal hernia. Given the high risk of diabetes mellitus, regular monitoring of glucose metabolism is warranted. An echocardiogram, ophthalmological and hearing assessments are also recommended.

[Lynch syndrome and risk of prostate cancer; review of the literature]. / Syndrome de Lynch et risque de cancer de la prostate; revue de la littérature.

INTRODUCTION: The association between Lynch syndrome and prostate cancer has been studied. Recent studies report an association between these two diseases. MATERIAL AND METHODS: Literature review based on PubMed search was performed using the following keywords: Lynch syndrome and prostate cancer. RESULTS: Eight articles analyzing cohorts of subjects carrying Lynch syndrome were analysed including 6786 patients with 175 cancers. Prostate cancers were more frequent with a standardized incidence ratio (SIR) from 0.93 (95% CI: 0.19-2.7) and 5.9 (95% CI 4.1-17.1) and occurs at a younger age than in the general population mainly for mutations in the MSH2 gene. CONCLUSION: Prostate cancer seem more frequent and occur earlier in individuals harboring a mutation in the MSH2 gene while it does not appear to be any difference compared to the general population for other mutations in Lynch syndrome.

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.

[Genetic testing in the context of the revision of the French law on bioethics]. / Les tests génétiques à l'heure de la deuxième révision des lois de bioéthique.

This article focuses on six questions raised by genetic testing in human: (1) the use of genetic tests, (2) information given to relatives of patients affected with genetic disorders, (3) prenatal and preimplantatory diagnosis for late onset genetic diseases and the use of pangenomic tests in prenatal diagnosis, (4) direct-to-consumer genetic testing, (5) population screening in the age of genomic medicine and (6) incidental findings when genetic testing are used.

Phenotypic variability in 49 cases of ESCO2 mutations, including novel missense and codon deletion in the acetyltransferase domain, correlates with ESCO2 expression and establishes the clinical criteria for Roberts syndrome.

BACKGROUND: Roberts syndrome (RBS) and SC phocomelia are caused by mutations in ESCO2, which codes for an acetyltransferase involved in the regulation of sister chromatid cohesion. Of 26 mutations described to date, only one missense mutation has been reported and all others are predicted to be truncating mutations. Genotype-phenotype analysis has been hampered by limited numbers of patients with clinical information available. OBJECTIVE: To provide unpublished clinical data for 31 patients with proven ESCO2 mutations and combine this series with previously reported clinical and mutation data on 18 cases. Methods Genotype-phenotype correlations and functional effects of two novel ESCO2 mutations were analysed. In situ hybridisation on human embryos at Carnegie stages 14, 17 and 21 was performed to study ESCO2 expression during development. RESULTS AND CONCLUSIONS: Using the cohort of 49 patients, the clinical criteria for RBS were delineated to include: growth retardation; symmetric mesomelic shortening of the limbs in which the upper limbs are more commonly and severely affected than the lower limbs; characteristic facies with microcephaly. The severity of malformations of the facies correlates with the severity of limb reduction. The occurrence of corneal opacities may be associated with specific mutations. Two new mutations, both in the ESCO2 acetyltransferase domain, are described and their acetylation effects in vitro demonstrated. In situ hybridisation on human embryos showed ESCO2 expression in the brain, face, limb, kidney and gonads, which corresponds to the structures affected in RBS.

[Psychological distress in applicants for genetic screening for colorectal cancer]. / Etude de la vulnérabilité psychologique des sujets inscrits à un dépistage génétique des cancers colorectaux héréditaires.

UNLABELLED: Introduction. The development of a DNA based diagnostic test has allowed for the genetic screening of many hereditary diseases. In addition to the identification of the deleterious gene, this screening process has led to the recognition of developing illnesses at high risk. In recent years, a number of genes predisposing to an inherited cancer syndrome have been identified. AIM OF THE STUDY: Our purpose in this study was to determine whether subjects at risk who test for inherited colorectal cancer, are likely to develop a higher level of psychological distress than the norm, taking into consideration the particular history of this familial disease. METHODS: The demographic and psychosocial aspects of our population was described using: 1) the State Trait Anxiety Inventory (STAI), 2) the Center for Epidemiologic Studies Depression (CES-D), 3) a perceived risk for the gene carrier, 4) subjective perception of personal vulnerability and 5) the role of the medical status (affected or not), which places the subject in either predisposition or predictive testing. RESULTS: Results show that our population had a higher predisposition for depressive disorders (chi2=9,3. p=0.002) and a significantly higher state of anxiety (chi2=9,3. p=0.002), prior to genetic counselling, compared with other populations. We found no evidence in the medical status, nor the perceived risk. However, the assessment of one's own personal vulnerability is related to psychological distress. DISCUSSION: These results highlight the particular vulnerability of subjects undergoing genetic testing as well as showing the pertinence of proposing psychological help throughout the process of these new specific diagnoses.

Genotype phenotype correlation of 30 patients with Smith-Magenis syndrome (SMS) using comparative genome hybridisation array: cleft palate in SMS is associated with larger deletions.

BACKGROUND: Smith-Magenis syndrome (SMS) is rare (prevalence 1 in 25 000) and is associated with psychomotor delay, a particular behavioural pattern and congenital anomalies. SMS is often due to a chromosomal deletion of <4 Mb at the 17p11.2 locus, leading to haploinsufficiency of numerous genes. Mutations of one of these gemes, RAI1, seems to be responsible for the main features found with heterozygous 17p11.2 deletions. METHODS: We studied DNA from 30 patients with SMS using a 300 bp amplimers comparative genome hybridisation array encompassing 75 loci from a 22 Mb section from the short arm of chromosome 17. RESULTS: Three patients had large deletions (10%). Genotype-phenotype correlation showed that two of them had cleft palate, which was not found in any of the other patients with SMS (p<0.007, Fisher's exact test). The smallest extra-deleted region associated with cleft palate in SMS is 1.4 Mb, contains <16 genes and is located at 17p11.2-17p12. Gene expression array data showed that the ubiquitin B precursor (UBB) is significantly expressed in the first branchial arch in the fourth and fifth weeks of human development. CONCLUSION: These data support UBB as a good candidate gene for isolated cleft palate.

Cleft lip/palate and CDH1/E-cadherin mutations in families with hereditary diffuse gastric cancer.

We report the association of CDH1/E-cadherin mutations with cleft lip, with or without cleft palate (CLP), in two families with hereditary diffuse gastric cancer (HDGC). In each family, the CDH1 mutation was a splicing mutation generating aberrant transcripts with an in-frame deletion, removing the extracellular cadherin repeat domains involved in cell-cell adhesion. Such transcripts might encode mutant proteins with trans-dominant negative effects. We found that CDH1 is highly expressed at 4 and 5 weeks in the frontonasal prominence, and at 6 weeks in the lateral and medial nasal prominences of human embryos, and is therefore expressed during the critical stages of lip and palate development. These findings suggest that alteration of the E-cadherin pathway can contribute to human clefting.

[Fatal neonatal respiratory distress in Niemann-Pick C2 and prenatal diagnosis with mutations in gene HE1/NPC2]. / Forme respiratoire néonatale létale de la maladie de Niemann-Pick C2 et diagnostic anténatal par l'étude des mutations du gène HE1/NPC2.

UNLABELLED: We report the fifth case of neonatal form of type C2 (NP-C2) Niemann-Pick disease with early and fatal respiratory distress. Eleven families presenting such cases are known to date in the world. Since December 2000, isolation of the underlying gene HE1/NPC2 and its mutations has allowed major advances in diagnosis. CASE REPORT: Elisa was born in May 2000. NP-C2 disease was associated with severe respiratory distress leading to death at the age of four months. On the next pregnancy in September 2000, prenatal diagnosis was performed by means of biological tests that required four weeks response time. In December 2000, isolation of the HE1/NPC2 gene located to 14q24.3 and of some of its mutations allowed to characterize the patient as being homozygote for the nonsense mutation E20X. On the the two next pregnancies, prenatal diagnosis was performed at 12 SA, in 48 hours, by the means of mutation analysis. The last fetus was heterozygote for the mutation E20X, allowing the birth at term of a healthy male newborn baby. CONCLUSION: Niemann-Pick type C disease is a rare lysosomal lipid storage disease with severe prognosis. It is characterized by abnormalities of intracellular transport of endocytosed cholesterol. Diagnosis relies on biological tests that require cultured cells. Genetic heterogeneity defines two different genetic complementation groups C1 and C2. Severe and early respiratory distress is more likely to be associated with the rare type C2. Since December 2000, after identification of the disease-causing mutations in the proband, mutation analysis of gene HE1/NPC2 on direct chorionic villus samples allows early and fast (48 hours) prenatal diagnosis.

[Constitutional deficiency of pulmonary surfactant protein B: clinical presentation, histologic and molecular diagnosis]. / Déficit constitutionnel en protéine B du surfactant pulmonaire: présentation clinique, diagnostic histologique et moléculaire.

We report a female full-term infant with fatal respiratory failure of early onset due to inherited SP-B deficiency. Lung biopsy was performed at 18 days after birth, with histopathological characterization indicating congenital alveolar proteinosis. Immunohistochemical studies of lung tissue revealed the absence of SP-B and the presence of intra-alveolar SP-A normal quantities. Analysis of genomic DNA showed homozygosity for the 121ins2 mutation of the SFTPB gene. The infant died 21 days after birth. Both parents were heterozygotes for the mutation. Chorionic villus sampling was performed at the first trimester of the following pregnancy. Restriction analysis of amplified fetal DNA, studies of microsatellite segregation and direct sequencing led to the diagnosis of homozygosity for the parental wild-type allele. The diagnosis of congenital SP-B deficiency should be suspected whenever an early and acute respiratory failure in a term or near-term infant does not resolve after five days of age: diagnostic confirmation can be easily and rapidly obtained with the analysis of genomic DNA and immunohistochemical characterization of lung tissue.

Autosomal recessive disorder otospondylomegaepiphyseal dysplasia is associated with loss-of-function mutations in the COL11A2 gene.

Otospondylomegaepiphyseal dysplasia (OSMED) is an autosomal recessive skeletal dysplasia accompanied by severe hearing loss. The phenotype overlaps that of the autosomal dominant disorders-Stickler and Marshall syndromes-but can be distinguished by disproportionately short limbs, severe hearing loss, and lack of ocular involvement. In one family with OSMED, a homozygous Gly-->Arg substitution has been described in COL11A2, which codes for the alpha2 chain of type XI collagen. We report seven further families with OSMED. All affected individuals had a remarkably similar phenotype: profound sensorineural hearing loss, skeletal dysplasia with limb shortening and large epiphyses, cleft palate, an extremely flat face, hypoplasia of the mandible, a short nose with anteverted nares, and a flat nasal bridge. We screened affected individuals for mutations in COL11A2 and found different mutations in each family. Individuals from four families, including three with consanguineous parents, were homozygous for mutations. Individuals from three other families, in whom parents were nonconsanguineous, were compound heterozygous. Of the 10 identified mutations, 9 are predicted to cause premature termination of translation, and 1 is predicted to cause an in-frame deletion. We conclude that the OSMED phenotype is highly homogenous and results from homozygosity or compound heterozygosity for COL11A2 mutations, most of which are predicted to cause complete absence of alpha2(XI) chains.

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.

New autosomal recessive syndrome of severe microcephaly and skeletal anomalies including posterior rib-gap defects.

We describe two female fetuses conceived by a nonconsanguineous couple. The pregnancies were interrupted at 31 and 26 weeks of gestation, respectively, because of severe microcephaly. Postmortem X-ray and autopsy studies showed in both fetuses: 1) severe intrauterine growth retardation; 2) facial anomalies characterized by severe microcephaly, sloping forehead, low set and posteriorly angulated ears, prominent eyes, down-slanting palpebral fissures, large nose, small mouth with full lips, and mild microretrognathia; 3) severe brain hypoplasia that was more pronounced in the second fetus; 4) severe rib hypoplasia with posterior rib-gap defects and in case 2 hypoplasia of several bones (right clavicle, right radius and ulna, several phalanges of hands and feet); 5) contracture at large joints. No other visceral malformations were observed, and chromosomes were normal in patient 2 and parents. This phenotype has some similarities with different syndromic entities but an identical malformation syndrome seems not to have been described previously. Autosomal recessive inheritance is the most likely cause of this putative "new syndrome."