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A case of osteopetrosis complicated by chronic osteomyelitis of the mandible, pathological fractures, pancytopenia and splenomegaly is presented. Family studies revealed a dominantly inherited pattern.
Sporadic occurrences of X-linked disorders can give insights into mutagenesis in man. In a case of sporadic hemophilia, associated with a partial deletion of the factor VIII gene, an unexpected inheritance pattern of gene rearrangements was observed. The factor VIII gene was found to be partially duplicated in the hemophiliac's mother. A pedigree analysis indicates that the mother has contributed both aberrant genes as well as the normal gene to her offspring. One simple model for the evolution of the deletion in this family is that the duplication is the precursor to the deletion.
Twelve cases of diffuse cystic angiomatosis of bone are presented in a family over four generations. The inheritance pattern of the disease appears to be one of an autosomal dominant distribution with no skipped generations and equal sex distribution. Individuals affected are clinically asymptomatic. All blood parameters are normal. Roentgenographically, the lesion occurs throughout the length of long bones and is osteolytic, with a thin sclerotic rim. The cortex of the bone is rarely involved and shows no periosteal reaction. Growth plate closure and remodeling are unaffected. The natural history is of increasing sclerosis, resulting in complete obliteration of the cyst with irregular reactive trabeculations. Although it resembles more serious conditions, the condition can be diagnosed clinically and radiographically, making invasive tests and treatment unnecessary.
Many genetic traits have complex modes of inheritance; they may exhibit incomplete or age-dependent penetrance or fail to show any clear Mendelian inheritance pattern. As primary linkage maps for the human genome near completion, it is becoming increasingly possible to map these traits. Prior to undertaking a linkage study, it is important to consider whether the pedigrees available for the proposed study are likely to provide sufficient information to demonstrate linkage, assuming a linked marker is tested. In the current paper, we describe a computer simulation method to estimate the power of a proposed study to detect linkage for a complex genetic trait, given a hypothesized genetic model for the trait. Our method simulates trait locus genotypes consistent with observed trait phenotypes, in such a way that the probability to detect linkage can be estimated by sample statistics of the maximum lod score distribution. The method uses terms available when calculating the likelihood of the trait phenotypes for the pedigree and is applicable to any trait determined by one or a few genetic loci; individual-specific environmental effects can also be dealt with. Our method provides an objective answer to the question, Will these pedigrees provide sufficient information to map this complex genetic trait?
A follow-up study of 1177 adult patients who had had atopic dermatitis (AD) (Groups 1 and 2) or respiratory allergy (Group 3) in childhood is reported. Patients who had had AD in childhood had received in-patient (Group 1) or out-patient treatment (Group 2) for their dermatitis. 183 patients in Group 1 and 162 in Group 2 were examined clinically. Further, 445 patients who had recently been treated for hand eczema at a department for occupational dermatoses were studied (Group 5). A group of 199 people who had no personal or family history of atopy served as controls (Group 4). The essential findings were as follows: The healing rate was lower (38%) in patients with severe (Group 1) than in those with moderate (60%) childhood dermatitis (Group 2). Although the healing rate was comparatively low in both groups, persistent eczema was in most cases of mild degree. The commonest localization of persistent dermatitis was the hands. The AD had developed earlier in patients who had had severe childhood dermatitis than in those whose childhood AD was moderate. Severe childhood AD was also associated with a significantly higher frequency of family history of atopy and associated respiratory allergy. The inheritance pattern was specific for the different types of atopic disease. A family history of AD was significantly commoner in people with AD than in people with respiratory allergy, and, conversely, people with a family history of respiratory allergy had developed asthma or allergic rhinitis rather than AD. The serum IgE level was raised in 45% and 26% of the clinically examined individuals in Groups 1 and 2, respectively. A comparatively large proportion of patients with persistent or recurrent dermatitis had normal IgE values. There was a strong correlation between the extent of persistent dermatitis and serum IgE levels. It is concluded that the serum IgE cannot be used to establish the diagnosis of atopic dermatitis. The number of contact sensitized people was greater in Group 2 (23%) than in Group 1 (17%). Occurrence of contact sensitivity, which was demonstrable in a total of 20% of the patch tested individuals from Groups 1 and 2, was not correlated to prevalence of healing at the time of examination. Fragrance-mix and balsam of Peru were the commonest contact sensitizers. People with a history of AD showed a higher incidence of recurrent (greater than 5 episodes per year) cold sores, upper respiratory infection, and herpes zoster than non-atopic controls.(ABSTRACT TRUNCATED AT 400 WORDS)
This article presents a detailed discussion of six genetic disorders with major cutaneous manifestations that might commonly be seen by the dermatologist or pediatrician. These include neurofibromatosis, tuberous sclerosis, xeroderma pigmentosum, incontinentia pigmenti, incontinentia pigmenti achromians, and Down's syndrome. The appearance of each disease at birth is described, and all manifestations of each entity are discussed in detail. Disorders with different inheritance patterns were chosen so that important genetic principles could be elucidated. The article concludes with a general discussion of genetic counseling, which draws upon the six genetic diseases for specific examples of important concepts.
We describe a family with typical epidermodysplasia verruciformis (EV) in which only male members are affected. Whereas none of the index patient's ten children have EV, four of eight grandsons born to his daughters have inherited the disorder. All are infected with human papillomavirus (HPV) 3 and HPV 8. The inheritance in this kindred most likely results from an X-linked recessive genetic defect. Since other kindreds have been described with autosomal inheritance, this novel inheritance pattern suggests that the persistent high clinical susceptibility to HPV infection characteristic of EV may result from defects in either of at least two different genetic loci, one of which may be located on the X chromosome.
A high incidence of 46,XX true hermaphroditism exists among southern African blacks. The gonadal distribution and clinical presentation of 38 patients are described. The aim of our study on 11 families with histologically proven XX true hermaphroditism was to determine whether a common genetic or environmental etiology could be identified. Pedigree analysis excluded the presence of a simple inheritance pattern, and no constant environmental factors could be implicated. Hybridization studies with Y chromosome--specific probes (pDP132, pDP61, pDP105, pDP31, pDP97, and pY431-HinfA) excluded the presence of a large portion of Yp in these patients. It is possible that smaller portions of the Y chromosome or one or more X-linked or autosomal mutations, either interacting and/or with incomplete penetrance, are present.
Foveomacular vitelliform degeneration, adult type (FVDAT) is a disciform, macular degeneration that is usually encountered in the fifth to seventh decade of life. It appears ophthalmoscopically similar to the vitelliform or "egg-yolk" stage of Best's disease (vitelliform degeneration), but shows no inheritance pattern. Electrooculographic (EOG) testing reveals a normal or only slightly reduced Arden ratio (light peak/dark trough). The prognosis is optimistic, as most patients retain reading vision throughout life. This case report describes an atypical case in which the signs and symptoms of FVDAT are not exactly those regularly seen. However, it does closely resemble the disease sufficiently to warrant this diagnosis.
Patients with microscopic hematuria are generally referred for urologic investigation. We describe 30 patients with normal renal function referred to our clinic during the years 1970 through 1987 for evaluation of hematuria, usually microscopic, in whom prior urologic and radiological studies had failed to determine the cause of bleeding. Urinary sediment from the patients and first-degree relatives revealed hemoglobin and red blood cell casts; the inheritance pattern was consistent with autosomal dominant transmission. During follow-up for up to 18 years, renal function remained normal, thus confirming the diagnosis of benign familial hematuria. Immunoglobulin A nephropathy and Alport's syndrome were less common than benign familial hematuria and could be differentiated from it by history, physical examination, and routine laboratory testing. Since benign familial hematuria is a common disorder in adults with hematuria and normal renal function, urinary sediment from patients and family members should be examined before extensive urologic and radiological procedures are performed.
A patient had a unique mechanobullous disease (Bart's syndrome). The characteristic congenital localized skin defects, trauma-induced erosions, and nail deformities are present. The inheritance pattern appears to be autosomal dominant but, as in this report, isolated cases have been recognized. In a review of the other mechanobullous diseases, Bart's syndrome appears to present a distinctive clinical picture and course and has a favorable prognosis. The progressive spontaneous improvement emphasizes the importance of early recognition and conservative treatment.
We have constructed a primary genetic map spanning most of human chromosome 13. A total of 14 polymorphic DNA sequences and one protein polymorphism provided, after construction of haplotypes, seven markers for the long arm of this chromosome. A panel of cell lines from 30 three-generation families with large sibship size served as the sample set. Pairwise cross analysis of the inheritance patterns of the marker loci established that six of the seven loci constituted a single linkage group; the seventh was localized by physical means. Significantly higher recombination rates were found in female than in male meioses in several intervals. The six closely linked loci were arranged, based on the two-point data, in three clusters, and a number of alternate gene orders were excluded by three-point linkage tests. The order and spacing of the individual loci were refined by linkage analyses that considered five loci jointly.
When arylsulfatase C, a microsomal membrane-bound enzyme, is assayed with its natural substrates, the 3-beta-hydroxysteroid sulfates, it is also known as steroid sulfatase. Whether arylsulfatase C and steroid sulfatase are identical enzymes or not, however, has long been disputed. We now report that two electrophoretic variants of arylsulfatase C occur in normal human fibroblasts: one has a single anodic band of activity, "s," and the other has an additional faster migrating band, "f". The two types, s and "f + s", occur in cells from either sex. When fibroblast strains with the f + s forms of arylsulfatase C were cloned, two types of primary clones were always obtained: s and f + s. A single f band was never seen. When these primary clones were subcloned, however, the arylsulfatase C phenotype remained unchanged: primary s clones gave rise to s subclones and f + s clones to f + s subclones only. Therefore, these forms were clonal in origin and demonstrated a novel inheritance pattern in human cultured cells. The appearance of increasing amounts of the f band was correlated with up to 4-fold increase of arylsulfatase C activity, whereas the steroid sulfatase activity remained constant, thus demonstrating that arylsulfatase C was not identical with steroid sulfatase activity. Polyclonal antibodies raised against the s form immunoprecipitated activities of the s form of arylsulfatase C and steroid sulfatase but not the f form of arylsulfatase C. Therefore, we conclude that only the s form of arylsulfatase C is immunologically related to steroid sulfatase so that arylsulfatase C per se is not necessarily identical with steroid sulfatase. In addition, a novel form of genetic heterogeneity of isozymes in human fibroblasts is demonstrated.
Ileal samples from 242 pigs, collected at 3 Michigan slaughterhouses, were studied to determine the prevalence of intestinal receptors for K99-positive Escherichia coli. A brush border adhesion test was used to identify the receptors. Of the 242 samples examined, receptors were demonstrated in 230 (95%). After storage of brush border preparations at 4 C, bacterial aggregates lacking identifiable brush border fragments were present in samples tested for adhesion, indicating that K99 receptors may be released from brush border membranes. Seemingly, most, if not all, pigs have intestinal receptors for K99 pili, and an inheritance pattern similar to that observed for K88 receptors probably does not exist for K99 receptors.
In this review, we have attempted to classify the genetically transmitted, generalized disorders of cornification according to available genetic, clinical, and biochemical data (Table 1). Admittedly, the list is long and sure to be lengthened, but this manner of delineation is required to uncover the underlying biochemical causes of the DOC. Grouping diseases according to artificial and outmoded standards clearly impedes this effort, as well as undermines a scholarly approach to patients, because important information about disease expression, differences in inheritance patterns, and subtle, but important, differences in responsiveness to therapy may be obscured by classification of an entity on the basis of overly simplified diagnostic criteria. Thus, clinicians should be wary of classification schemes based solely upon phenotypic similarities, because they may not be based upon valid genetic or biochemical criteria. Clearly, the classification offered in this article must be considered provisional, and it should be modified as new information is acquired. Despite our desire to recognize and codify distinct genetic disorders, this has not been possible in all cases, such as in DOC 17 (chondrodysplasia punctata syndromes), which almost certainly includes more than one genetic entity.
A family with hereditary emotional hyperhidrosis is described. The inheritance pattern is autosomal dominant. A simple quantitative palmar sweat test was used to objectively confirm historical data. Of two family members tested, both had a marked decrease in palmar sweat secretion during administration of diltiazem, a calcium-channel blocker. Additional studies in a large group of patients are needed to extend this observation.
Idiopathic congestive (dilated) cardiomyopathy with an autosomal dominant inheritance pattern affected eight individuals (four males) in three of four generations of a 63-member kindred of non-consanguineous ancestry. Average age at presentation was 39.5 years (range 32-54). A malignant course with relentless cardiac failure occurred in six cases; one member who died suddenly had been asymptomatic and the eighth is alive but in cardiac failure 44 months after initial presentation. Average time course to death from onset of symptoms suggestive of cardiomyopathy in six affected members was 16 months (range three to 55 months). In three cases, sudden death occurred and was the mode of presentation in one. Myocardial histological examination, available from three cases, showed variation in muscle fibre size with interstitial fibrosis. Forty-two family members in two generations including the propositus (19 males), age range three to 46 years (mean 17.9) when first assessed were prospectively evaluated. Two had basal systolic murmurs and two had right bundle branch block. Excluding the propositus, three members showed Doppler echocardiographic evidence of regurgitation without associated structural anomalies and three had valve prolapse with Doppler echocardiographic evidence of regurgitation. Cardiac chamber dimensions were within normal limits in all members and no cardiac arrhythmias were seen. Among the various therapeutic approaches now available cardiac transplantation, especially in younger patients with unremitting disease, is a potential option which should be considered.
Classification of central defect of the hand includes three general categories--Type I (typical), Type II (atypical), and Type III (two, three, and four digit hand). These three types of central defect have one common denominator--central metacarpal deficiency or absence. Otherwise, these three distinct types differ completely in inheritance pattern, characteristic features, bilaterality, and functional management. Functional management of the Type I central defect combines release of the tethered thumb metacarpal from its adduction contracture and simultaneous closure of the cleft using that redundant skin to fabricate a physiologic thumb-index web. Type II reconstructive procedures should be planned to provide as effective a pinch and grasp as possible between the radial and ulnar columns by deepening the central cleft, excising "digital nubbins" and any impinging skeleton, and performing rotational osteotomies of either metacarpal base or both and, occasionally, transfers to provide active digital flexion. Type III reconstructive procedures should release the adducted thumb and fabricate a physiologic thumb-index web along with appropriate releases of syndactyly. In the two-digit hand, rotational osteotomies may increase function.