The emerging microduplication 3q13.31: Expanding the genotype-phenotype correlations of the reciprocal microdeletion 3q13.31 syndrome.

Microdeletion and microduplication syndromes are well-known causes of developmental delay and/or malformations of differing severity. It was recently reported that a microdeletion at the 3q13.31 locus is associated with a new syndrome combining developmental delay, postnatal overgrowth and dysmorphic features. However, the reciprocal microduplication has only been described in a few case reports displaying some clinical features of the microdeletion syndrome. Here, we report on a female infant with a 3.34 Mb microduplication of the 3q13.2q13.31 region inherited from her mother. The infant presented with severe intellectual disability, learning difficulties, intrauterine and postnatal growth retardation and skeletal particularities but no dysmorphic traits. This microduplication encompassed the previously described shortest region of overlap, which contains five genes (DRD3, ZNF80, TIGIT, MIR568 and ZBTB20). We reviewed the phenotypes described in the literature on microduplications and in the well-characterized 3q13.31 microdeletion syndrome. In agreement with the literature data, DRD3 and ZBTB20 appear to be strong candidate genes for neurodevelopmental defects and growth retardation. Lastly, we consider the putative mechanism of this rearrangement, which may involve a particular kind of nonallelic homologous recombination of human endogenous retrovirus elements.

Low-level mosaicism of a de novo derivative chromosome 9 from a t(5;9)(q35.1;q34.3) has a major phenotypic impact.

Microdeletion and microduplication syndromes are well-known causes of developmental delay and/or malformations of differing severity. Although homogeneous abnormalities can now be detected relatively easily using microarray technologies, they are more difficult to detect and interpret in cases of mosaicism. Here, we report on a male infant with a mosaic de novo derivative chromosome 9, featuring a 10.2 Mb 5q35 duplication (including the NSD1 gene) and a 687 kb 9q34 deletion (including EHMT1). The infant presented developmental delay, short stature, brachy/plagiocephaly and hyperactivity. The proportion of abnormal cells was 50% in saliva (in a microarray analysis) and 25% in lymphocytes (in a FISH analysis). Despite the low-level mosaicism in lymphocytes, this imbalance appears to be responsible for a distinctive phenotype (suggesting the presence of variable clinical expression and/or major somatic mosaicism).

Diagnosis and treatment of pulmonary arteriovenous malformations in hereditary hemorrhagic telangiectasia: An overview.

Hereditary hemorrhagic telangiectasia (HHT) or Rendu-Osler-Weber disease is an autosomic dominant disorder, which is characterized by the development of multiple arteriovenous malformations in either the skin, mucous membranes, and/or visceral organs. Pulmonary arteriovenous malformations (PAVMs) may either rupture, and lead to life-threatening hemoptysis/hemothorax or be responsible for a right-to-left shunting leading to paradoxical embolism, causing stroke or cerebral abscess. PAVMs patients should systematically be screened as the spontaneous complication rate is high, by reaching almost 50%. Neurological complications rate is considerably higher in patients presenting with diffuse pulmonary involvement. PAVM diagnosis is mainly based upon transthoracic contrast echocardiography and CT scanner examination. The latter also allows the planification of treatments to adopt, which consists of percutaneous embolization, having replaced surgery in most of the cases. The anchor technique consists of percutaneous coil embolization of the afferent pulmonary arteries of the PAVM, by firstly placing a coil into a small afferent arterial branch closely upstream the PAVM. Enhanced contrast CT scanner is the key follow-up examination that depicts the PAVM enlargement, indicating the various mechanisms of PAVM reperfusion. When performed by experienced operators as the prime treatment, percutaneous embolization of PAVMs, is a safe, efficient and sustained therapy in the great majority of HHT patients.

Prenatal diagnosis of the duplication 17p11.2 associated with Potocki-Lupski syndrome in a foetus presenting with mildly dysmorphic features.

Duplication 17p11.2 (Potocki-Lupski syndrome (PTLS) MIM# 610883) is a genomic disorder with an estimated incidence of 1 in 25,000 births. As for other genomic disorders this duplication is typically de novo and is not associated with advanced maternal age or advanced paternal age. Herein we describe a prenatal diagnosis of duplication 17p11.2. This diagnosis was not suspected as the prenatal ultrasound findings were non-specific; however, BACs-on-Beads™ technology and array comparative genomic hybridization (aCGH) confirmed the common ∼3.7 Mb duplication. Evaluation of the foetus following termination of pregnancy revealed mildly dysmorphic features as well as congenital anomalies not previously reported in PTLS, specifically left pulmonary isomerism, an abnormally positioned left coronary orifice and nodular cerebellar heterotopia. This report exemplifies the utility of prenatal testing using new genomic technologies even when there are no multiple anomalies on foetal ultrasound. This report also exemplifies the utility of foetal autopsy in the identification of "occult" congenital anomalies.

ACVRL1 germinal mosaic with two mutant alleles in hereditary hemorrhagic telangiectasia associated with pulmonary arterial hypertension.

Germline mutations in genes encoding members of the transforming growth factor-ß (TGF-ß)/bone morphogenetic protein (BMP) superfamily are causal for two hereditary vascular disorders, hereditary hemorrhagic telangiectasia (HHT) and heritable pulmonary arterial hypertension (PAH). When the two diseases coexist, activin A receptor type II-like kinase-1 (ACVRL1) gene mutations are usually identified. We report a remarkable ACVRL1 germinal and somatic mosaicism characterized by the presence of two distinct mutant alleles and a non-mutant ACVRL1 allele in a woman diagnosed with PAH at the age 40. She also met the Curaçao diagnostic criteria for HHT based on additional findings of telangiectases, epistaxis and arteriovenous malformations. Mutation analysis of ACVRL1 identified two adjacent heterozygous deleterious mutations within exon 10: c.1388del (p.Gly463fsX2) and c.1390del (p.Leu464X) in a region enriched by mutation-associated DNA motifs. The mother transmitted the c.1388del to one child and the c.1390del to two children confirming germinal mosaicism. Allele-specific polymerase chain reaction analysis showed that c.1388del is the predominant mutation in lymphocytes of the index case. Haplotype analysis revealed that both mutant alleles have a common chromosomal origin which is distinct from that of the mother's non-mutant ACVRL1 allele. These distinct mutant alleles in tissues and germline could have arisen by DNA structure-mediated events occurring in the early stages of the mother's embryogenesis, prior to the segregation of her germline, which ultimately led to the independent transmission of each allele. These highlight the complexity of genomic events occurring during early embryogenesis and the consequences of mutational mosaicism upon pathogenic variability.

[Hypoplasia adrenal congenita of anencephalic type: two cases with pituitary abnormalities and review of literature]. / L'hypoplasie surrénale congénitale de type anencéphalique: deux cas avec anomalies hypophysaires, sans mutation de DAX-1 et SF-1 et revue de la littérature.

Hypoplasia adrenal congenita is an extremely uncommon disease of early onset. This condition can be lethal in the absence of treatment. Some forms are due to the congenital adrenal hypoplasia of anencephalic type whose origin is even unknown. Here, we present two cases of congenital adrenal hypoplasia of anencephalic type with pituitary abnormalities. The two male newborns died because adrenal insufficiency in the neonatal period. The adrenal glands were hypoplastic with a histological structure of anencephalic type Immunocytochemical study of the pituitary revealed an absence of the gonadotrophs. No mutation of DAX 1 and SF-1 was found.

Identification of 28 novel mutations in the Bardet-Biedl syndrome genes: the burden of private mutations in an extensively heterogeneous disease.

Bardet-Biedl syndrome (BBS), an emblematic disease in the rapidly evolving field of ciliopathies, is characterized by pleiotropic clinical features and extensive genetic heterogeneity. To date, 14 BBS genes have been identified, 3 of which have been found mutated only in a single BBS family each (BBS11/TRIM32, BBS13/MKS1 and BBS14/MKS4/NPHP6). Previous reports of systematic mutation detection in large cohorts of BBS families (n > 90) have dealt only with a single gene, or at most small subsets of the known BBS genes. Here we report extensive analysis of a cohort of 174 BBS families for 12/14 genes, leading to the identification of 28 novel mutations. Two pathogenic mutations in a single gene have been found in 117 families, and a single heterozygous mutation in 17 families (of which 8 involve the BBS1 recurrent mutation, M390R). We confirm that BBS1 and BBS10 are the most frequently mutated genes, followed by BBS12. No mutations have been found in BBS11/TRIM32, the identification of which as a BBS gene only relies on a single missense mutation in a single consanguineous family. While a third variant allele has been observed in a few families, they are in most cases missenses of uncertain pathogenicity, contrasting with the type of mutations observed as two alleles in a single gene. We discuss the various strategies for diagnostic mutation detection, including homozygosity mapping and targeted arrays for the detection of previously reported mutations.

Array comparative genomic hybridization in prenatal diagnosis: another experience.

OBJECTIVES: Etiologic diagnosis of multiple congenital abnormalities (MCAs) is often lacking. Large chromosome abnormalities can be detected by conventional cytogenetic methods, but more subtle chromosome micro-rearrangements and/or de novo abnormalities require multi-FISH analysis, which is hampered by the amount of material available in prenatal testing. METHODS: We used the comparative genomic hybridization (CGH) array, Genosensor Array 300, to screen for classic microdeletion syndromes and subtelomeric rearrangements in 39 consecutive fetuses with MCAs, after termination of pregnancy, in a prospective study. Thirty-seven of them had a normal karyotype, and two had a de novo unbalanced karyotype that could not be characterized with conventional cytogenetic methods. RESULTS: Two de novo unbalanced karyotypes were characterized by array CGH, and four additional abnormalities were diagnosed: an unbalanced inherited cryptic translocation, a deletion in band 22q11.2, a 1p36 deletion, and a 6p12.1-21.2 duplication. CONCLUSION: Chromosomal imbalances were therefore detected and/or characterized in 6 of 39 (15.4%) fetuses, indicating the value of routine array CGH in cases of MCAs and in uncharacterized chromosome rearrangements. Extension to all prenatal diagnoses may be warranted when copy number variation is identified and all FISH probes are commercially available.

Case report: Meiotic segregation in spermatozoa of a 46,X,t(Y;10)(q11.2;p15.2) fertile translocation carrier.

Translocations involving gonosomes are frequent in azoospermic patients and sometimes in oligozoospermic ones, conditions that lead to request for assisted reproduction treatment. This study reports an unexpectedly fertile 49-year-old man bearing a de-novo translocation 46,X,t(Y;10)(q11.2;q15.2) associated with a high chromosomal risk for offspring, and referred for familial investigations after the diagnosis of an unbalanced translocation 46,XX,der(10)t(Y;10)(q11.2;p15.2) in his naturally conceived and mentally retarded daughter. Chromosome molecular investigation confirmed Y long-arm inheritance in the daughter and absence of the Yq deletion in the father. Semen analysis showed a normal sperm count associated with moderate asthenospermia and severe teratospermia. A total of 984 spermatozoa were analysed using fluorescence in-situ hybridization (FISH). Alternate segregation pattern was found in 50.31% of the spermatozoa studied. The frequencies of adjacent I, adjacent II, 3:1 segregation, and diploidy (or 4:0 segregation) were respectively 39.62, 1.63, 7.83, and 0.61%. No interchromosomal effect was observed. This patient is the first fertile man in whom the meiotic segregation pattern of a Y-autosome translocation has been analysed. The imbalance risk was close to those observed for reciprocal translocations, and emphasizes the value of FISH studies in males with a chromosomal translocation in order to provide them a personalized risk evaluation.

Twins discordant for fetal skeletal abnormalities: a natural confrontation between the two siblings.

BACKGROUND: Skeletal abnormalities encompass a heterogeneous group of disorders characterized by anomalies of cartilage as well as bone growth and development. Some are lethal and express early during fetal life, making them amenable to prenatal diagnosis. The increasing use of routine ultrasonography (US) during pregnancy permits a reliable primary evaluation of the fetal skeleton. However, when a skeletal dysplasia is suspected, it is more difficult to establish a specific diagnosis. Moreover, detailed ultrasonographic evaluation of the whole fetal skeleton may be limited in some circumstances, especially during the third trimester due to the fetal position and in the case of multiple pregnancies. METHODS: Retrospective study of twin pregnancies complicated with skeletal abnormalities. RESULTS: 6 twin pregnancies were reviewed. The prenatal diagnosis was correctly made in 66.66% (4/6) with the primary use of combined 2D and 3D-US. 3D-HCT permits to improve the simultaneous assessment of both fetuses, and is of greater value than US in 16.66% (1/6). CONCLUSION: The combined use of 2D or 3D-US with 3D-HCT permits the best imaging evaluation.

[Embolization of localized pulmonary arteriovenous malformations in adults]. / Embolisation des malformations artérioveineuses pulmonaires localisées de l'adulte.

OBJECTIVES: To report our experience using embolization in managing localized pulmonary arteriovenous malformations in adults. MATERIAL: and methods. All patients presenting with localized pulmonary arteriovenous malformations treated with embolization were included in the study. Clinical presentation (respiratory symptoms and previous history of paradoxical embolism) and the characteristics of pulmonary arteriovenous malformations (single or multiple, location, diameter of the afferent artery and simple or complex angioarchitecture) before embolization were analyzed. The details of the procedure, including the number of pulmonary arteriovenous malformations embolized, the number of coils used, and the type of intraoperative complications were recorded. Postembolization clinical and imaging follow-up were described. RESULTS: Forty-two patients (26 women, 16 men; mean age, 45 years), including 36 with hereditary hemorrhagic telangiectasia were treated with embolization. Twenty-two patients (53%) were dyspneic and 12 (29%) had a previous history of paradoxical embolism prior to embolization. Forty-seven procedures were carried out on a total of 99 pulmonary arteriovenous malformations (mean, 2.3 per patient), using 530 coils (12.6 per patient). The pulmonary arteriovenous malformations were located in the lower lobes in 60% of cases and a simple architecture was reported in 81% of cases. The average diameter of the afferent artery was 6mm. No preoperative complications were reported. After embolization, two patients (5%) presented with a paradoxical embolism and five patients out of 22 (23%) remained dyspneic. The rate of complete occlusion of treated arteriovenous malformations was 92% using computer tomography. CONCLUSION: Embolization is a highly effective and safe technique for treating pulmonary arteriovenous malformations. Improvement in dyspnea and prevention of paradoxical embolism can be expected. A high technical success rate can be obtained by experienced interventional radiologists.

Familial diseases revealed by a fetal anomaly.

OBJECTIVES: The recognition of a fetal anomaly can lead to the same diagnosis being made in one of the asymptomatic parents unaware of the problem. We analyzed cases in which the discovery of a fetal anomaly led to the discovery of a genetic familial disorder. METHODS: Families in which the recognition of a fetal anomaly led to the same diagnosis being made in one of the asymptomatic parents were included. RESULTS: Twenty couples were included in the study. The fetal anomalies were cleft lip and palate (4), cardiac anomalies (2), cerebral anomalies (1), bilateral club feet with polyhydramnios, akinesia or camptodactily (5), nuchal anomalies (2), micromelia (3), polydactyly (2), and limited elbow extension (1). Genetic counselling helped establish nine maternal diseases as follows: Steinert disease (3), spinal muscular atrophy (1), antecubital pterygium (1), DiGeorge (1), Wardenburg type II (1), Charge (1) and Greig syndromes (1). Eleven paternal diseases were discovered, which were Noonan-like syndrome (1), paternal cervical anomalies (1), Goldenhar syndrome (1), dominant autosomal arthrogryposis (1), osteogenesis imperfecta (3), tuberous sclerosis (1), dominant transposition of great vessels (1), Weyers acrofacial dysostosis (1), and autosomal dominant holoprosencephaly (1). Twelve couples continued with pregnancy and eight opted for termination of pregnancy. CONCLUSION: The fetus is central in giving the first insight into a familial disorder. It can reveal familial diseases undiscovered in the parent and help understand the mode of transmission of an anomaly, mainly the autosomal dominant diseases with variable expressions.

Prenatal diagnosis of fetal skeletal dysplasias by combining two-dimensional and three-dimensional ultrasound and intrauterine three-dimensional helical computer tomography.

OBJECTIVE: To evaluate the contribution of new imaging techniques in the prenatal diagnosis of skeletal dysplasia. METHODS: Between May and October 2003, a prospective study was conducted in a single referral center. Three-dimensional ultrasound (3D-US) and three-dimensional helical computer tomography (3D-HCT) were performed after two-dimensional ultrasound (2D-US) in six cases of skeletal dysplasia. Diagnostic accuracy and detailed findings with each of the three techniques were compared with postnatal radiological findings. RESULTS: There were three cases of achondroplasia, two cases of osteogenesis imperfecta type II and one case of chondrodysplasia punctata. Termination of pregnancy was performed in five cases and one fetus with osteogenesis imperfecta type II was delivered at term by Cesarean section. 2D-US made the correct diagnosis in four cases. 3D-US and 3D-HCT achieved an accurate diagnosis in all six cases. 3D-HCT and 3D-US identified significantly more abnormalities than did 2D-US (3D-HCT: 94.3% (33/35); 3D-US: 77.1% (27/35); 2D-US: 51.4% (18/35); P < 0.01). The diagnosis was made between 27 and 36 weeks' gestation in all cases. The advantage of 3D-HCT over 3D-US was the possibility of imaging the entire fetus. CONCLUSION: 3D-US and 3D-HCT seem to be useful complementary methods to 2D-US, and may improve accuracy of the prenatal diagnosis of skeletal disorders. These new imaging technologies may have a role in the prenatal multidisciplinary approach to the diagnosis of skeletal dysplasias.

Perinatal-lethal Gaucher disease.

Gaucher disease is a lysosomal storage disease caused by glucocerebrosidase deficiency. Although purely visceral in most cases, some Gaucher disease patients have neurological signs. Signs of Gaucher disease appear after a symptom-free period, except in rare cases with fetal onset. The description of such cases was based mainly on single reports and siblings. We report here a series of perinatal-lethal Gaucher disease cases highlighting the specificity of this phenotype. We retrospectively studied eight original cases of proven Gaucher disease with fetal onset. Non-immune hydrops fetalis was present in all cases but one, and associated with hepatosplenomegaly, ichthyosis, arthrogryposis, and facial dysmorphy. The similarities between our cases and 33 previously described cases allow us to better delineate the perinatal-lethal Gaucher disease phenotype. Hydrops fetalis, in utero fetal death and neonatal distress are prominent features. When hydrops is absent, neurological involvement begins in the first week and leads to death within three months. Hepatosplenomegaly is a major sign, and associated with ichthyosis, arthrogryposis, and facial dysmorphy in some 35-43% of cases. Perinatal-lethal Gaucher disease is a specific entity defined by its particular course and signs that are absent in classical type 2 Gaucher disease. Our study provides clues to the diagnosis of this likely underdiagnosed condition, which must be biochemically confirmed in order to propose appropriate genetic counselling.

Prenatal diagnosis of a 45,X male with a SRY-bearing chromosome 21.

Male phenotype associated with a 45,X karyotype is an infrequent finding. We present a case diagnosed prenatally on amniocentesis performed for maternal age. The male phenotype was associated with a translocation of a distal part of Yp including the pseudoautosomal SHOX gene and SRY gene on the short arm of a chromosome 21. By DNA analysis we could show that the X chromosome was of maternal origin and that the breakpoint was in interval 3 of the Y chromosome. Mechanisms and genetic counselling are discussed based on a review of published cases of 45,X and XX males.

Fetal gender: antenatal discrepancy between phenotype and genotype.

Sexual discrepancy is reported in both 46,XY females and 46,XX males, and most diagnoses of sex reversal are made in the postpubertal period. We report three cases of sexual discrepancy, which were revealed by karyotyping following genetic amniocentesis, chorionic villus sampling and fetal blood sampling. The etiologies of 46,XX male, 45,X male and 46,XY female subjects are reviewed. When sexual discrepancy between fetal karyotype and ultrasonographic fetal phenotype is encountered, sample error and placental mosaicism should be excluded. A detailed fetal ultrasound examination should be performed to check for syndromic gender discrepancy. When repeat karyotyping is indicated, localization of the Sox related Y chromosome gene should be carried out.

Absence of functional type 1 parathyroid hormone (PTH)/PTH-related protein receptors in humans is associated with abnormal breast development and tooth impaction.

Recent studies in transgenic mice have demonstrated that PTH-related protein (PTHrP), signaling through the type 1 PTH/PTHrP receptor (PTHR1), regulates endochondral bone development and epithelial-mesenchymal interactions during the formation of the mammary glands and teeth. Recently, it has been shown that loss-of-function mutations in the PTHR1 gene result in a rare, lethal form of dwarfism known as Blomstrand chondrodysplasia. These patients suffer from severe defects in endochondral bone formation, but abnormalities in breast and tooth development have not been reported. To ascertain whether PTHrP signaling was important to human breast and tooth development, we studied two fetuses with Blomstrand chondrodysplasia. These fetuses lack nipples and breasts. Developing teeth were present, but they were severely impacted within the surrounding alveolar bone, leading to distortions in their architecture and orientation. Compatible with the involvement of PTHR1 and PTHrP in human breast and tooth morphogenesis, both were expressed within the developing breasts and teeth of normal human fetuses. Therefore, impairment of the PTHrP/PTHR1 signaling pathway in humans is associated with severe abnormalities in tooth and breast development. In addition to regulating human bone formation, this signaling pathway is also necessary for the normal development of the human breast and tooth.

Prenatal diagnosis of hydrocephalus-stenosis of the aqueduct of Sylvius by ultrasound in the first trimester of pregnancy. Report of two cases.

Hydrocephalus-stenosis of the acqueduct of Sylvius sequence (HSAS) is characterized by hydrocephalus, macrocephaly, adducted thumbs, spasticity, agenesis of the corpus callosum and mental retardation. X-linked hydrocephalus is known to be due to mutations in the gene coding for the neural cell adhesion molecule L1 (L1-CAM) and diagnosis is made by identification of a mutation in the L1-CAM gene. Prenatal diagnosis of HSAS is usually suggested on ultrasound examination showing hydrocephalus in a male fetus associated with bilateral adducted thumbs. Mutation screening of the L1-CAM gene is indicated when neuropathological examination shows hypoplasia of the corticospinal tract associated with aqueductal stenosis. We report here two cases of HSAS diagnosed within the same family by ultrasound examination in the first trimester of pregnancy when bilateral adducted thumbs were the only early ultrasound marker.