Lack of evidence for connexin 43 gene mutations in human autosomal recessive lateralization defects

Heterotaxy is the failure of the developing embryo to establish normal left-right asymmetry, which is often associated with multiple malformations. Previous studies have identified different mutations in the cytoplasmic tail of the connexin 43 (cx 43) gene in six patients from a series of six sporadic cases with defects of laterality and severe heart malformations. These cases showed that of the genes involved in lateralization defects with autosomal recessive transmission, cx 43 was the most important. This result was challenged by two different teams, which, on sequencing only the carboxyl terminal end of the cx 43 gene in 30 patients, found no mutations. To assess the responsibility of the cx 43 gene in human autosomal recessive lateralization defects, we tested its involvement in a selected group of 25 patients (19 familial cases) with a wide variety of lateralization defects and cardiovascular malformations. The whole coding sequence and direct flanking sequences were screened for mutations, both by single strand conformation analysis and direct fluorescent sequencing. We could only detect a single base pair insertion in the 3' untranslated region of one patient. To test the possibility of mutations in other parts of the cx 43 gene, the gene was located onto the physical map of chromosome 6, and flanking polymorphic markers were genotyped. Haplotype analysis excluded the cx 43 gene locus in nearly all of the familial cases of lateralization defects. Thus, our results do not support the suggestion that this gene is implicated in human autosomal recessive lateralization defects.     

The syndrome of ankyloblepharon, ectodermal defects and cleft lip and palate: an autosomal dominant condition

Seven patients from four families are reported who had an inherited condition of which the main features were ankyloblepharon, ectodermal defects and cleft lip and palate. The ectodermal defects were partial or complete hair loss, absent or dystrophic nails, pointed widely spaced teeth and partial anhidrosis. Associated anomalies included lacrimal duct atresia, supernumerary nipples, syndactyly and auricular deformities. The inheritance of this abnormality was consistent with that of an autosomal dominant trait. The relationship between this and similar syndromes is discussed.     

Familial craniosynostosis, anal anomalies, and porokeratosis: CAP syndrome

We report on the occurrence of coronal craniosynostosis, anal anomalies, and porokeratosis in two male sibs. A third male sib was phenotypically normal as were the parents. The occurrence of these three clinical features has, to our knowledge, not been reported before. Cutaneous or anal anomalies or both have been reported in a number of syndromes associated with craniosynostosis, including Crouzon, Pfeiffer, Apert, and Beare-Stevenson syndromes. These syndromes are associated with mutations in the fibroblast growth factor receptor genes FGFR1, FGFR2, and FGFR3. They are inherited in an autosomal dominant fashion. In contrast, the cases we report do not carry any of the common FGFR mutations and the pedigree suggests autosomal or X linked recessive inheritance.     

Congenital abnormalities associated with limb deficiency defects: a population study based on cases from the Hungarian Congenital Malformation Registry (1975-1984)

Limb deficiency defects (LD) occurring among 1,575,904 births in Hungary during 1975-1984 were reviewed. The overall birth prevalence of LD was 1 in 1,816. This paper discusses the nature and distribution of the limb and other defects in the 275 (32%) children who had structural malformations in other systems. Two main forms of classification were used: morphologic and causal. Additional malformations were most commonly seen in infants with amelia, rudimentary limb (RL), radial/tibial (RT), intercalary or central axis (CA) LD and rarely in those with terminal transverse (TT) or ulnar/fibular (UF) defects. Upper limbs (81%) were involved significantly more often than lower limbs (42%) and there were more right-sided defects (83% vs. 71%) due to an excess of right arm involvement especially with radial ray and split hand anomalies. Single limb involvement was relatively common with amelia (88%), UF (82%), RT (50%), and TT (50%) defects. With other LD, multimelic involvement was more characteristic. This was usually symmetric with intercalary and RL defects but asymmetric with CA anomalies and digital deficiencies (DD). From a causal perspective, 17% of cases had genetic disorders, 52% had recognized associations, anomalies, sequences, environmental causes or patterns of unknown origin, and 31% had unknown patterns of malformations. The commonest entities were amnion disruption sequence (16% of cases) and VACTERL association (8%). Both of these disorders showed unusual temporal distribution. As anticipated, patterns of malformations differed with the type of LD. Amelia and digital amputations were often seen with body wall defects, atypical anencephaly or encephalocele, and cleft lip reflecting amnion disruption. Rudimentary limb was seen with anencephaly, omphalocele, renal agenesis, aberrant genitalia, and imperforate anus, reflecting defects of blastogenesis including the cloacal exstrophy and caudal regression sequences and Schisis association. Radial/tibial defects were associated with different patterns depending on whether the limb defects were unilateral or bilateral. Unilateral defects occurred with anomalies suggesting VACTERL association or the facio-auriculo-vertebral anomaly, while bilateral defects occurred more often in genetic or potentially genetic disorders including VACTERL with hydrocephalus. Central axis defects showed three main patterns of association: one reflecting the ectrodactyly-ectodermal dysplasia-clefting syndrome; one with tongue anomalies representing a variant of oro-mandibular-limb (Hanhart) anomaly, and the last with hydronephrosis indicating a group of "acro-renal" syndromes. Strong associations with other anomalies were not seen in the groups with TT, UF, or intercalary defects.     

New syndrome: autosomal dominant microcephaly and radio-ulnar synostosis

To date, the combination of microcephaly and radio-ulnar synostosis has not been recognized as a distinct clinical and genetic entity. We report on 4 familial cases with this previously undescribed combination of defects, showing autosomal dominant inheritance (Fig. 1).     

Thyroiditis and thyroid cancer

We studied a patient with microcephaly, short stature, type B brachydactyly, nail dysplasia, skeletal anomalies, and mental retardation. The mother of the propositus has brachydactyly of thumbs and a similar physiognomy without mental retardation. This appears to be another observation of the Tonoki syndrome, a distinct autosomal dominant or X-linked clinical entity.     

Letrozole, a new oral non-steroidal aromastase inhibitor in treating postmenopausal patients with advanced breast cancer. A pilot study

Chromosome analysis was performed in 160 patients with cryptorchidism. Chromosomal anomalies were found in 7 patients (4.4%). The incidence of chromosomal abnormalities was not significantly different between patients with bilateral or unilateral cryptorchidism. Of 7 patients, 1 had sex chromosomal aberration, 2 had marker chromosome and 4 had autosomal anomalies. Additional congenital anomalies were observed in 1 with sex chromosomal aberration, 2 with marker chromosome and 2 with autosomal anomaly. These facts indicate that we had better perform chromosome analysis in all patients with bilateral or unilateral cryptorchidism.     

Autosomal dominant hereditary atrial septal defect with heart conduction defects and mitral valve insufficiency

An autosomal dominant inherited ASD with conduction defects in one family is described. 6 members of 4 generations were fallen ill. In 4 patients the diagnosis was made clinically, in 2 sisters the diagnosis was confirmed by operation. Moreover, the last 2 patients had a mitral insufficiency--probably congenital. The ecg-findings of 4 patients additionally showed conduction defects in form of AV-and bundle branch blocks.     

Cervical vertebral fusion (Klippel-Feil) syndrome with consanguineous parents

We describe a female infant with the cervical vertebral fusion (Klippel-Feil) syndrome whom we recognized at birth because of her short neck, restriction of cervical movement, and low posterior hairline. X-ray examination showed anomalies of C1, and between C2-3 and C3-4; thus, we classified her as type II, with variable cervical fusion. At 24 months she was small and manifested hearing deficiency. The mother and father were consanguineous with five common ancestors four generations ago, which resulted in a coefficient of inbreeding equivalent to a second cousin relationship. The parents and grandparents were phenotypically normal, and the parents were radiologically normal. This form of the syndrome has previously been said to be autosomal dominant. Our conclusion of determination by a single autosomal recessive gene is evidence of genetic heterogeneity.     

The type II collagenopathies: a spectrum of chondrodysplasias

With the application of molecular techniques the aetiopathogenesis of skeletal dysplasias is gradually elucidated. Recent advances show that some bone dysplasias result from defects in the biosynthesis of type II (cartilage) collagen. Clinical entities caused by mutations in the COL2A1 gene coding for type II collagen comprise achondrogenesis II, hypochondrogenesis, spondyloepiphyseal dysplasia congenita, Kniest dysplasia, Stickler arthroophthalmopathy and mild dominant spondyloarthropathy. The mutations are expressed in the heterozygous state, and inheritance of type II collagenopathies is autosomal dominant. The wide range of clinical manifestations is not well understood but characterization of the basic defect may provide clues to establish specific genotype-phenotype correlations.     

Lectin cytochemistry of the rabbit conjunctiva and lacrimal sac

The Branchio-oto-renal (BOR) syndrome is an autosomal dominant disorder characterized by branchial clefts, preauricular sinuses, hearing loss, and renal anomalies. Recent studies have shown that mutations in EYA1 are associated with BOR. However, the underlying molecular mechanisms by which mutations in the EYA1 gene cause BOR syndrome are unknown. We have investigated 12 unrelated Caucasian families for mutations by heteroduplex analysis and direct sequencing of products from the polymerase chain reaction. In this study, we identified two novel frameshift deletions and a single base substitution that introduces a stop codon mutation in the C-terminal region of the EYA1 gene. No obvious relationships were observed between the nature of the mutations and the variable clinical features associated with BOR syndrome.     

Severe renal dysgenesis produced by a dominant gene

A woman with the autosomal dominant syndrome of preauricular pits, cervical fistulae, and partial deafness gave birth to two children with preauricular pits and severe renal dysgenesis. The facies had some features of the Potter facies of renal agenesis. One child died soon after birth because of pneumothorax and immature development of the lungs. We suggest that all infants with renal agenesis or dysgenesis be examined for preauricular pits because of the high recurrence risk of renal anomalies in families with this syndrome.     

Solitary maxillary central incisor in the midline associated with systemic disorders

A single maxillary central incisor in the midline is a rare developmental anomaly. The appearance of a single incisor in place of two teeth may occur as an isolated dental finding that can be related to fusion of two neighboring teeth or to agenesis of a tooth germ. However, the condition has also been reported to occur in association with autosomal dominant holoprosencephaly, growth retardation, and midline developmental defects. This article reports on other systemic defects that can be found in association with a single maxillary central incisor.     

Developmental instability and cerebral lateralization

On the basis of prior studies of handedness, it was predicted that variations from modal asymmetry scores on cognitive tasks, in either direction from the mean, would be associated with an elevated incidence of classic markers of developmental instability (minor physical anomalies and fluctuating anatomic asymmetries). University students (N = 146) were administered 4 tasks that typically reveal functional asymmetries: the fused rhymed words dichotic listening task, the line bisection task, the chimeric faces task, and the cartoon faces task. A composite measure of developmental instability was computed from minor physical anomalies and fluctuating asymmetries. Participants with greater evidence of developmental instability had more atypical lateralization scores, deviating more from the sample mean, in either direction. Directional asymmetries were unrelated to developmental instability. These results suggest that developmental instability influences variation in the lateralization of cognitive skills as well as handedness.     

Effects of ionizing radiation (neutrons/gamma rays) on plasma lipids and lipoproteins in rats

Two closely related genes, the presenilins ( PS ), located at chromosomes 14q24.3 and 1q42.1, have been identified for autosomal dominant Alzheimer disease (AD) with onset age below 65 years (presenile AD). We performed a systematic mutation analysis of all coding and 5'-non-coding exons of PS -1 and PS -2 in a population-based epidemiological series of 101 unrelated familial and sporadic presenile AD cases. The familial cases included 10 patients of autosomal dominant AD families sampled for linkage analysis studies. In all patients mutations in the amyloid precursor protein gene ( APP ) had previously been excluded. Four different PS -1 missense mutations were identified in six familial cases, two of which where autosomal dominant cases. Three mutations resulted in onset ages above 55 years, with one segregating in an autosomal dominant family with mean onset age 64 years (range 50-78 years). One PS -2 mutation was identified in a sporadic case with onset age 62 years. Our mutation data provided estimates for PS -1 and PS -2 mutation frequencies in presenile AD of 6 and 1% respectively. When family history was accounted for mutation frequencies for PS -1 were 9% in familial cases and 18% in autosomal dominant cases. Further, polymorphisms were detected in the promoter and the 5'-non-coding region of PS -1 and in intronic and exonic sequences of PS -2 that will be useful in genetic association studies.     

Facial affect recognition in criminal psychopaths.

Prior studies provide consistent evidence of deficits for psychopaths in processing verbal emotional material but are inconsistent regarding nonverbal emotional material. To examine whether psychopaths exhibit general versus specific deficits in nonverbal emotional processing, 34 psychopaths and 33 nonpsychopaths identified with Hare's (R. D. Hare, 1991) Psychopathy Checklist-Revised were asked to complete a facial affect recognition test. Slides of prototypic facial expressions were presented. Three hypotheses regarding hemispheric lateralization anomalies in psychopaths were also tested (right-hemisphere dysfunction, reduced lateralization, and reversed lateralization). Psychopaths were less accurate than nonpsychopaths at classifying facial affect under conditions promoting reliance on right-hemisphere resources and displayed a specific deficit in classifying disgust. These findings demonstrate that psychopaths exhibit specific deficits in nonverbal emotional processing. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

How to appoint a senior house officer

A considerable body of evidence exists to suggest that genes play a dominant role in the etiology of the dental anomalies reviewed. It has been postulated that some kind of genetically controlled interrelationship may exist for some of these coincidental dental anomalies, as evidenced by their frequency of association. It has also been speculated that a "common genetic defect" may give rise to different phenotypic manifestations, including missing, malformed, and even ectopic and malpositioned teeth. The maxillary teeth that develop in the critical marginal areas of the dental lamina, namely the lateral incisors, canines and second premolars, seem most susceptible. Such dental anomalies may be symptoms of an inheritable developmental disturbance of tooth structures. Knowing that these dental anomalies can be inherited, a familial history and early clinical or radiographic detection of one anomaly, could alert parents and clinicians to the high likelihood of detection of other defects in the same individual and similar defects in other family members. Early diagnosis is important so that interceptive pediatric and orthodontic opportunities in relation to missing, malformed and ectopically erupting teeth are not overlooked. Further family studies are necessary to reveal the mode of inheritance of some of these dental anomalies and twin studies comparing monozygous and dizygous twins would enable an estimation of the extent of their inheritance.     

Cochlear implants

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.     

Effects on intraocular pressure and aqueous flow of various dose regimens of latanoprost in human eyes

A "new" syndrome was identified by McPherson and Clemens [1996: Am J Med Genet 62:58-60] in a brother and sister with bilateral cleft lip and palate, hypertelorism, flat facial profile, flat occiput, and complex heart defects. The brother also had a bilobed tongue and the sister had malrotation of the intestine and bifid thumbs. We describe three brothers with similar anomalies apart from the bilobed tongue, malrotation of the intestine, and bifid thumbs. McPherson and Clemens [1996: Am J Med Genet 62:58-60] suggested autosomal recessive inheritance. Our observation of three affected brothers also raises the possibility of X-linked recessive inheritance.     

Alagille syndrome: family studies

Alagille syndrome (AGS) is one of the major forms of chronic liver disease in childhood with severe morbidity and a mortality of 10 to 20%. It is characterised by cholestasis of variable severity with paucity of interlobular bile ducts and anomalies of the cardiovascular system, skeleton, eyes, and face. Previous studies suggest a wide variation in the expression of the disease and a high incidence of new mutations. To determine more accurately the rate of new mutations and to develop criteria for detecting the disorder in parents we systematically investigated parents in 14 families with an affected child. Clinical examination was supplemented by liver function tests, echocardiography, radiographic examination of the spine and forearm, ophthalmological assessment, and chromosome analysis. Six parents had typical anomalies in two or more systems pointing to the presence of autosomal dominant inheritance. Systematic screening of parents for the features defined in this study should improve the accuracy of genetic counselling.