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We report on tetramelic monodactyly with autosomal dominant inheritance. The propositus and all affected relatives had only digital malformations as determined by physical examination or history. Since it could not be determined that the involved digits of the propositus or relatives were fifth fingers and toes, we conclude this to be the first report of this type of hand and foot malformation with autosomal dominant inheritance.
Sixty-three families with dominantly inherited Charcot-Marie-Tooth (CMT) neuropathies including 730 subjects (total) from which 356 affected were studied clinically, electrophysiologically (MNCVs and EMGs), by genetic linkage, and screened for DNA duplication. Thirty-eight families (60.3%) were type 1A (demyelinating CMT mapped on chromosome 17). DNA duplication was present in 36 families (94.8% of CMT1A families). One CMT1A family (2.6%) showed no duplication but suggested genetic linkage with markers of chromosome 17. One CMT1A family (2.6%) revealed nonduplication in some affected members and duplication in other affected members. The disease in that family segregated with the same chromosome 17 markers regardless of duplication status. The other CMT families with dominant inheritance but without duplication included one family with CMT1B (demyelinating CMT mapped on chromosome 1) (1.6%), 14 families with CMT2 axonal neuropathy (22.2%), and 10 families with X-linked dominant CMT (15.9%).
Spinocerebellar ataxia type 1 (SCA 1) is an autosomal dominant disorder characterized by neurodegeneration of the cerebellum, spinal cord and brainstem. This neurodegeneration disease is associated with expansion of unstable CAG repeats within the coding region of the gene. We are conducting a local survey of the normal population and candidate patients to analyze the CAG repeats in SCA 1 gene. So far, we have collected peripheral blood from 78 normal individuals and 10 patients with dominant inherited ataxia disorders, and assayed the SCA1 CAG trinucleotide repeat using genomic polymerase chain reaction (PCR). Even though no local SCA 1 patients have been identified, we have established the distributions of the CAG repeat units of SCA 1 gene in the normal population in Taiwan. The normal range of CAG repeats is from 22 to 33 repeats, with the most common being 30 repeats. The range is relatively narrow compared to that reported for other ethnic groups. In addition, direct genomic PCR analysis of the SCA 1 gene from villous DNA has been successful in our laboratory. Screening of SCA 1 patients from patients with dominant inherited ataxia is currently underway in our laboratory. Here, we demonstrate that our molecular analysis technique makes possible the quick and accurate diagnosis of SCA1 patients and prenatal screening for SCA 1 families.
The autosomal dominantly inherited spinocerebellar ataxias (SCAs) are a heterogeneous group of disorders. To date, three loci have been identified: the SCA1 locus (on chr 6p), the SCA2 locus (on chr 12q), and more recently a Machado-Joseph disease (MJD) locus (on chr 14q). We have studied one large French-Canadian kindred with four generations of living affected individuals segregating an autosomal dominant form of SCA. Linkage analysis using anonymous DNA markers that flank the three previously described loci significantly exclude the French-Canadian kindred from the SCA1, SCA2, and MJD loci. Therefore, a fourth, still unmapped SCA locus remains to be identified. In addition, the unique clinical phenotype present in all affected individuals of the French-Canadian kindred might be characteristic of this still unmapped SCA locus.
Autosomal dominantly inherited isolated GH deficiency is caused by mutations of GH-1 that alter the normal structure of GH. We studied 16 familial cases and 1 sporadic case with isolated GH deficiency type II from 1 Dutch and 4 German families by direct sequencing of PCR-amplified genomic DNA and ectopic transcript analysis of lymphocyte mRNA. In addition, the clinical data of the affected individuals were analyzed. Two previously reported mutations and 1 novel splice site mutation in intron III of GH-1 (+1G to C and +1G to A; new, +2T to C) were detected that cause exon 3 skipping. We also discovered a novel G6191 to T missense mutation in exon 4 of GH-1 that changes valine 110, which is highly conserved in mammalian and several nonmammalian GH, to phenylalanine. Splicing of the primary RNA transcript was not affected by this mutation, which is very likely to alter the normal GH structure at the protein level. The onset of growth failure was earlier, and the degree was more severe in affected children with GH-1 splice site mutations compared with those in children with the GH-1 missense mutation. In addition, the severity of the phenotype was variable, even within the same family. The age at diagnosis was between 0.8-9.6 yr (median, 5.1 yr); height at diagnosis was between -2.5 and -8.1 SD score (median, -4.0). Most of the children were lean at diagnosis, with a body mass index ranging from -1.7 to +3.3 SD score (median, -0.5). The 5 affected adults had final heights between -1.8 and -4.5 SD score (median, -3.6), centripetal obesity, and muscular hypotrophy. Before therapy, IGF-I and IGF-binding protein-3 serum levels of all affected children were severely diminished (<<5th percentiles for age). The maximum GH peak in a total of 25 stimulation tests was between 0.1-5.0 microg/liter (median, 0.9), indicating severe GH deficiency. The height of the adenohypophysis studied by magnetic resonance imaging was normal in 2 affected children and mildly decreased in 2 others. Substitution with GH resulted in good catch-up growth in all treated children. Children with severe GH and IGF-I deficiencies, but normal size of the adenohypophysis should be examined for GH-1 splice site and missense mutations. The observed discrepancy between the very homogeneous hormone data proving severe GH and IGF-I deficiencies and the high variability of growth failure even within the same family suggests that the onset and predominance of GH-dependent growth during infancy are individually different and modified by as yet unknown factors.
Dominantly inherited isolated hyperparathyroidism (DIIH) is rare in childhood. It may be the first biochemical abnormality in the multiple endocrine neoplasia type I (MEN I) and type II (MEN II) syndromes. Its clinical course is usually asymptomatic or of low morbidity. Radiographic examination is most often normal. We describe six members of a family with distinctive phenotype and DIIH. Limited systemic symptoms and severe radiographic osteitis fibrosa cystica were further unusual features in this family. The diagnosis of DIIH was made only after a 9-year-old girl developed hypercalcaemic crisis after a pathological femoral fracture. Distinctive phenotype, unusual clinical course and unparalleled radiographic changes suggest a not yet described syndromic association.
Molecular genetic studies in the past decade have demonstrated the enormous genetic heterogeneity among the dominantly inherited ataxias. Mutations at several distinct loci give rise to the progressive dominant ataxias and at least 2 different mutations cause episodic ataxias with dominant inheritance. The well-established genotypes for progressive dominant ataxias have all involved expansions of repeated CAG sequences. Clinically these patients present with progressive cerebellar deficits as well as signs relating to pathology in other neural systems in a variable fashion. Some of these other signs serve as diagnostic clues to the underlying genotype, but the identification of the genotype from the clinical phenotype alone is usually difficult. The CAG expansions involved usually are unstable with intergenerational expansions as well as contractions of the repeat size. Phenotypic features such as age of onset and to a lesser extent disease progression rate and the presence of specific clinical signs depend on the CAG repeat size. Identification of the mutations has allowed precise genotypic diagnosis in several families allowing more accurate genetic counseling, including predictive testing of at risk individuals when sought. Also, increasing information about the gene products and their abnormal distributions in disease brain is rapidly giving rise to rational ideas about the pathogenesis of neuronal degeneration in these diseases and raising hope for meaningful treatment strategies.
The dominantly inherited ataxias are characterized both by phenotypic variability (phenotypic heterogeneity) within the same genotype and overlapping phenotypes from different genotypes (genotypic heterogeneity). Therefore it is important to characterize specific clinical-neuropathologic phenotypes as precisely as possible at the genetic level. We describe a family with dominantly inherited ataxia of late adult onset with relatively "pure" cerebellar signs. Neuropathologic examination in two individuals from this family revealed findings consistent with cerebello-olivary atrophy, suggesting that this neuropathologic phenotype many run true within f families. Mutations at the spinocerebellar ataxia-I, Machado-Joseph disease, and dentatorubropallidoluysian atrophy loci were excluded by direct DNA analysis on the leukocytes of one living affected member. Thus we provide evidence that these mutations are not responsible for this particular phenotype of dominantly inherited ataxia.
A family is described with apparent dominantly inherited complete cleft of the soft palate. The complexity of the genetics of oral clefts is emphasized. The inheritance of oral clefts is complex. Different modes of inheritance have been reported for clefts both simple and in syndromes (Gorlin et al., 1971), but the majority of cases of nonsyndromal clefts appears to have a low, yet significant, genetic component (Fraser et al., 1974). This report describes a family with cleft of the soft palate which appears to follow a dominant pattern of inheritance. To our knowledge this is the first reported instance of dominantly inherited cleft palate.
The data presented here show that normal skin fibroblasts from individuals with dominantly inherited retinoblastoma, polyposis coli, and nevoid basal cell carcinoma (predisposed cells), grown in the presence of [35S]methionine, contain more than 2.5-fold [35S]methionine-labeled actin as compared to normal fibroblasts from individuals without a prior history of predisposition to cancer (normal cells). The rate of incorporation of [35S]methionine into actin in predisposed cells is rapid and is not correlated with an increase in the total protein and actin contents of the cells, in the intracellular pool size of [35S]methionine, or in the synthesis of beta-actin-specific mRNA, as compared to normal cells. However, the half-life of actin in predisposed cells is less than 5 h, as compared to at least 48 h for normal cells. The significantly reduced half-life of actin and an increased incorporation of [35S]methionine specifically into actin in all predisposed cells studied may represent an inherited biochemical defect which leads to cytoskeletal disorganization previously observed in these cells. It can be speculated that the altered properties of actin in predisposed cells may be caused by the same genetic lesion(s) which is responsible for the induction of dominantly inherited cancers.
OBJECTIVE: To describe the clinical and pathologic features of a new dominantly inherited audiovestibular syndrome. METHODS: History, examination, and audiometric testing in the proband, brother, and son; quantitative rotational testing in the proband and son; histopathology of the cochlea and vestibular labyrinth in the proband; sequencing candidate genes COCH and MYO7A in the brother and son. RESULTS: Affected family members developed slowly progressive hearing loss beginning in their late 30s and progressive imbalance in their early 70s. Three of four affected had brief (minutes) episodes of vertigo typically occurring a few times per year. Auditory and vestibular function testing documented a slowly progressive loss of auditory and vestibular function. Postmortem examination showed a loss of hair cells in the cochlea and vestibular receptor organs. There were no cellular infiltrates or acidophilic deposits. No mutations were found in the COCH or MYO7A genes. CONCLUSIONS: This dominantly inherited audiovestibular syndrome results in a selective loss of hair cells in the auditory and vestibular end organs. Finding the causative gene could have important implications for understanding the pathophysiology of presbycusis and dysequilibrium of aging.
We report here a pedigree of basal ganglia calcification with autosomal dominant inheritance. Following a traffic accident, the proband, a seven-year-old boy, was incidentally noted by cranial computed tomography to have calcification of the bilateral basal ganglia. Six affected members spanning three generations, aged from 5 to 57 years, also had calcification in various degree. None of them had clinical symptoms. There were neither abnormal data nor any characteristic physical symptoms associated with parathyroid disorders. There was no consanguinity. Both sexes were affected and the sex ratio was 0.5. Male-to-male transmission was documented. These findings suggested an autosomal dominant trait. The clinico-radiological findings in our pedigree were different from those of the previously reported cases of familial basal ganglia calcification, that infants were affected and that clinical symptoms were absent in elderly patients. These facts suggest our pedigree is a new type of familial basal ganglia calcification with autosomal dominant inheritance.
Previous familial cases of recurrent heterotaxia have suggested an autosomal recessive or exceptionally X-linked or dominant inheritance. Here, we report six families including 18 affected members, consistent with autosomal dominant inheritance. Among these, four families have more than one case of heterotaxia. The other two families have one member with heterotaxia and at least one other affected member with an "isolated" heart malformation, which could be considered as a mild form of heterotaxia. In five families, the disorder is transmitted through two or three generations. In one family, the patients are of the same generation but are linked to each other by obligate carriers. We suggest a rule to classify these families with heart malformations, according to the etiologic factor involved (rule of precocity). This rule might be useful to other disruptions of morphogenetic processes.
To facilitate the study of cerebellar degenerative disorders, improved clinical diagnosis is needed. Cerebello-olivary atrophy is pathologically distinct, but until now its diagnosis has been thought to require postmortem examination. This condition was considered as a possible diagnosis in two patients from different families with dominantly inherited ataxia. The affected members of each family demonstrated a stereotyped, progressive, "pure" cerebellar syndrome, which began with gait ataxia followed years later by dysarthria and limb ataxia. The autopsy findings for the first patient's father revealed paleocerebellar and olivary atrophy, characteristic of cerebello-olivary atrophy. Magnetic resonance imaging (MRI) of the brain of both patients revealed medullary, vermian and, to a lesser extent, cerebellar hemispheric atrophy but a normal pons. Dominantly inherited cerebello-olivary atrophy was diagnosed in both patients. Characteristic clinical and MRI features thus permit a confident clinical diagnosis of dominantly inherited cerebello-olivary atrophy. Recognition of this entity during life should advance the classification of cerebellar degenerative disorders.
A mother and daughter with suspected dominantly inherited, early-onset, non-progressive cerebellar ataxia syndrome have been reported. A review of the literature and the clinical features of the present cases revealed the nosologic features of this rare disorder, possibly dominant inheritance, floppiness and delayed milestones preceding early-onset mild cerebellar ataxia, non-progressive clinical course, retained or even brisk tendon reflexes without pyramidal tract involvement, normal or slightly delayed intelligence, and occasional nystagmus. Neuroimaging reveals selective involvement of the cerebellum, which is prominent in the vermis and the anterior part of the hemispheres.
Holoprosencephaly (HPC) may be an isolated trait or may be associated with other craniofacial defects. As an isolated trait, HPC has been reported to be inherited as an autosomal recessive, while autosomal dominant inheritance has been reported for sequences or syndromes in which HPC occurs. This paper presents a family in which several people have variable combinations of craniofacial defects. The most severely affected relatives have HPC, while others have only mild facial dysmorphia and decreased bitemporal diameters. One relative has a single central incisor in the maxilla. The pattern of defects in this family is inherited as an autosomal dominant. Other families with the reported pattern of defects, including single central incisors as minimal manifestations, are cited. Because HPC is found only occasionally in the pattern of defects, the term DeMyer Sequence is proposed as a more appropriate designator than the more commonly used Holoprosencephaly Sequence.
Most patients with dominantly inherited osteogenesis imperfecta have blue sclerae and relatively mild symptoms. However, in a small group of families the patients have normal sclerae and this disorder has been classified as Type 4 osteogenesis imperfecta. This paper reports the clinical and radiographical features of 48 patients from 16 families with Type 4 osteogenesis imperfecta and compares the findings with those of the classical disorder with blue sclerae (Type 1 osteogenesis imperfecta). The two types are similar in usually causing a mild disease but with a wide range of severity, and in both types the rate of fracture declines in adolescence. There are, however, some significant differences apart from the colour of the sclerae. In Type 4 the first fracture more commonly occurs at birth, dentinogenesis imperfecta is more frequent than in Type 1 and bruising and nose-bleeds are less common. As in Type 1, the radiographic appearances of the bones may be normal. It is important that Type 4 osteogenesis imperfecta should be recognised because of the need for competent genetic counselling, because the management may be different from that appropriate for Type 1 and because it may be mistaken for idiopathic juvenile osteoporosis or child abuse.
Anterior sacral meningoceles and presacral teratomas are rare congenital malformations associated with a sacrococcygeal bony defect. The inheritance of anterior sacral meningoceles has been proposed to be X-linked dominant, whereas presacral teratomas have been reported to be autosomal dominantly inherited. Anterior meningoceles and teratomas may occur independently or in combination. We report a family in whom at least 11 individuals of three generations have partial sacral agenesis and have had either anterior sacral meningoceles, teratomas, or both. Male-to-male transmission has been documented. Although the existing literature differentiates the inheritance of anterior meningoceles from that of the teratomas, the pleiotropic effects of the gene causing these anterior sacral defects in this family is evident and is consistent with autosomal-dominant inheritance.