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Objective: To report four foetal cases of the Binder phenotype associated with maternal autoimmune disorders. Patients and Methods: In three mothers with autoimmune diseases, 2D and 3D ultrasonographic measurements were made on four foetuses with the Binder profile, and were compared with postnatal phenotypes. Results: The Binder phenotype can be detected in early pregnancy (14.5 WG). All foetuses had verticalized nasal bones and midfacial hypoplasia. Punctuate calcifications were found in almost all the cases. No specific maternal auto-antibody has been associated with foetal Binder phenotype. Conclusion: Since the Binder phenotype can be diagnosed at ultrasound examination during pregnancy, it is important to establish the underlying cause so as to assess the foetal prognosis. This study stresses the importance of systematic checks for maternal autoimmune disease in cases of prenatally diagnosed Binder phenotypes. [ABSTRACT FROM AUTHOR]

Background: Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability (ID), as well as the most frequent monogenic cause of autism spectrum disorder (ASD). Men with FXS exhibit ID, often associated with autistics features, whereas women heterozygous for the full mutation are typically less severely affected; about half have a normal or borderline intelligence quotient (IQ). Previous findings have shown a strong association between ID and ASD in both men and women with FXS. We describe here the case of two sisters with ASD and FXS but without ID. One of the sisters presented with high-functioning autism, the other one with pervasive developmental disorder not otherwise specified and low normal IQ., Methods: The methylation status of the mutated FMR1 alleles was examined by Southern blot and methylation-sensitive polymerase chain reaction. The X-chromosome inactivation was determined by analyzing the methylation status of the androgen receptor at Xq12., Results: Both sisters carried a full mutation in the FMR1 gene, with complete methylation and random X chromosome inactivation. We present the phenotype of the two sisters and other family members., Conclusions: These findings suggest that autistic behaviors and cognitive impairment can manifest as independent traits in FXS. Mutations in FMR1, known to cause syndromic autism, may also contribute to the etiology of high-functioning, non-syndromic ASD, particularly in women. Thus, screening for FXS in patients with ASD should not be limited to those with comorbid ID.

In 65 patients, who had unexplained ocular developmental anomalies (ODAs) with at least one other birth defect and/or intellectual disability, we performed oligonucleotide comparative genome hybridisation-based microarray analysis (array-CGH; 105A or 180K, Agilent Technologies). In four patients, array-CGH identified clinically relevant deletions encompassing a gene known to be involved in ocular development (FOXC1 or OTX2). In four other patients, we found three pathogenic deletions not classically associated with abnormal ocular morphogenesis, namely, del(17)(p13.3p13.3), del(10)(p14p15.3), and del(16)(p11.2p11.2). We also detected copy number variations of uncertain pathogenicity in two other patients. Rearranged segments ranged in size from 0.04 to 5.68 Mb. These results show that array-CGH provides a high diagnostic yield (15%) in patients with syndromal ODAs and can identify previously unknown chromosomal regions associated with these conditions. In addition to their importance for diagnosis and genetic counselling, these data may help identify genes involved in ocular development.

We report the association of aphallia, with imperforate anus, bilateral renal dysplasia and complete right lung agenesis in a fetus born of non-consanguineous parents. No maternal diabetes was present. The multiple mesodermal anomalies present in this male fetus, with a severe form of Uro-Rectal-Septum Malformation Sequence associated with unilateral lung agenesis, and rib segmentation anomaly is consistent with an extended defect of blastogenesis, with apparent common timing of the malformations around the 5th to 7th weeks of gestation.

Objective: We studied hypophosphatasia (HP) mutations in 19 cases prenatally detected by ultrasonography without familial history of HP. We correlated the mutations with the reported ultrasound signs, and discussed genetic counseling with regard to the particular dominantly inherited prenatal benign form of HP., Method: The coding sequence of the tissue nonspecific alkaline phosphatase (TNSALP) gene was analyzed by DNA sequencing, and 3D modeling was used to locate the mutated amino acids with regard to the functional domains of TNSALP., Results: Although reported ultrasound signs were heterogeneous, two mutated alleles were found in 18 of the 19 cases studied, indicating recessive transmission of the disease. Functional domains of TNSALP were affected by 74% of missense mutations. In all the cases, including one with only a heterozygous mutation, molecular, biological, and familial data do not corroborate the hypothesis of prenatal benign HP. The mutation c.1133A>T observed in the prenatal benign form of HP and common in USA was not found in this series., Conclusion: The results point out the prenatally detectable allelic heterogeneity of HP. The nature of the detected mutations and the evidence of recessive inheritance do not support these cases being affected with prenatal benign HP.

Small supernumerary marker chromosomes are present in about 0.05% of the human population. In approximately 28% of persons with these markers (excluding the approximately 60% derived from one of the acrocentric chromosomes), an abnormal phenotype is observed. We report on a 3-month-old girl with intrauterine growth retardation, craniofacial features, hypotonia, partial coloboma of iris and total anomalous pulmonary venous return. Cytogenetic analysis showed the presence of a supernumerary marker chromosome, identified by fluorescence in situ hybridization as part of chromosome 22, and conferring a proximal partial trisomy 22q22.21, not encompassing the DiGeorge critical region (RP11-154H4 + , TBX1-). This observation adds new information relevant to cat eye syndrome and partial trisomy of 22q., (2008 Wiley-Liss, Inc.)

We report on the case of dizygotic twin boys, born prematurely to an asymptomatic mother. Bilateral periventricular heterotopias with enlarged ventricles were discovered at birth in both twins. One of the twins died prematurely of bronchopulmonary complications, and was shown to have several neuropathological anomalies (microgyria, thin corpus callosum, and reduced white matter). The surviving twin had mental retardation, without epilepsy. MRI of the mother showed asymptomatic periventricular heterotopias without ventricular enlargement. She had two affected daughters also with asymptomatic periventricular heterotopias. A point mutation in the last coding exon 48 of the Filamin A (FLNA) gene (7922c > t) was discovered on sequencing and segregated with the affected individuals. This family has a classical X-linked dominant BPNH pathology, with greater severity in males than females. The location of the FLNA mutation is discussed in light of the neuropathological anomalies and mental retardation in male patients.

Background: Prenatal diagnosis of multiple congenital anomalies is difficult, and usually molecular biology cannot immediately confirm the suspected syndrome. Fetal dysmorphology is useful tool in the diagnosis process, with limitations., Methods: We report the thorough prenatal investigation by 2D and 3D ultrasonography in a case of suspected Costello syndrome., Results: Prenatal abnormalities were: increased nuchal translucency, polyhydramnios, bilateral pyelectasis and ventriculomegaly. Ultrasonographic morphological fetal face analysis found abnormal thickness of the skin in the prefrontal area, thick dysplastic ears, thick lips and deep-set creases in the hands and feet. As Costello and Noonan syndromes overlap, a PTPN11 analysis was done, with presence of a mutation (T854C)., Conclusion: Prenatal overlap of feature of severe Noonan syndrome and Costello syndrome is confirmed, with dysmorphological similarities, due to edema of fetal skin in face and extremities., (Copyright 2006 John Wiley & Sons, Ltd.)

The WAGR contiguous gene deletion syndrome is a combination of Wilms tumor, Aniridia, Genito-urinary abnormalities, and growth and mental retardation which is invariably associated with an 11p13 deletion. We report two monozygotic twins and a third, unrelated patient with WAGR syndrome and additional clinical features not usually associated with WAGR. Both twins had developmental delay, growth deficiency, severe ocular involvement (nystagmus, aniridia, cataracts), atrial septal defect and two uncommon findings: agenesis of the corpus callosum and duplication of the halluces. One twin developed Wilms tumors aged 19 months while her sister remained tumor free by the age of 6.5 years. The singleton patient showed typical WAGR syndrome and preaxial hallucal polydactyly. Molecular cytogenetic studies refined the identification of the extent of the deleted segments, which were not identical in the two families. The two deletions included the PAX6 and WT1 genes as previously reported in typical WAGR patients. The unusual anomalies described in this report, may represent the expression of low penetrant traits associated with haploinsufficency of one or more of the genes present in the deletion (PAX6 is expressed in CNS) or may indicate epistatic influences of modifier genes on the expression of gene(s) present in the WAGR region., (2005 Wiley-Liss, Inc.)

Fragile X syndrome diagnosis is not so easy to make in the first years. Morphological anomalies may be subtle, with high forehead, long face and large ears with soft cartilage. Autistic behaviour is frequent, with hand flapping, lone playing, eye contact avoidance and no language. Early diagnosis of X fragile syndrome is needed, as it is a genetic disease, with a recurrence risk in the family. Early diagnosis is also useful for the care of these children, with psychological and educational special management.

We report a girl with mild mental retardation with onset of infantile spasms at age of 9 months. Treatment with a short course of adrenocorticotropic hormone (ACTH) was successful. Initially, a diagnosis of idiopathic West syndrome, with good neurological outcome and disappearance of epilepsy after treatment, was made. Conventional karyotype was normal. Reinvestigations were done at age 8 years, because of a new pregnancy. Karyotyping of both parents was done because of mild dysmorphic features in the proband, and to eliminate other causes than early age epilepsy as the etiology of her mental retardation. Parental karyotypes showed a balanced paternal translocation (4p;17q) resulting in partial 4p trisomy, without significant 17q monosomy in the proband. Chromosomal abnormalities usually lead to a severe West syndrome with poor prognosis of neurological outcome (persistent severe epilepsy, mental retardation, and behavioral disturbances). The presence of an undetected cytogenetic anomaly in our proband with transient hypsarythmia is unusual and led us to propose systematic telomeric screening in apparently "idiopathic" West syndrome patients with mild mental retardation and subtle dysmorphic features.

We report a case of severe Beckwith-Wiedemann syndrome (BWS) in a fetus at 16 weeks of gestation. This presentation, incompatible with life, included a giant omphalocele and absence of abdominal wall musculature with extremely dilated bladder, as in the "prune belly" sequence. Adrenal cytomegaly pointed to BWS. Molecular analysis confirmed the diagnosis of BWS and showed an isolated demethylation of the KCNQ1OT1 gene. This report demonstrates that lethal fetal abdominal wall defects associated with adrenal cytomegaly are linked to epigenetic change of the 11p15 imprinted region., (Copyright 2004 Wiley-Liss, Inc.)

The main features of trisomy 9 syndrome in mosaic and non-mosaic forms have been thoroughly described. Characteristic traits are low-set malformed ears, micrognathia, broad nose with bulbous tip, abnormal brain, congenital heart defects, abnormal hands and feet, genital abnormalities, and early death. We report a case of mosaic trisomy 9 with holoprosencephaly (HPE). The propositi was born at 37 weeks, with intra-uterine growth retardation, hypotelorism and single nostril, ventricular septal defect, anterior placement of anus, clenched hands with thumb adduction and ulnar deviation. Facial anomalies characteristic of trisomy 9 included deeply set eyes and short palpebral fissures, flat face with maxillary hypoplasia, small mouth, and low-set posteriorly angulated ears. Cytogenetic analysis showed mosaic trisomy 9 with 17% trisomic cells. Pathology confirmed lobar HPE. In literature, isolated arrhinia, related to the HPE spectrum, was reported in one case of mosaic trisomy 9. Our case raises the question of the causative role of trisomy 9 in full blown HPE., (Copyright 2002 Wiley-Liss, Inc.)

We report a case of mosaic trisomy 15 with mental retardation, facial dysmorphism, and hemihypertrophy, but no manifestations of Prader-Willi or Angelman syndromes. Mosaic trisomy 15 (11%) was discovered at the amniocentesis. Uniparental disomy for chromosome 15 was excluded by molecular analysis. Post-natal blood karyotype and examination were normal. Mosaic was confirmed on skin fibroblasts, placenta and cord. Evolution was marked by progressive right hemi-hypertrophy, and developmental delay. Our case is the first patient reported with hemihypertrophy associated with mosaic trisomy 15. The relevant literature is reviewed.