Mutation of the PAX2 gene in a family with optic nerve colobomas, renal anomalies and vesicoureteral reflux.

Paired box (PAX) genes play a critical role in human development and disease. The PAX2 gene is expressed in primitive cells of the kidney, ureter, eye, ear and central nervous system. We have conducted a mutational analysis of PAX2 in a family with optic nerve colobomas, renal hypoplasia, mild proteinuria and vesicoureteral reflux. We report a single nucleotide deletion in exon five, causing a frame-shift of the PAX2 coding region in the octapeptide domain. The phenotype resulting from the PAX2 mutation in this family was very similar to abnormalities that have been reported in Krd mutant mice. These data suggest that PAX2 is required for normal kidney and eye development.

Mutations in TFAP2B cause Char syndrome, a familial form of patent ductus arteriosus.

Char syndrome is an autosomal dominant trait characterized by patent ductus arteriosus, facial dysmorphism and hand anomalies. Using a positional candidacy strategy, we mapped TFAP2B, encoding a transcription factor expressed in neural crest cells, to the Char syndrome critical region and identified missense mutations altering conserved residues in two affected families. Mutant TFAP2B proteins dimerized properly in vitro, but showed abnormal binding to TFAP2 target sequence. Dimerization of both mutants with normal TFAP2B adversely affected transactivation, demonstrating a dominant-negative mechanism. Our work shows that TFAP2B has a role in ductal, facial and limb development and suggests that Char syndrome results from derangement of neural-crest-cell derivatives.

Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1.

Alagille syndrome is an autosomal dominant disorder characterized by abnormal development of liver, heart, skeleton, eye, face and, less frequently, kidney. Analyses of many patients with cytogenetic deletions or rearrangements have mapped the gene to chromosome 20p12, although deletions are found in a relatively small proportion of patients (< 7%). We have mapped the human Jagged1 gene (JAG1), encoding a ligand for the developmentally important Notch transmembrane receptor, to the Alagille syndrome critical region within 20p12. The Notch intercellular signalling pathway has been shown to mediate cell fate decisions during development in invertebrates and vertebrates. We demonstrate four distinct coding mutations in JAG1 from four Alagille syndrome families, providing evidence that it is the causal gene for Alagille syndrome. All four mutations lie within conserved regions of the gene and cause translational frameshifts, resulting in gross alterations of the protein product Patients with cytogenetically detectable deletions including JAG1 have Alagille syndrome, supporting the hypothesis that haploinsufficiency for this gene is one of the mechanisms causing the Alagille syndrome phenotype.

Char syndrome, an inherited disorder with patent ductus arteriosus, maps to chromosome 6p12-p21.

BACKGROUND: Patent ductus arteriosus (PDA) is a relatively common form of congenital heart disease. Although polygenic inheritance has been implicated, no specific gene defects causing PDA have been identified to date. Thus, a positional cloning strategy was undertaken to determine the gene responsible for the Char syndrome, an autosomal dominant disorder characterized by PDA, facial dysmorphism, and hand anomalies. METHODS AND RESULTS: A genome scan was performed with 46 members of 2 unrelated families in which the disease was fully penetrant but the phenotype differed. Significant linkage was achieved with several polymorphic DNA markers mapping to chromosome 6p12-p21 (maximal 2-point LOD score of 8.39 with D6S1638 at theta=0.00). Haplotype analysis identified recombinant events that defined the Char syndrome locus with high probability to a 3. 1-cM region between D6S459/D6S1632/D6S1541 and D6S1024. CONCLUSIONS: A familial syndrome in which PDA is a common feature was mapped to a narrow region of chromosome 6p12-p21. Additional analysis with other families and polymorphic markers as well as evaluation of potential candidate genes should lead to the identification of the Char syndrome gene, which will provide insights into cardiogenesis as well as limb and craniofacial development.

Cardiac and skeletal muscle abnormalities in cardiomyopathy: comparison of patients with ventricular tachycardia or congestive heart failure.

Results of cardiac muscle and skeletal muscle biopsies were compared in 22 patients with cardiomyopathy; 11 patients presented with symptoms secondary to ventricular tachycardia (Group 1) and 11 had symptoms of severe congestive heart failure (Group 2). No patient had structural or ischemic cardiac disease. In Group 1 patients, hemodynamic abnormalities were subtle, but invasive study demonstrated dilated cardiomyopathy in two patients and restrictive cardiomyopathy in nine. In Group 2, eight patients had dilated cardiomyopathy and three had restrictive cardiomyopathy. Cardiac biopsy results were abnormal in all 22 patients and the abnormalities were similar for the two groups. Cardiac histologic study revealed a spectrum of abnormalities including fibrosis, dilated sarcoplasmic reticulum, increased numbers of intercalated discs and mitochondrial abnormalities. Histologic abnormalities of skeletal muscle were similar in each group, consisting of endomysial fibrosis and increased lipid deposits. Slightly more than half of the Group 1 and Group 2 patients also had a low concentration of skeletal muscle long chain acylcarnitine. These data demonstrate that abnormalities of both cardiac and skeletal muscle are common in patients with cardiomyopathy; abnormalities are similar whether initial symptoms are due to ventricular tachycardia or congestive heart failure. It is suggested that these patients with cardiomyopathy may have a generalized myopathy.

Exercise reduces persistent ductus arteriosus shunting in piglets.

To determine the effects of dynamic exercise on ductal left to right shunting and skeletal and myocardial blood flow distribution, a persistent ductus arteriosus was created by balloon catheters in neonatal piglets. At 8-10 weeks of age, aortic, pulmonary artery, and left atrial catheters were placed and radiolabelled microspheres injected for measuring left ventricular output, organ blood flows, and ductus left to right shunting at rest and during treadmill exercise (1.6 mph). At rest, effective left ventricular output and myocardial and skeletal muscle blood flows were similar in the study group and controls. Exercise increased skeletal muscle and left ventricular blood flows similarly in the control and study group and did not accentuate the exercise induced small reduction in the left ventricular subendocardial to subepicardial blood flow ratio. This was due to a significant reduction in the ductus left to right shunt during exercise (mean(SD) 34(15) vs 18(7)%, p less than 0.02) and maintenance of effective left ventricular output in the study group (447(144) vs 446(98) ml.min-1.kg-1 in controls). The reduction in ductus shunting during exercise was due to a significant decrease in systemic vascular resistance and a small increase in pulmonary vascular and ductus resistance. Thus, reduced persistent ductus arteriosus shunting and maintenance of effective left ventricular output prevents myocardial perfusion abnormalities during dynamic exercise in swine with a persistent ductus and small to moderate left to right shunts.

Specific mitochondrial DNA deletions in idiopathic dilated cardiomyopathy.

OBJECTIVE: Structural changes in human mitochondrial DNA (mtDNA) have been implicated in a number of clinical conditions with dysfunctions in oxidative phosphorylation called OX-PHOS diseases, some of which have cardiac involvement. The objective of this study was to assess the frequency and extent of specific mitochondrial DNA deletions in idiopathic dilated cardiomyopathy. METHODS: DNA extracted from tissue derived from the left ventricle of 41 patients with idiopathic dilated cardiomyopathy and 17 controls was amplified by polymerase chain reaction using specific primers to assess the incidence and proportion of 5-kb and 7.4-kb deletions in mitochondrial DNA. RESULTS: In reactions using primers to detect the 5-kb deletion, an amplified product of 593 bp was found in low abundance relative to undeleted mitochondrial DNA but with high frequency in a number of controls and patients. A second deletion of 7.4 kb in size was also frequently present in controls and patients. In contrast to previous reports, these deletions were found to be present in both controls and in cardiomyopathic patients, 18 years and younger, including several infants. The 7.4-kb deletion was prominently increased in both frequency and in its proportion relative to undeleted mitochondrial DNA in patients 40 years and older with idiopathic dilated cardiomyopathy. CONCLUSIONS: At variance with current literature our study reports a significant presence of both 5 and 7.4-kb deletions in the young and a higher frequency and quantity of the 7.4-kb deletion in the older cardiomyopathic patients in comparison with controls. The increased accumulation of the 7.4-kb deletion as both a function of aging and cardiomyopathy is suggestive that this specific mitochondrial DNA deletion arises more likely as an effect of heart dysfunction rather than as a primary cause of cardiomyopathy.

Bilateral periventricular nodular heterotopia with mental retardation and syndactyly in boys: a new X-linked mental retardation syndrome.

Bilateral periventricular nodular heterotopia (BPNH) is a recently recognized malformation of neuronal migration, and perhaps proliferation, in which nodular masses of gray matter line the walls of the lateral ventricles. Most affected individuals have epilepsy and normal intelligence with no other congenital anomalies. A striking skew of the sex ratio has been observed because 31 of 38 probands have been female, and one gene associated with BPNH was recently mapped to chromosome Xq28. We report three unrelated boys with a new multiple congenital anomaly-mental retardation syndrome that consists of BPNH, cerebellar hypoplasia, severe mental retardation, epilepsy, and syndactyly. Variable abnormalities included focal or regional cortical dysplasia, cataracts, and hypospadius. We hypothesize that this syndrome involves the same Xq28 locus as isolated BPNH, and we review the expanding number of syndromes associated with BPNH.

Cardiac and skeletal myopathy associated with cardiac dysrhythmias.

Electrophysiologic studies, echocardiograms, cardiac catheterizations and histologic and biochemical analyses of skeletal muscle biopsies were performed in 10 patients (aged 10 to 37 years, mean 21) who had dysrhythmias as the initial manifestation of cardiomyopathy. Presenting symptoms and signs attributable to dysrhythmias included sudden cardiac arrest in 2 patients, syncope in 3, presyncope in 3 and palpitations in 2. There was no clinical evidence of skeletal muscle weakness in any patient. Multicatheter electrophysiologic evaluation established diagnoses of ventricular tachycardia in 6 patients, primary atrial tachycardia in 2 and third degree infra-Hisian heart block in 1 patient. One patient presenting with palpitations had no inducible arrhythmia or conduction disturbance. Echocardiographic, angiographic and hemodynamic studies demonstrated previously unsuspected dilated cardiomyopathy in 7 patients and restrictive cardiomyopathy in 3. Skeletal muscle histologic characteristics were abnormal in all 10 patients; increases in lipid droplets and endomysial fibrosis were the characteristic findings. Serum free carnitine and short- and long-chain acylcarnitine were normal in 9 patients. However, skeletal muscle long-chain acylcarnitine was reduced in 9 patients. These findings support the concept that in certain patients presenting with dysrhythmias, the dysrhythmia may be a manifestation of cardiac and skeletal (that is, generalized) myopathy.

Cardiac malformations in relatives of children with truncus arteriosus or interruption of the aortic arch.

Familial recurrence risks for congenital cardiac malformations have been estimated at 1 to 4%, but little is known of recurrence risks for uncommon congenital cardiac malformations. This study determined the incidence of congenital cardiac malformations in relatives of patients with either truncus arteriosus (TA) or interruption of the aortic arch (IAA) seen between 1955 and 1985. Prior to this study, only 2 cases of IAA in siblings had been reported and the recurrence risk of TA had been estimated at 1.2%. In the families of 36 index cases of IAA, there were 98 siblings, 2 with congenital cardiac malformations (2.1%). All recurrences were in IAA type B families. Single cases of congenital cardiac malformations were found in second- and third-degree relatives and 2 cases in more distant relatives. In the families of 49 index cases of TA, there were 106 siblings, 7 with congenital cardiac malformations (6.6%). Two had TA, 3 had other conotruncal anomalies and 2 had other congenital cardiac malformations. Two parents had congenital cardiac malformations, 1 with TA and 1 with conotruncal malformation. Among second- and third-degree relatives, 7 had congenital cardiac malformations (5 were conotruncal, including 1 half sibling). Among greater than third-degree relatives, 3 had congenital cardiac malformations. Thus, in IAA, the recurrence rate of congenital cardiac malformations (2.1%) was higher than expected and could be related to the etiology of IAA type B as a conotruncal malformation. In TA, the recurrence rate of congenital cardiac malformations was 6.6%, higher than previously reported. When TA was complex the recurrence risk was higher (13.6%). These findings must be taken into consideration for satisfactory genetic counseling.

Myocardial carnitine in end-stage congestive heart failure.

To test the hypothesis that carnitine is decreased in the myocardial tissue of patients with end-stage congestive heart failure (CHF), left ventricular myocardial carnitine was measured in 51 patients undergoing orthotopic cardiac transplantation. The study group included patients with idiopathic dilated cardiomyopathy, coronary artery disease, myocarditis and rheumatic heart disease. Myocardial carnitine varied in different cardiac chambers. In normal control hearts, the left and right ventricular total carnitine was similar, but the ventricles had higher levels than the atria (p less than 0.005); in 30 hearts in CHF, the left ventricular total carnitine was higher than in the right ventricle (p less than 0.001) and both ventricles had higher total carnitine than the atria (p less than 0.005). Only 7 of 51 patients with CHF had low myocardial carnitine, whereas plasma carnitine was elevated in all diagnostic groups of end-stage CHF studied.

Familial occurrence of patent ductus arteriosus.

We describe 7 relatives with patent ductus arteriosus (PDA) and a slightly unusual facial appearance with prominent midface with nose elongation and flattening of the nasal bridge, wide-set eyes, downturned palpebral fissures, mild ptosis, thickened lips, and apparently slightly low-set ears. Autosomal dominant inheritance is suggested in this family. Other families where affected members have PDA and a similar facial appearance and autosomal dominant inheritance were described previously by Char [1978: BD:OAS XIV (6B):303-305] and Temple [1992: Clin Dysmorphol 1:17-21].

Variation in severity of cardiac disease in Holt-Oram syndrome.

We describe a family with Holt-Oram syndrome (HOS) with variable hand and cardiac manifestations. One affected relative had complex congenital malformations of the heart consisting of an endocardial cushion defect and hypoplasia of the left ventricle. The literature from 1974 to 1995 is reviewed. Atrial septal defect is the most cardiac abnormality (60.3% of 189 cases) occurring singly or in combination with other malformations. Thirty-three individuals (17.5%) of literature cases) have more complex congenital malformations of the heart requiring complicated medical management and extensive cardiac surgery. Many genetic reference sources of HOS indicate that single or less severe cardiac malformations are expected in this disorder. It is important to provide more information about the occurrence and spectrum of severity of malformations of the heart to individuals and families where HOS is present.

Cerebello-oculo-renal syndromes including Arima, Senior-Löken and COACH syndromes: more than just variants of Joubert syndrome.

Cerebellar vermis hypoplasia (CVH) is part of many different malformation syndromes, especially Joubert syndrome. However, the nosology of these disorders remains uncertain. We reviewed reports of 100 children with cerebellar vermis hypoplasia, and ocular or renal involvement. Although the status of the upper brainstem was not adequately documented in most of these patients, some had hypoplasia and dysplasia of the ponto-mesencephalic isthmus and the superior portion of the cerebellar vermis, which results in a "molar tooth" sign on MRI scan. Several distinct syndromes were apparent among this group. We conclude that (a) hypoplasia of the cerebellar vermis, especially the anterior vermis, is often associated with a complex brainstem malformation; (b) the latter comprises a "molar tooth" brainstem and vermis hypoplasia-dysplasia malformation complex; (c) this complex may include the Dandy-Walker malformation, occipital cephalocele, and some abnormalities of the cerebrum as evidenced by frequent mental retardation; and (d) the "molar tooth" sign or malformation is causally heterogeneous as it occurs in several distinct malformation syndromes including Joubert syndrome, Arima syndrome, Senior-Löken syndrome, COACH syndrome, and probably familial juvenile nephronophthisis.

Jarcho-Levin syndrome: four new cases and classification of subtypes.

The Jarcho-Levin syndrome is a condition manifested by vertebral body and related rib malformations. We report on four new cases and review 57 cases from the literature. Analysis of the 61 cases suggests that there are two major subtypes (spondylocostal dysostosis and spondylothoracic dysostosis) with different survival rates, associated malformations, and inheritance patterns. Individuals with spondylothoracic dysostosis have vertebral body malformations and ribs which flare in a fanlike pattern but which are not significantly malformed. This is an autosomal recessive trait, and the patients have a higher mortality rate and greater incidence of neural tube defects. Individuals with spondylocostal dysostosis have vertebral malformations, frequent dramatic rib malformations, and short stature, but do not have a fanlike thoracic configuration. Most cases of spondylocostal dysostosis are inherited in an autosomal recessive fashion, although in a few families it is a dominant trait which is correlated with better survival. Respiratory compromise previously accounted for the high mortality in these conditions, but improvements in respiratory technology have increased survival. Appropriate classification of these similar phenotypes will improve counseling concerning recurrence risk, management, and prognosis.

Interstitial deletion of 10q: clinical features and literature review.

We report on a patient with interstitial deletion of 10q and compare her to 8 previously described patients, 2 of whom have chromosomal breakpoints similar to our patient. Minor anomalies including broad forehead, hypertelorism, strabismus, prominent philtrum, and "dysplastic" pinnae are present in our patient. Psychomotor retardation and hypotonia are universal findings in 10q interstitial deletion. Growth retardation, not present in our patient, is seen in some. These clinical findings are sufficiently distinct to suggest early chromosome studies.

Duplication 6q22-->qter: definition of the phenotype.

We report on a girl with duplication of 6q22.32 --> qter and microcephaly, frontal bossing, facial anomalies, and webbed neck. She has congenital heart disease, renal hypoplasia, and hearing loss along with severe developmental delay. Published reports of seven other patients are reviewed and compared. The most frequent anomalies include microcephaly, abnormal face, webbed neck, congenital heart disease, limb contractures, and developmental delay.

Plantar lipomatosis, unusual facial phenotype and developmental delay: a new MCA/MR syndrome.

We describe two boys with global developmental delay and a phenotype of microcephaly, midface hypoplasia, enlarged fleshy ears, depressed nasal bridge, anteverted nostrils, central palatal ridge, and high forehead. Bilateral congenital fat pads are present anteromedial to the heels. Fetal finger and toe pads are present and palmar and plantar grooves are deeper than normal with "pillowing" of the areas between the grooves. No patients with similar clinical findings have been located, but these two children have a remarkably similar clinical presentation which we consider a "new" syndrome.