19p13.2 microduplication causes a Sotos syndrome-like phenotype and alters gene expression.

Up to 90% of individuals affected by Sotos syndrome have a pathogenic alteration of NSD1 (encodes nuclear receptor-binding Su-var, enhancer of zeste, and trithorax domain protein 1), a histone methyltransferase that functions as both a transcriptional activator and a repressor. Genomic copy number variations may also cause a Sotos-like phenotype. We evaluated a three-generation family segregating a Sotos-like disorder characterized by typical facial features, overgrowth, learning disabilities, and advanced bone age. Affected individuals did not have a detectable NSD1 mutation, but rather were found to have a 1.9 Mb microduplication of 19p13.2 with breakpoints in two highly homologous Alu elements. Because the duplication included the DNA methyltransferase gene (DNMT1), we assessed DNA methylation of peripheral blood and buccal cell DNA and detected no alterations. We also examined peripheral blood gene expression and found evidence for increased expression of genes within the duplicated region. We conclude that microduplication of 19p13.2 is a novel genomic disorder characterized by variable neurocognitive disability, overgrowth, and facial dysmorphism similar to Sotos syndrome. Failed compensation of gene duplication at the transcriptional level, as seen in peripheral blood, supports gene dosage as the cause of this disorder.

Co-occurrence of Joubert syndrome and Jeune asphyxiating thoracic dystrophy.

Ciliary disorders share typical features, such as polydactyly, renal and biliary cystic dysplasia, and retinitis pigmentosa, which often overlap across diagnostic entities. We report on two siblings of consanguineous parents and two unrelated children, both of unrelated parents, with co-occurrence of Joubert syndrome and Jeune asphyxiating thoracic dystrophy, an association that adds to the observation of common final patterns of malformations in ciliary disorders. Using homozygosity mapping in the siblings, we were able to exclude all known genes/loci for both syndromes except for INVS, AHI1, and three genes from the previously described Jeune locus at 15q13. No pathogenic variants were found in these genes by direct sequencing. In the third child reported, sequencing of RPGRIP1L, ARL13B, AHI1, TMEM67, OFD1, CC2D2A, and deletion analysis of NPHP1 showed no mutations. Although this study failed to identify a mutation in the patients tested, the co-occurrence of Joubert and Jeune syndromes is likely to represent a distinct entity caused by mutations in a yet to be discovered gene. The mechanisms by which certain organ systems are affected more than others in the spectrum of ciliary diseases remain largely unknown.

A patient with vertebral, cognitive and behavioural abnormalities and a de novo deletion of NRXN1alpha.

The authors report a patient with mild mental retardation, autistic features, multiple vertebral malformations, and an unusual facial appearance who carries a de novo submicroscopic deletion of chromosome 2p16.3. The patient's deletion is approximately 320 kb in size and includes only the part of the NRXN1 gene that codes for the neurexin1alpha promoter and initial coding exons. The more downstream neurexin1beta promoter and the region surrounding it are intact. Neurexin1beta has been associated with autism in several recent studies, but this is the first reported patient with loss of only neurexin1alpha and not of neurexin1beta. These findings suggest that neurexin1alpha function in correct dosage is necessary for normal neurological development.

Demonstration of human kidney differentiation antigens with monoclonal antibodies.

Six human differentiation antigens (EE24.6, EG9.11, EG14.1, EI16.1, EK8.1, EK17.1) have been defined using monoclonal antibodies obtained from mice immunized with embryonic kidney cells. Their histologic distribution was determined on frozen sections of embryonic, fetal, and adult human kidneys by immunofluorescence assay. EE24.6, an ureteral bud marker, was detected only on the germ layer of mature kidney urothelium. EG9.11 and EG14.1 were detected on the S-shaped bodies and also on the adult proximal convoluted tubule for the former and the glomerular basement membrane for the latter. EI16.1, a marker of condensed mesenchyme, was detected only on epithelial cells of adult proximal convoluted tubule. EK8.1 was found in the mesangium, connective tissue, and with particularly dense labeling in the basement membranes. This labeling pattern was present throughout renal organogenesis. EK17.1 recognized both cell and plasma human fibronectins. Staining for all antibodies was nearly identical in mesonephros and metanephros. These results demonstate that some antigens follow their embryonic destiny. They indicate an antigenic similarity between the mesonephros and the metanephros and, therefore, a very early appearance of these antigens. During differentiation, these antigens concentrate on more defined structures, and staining became increased with an increased degree of differentiation.

Phenotypic manifestation in a child with 46,X,der(X)t(X;1)(q24;q31.1).

We report on a 5-year-old girl with multiple congenital anomalies, developmental delay, and a de novo unbalanced translocation between chromosomes X and 1[46,X,der(X)-t(X;1)(q24;q31.1)] resulting in partial trisomy 1q and partial monosomy Xq. The karyotype shows inactivation of the abnormal X chromosome. The translocated portion of 1q remains active in the tissues studied. This is the third case report with partial trisomy 1q and partial monosomy Xq. However, it is the first with specific breakpoints at 1q31.1 and Xq24.

New form of bone dysplasia with multiple fractures associated with monosomy X.

We report on the clinical, radiologic, and pathologic findings in a 20-week-old fetus with monosomy X and severe hydrops associated with fetal dwarfism. The fetus presented with osteoporosis, bent bones, multiple fractures, and distinctive symmetric submetaphyseal transverse bone interruptions or pseudofractures. We excluded by radiologic and histopathologic examination the diagnoses of osteogenesis imperfecta, hypophosphatasia, campomelic dysplasia, achondrogenesis, hypochondrogenesis, and other types of bone dysplasia. To our knowledge, this is a previously undescribed bone dysplasia associated with monosomy X. This bone dysplasia may be inherited as an X-linked recessive disorder.

Deletion of 22q11 in two brothers with different phenotype.

We have studied two brothers with submicroscopic 22q11 deletion. One brother had findings suggestive of DiGeorge syndrome, while the other had milder anomalies, including polydactyly. Fluorescence in situ hybridization (FISH) showed a minor cell line with deletion 22q11 in the mother. To our knowledge, this is the first report of a deletion of 22q11 in two sibs with different phenotypes and apparent maternal mosaicism detected with FISH. This family illustrates the variability of the syndrome and further demonstrates the possibility of gonadal mosaicism for a microdeletion. Prenatal diagnosis may be offered after the birth of a child with a 22q11 deletion, even in the absence of parental chromosomal anomalies.

Fetus with Casamassima-Morton-Nance syndrome and an inherited (6;9) balanced translocation.

We report on a fetus with cranio-facial anomalies, a narrow thorax, imperforate anus with cloacal cyst, and a genitourinary malformation with absent uterus, vagina, and external genitalia. Major thoracic defects were seen on roentgenographic examination, including absent vertebrae and ribs, a supernumerary vertebra, a hemivertebra, and rib fusion. These findings are compatible with Casamassima-Morton-Nance syndrome. The patient was the carrier of a translocation t(6;9)(p12;q12), inherited from the mother. Although the occurrence of this rearrangement may be coincidental, it may also indicate a possible locus for this autosomal recessive thoracic dysplasia.

Skeletal and cardiac malformations with thrombocytopenia: a new syndrome?

We describe a female patient with multiple anomalies suggestive of a new syndrome. Manifestations include: VSD and ASD, mild developmental delay, conductive hearing loss, minor facial anomalies, thrombocytopenia, and radiological findings (including carpal fusion). Some of these manifestations may be present in the Keutel syndrome, IVIC syndrome, and the 10qter deletion syndrome. However, none of these syndromes can explain the spectrum of anomalies seen in our patient.

Possible new variant of Nijmegen breakage syndrome.

We report on a child with microcephaly, small facial and body size, and immune deficiency. The phenotype is consistent with Nijmegen breakage syndrome (NBS), with additional clinical manifestations and laboratory findings not reported heretofore. Most investigations, including the results of radiation-resistant DNA synthesis, concurred with the diagnosis of NBS. Cytogenetic analysis documented abnormalities in virtually all cells examined. Along with the high frequency of breaks and rearrangements of chromosomes 7 and 14, we found breakage and monosomies involving numerous other chromosomes. Because of some variation in the clinical presentation and some unusual cytogenetic findings, we suggest that our patient may represent a new variant of Nijmegen breakage syndrome.

Trisomy of chromosome 10 in two cases of ovarian carcinoma.

Simple numerical chromosome aberrations have been observed in tumorigenesis and may point to indicative initiating or early events in tumorigenesis. We have identified two cases of ovarian carcinomas with trisomy of chromosome 10 using conventional GTG-banding and fluorescence in situ hybridization. This is, to our knowledge, the first report of trisomy 10 as a simple karyotypic abnormality observed in ovarian carcinoma. These results suggest that further studies investigating whether chromosome 10 genes are associated with the pathogenesis of some ovarian tumors are warranted.

Chorionic villus sampling after first trimester diagnosis of fetal cystic hygroma colli.

Diagnostic findings of four cases of cystic hygroma discovered at 11 weeks of gestation are reported. The discovery of cystic hygroma by echotomography was followed by sample taking of chorionic villi which revealed one case of monosomy X and three cases of trisomy 18. Caryotype determination in the presence of cystic hydroma is essential for diagnostic confirmation and subsequent genetic counselling.

Chorionic villus sampling (CVS). Randomized study of efficacy of two transcervical biopsy methods: aspiration canulas and small forceps.

A randomized study of two transcervical biopsy methods was performed. One method involved the use of an aspiration catheter and the other a tissue biopsy forceps. 120 chorionic villus samplings were performed in 30 patients. The percentage of success in taking biopsies and the resulting number of karyotypes were identical in both groups. The amount of removed trophoblastic tissue was greater when the forceps was employed. When the aspiration catheter was used, a sufficient amount of trophoblastic tissue was obtained for karyotyping purposes. It was easier to insert the aspiration catheter than the forceps. The echogenicity of the catheter and forceps were identical. The aspiration catheter has two advantages. Firstly, it is malleable and fits to the anatomy of the cervical canal and the site from which the biopsy is to be taken. Secondly, it is disposable.

[Clinical spectrum of prenatal tetralogy of Fallot]. / Spectre clinique de la tétralogie de Fallot anténatale.

The aim of this study of 44 cases of tetralogy of Fallot was to assess the echocardiographic aspects and the prognosis with respect to associated abnormalities and the potential evolution in utero. Group I, tetralogy of Fallot with other abnormalities (N = 27: 2 valvular agenesis, 26.5 5.3 weeks), had genetic anomalies in 18 of the foetus (10 trisomies including 5 trisomy 21, 5 structural abnormalities including 2 micro-deletions 22q11 in the two cases of valvular agenesis, and one deletion of chromosome 8p23.1, 3 mendelian syndromes) and other abnormalities in 9 cases. Hypoplasia of the pulmonary artery was present in 60% of cases with a non-dilated aorta in 72%, infundibular hypertrophy in 33% and 2 evolutions to pulmonary atresia. Aspect of "isolated" ventricular septal defect were observed in 20% of cases. Survival was 10%. In Group II, tetralogy of Fallot was isolated (N = 17, including 2 pulmonary valve agenesis, 31 +/- 6 weeks) (p < 0.01 versus Group I). Pulmonary artery hypoplasia was observed in 50% of cases with dilatation of the aorta and infundibular hypertrophy in all and in one a postnatal progression towards pulmonary atresia. A correlation between growth of the pulmonary artery and gestational age was found in 5 foetus out of 9 studied sequentially (p between 0.03 and 0.007) and between age at first surgery and size of the pulmonary artery (r = 0.80, p = 0.001). Survival was 84%. The risk of malformation (61%) and the prenatal potential evolution of this disease justifies continuous follow-up of all cases of tetralogy of Fallot, high resolution karyotyping and postnatal evaluation in a specialized centre.

Heart defects and other malformations in the Inuit in Canada: a baseline study.

OBJECTIVES: Birth defects occur in all ethnic groups, remaining an important world-wide cause of perinatal and infant morbidity. This contributes greatly to an excess of health care dollars allocated to the care and repair of those affected. This is especially true when those affected live in remote geographical locations. STUDY DESIGN: A chart review of 2567 live births of children of Inuit parents residing in Arctic Quebec (Nunavik) and on Baffin Island (Nunavut) between 1989 and 1994 (five years) was carried out compared to rates of anomalies of the Alberta Congenital Anomalies Surveillance System (ACASS). RESULTS: Birth defects were higher in the Inuit sample in nearly every major ICD-9 category with the exception of neural tube defects, eye anomalies and chromosome abnormalities. (Total: 99.7/1000 Vs 51.5/1000; OR 1.93 95% CI 1.7-2.3). Congenital heart defects were significantly increased 22.9/1000 Vs 5.6/1000, with an OR of 4.18 (95% CI 3.2-5.4) in the ICD-9 category 745. In particular, ventricular septal defects (VSDs) and atrial septal defects (ASDs) (OR 4.9 CI 3.5-6.9 and 4.6 CI 2.9-7.2) were frequent. CONCLUSIONS: A high rate of heart defects was an important contributor to the nearly two times rate of total birth defects in the Inuit compared to the ACASS. Further study should be carried out to determine the contributing factors. Genetic predisposition to specific heart defects, and a diet low in folate and vitamin A are considerations. The use of alcohol may exacerbate vitamin status in pregnancy. Optimizing vitamin status in the periconceptional period may reduce the rate of birth defects.

[Percutaneous ultrasound-guided sampling of fetal blood]. / Prélèvement percutané de sang foetal avec échoguidage.

The authors give their experience of percutaneous ultrasound-guided sampling of fetal blood carried out over a period of two years. They suggest a modification of the technique, using linear screening scanning. This has made it possible to reduce the number of unsuccessful attempts at sampling. An analysis of the indications and of the results in 49 attempts at puncture shows how to select the indications better. This is particularly so when fetal abnormalities have been found on ultrasound examination. The authors think that this method, because of its reliability and the speed with which results are obtained, should be a method of choice for screening for chromosome abnormalities which might be thought to exist from the pictures obtained by ultrasound.

[Isolated antenatal pyelic dilatation: postnatal follow-up and care for vesico-ureteral reflux]. / Dilatations pyéliques isolées: diagnostic prénatal, suivi postnatal et prise en charge des reflux vésico-urétéraux.

OBJECTIVE: To assess the risk of aneuploidia in case of isolated antenatal pyelic dilatation and to detail urological care for these children. METHODS: Prenatal and postnatal follow-up was analyzed in 350 cases. RESULTS: The overall rate of chromosome anomalies was 1.3%. Trisomy 21 was found alone in one case (0.3%). The sex ratio was 26% girls and 74% boys. Vesico-ureteral reflux was similar in both sexes (13%). CONCLUSION: The question of proposing karyotyping in case of isolated pyelic dilatation remains unsolved because minimal subjective signs such as slightly excessive amniotic fluid can completely change the assessment of the risk of aneuploidia. The frequency of postnatal vesico-ureteral reflux associated with prenatal pyelic dilatation warrants complete prenatal ultrasound screening.

The c.7409G>A (p.Cys2470Tyr) Variant of FBN1: Phenotypic Variability across Three Generations.

Marfan syndrome is an autosomal dominant connective tissue disorder caused by mutations in the fibrillin gene FBN1, which encodes an extracellular matrix glycoprotein. Major features of Marfan syndrome occur in the ocular, cardiovascular, and skeletal systems as well as in the dura mater. Approximately 60% of known disease-causing mutations are missense mutations of single amino acid residues. Effects on the cardiovascular system are classically associated with mutations in exons 24-32 of the 65 FBN1 exons and many, though not all, reports associate missense mutations in exons 59-65 with a mild cardiovascular phenotype. Here we present 5 related individuals among whom a c.7409G>A (p.Cys2470Tyr) missense variant in exon 59 of FBN1 is associated with significant cardiovascular features. The index case also had an apparently de novo 46,XX,del(5)(q33.1q33.3) deletion on chromosome 5. This family demonstrates skeletal, dermatological and neurological features consistent with Marfan syndrome but lacks significant ophthalmological findings to date. These findings suggest that FBN1 C-terminal missense mutations may not confer the ophthalmological features of Marfan syndrome, but they also confer a more significant risk for cardiovascular pathology than that suggested by previous studies. Furthermore, clinical data from this family supports the previously reported association of dural ectasia with C-terminal mutations.