Autosomal Dominant Mode Of Transmission Research Articles

Carcinoma of the esophagus and tylosis. A lethal genetic combination

Hyperkeratosis of the palms and soles (tylosis) is an uncommon genetic disorder. A small number of English families, however, have been described in which it is associated with carcinoma of the esophagus. The current report is of the first American family described with this condition. Members of those families affected with tylosis have at least a 90% risk of esophageal carcinoma by age 65 years. The paired conditions have an autosomal dominant mode of transmission and probably are controlled at a single genetic locus. The actual pathologic state might be mediated through an increase in epidermal growth factor receptors in the abnormal tissues.

Genetics of dyseidetic dyslexia.

The nine pedigrees presented here suggest an autosomal dominant mode of transmission for the dyseidetic type of dyslexia. Sex-influence probably accounts for the high male to female ratio. Other modes of transmission are highly unlikely for dyseidesia but possible for other types of dyslexia, with the multifactorial mode being most likely. Genetic counseling is particularly feasible in cases of dyseidetic dyslexia.

Type I Pseudohypoaldosteronism Includes Two Clinically and Genetically Distinct Entities with either Renal or Multiple Target Organ Defects

Type I pseudohypoaldosteronism (PHA) is a hereditary disease characterized by salt wasting resulting from target organ unresponsiveness to mineralocorticoids. We have studied two kindreds including a total of nine patients with PHA. In kindred I, the propositus presented with renal salt wasting in infancy (vomiting, failure to thrive, short stature, hyponatremia, hyperkalemia) and responded dramatically to a high salt diet (2.5 g/day). Sodium supplementation was discontinued at the age of two. In seven additional family members from three generations, clinical expression of PHA varied from asymptomatic to moderate. In affected members (propositus, mother, and two brothers), hyperaldosteronism persisted over 13 yr; however, the PRA decreased gradually to near normal values. Persistent hyperaldosteronism in the face of a decrease in PRA indicated the development of tertiary hyperaldosteronism due to autonomously functioning zona glomerulosa. The pedigree was consistent with an autosomal dominant mode of transmission with variable expression. In kindred II, the propositus, who was the product of a consanguineous marriage, developed severe renal salt losing at age 9 days. She had also increased salivary and sweat electrolytes consistent with PHA resulting from multiple organ unresponsiveness to mineralocorticoids. Life threatening episodes of salt wasting recurred beyond the age of 2 yr. At 5 yr of age she still requires high amounts of salt supplements (14 g/day). A sister died at 9 days of age with PHA symptoms. Six close relatives (parents, three siblings, maternal uncle) showed no biochemical abnormalities. This pedigree was consistent with an autosomal recessive mode of inheritance. In view of the findings on these two kindreds and the analysis of those in the literature, we conclude that type I PHA includes two clinically and genetically distinct entities with either renal or multiple target organ defects.

Pseudohypoaldosteronism in Eight Families: Different Forms of Inheritance Are Evidence for Various Genetic Defects

Pseudohypoaldosteronism is a rare hereditary disorder presenting in early infancy with renal salt loss leading to hyponatremia and hyperkalemia despite high levels of plasma aldosterone. The patients are insensitive to mineralocorticoids; however, sodium supplementation is able to correct electrolyte abnormalities. Absent or greatly diminished type I aldosterone receptors in peripheral mononuclear leucocytes have been recently demonstrated and explain the lack of response to mineralocorticoids. We have studied the mode of inheritance in eight families with a total of nine patients. There was evidence for an autosomal recessive form of inheritance in four families, while the other four families appeared to have an autosomal dominant mode of transmission. In three families the autosomal recessive form was characterized by normal receptor as well as hormone data in both parents, while in one family receptor levels in both parents were greatly reduced, but hormone levels were normal. In the four families with an autosomal dominant mode of transmission there was always one parent with reduced receptor binding in peripheral mononuclear leucocytes and elevated serum hormone levels. These parents were entirely asymptomatic. In an extended family we were able to study an aunt and her newborn daughter, who were both also biochemically affected but clinically asymptomatic. It, therefore, appears that this dual pattern of genetic transmission may indicate differing genetic defects which cause the same clinical picture of pseudohypoaldosteronism.

The familial occurrence of acoustic neuroma report of a family with seven affected members

Seven members spanning three generations of a family affected with bilateral or unilateral acoustic neuromas are described. The inheritance pattern of affected members supports a Mendelian autosomal dominant mode of transmission. Relevant literature is reviewed.

Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): Review of 80 cases

We have observed two types of paucity of interlobular bile ducts (PILBD) in children with chronic cholestasis: the syndromic type, which is more frequent (80 cases), and the nonsyndromic type (31 cases). Study of patients with syndromic PILBD has enabled us to recognize five major features: peculiar facies (95%), chronic cholestasis (91%), posterior embryotoxon (88%), butterfly-like vertebral arch defects (87%), and peripheral pulmonary artery hypoplasia or stenosis, either isolated or associated with complex cardiovascular abnormalities (85%). By observing these major features, it is possible to differentiate the "complete" syndrome, in which all five features are present (26 cases), from the "partial" syndrome, in which only four (42 cases) or three (12 cases) major features are present. Other less frequent features were observed in patients with complete or partial syndrome: growth retardation (50%), mental retardation (16%), renal disturbances, other vascular malformations, bone abnormalities, high-pitched voice, and delayed puberty. Death occurred in 21 (26%) patients with syndromic PILBD. Therapy consisted of supplementation of medium-chain triglycerides and fat-soluble vitamins and administration of cholestyramine or phenobarbital. An autosomal dominant mode of transmission, with variable penetrance, seems likely.

Laboratory studies of a family manifesting premature exfoliation of deciduous teeth

In a previous publication, we described the clinical and radiographic findings of a family in which the children manifested premature exfoliation of the deciduous teeth. We now report for the same family the results of extensive laboratory studies performed on blood and urine, analysis of periodontal microflora, and a family pedigree. We demonstrated the presence of putative periodontal pathogens in the subgingival microflora, elevated levels of serum antibodies reacting to Bacteroides gingivalis, Capnocytophaga gingivalis, and C. sputigena in 2 of the children, and significantly suppressed monocyte chemotaxis in all 3 children. Phosphoethanolamine was found in the urine of the father and all 3 children, but not in the mother. Likewise, serum alkaline phosphatase was abnormally low for all 3 children, and was at the extreme low end of normal range for the father, but was normal for the mother. On the basis of the alkaline phosphatase and phosphoethanolamine measurements, we assigned a diagnosis of hypophosphatasia to the 3 children. Phosphoethanolamine and alkaline phosphatase were also abnormal in the paternal grandmother and her brother. The son of this brother who was deceased had a daughter manifesting premature loss of the primary teeth. The data are consistent with an autosomal dominant mode of transmission. In the light of our findings, hypoplastic cementum must be considered in the etiology of some forms of early-onset periodontitis.

Slowly progressive autosomal dominant spastic paraplegia with late onset, variable expression and reduced penetrance: a basis for diagnosis and counseling.

We have examined a pedigree in which familial spastic paraplegia (FSP) is segregating in four generations. The data show a high rate of transmission of the trait, late onset, reduced penetrance, variable age and symptom expressivity, and an autosomal dominant mode of transmission. A summary of our data together with the FSP data of other shows a 1:1 transmission from males and from females, and an overall 1:1 transmission ratio. The risks for the children of symptomatic and non-symptomatic parents are illustrated.

Pseudohypoparathyroidism: report on a family with four affected sisters

A family consisting of a mother, a father with probable pseudopseudohypoparathyroidism (PPHP), two normal daughters, and four daughters with pseudohypoparathyroidism (PHP) have been observed for more than 15 years at North Carolina Memorial Hospital (NCMH). The studies performed on family members included (1) roentgenographic examinations of the chest, skull, hands, and soft tissues; (2) serum calcium, phosphorus, and immunoreactive parathyroid hormone measurements; (3) urinary cyclic adenosine 3'5'-monophosphate determinations following parathyroid injection; and (4) HLA and blood-type determinations. We review the genetic aspects of PHP. The findings in this family suggest an autosomal dominant mode of transmission in PHP.

Segregation and linkage analyses of a large pedigree with hypertriglyceridemia.

AbstractBlood, urine, and saliva samples were obtained from 100 members (42 males and 58 females) of a large family with an increased incidence of cardiac illness to study the mode of genetic transmission of hyperlipidemia, and the linkage relations of this trait with polymorphic markers. Total cholesterol, triglycerides, and lipoprotein Svedberg fractions were determined, the atherogenic index was computed, and 30 markers, including 27 polymorphic ones, were determined.The fit of one distribution and mixtures of two and three distributions, on both the original and the logarithmic scale, were examined for each quantitative trait. Triglyceride levels showed a significantly better fit to a mixture of two lognormal distributions than to a single lognormal distribution. Triglycerides showed the highest proportion of variance accountable by genetic transmission (74.9%), followed by cholesterol (52.1%); these two traits were chosen for major gene pedigree analyses. Hypertriglyceridemia gave a good fit to an autosomal dominant mode of transmission, the minimum probability of miclassification being 9.3%. From a bivariate analysis of these two variables the linear function that best separates the two groups was derived and the minimum percentage of misclassification for this function was found to be 6.8%.Linkage analysis between the possible major locus for elevated triglycerides and the 27 polymorphic markers indicated no significant lod scores; but a positive lod score of 0.73 was obtained with pepsinogen, at equal male and female recombination fractions of 0.1. More data are needed to confirm or deny this possible linkage.

Familial hyperproinsulinemia. An autosomal dominant defect.

We describe a genetic defect in a kindred in whom proinsulin or a proinsulin-like material constitutes the major fraction of circulating insulin immunoreactivity in both the fasting and stimulated states. The defect, familial hyperproinsulinemia, affects eight males and 10 females in four generations of the kindred, with an autosomal dominant mode of transmission. Familial hyperproinsulinemia is asymptomatic in the affected progeny, with no apparent relation to hypoglycemia or to the development of diabetes mellitus. This genetic defect may represent either a deficiency in the proinsulin cleaving enzyme (or enzymes) within the beta cell, or more probably, an abnormal species of proinsulin.

Autosomal dominant transmission of isolated growth hormone deficiency in iris-dental dysplasia (Rieger's syndrome)

A boy with Rieger's syndrome was short and lacked GH. His father and sister, each of whom had Rieger's syndrome, also had an isolated deficiency of GH. The paternal grandmother and a paternal uncle, in all likelihood, were similarly affected. Therapy with GH led to enhanced growth in the propositus. The GH-deficient subjects were sensitive to insulin and had a normal increase of insulin in response to arginine and to orally administered glucose. It is suggested that GH deficiency, in this family, is an inconstant component of Rieger's syndrome and follows an autosomal dominant mode of transmission. A common embryologic developmental defect of the neural crest is postulated.

Clinical manifestations of essential tremor.

A clinical study of 42 patients with essential tremor is presented. In the case of 12 patients the family history strongly suggested an autosomal dominant mode of transmission, in four the mode of inheritance was indeterminate, and the remaining 26 patients were sporadic cases without an established genetic basis. The tremor involved the upper extremities in 41 patients, the head in 25, lower limbs in 15, and trunk in two. Seven patients showed involvement of speech. Variations were found in the speed and regularity of the tremor. Leg involvement took a variety of forms: (1) direct involvement by tremor; (2) a painful limp associated with forearm tremor; (3) associated dyskinetic movements; (4) ataxia; (5) foot clubbing; and (6) evidence of peroneal muscular atrophy. Several minor symptoms-hyperhidrosis, cramps, dyskinetic movements, and ataxia-were associated with essential tremor. Other features were linked phenotypically to the ataxias and system degenerations. Apart from minor alterations in tone, expression, and arm swing, features of Parkinsonism were notably absent.

22. IgA deficiency—hereditary aspects

Familial cases of selective immunoglobulin A deficiency have been documented, but the mode of inheritance remains unsettled. The propositus of the present study, a 9-year-old girl with a past history of frequent upper respiratory tract infections, had an unusually low serum IgA level, between 0.5 and 2.0 mg/100 ml (i.e., IgA detectable by double diffusion but not by the radial immunodiffusion technique). The mother of the patient showed a total lack of serum IgA and suffered from chronic urinary tract infection. The father and brother of the propositus and the maternal relatives tested had normal IgA levels. Bothe patients had normal karyotypes. In the propositus. IgA was detected in saliva and intestinal juice, but IgM was present in higher concentrations in these secretions. Direct immunofluorescent studies of both rectal and small intestinal mucosa revealed IgA-containing cells, but IgM-containing cells were predominant. In the mother, no IgA was detectable in whole saliva concentrated 20 times, and the rectal mucosa was completely devoid of IgA-containing cells, whereas IgM-containing cells were abundant. These findings suggest that IgA deficiency may differ in degree of severity. The daughter in this family could be heterozygous for a recessive trait, while the mother is homozygous. On the other hand, an autosomal dominant mode of transmission with variable gene expressivity cannot be ruled out.

A genetic study of class III malocclusion

The families of fifty-one probands demonstrating Angle Class III malocclusion were examined. Approximately 13 per cent of the siblings of the probands exhibited the trait, suggesting a strong genetic influence in the transmission of Class III malocclusion. No evidence was found to suggest that the trait is sex linked. The results did not support a simple autosomal dominant mode of transmission. The results also did not support a simple autosomal recessive transmission. The explanation most compatible with the results seems to be a polygenic method of transmission depending on a threshold beyond which persons are at risk. The possibility that different methods of transmission exist in different families or different populations has not been ruled out.

Hyperkeratosis lenticularis perstans. A clinical, histopathologic, and genetic study.

The clinical, histologic, and genetic characteristics of four patients with hyperkeratosis lenticularis perstans are reported. The clinical lesions are multiple pink to reddish-brown, scaly papules occurring most frequently over the dorsa of the feet, legs, hands, and arms. The histologic findings include hyperkeratosis and parakeratosis, an atrophic or acanthotic epidermis, and a bandlike or perivascular round cell infiltrate. Three of the patients studied were from the same family and represent the first related cases to be reported. This familial incidence suggests that hyperkeratosis lenticularis perstans is a genodermatosis with an autosomal dominant mode of transmission. The title of benign familial acrokeratoses is proposed.

Genetic Aspects of Urticaria Pigmentosa

Three members from one family add support to a possible genetic basis for urticaria pigmentosa. A search of the world literature disclosed 28 additional individuals with various forms of urticaria pigmentosa among their relations. These came from 13 different families. The pedigrees of the 31 patients suggest an autosomal dominant mode of transmission.

DYSCHONDROSTEOSIS, A HEREDITABLE BONE DYSPLASIA WITH CHARACTERISTIC ROENTGENOGRAPHIC FEATURES.

Seven cases of dyschondrosteosis are reported. This is a hereditary bone dysplasia with an autosomal dominant mode of transmission characterized by a typical deformity of the distal radius and ulna and proximal carpal bones and mesomelic dwarfism. The wrist deformity has been widely reported in the medical literature under the eponym, Madelung's disease.

Lériʼs Pleonosteosis

A study of a family in which features of a systemic disease were exhibited consistent with the diagnosis of Léri's pleonosteosis has been presented. It is believed to be the first North American family to be reported. The findings are those of a widespread constitutional disease which involves chiefly the connectivetissue system. The syndrome appears to be the consequence of a gene exhibiting an autosomal dominant mode of transmission. The gene presents good penetrance and a considerable variance in its range of expressivity. Certain ophthalmological, cutaneous, osseous, and roentgenographic findings present in the reported family and mentioned in the literature are considered as possibly being additional expressions of this pleiotropic syndrome. More necropsy material is needed with which to understand this important syndrome better.