Cardiovascular malformations caused by NOTCH1 mutations do not keep left: data on 428 probands with left-sided CHD and their families.

PURPOSE: We aimed to determine the prevalence and phenotypic spectrum of NOTCH1 mutations in left-sided congenital heart disease (LS-CHD). LS-CHD includes aortic valve stenosis, a bicuspid aortic valve, coarctation of the aorta, and hypoplastic left heart syndrome. METHODS: NOTCH1 was screened for mutations in 428 nonsyndromic probands with LS-CHD, and family histories were obtained for all. When a mutation was detected, relatives were also tested. RESULTS: In 148/428 patients (35%), LS-CHD was familial. Fourteen mutations (3%; 5 RNA splicing mutations, 8 truncating mutations, 1 whole-gene deletion) were detected, 11 in familial disease (11/148 (7%)) and 3 in sporadic disease (3/280 (1%)). Forty-nine additional mutation carriers were identified among the 14 families, of whom 12 (25%) were asymptomatic. Most of these mutation carriers had LS-CHD, but 9 (18%) had right-sided congenital heart disease (RS-CHD) or conotruncal heart disease (CTD). Thoracic aortic aneurysms (TAAs) occurred in 6 mutation carriers (probands included 6/63 (10%)). CONCLUSION: Pathogenic mutations in NOTCH1 were identified in 7% of familial LS-CHD and in 1% of sporadic LS-CHD. The penetrance is high; a cardiovascular malformation was found in 75% of NOTCH1 mutation carriers. The phenotypic spectrum includes LS-CHD, RS-CHD, CTD, and TAA. Testing NOTCH1 for an early diagnosis in LS-CHD/RS-CHD/CTD/TAA is warranted.Genet Med 18 9, 914-923.

Genetic factors in non-syndromic congenital heart malformations.

The genetic defect in most patients with non-syndromic congenital heart malformations (CHM) is unknown, although more than 40 different genes have already been implicated. Only a minority of CHM seems to be due to monogenetic mutations, and the majority occurs sporadically. The multifactorial inheritance hypothesis of common diseases suggesting that the cumulative effect of multiple genetic and environmental risk factors leads to disease, might also apply for CHM. We review here the monogenic disease genes with high-penetrance mutations, susceptibility genes with reduced-penetrance mutations, and somatic mutations implicated in non-syndromic CHM.

Cornelia de lange syndrome: a recognizable fetal phenotype.

We describe a fetus with Cornelia de Lange syndrome diagnosed after termination of pregnancy at 21 weeks. Prenatally, growth retardation, diaphragmatic hernia, cystic hygroma and a right hand with only three rays were diagnosed by ultrasound in the second trimester of pregnancy. Postnatal magnetic resonance imaging confirmed the prenatal findings, and the presence of the typical dysmorphic features led to the diagnosis of Cornelia de Lange syndrome. The diagnosis was confirmed by the finding of a truncating mutation in the NIPBL gene. This case illustrates that the diagnosis Cornelia the Lange syndrome can be suspected prenatally in the second trimester, and can be diagnosed in fetuses after induction or newborns at birth as the typical phenotype is present early.

Postural orthostatic tachycardia syndrome (POTS): a common but unfamiliar syndrome.

Postural orthostatic tachycardia syndrome (POTS) is a condition in which a change from a supine to an upright position causes an abnormally large increase in heart rate which may be accompanied by a variety of physical complaints. We report two cases illustrating the heterogeneity of this syndrome. We give an update on the etiology of POTS, which is still poorly understood, and its overlap with other syndromes such as chronic fatigue syndrome. Clinicians should be aware of POTS, a fairly common clinical entity, that can result in significant impairments to a patient's quality of life. Lifestyle measures (under which adequate fluid and salt intake, exercise) are a first line of treatment; if insufficient, pharmacotherapy can be considered to improve quality of life.

Mutations in FLNB cause boomerang dysplasia.

Boomerang dysplasia (BD) is a perinatal lethal osteochondrodysplasia, characterised by absence or underossification of the limb bones and vertebrae. The BD phenotype is similar to a group of disorders including atelosteogenesis I, atelosteogenesis III, and dominantly inherited Larsen syndrome that we have recently shown to be associated with mutations in FLNB, the gene encoding the actin binding cytoskeletal protein, filamin B. We report the identification of mutations in FLNB in two unrelated individuals with boomerang dysplasia. The resultant substitutions, L171R and S235P, lie within the calponin homology 2 region of the actin binding domain of filamin B and occur at sites that are evolutionarily well conserved. These findings expand the phenotypic spectrum resulting from mutations in FLNB and underline the central role this protein plays during skeletogenesis in humans.

Homozygosity mapping of a gene for arterial tortuosity syndrome to chromosome 20q13.

BACKGROUND: Arterial tortuosity syndrome (ATS) is an uncommon connective tissue disorder of unknown aetiology. The most prominent feature is tortuosity of the large arteries, but lengthening, stenosis, and aneurysm formation are also frequent. METHODS: We performed a genomewide screen by homozygosity mapping of three consanguineous multiplex families, two from Morocco, and one from Italy, which included 11 ATS patients. The two families from Morocco may possibly have a common ancestor. RESULTS: We mapped the ATS gene to chromosome 20q13. Recombinations within an extended haplotype of 11 microsatellite markers localised the ATS gene between markers D20S836 and D20S109, an interval of 9.5 cM. CONCLUSIONS: Cloning and completing functional and structural analysis of the ATS gene may provide new insights into the molecular mechanisms of elastogenesis.

Unexpected life-threatening complications in Kabuki syndrome.

Kabuki syndrome is a rare multiple congenital anomalies/mental retardation syndrome comprising a distinct facial appearance and fetal fingertip pads. We observed two patients with Kabuki syndrome and describe unusual life-threatening complications, including stenosis of the central airways (not previously reported), extrahepatic biliary atresia, and congenital diaphragmatic hernia.

Prenatal diagnosis and confirmation of the acrofacial dysostosis syndrome type Rodriguez.

The group of acrofacial dysostosis (AFD) syndromes is very heterogeneous and contains many different entities. In 1990, Rodriguez et al. [1990: Am J Med Genet 35:484-489] described a new type of AFD characterized by severe mandibular hypoplasia, phocomelia and oligodactyly of the upper limbs, absence of fibulae, microtia, cleft palate, internal organ anomalies including arrhinencephaly and abnormal lung lobulation, and early lethality. We describe another case of AFD type Rodriguez, identified by prenatal ultrasonography at 25 weeks of gestation.

[Maternal complications of fetal hydrops]. / Maternale complicaties bij hydrops foetalis.

Three women, aged 28, 27 and 25 years, two primigravidae and one woman who had given birth to a hydropic child previously, had four pregnancies with hydrops of the foetus and the placenta: two (in the same patient) due to foetal cardiomyopathy and two with foetal heart block. The patients developed severe oedema and preeclampsia. After the delivery they recovered well. Since the introduction of anti-D rhesus immunoprophylaxis, foetal hydrops has become less frequent. The resulting maternal complications (the maternal hydrops syndrome and enlarged polycystic ovaries) are therefore less well-known. Serious maternal complications occur in around 50% of cases of foetal hydrops. Careful monitoring of the maternal condition in cases of foetal hydrops is therefore warranted.

Distinctive Phenotypic Abnormalities Associated with Submicroscopic 21q22 Deletion Including DYRK1A.

Partial monosomy 21 has been reported, but the phenotypes described are variable with location and size of the deletion. We present 2 patients with a partially overlapping microdeletion of 21q22 and a striking phenotypic resemblance. They both presented with severe psychomotor delay, behavioral problems, no speech, microcephaly, feeding problems with frequent regurgitation, idiopathic thrombocytopenia, obesity, deep set eyes, down turned corners of the mouth, dysplastic ears, and small chin. Brain MRI showed cerebral atrophy mostly evident in frontal and temporal lobes, widened ventricles and thin corpus callosum in both cases, and in one patient evidence of a migration disorder. The first patient also presented with epilepsy and a ventricular septum defect. The second patient had a unilateral Peters anomaly. Microarray analysis showed a partially overlapping microdeletion spanning about 2.5 Mb in the 21q22.1-q22.2 region including the DYRK1A gene and excluding RUNX1. These patients present with a recognizable phenotype specific for this 21q22.1-q22.2 locus. We searched the literature for patients with overlapping deletions including the DYRK1A gene, in order to define other genes responsible for this presentation.

In utero diagnosis of infra-diaphragmatic total anomalous pulmonary venous return.

This report describes the diagnosis of infra-diaphragmatic total anomalous pulmonary venous return in a fetus at 25 weeks of gestation. Abnormal venous pathways were visualized with real-time, pulsed and color Doppler ultrasound. The growth of cardiac structures, especially the left ventricle, was evaluated during subsequent ultrasound examinations.

Prenatal ultrasonographic diagnosis of posteromedial bowing of the leg: two case reports.

Congenital posteromedial bowing of the leg was prenatally detected in two pregnancies, at 20 and 31 weeks of gestation. Posteromedial bowing is a rare anomaly of unknown etiology. The prenatal course, monitored by ultrasonography, and the postnatal clinical and radiographic outcomes are discussed and show a complex differential diagnosis. The initial postnatal therapy is conservative. Leg length discrepancy can eventually be treated by lengthening or epiphysiodesis on the contralateral side.

IgE antibodies to Pityrosporum ovale in atopic dermatitis.

An enzyme-linked immunosorbent assay (ELISA) was developed to assess serum IgE antibodies directed against Pityrosporum ovale in patients with atopic dermatitis (AD), atopic patients with allergic respiratory disease (ARD: rhinitis or asthma) but without eczema, and in healthy controls. IgE binding to P. ovale extract was demonstrated in 49% (35/72) of AD patients. In contrast, anti-P. ovale IgE was found in only one of 27 atopic controls without eczema; all healthy control sera (n = 17) were negative. Of 37 AD patients tested intracutaneously with P. ovale, 31 showed immediate-type reactivity, and 20 of these 31 patients had anti-P. ovale IgE detectable by ELISA, while sera from the six non-responders were all negative. Levels of anti-P. ovale IgE were highest in AD patients aged 20-30 years. No correlation was found with the severity of AD, but there was a non-significant tendency (P = 0.06) to higher levels in AD patients with concomittant respiratory allergy. Anti-P. ovale IgE was significantly correlated with total serum IgE, with specific IgE against various aeroallergens as measured by RAST, and with levels of anti-Candida albicans IgE, measured with a similar ELISA. Thus, production of IgE antibodies against P. ovale occurs very frequently in AD, and rarely in patients with atopic disease without skin involvement.

Early fetal anomaly scanning in a population at increased risk of abnormalities.

OBJECTIVES: To determine the effectiveness of early fetal anomaly scanning in a population at risk of fetal anomalies. DESIGN: A prospective study in a tertiary center of 101 consecutive fetuses at risk of congenital anomalies at 11-14 weeks of gestation. RESULTS: The principal (93/101 = 92%) reason for referral was having a previously affected infant. Nine (9/101 = 9%) fetuses were shown to have structural anomalies at the 11-14-week scan. In five of nine structurally affected fetuses, the nature of the anomalies was similar to that established in a previously affected pregnancy, four of which had a recurrence of an autosomal recessive syndrome. In two fetuses with a normal 11-14-week scan, anomalies were detected at the 18-21-week (arthrogryposis) or 30-week (cardiomyopathy) scans. CONCLUSIONS: The majority of fetal anomalies can be diagnosed in the late first/early second trimesters of pregnancy. This will be of particular advantage to those women who are at high risk of having affected offspring. However, as fetal anomalies may present at varying gestational ages, the standard 18-21-week scan cannot be abandoned. The effectiveness of the early pregnancy scan depends on the natural history of anomalies (gestational age at onset) and the variable phenotypic expression of anomalies/syndromes.

Congenital microcephaly detected by prenatal ultrasound: genetic aspects and clinical significance.

OBJECTIVE: The aim of this study was to analyze fetuses with prenatally diagnosed microcephaly including the nature of associated anomalies and the genetic-diagnostic implications. DESIGN: Retrospective study design. METHODS: A total of 30 fetuses with reliable dates and with prenatally diagnosed microcephaly as a common feature were analyzed. RESULTS: Microcephaly was diagnosed at a mean gestational age of 28 weeks. More than half of the fetuses were also small for gestational age. Five subsets of microcephaly emerged from this study: (1) isolated microcephaly (16.7%); (2) microcephaly due to holoprosencephaly (16.7%); (3) microcephaly associated with chromosomal disorders (23.3%); (4) microcephaly as part of a genetic syndrome (20.0%); and (5) microcephaly as part of multiple anomalies (23.3%). CONCLUSIONS: In 25 out of 30 infants microcephaly proved to be part of a complex problem, emphasizing the need of a meticulous search for structural anomalies and fetal karyotyping when biometric data are not according to gestational age. The etiologic heterogeneity and variability of microcephaly in genetic syndromes are among the more difficult issues in prenatal ultrasound in pregnancies either with an incidental finding of this anomaly, or in cases with a recurrence risk. The complex situations described in this study demonstrate the importance of follow up, post-mortem investigation and careful genetic counseling.

Poor outcome in Down syndrome fetuses with cardiac anomalies or growth retardation.

The outcome of Down syndrome fetuses presenting with sonographic abnormalities in the second or third trimester is unclear. Therefore, we studied 55 pregnancies referred because of sonographically suspected fetal structural anomalies or growth retardation due to trisomy 21. A detailed ultrasound scan was performed in all cases to delineate the structural anomalies. Congenital heart malformations (CHMs) were diagnosed pre- and postnatally in 29 out of 55 Down fetuses (53%), with complete or incomplete atrioventricular septal defects (AVSDs) and ventricular septal defects (VSDs) being the most frequent anomalies. The most frequent noncardiac findings were a short femur (45%) and a small-for-gestational age (SGA) fetus (27%). Termination of pregnancy was carried out in 25 out of 55 pregnancies (45%). Of the 30 continued pregnancies, 10 ended with intrauterine death. The remaining 20 pregnancies resulted in the delivery of a live-born infant whose prognosis was poor, with a 1-year survival of only 60%. Combining intrauterine death and death in the first year indicated that the overall survival rate was only 40%. Fatal outcome was noted in 68% (13/19) in the presence of CHM, in 83% (10/12) in SGA fetuses, in 86% (6/7) in combined CHM and SGA, but only in 17% (1/6) in the absence of CHM and SGA. This study indictes that second- and third-trimester in utero diagnosis of Down syndrome has a poor outcome when associated with CHM and/or SGA. This is important in the genetic counseling of the parents.