A familial CHARGE syndrome with a CHD7 nonsense mutation and new clinical features

The autosomal dominant CHARGE syndrome (MIM musical sharp214800) is caused by mutations in the CHD7 gene. It is usually sporadic but a few cases with gonadal mosaicism and familial inheritance have been reported. We describe a familial CHARGE syndrome in a two-generation Finnish family with a nonsense mutation in the CHD7 gene. Detailed clinical examination of the affected family members was performed, and mutations in the CHD7 gene were analysed with direct sequencing and multiplex ligation-dependent probe amplification. A nonsense mutation, p.Q1599X, was detected in exon 21 of the CHD7 gene in three affected family members. The father was only mildly affected, whereas his son had a very severe manifestation of the syndrome, causing death at the age of 3 months. The second pregnancy was prematurely terminated in the 23rd week because of cardiac anomalies detected in the ultrasound scan. The father's brother also had mild symptoms, but no mutation was detected in him. In this report, the variability of clinical symptoms within families and the clinical importance of mildly affected patients with the CHARGE syndrome are underlined with implications for molecular genetic diagnostics of the syndrome. Features not described in the CHARGE syndrome before are also presented.     

Genetic heterogeneity and phenotypic anomalies in children with atrioventricular canal defect and tetralogy of Fallot

Tetralogy of Fallot associated with the atrioventricular canal defect has been usually reported in association with Down syndrome. The aim of the present study was to describe the cardiac aspects and the genetic anomalies in children with this association of heart defects. We identified 64 patients with atrioventricular canal defect tetralogy of Fallot. All children underwent complete cardiovascular, clinical phenotypic and genetic evaluation. A genetic syndrome or extracardiac anomalies were found in 56 patients (87.5%). Down syndrome (43 patients, 67.2%) was the most frequent genetic diagnosis. Other syndromes were 8p deletion, trisomy 13, duplication 5p, cranio-cerebello-cardiac syndrome, Cantrell syndrome, CHARGE association, VACTERL association, and DiGeorge syndrome related to maternal diabetes. No patients in our series had 22q11 deletion. Tetralogy of Fallot with extreme dextroposition of the aorta was found in seven patients (only one with Down syndrome). Additional cardiac malformations were present in 23 patients (only 11 with Down syndrome). The association between atrioventricular canal defect and tetralogy of Fallot represents a cardiac phenotype with strong genetic characteristics. For this reason, a careful genetic examination is required. Our study confirms the high prevalence of Down syndrome, but also reveals a significant genetic heterogeneity. Additional cardiac defects are prevalent in patients without Down syndrome.     

Hemifacial microsomia,external auditory canal atresia,deafness and Mullerian anomalies associated with acro-osteolysis: a new autosomal recessive syndrome?

We report the combination of hemifacial microsomia, external auditory canal atresia, deafness and acro-osteolysis in several members of a highly consanguineous Asian family. In addition Mullerian anomalies have been found in two female members of the family. The external auditory canal stenosis and Mullerian anomalies in this family are similar to those reported by Winter et al. [(1968) J Pediatr 72 : 88-93] and overlap with those found in Goldenhar syndrome and Mullerian duct/renal aplasia/cervicothoracic somite dysplasia (MURCS), CHARGE and VATER associations. However, to the authors' knowledge, acro-osteolysis has not been reported in patients with any of these conditions. Overall, the findings in this family appear to be unique and the presence of consanguinity suggests an autosomal recessive condition with variable expression.     

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.     

Syndromes and disorders associated with omphalocele (III): single gene disorders, neural tube defects, diaphragmatic defects and others

Omphalocele can be associated with single gene disorders, neural tube defects, diaphragmatic defects, fetal valproate syndrome, and syndromes of unknown etiology. This article provides a comprehensive review of omphalocele-related disorders: otopalatodigital syndrome type II; Melnick-Needles syndrome; Rieger syndrome; neural tube defects; Meckel syndrome; Shprintzen-Goldberg omphalocele syndrome; lethal omphalocele-cleft palate syndrome; cerebro-costo-mandibular syndrome; fetal valproate syndrome; Marshall-Smith syndrome; fibrochondrogenesis; hydrolethalus syndrome; Fryns syndrome; omphalocele, diaphragmatic defects, radial anomalies and various internal malformations; diaphragmatic defects, limb deficiencies and ossification defects of skull; Donnai-Barrow syndrome; CHARGE syndrome; Goltz syndrome; Carpenter syndrome; Toriello-Carey syndrome; familial omphalocele; Cornelia de Lange syndrome; C syndrome; Elejalde syndrome; Malpuech syndrome; cervical ribs, Sprengel anomaly, anal atresia and urethral obstruction; hydrocephalus with associated malformations; Kennerknecht syndrome; lymphedema, atrial septal defect and facial changes; and craniosynostosismental retardation syndrome of Lin and Gettig. Perinatal identification of omphalocele should alert one to the possibility of omphalocele-related disorders and familial inheritance and prompt a thorough genetic counseling for these disorders.     

Microtia, severe micrognathia and absent ossicles: auriculo-condylar syndrome or new entity?

The differential diagnosis of syndromes with anomalies of the first and second branchial arches includes the oculo-auriculo-vertebral syndrome, the Treacher-Collins syndrome, the acrofacial dysostoses (including Nager and Miller syndromes), the dysgnathia complex and the auriculo-condylar syndrome. Isolated microtia may also be present with involvement of other facial structures and distant organs. We report here a patient with first and second branchial arch anomalies, born to consanguineous parents. Pertinent physical findings include severe micrognathia, absence of the upper portion of the helices, atresia of the external meati and absence of the middle ear ossicles, mildly down-slanting palpebral fissures and a highly arched palate with a submucous cleft. Discussion of the differential diagnosis highlights the clinical overlap between these conditions. This constellation of findings may represent a more severe manifestation of the auriculo-condylar syndrome or a previously undescribed syndrome.     

Prospective ultrasound diagnosis of Pallister-Killian syndrome in the second trimester of pregnancy: the importance of the fetal facial profile

The Pallister-Killian syndrome (PKS) represents a rare polymalformative complex characterized by a tissue-specific mosaic distribution of an additional isochromosome 12p and characterized by diaphragmatic hernia, rhizomelic limb shortening, facial anomalies and, rarely, acral hypoplasia. Since diaphragmatic hernia and acral hypoplasia can be also found in Fryns syndrome, the differential diagnosis between the two conditions depends on the demonstration of the 12p isochromosome by FISH. Prenatal diagnosis of PKS has been reported in cases submitted to karyotyping due to advanced maternal age or congenital anomalies detected on second trimester ultrasound. Among the ultrasound-detected malformations, little attention has been paid to facial anomalies. We describe a case in which PKS was prospectively suspected on the basis of the various anomalies detected at ultrasound, namely diaphragmatic hernia, rhizomelic limb shortening, and abnormal facial profile. The diagnosis was then confirmed by FISH on amniocytes and peripheral lymphocytes. In the present case, the disclosure of typical facial abnormalities significantly contributed to the differentiation between PKS and Fryns syndrome.     

Guadalajara camptodactyly syndrome type I: report on a new case

We report a Brazilian female patient with a thin and long face, blepharophimosis, minor auricular anomalies, camptodactyly and thoracic and spinal anomalies. The constellation of clinical signs present in this patient is consistent with the diagnosis of Guadalajara camptodactyly syndrome type I. Clinical and genetic aspects concerning this condition are discussed.     

Prenatal diagnosis of a partial trisomy 19q

Phenotypic anomalies due to a genetic imbalance of chromosome 19 have been reported in very rare postnatal cases. Here a case of partial trisomy 19 diagnosed prenatally by ultrasonography and cytogenetic analysis is presented. Detailed evaluation by sonography showed major anomalies which could be correlated to the typical appearance of this chromosomal anomaly. Termination of pregnancy at 21 weeks of gestation was performed, and the prenatal diagnosis was confirmed postnatally by autopsy. The syndrome in this case was caused by a duplication of the long arm of chromosome 19 (46,XY, dup(19) (q13.1-->qter).     

Anterior sacral meningocele as a pelvic complication of Marfan syndrome

Anterior sacral meningocele (ASM) is well recognized in Marfan syndrome as a consequence of dural ectasia. Two cases presenting as nongynaecological pelvic masses are described highlighting the clinical difficulty in diagnosis and the classical radiological findings. The classification of ASM and associated anomalies of the sacrum are reviewed.     

Prenatal ultrasound diagnosis of Toriello-Carey syndrome

Toriello-Carey syndrome is a rare malformative complex, described for the first time in 1988, characterized by agenesis of the corpus callosum, facial anomalies, cardiac defects and hypotonia. Relatively few neonatal cases have been reported. We describe here the first prenatal ultrasound diagnosis of the syndrome based on the detection of agenesis of the corpus callosum and spongious cardiomyopathy in a 22-week-old fetus of a couple with positive family history. The first sib of the couple was diagnosed with Toriello-Carey syndrome at 1 year of age, and had, in addition to the typical facial anomalies not detectable by ultrasound, agenesis of the corpus callosum and the same heart lesion (spongious cardiomyopathy). This report demonstrates that prenatal diagnosis of Toriello-Carey syndrome is feasible in the second trimester of pregnancy.     

Split notochord syndrome - prenatal ultrasonographic diagnosis.

Split notochord syndrome is a rare condition that is characterized by a persistent connection of the gut and dorsal skin of the back, an enteric cyst and vertebral anomalies. We present two cases in which prenatal ultrasound showed polyhydramnios. In one case it was associated with vertebral abnormalities and a right-sided mediastinal cyst found to be the stomach. Postnatal evaluation confirmed the diagnosis of split notochord syndrome. The association of sonographic findings of hydramnios, thoracic cysts and vertebral anomalies suggests prenatal diagnosis of split notochord syndrome.     

Utility of fetal ultrasonography in the prenatal diagnosis of Smith-Lemli-Opitz syndrome

Smith-Lemli-Opitz syndrome is a rare autosomal recessive genetic disorder which diagnosis is usually made postnatally. We describe a case of a prenatal diagnosis based only on specific ultrasound findings: intra-uterine growth retardation with facial dysmorphia, polydactyly and genital anomalies. We suggest giving more consideration to the ultrasound scanning for the diagnosis of the syndrome in the prenatal period.     

Successful pregnancy in a Noonan syndrome patient after 3 unsuccessful pregnancies from severe fetal hydrops: a case report

BACKGROUND: Noonan syndrome is a very rare disorder; its prevalence is 1/1,000-2,500 births. The special facial features, short stature, eventual cardiac anomalies and familiar history are the most important characteristics of the diagnosis. CASE: A Noonan syndrome patient delivered a healthy infant after a complicated delivery. The delivery followed 3 unsuccessful pregnancies. The previous pregnancies were terminated before the 24th gestational week because of general fetal hydrops as well as other malformations. CONCLUSION: In the prenatal care of a patient with Noonan syndrome the genetic and obstetric aspects are equally important. In establishing the diagnosis, ultrasonography is of utmost importance. As in our case, complications after cesarean section highlight the higher risk of delivery in women with Noonan syndrome.     

Embryology of neural tube defects: information provided by associated malformations

OBJECTIVES: To get information about embryologic mechanisms of neural tube defects (NTD), by studying the associated malformations. METHODS: Eighty three cases of NTD, seen at the prenatal diagnosis unit of Rennes University Hospital (France) between May 1999 and December 2002, were retrospectively studied. Cases with chromosomal anomalies (5/83), cases without available karyotype or pathologic examination were excluded. 24 spina bifida, and 27 cephalic forms (anencephalies, exencephalies, and encephaloceles) were thus analyzed. RESULTS: Only 22/51 cases (43%) were strictly isolated NTD. Anomalies of tissues arising from neural crests were noted in 8/51 fetuses (16%), midline or lateralization anomalies in 12/51 (24%), and anomalies of mesoblastic tissues in 17/51 (33%). An already known syndrome was found in 4/51 cases (8%). CONCLUSION: NDT are more extensive congenital damages that would suggest the restrictive terminology. That prompts to assess cautiously prenatal diagnosis of NTD, and to get detailed pathological examination after termination of pregnancy.     

Whole exome sequencing identifies a novel FRAS1 mutation and aids in vitro fertilization with preimplantation genetic diagnosis in Fraser syndrome

ObjectiveTo demonstrate the picture of a woman who had three times of pregnancies but fetuses were complicated with Fraser syndrome, a rare genetic disorder with multiple congenital anomalies.Case reportHere are three complicated pregnancies with predominant features of severe oligohydramnios and other variable intrafamilial presentations. We made a definite diagnosis, Fraser syndrome, with the assistance of whole exome sequencing (WES) via umbilical blood of the second and third fetus. The provision of a preimplantation diagnosis helped contribute a healthy newborn in this family.ConclusionThis paper provides insights into obscure antenatal presentations of Fraser syndrome with intrafamilial variance. Clinical uncertainty at the fetal stage suggests the role of WES to reach a final diagnosis, and a preimplantation diagnosis is applicable to avoid recurrence of genetic disorders in subsequent pregnancies.     

Fetal and early postnatal magnetic resonance imaging--is there a difference?

AIM: To evaluate whether fetal magnetic resonance imaging (MRI) could replace early postnatal MRI in fetuses with central nervous system (CNS) anomalies. METHODS: Thirteen pregnancies presenting with fetal CNS anomalies were investigated using MRI. Indications included ventriculomegaly combined with additional CNS anomaly (n=5), isolated ventriculomegaly (n=2), arachnoid cyst (n=2), holoprosencephaly (n=1), complex malformation syndrome (n=1), Dandy walker malformation (n=1) and midline cyst (n=1). Early postnatal MRI followed within the first six weeks of life. RESULTS: Investigation with early postnatal MRI confirmed the fetal MRI diagnosis in all cases. Investigation with postnatal MRI presented additional information in two cases. However, there was no change in patient care. CONCLUSIONS: Fetal MRI should replace early postnatal MRI in infants with CNS anomalies.     

Drug-induced pineal gigantism in rabbits as a tool to study the pineal—gonadal interaction

The combination of the Mayer—Rokitansky—Küster (MRK) syndrome with renal anomalies is well known (incidence: 36%). The combination with skeletal anomalies is also known (incidence: 10%). However, the coincidence with ear anomalies is rare, and the coincidence with facial anomalies is extremely rare. The combination of the MRK syndrome with renal, skeletal, ear and facial anomalies is described in a case report with a review of the literature. It is not only worthwhile to be alert for urinary tract anomalies in patients with the MRK syndrome, but also to study the skeletal and auditory systems in these patients.     

Information for patients undergoing a prenatal diagnosis

OBJECTIVES: Lack of information is a frequent complaint with regard to physicians dealing with prenatal diagnosis (PD). The aim of the study was to find out how information on PD was perceived by patients and if they considered that they had been correctly informed by their physicians. METHODS: We conducted a prospective study in Lariboisière Hospital (Paris) with 86 patients undergoing prenatal diagnosis between 2001 and 2003. A 23-item questionnaire was given to patients after delivery or termination of pregnancy (TP). RESULTS: Fifty patients out of 86 answered the questionnaire. Twelve patients out of 50 underwent a TP. Information on foetal anomaly was insufficient for 11 patients out of 50 (22%). Some patients found the information too technical; others would like to see photos to illustrate the anomalies and the possible surgical repairs to be performed. Information was insufficient for one in four patients concerning maternal serum screening for Down's syndrome. Information before amniocentesis was considered sufficient by 9 out of 10 patients. Information on the risks of TP was not given or not understood by 10 out of 12 patients. CONCLUSION: Information on prenatal diagnosis could be improved by using simple and accessible language, supported by written documents and photos for certain anomalies. More information should be given in cases of abstract anomalies and should be adapted to the social, ethnic and cultural background of the patient.