Autosomal recessive inheritance of erythrokeratoderma variabilis

Erythrokeratoderma variabilis is a rare genodermatosis conventionally regarded as autosomal dominant in inheritance. We describe the clinical features and light and electron microscopic findings in two affected siblings born to unaffected parents and suggest an autosomal recessive mode of inheritance in this family. We also briefly review the literature on this disorder.     

Ectrodactyly and absence (hypoplasia) of the tibia: are there dominant and recessive types?

We present a kindred of brother, sister, and cousin with ectrodactyly and hypoplasia of the tibia. The parents of the cousin are consanguineous; the parents of the sibs originate from the same small Algerian village. We also report on a boy with tibial defect and split hands and feet with consanguineous parents. These observations are further hints for an autosomal recessive type of ectrodactyly with aplasia (hypoplasia) of the tibia, as was favoured by some authors. However, review of the present and reported cases does not demonstrate any clinical differences between the seemingly recessive and the dominant types. Statistical analysis of 17 families with affected sibs and normal parents showed a 1:3.1 ratio of affected:unaffected by the proband method. Despite consanguinity among nine sets of parents, this ratio, and approximately 30 additionally reported families generally are in favour of autosomal dominance with reduced penetrance.     

A Bedouin kindred with infantile nephronophthisis demonstrates linkage to chromosome 9 by homozygosity mapping

A novel type of infantile nephronophthisis was identified in an extended Bedouin family from Israel. This disease has an autosomal recessive mode of inheritance, with the phenotypic presentation ranging from a Potter-like syndrome to hyperechogenic kidneys, renal insufficiency, hypertension, and hyperkalemia. Affected individuals show rapid deterioration of kidney function, leading to end-stage renal failure within 3 years. Histopathologic examination of renal tissue revealed variable findings, ranging from infantile polycystic kidneys to chronic tubulointerstitial nephritis, fibrosis, and cortical microcysts. A known familial juvenile nephronophthisis locus on chromosome 2q13 and autosomal recessive polycystic kidney disease on chromosome 6p21.1-p12 were excluded by genetic linkage analysis. A genomewide screen for linkage was conducted by searching for a locus inherited by descent in all affected individuals. Pooled DNA samples from parents and unaffected siblings and individual DNA samples from four affected individuals were used as PCR templates with trinucleotide- and tetranucleotide-repeat polymorphic markers. Using this approach, we identified linkage to infantile nephronophthisis for markers on chromosome 9q22-31. The disorder maps to a 12.9-cM region flanked by markers D9S280 and GGAT3G09.     

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.     

Extreme variation in X-linked agammaglobulinemia phenotype in a three-generation family

BACKGROUND: X-linked agammaglobulinemia is typically a severe life-threatening disease characterized by the failure of B-cell differentiation and antibody production, which manifests in infancy and early childhood. Recently, we reported a novel mutation (Cys145-->STOP) in Bruton's tyrosine kinase in a 51-year-old man who was referred for evaluation because of chronic nasal congestion, recurrent sinusitis, sporadic pneumonia, and a family history suggestive of an X-linked immunodeficiency disease. He had not been treated with gammaglobulin. OBJECTIVE: This study was performed to investigate the clinical and immunologic phenotypes of this patient's other affected male family members. METHODS: A detailed family history and comprehensive review of medical records was carried out. Genetic mutation analysis of the gene encoding Bruton's tyrosine kinase was carried out in the proband's brother and nephew. RESULTS: Clinically affected male family members exhibit marked phenotypic variation with manifestations ranging from extremely mild to severe recurrent infections. Immunologic evaluation revealed extreme variation in immunoglobulin levels, B-cell numbers, and functional antibody titers. Genetic analysis documented a novel mutation in the gene encoding Bruton's tyrosine kinase in the proband, his brother, and his nephew. CONCLUSIONS: Despite their sharing the same genetic abnormality, extreme variation was noted in the immunologic findings and phenotypic expression of affected family members. This family study is extraordinary in that clinically affected male members who did not receive aggressive medical treatment died of the disease in childhood or survived into late adulthood.     

Ocular manifestations of autosomal recessive Alport syndrome

Ocular abnormalities are common in X-linked Alport syndrome, but they have not been studied in patients with the rarer autosomal recessive disease. We have examined the eyes of a family with autosomal recessive Alport syndrome. Four of the eight offspring of a consanguineous marriage had renal failure and deafness by the age of 20 years. The diagnosis of Alport syndrome was confirmed on the ultrastructural demonstration of a lamellated glomerular basement membrane (GBM) in one affected family member. Autosomal recessive inheritance was suggested by the lack of linkage to the COL4A5/COL4A6 locus, and by linkage to the COL4A3/COL4A4 locus. All four affected family members had anterior lenticonus (or had had a lens replacement for this) and the three who were examined had a dot-and-fleck retinopathy. Neither of the two unaffected offspring who were examined nor the father had these abnormalities. The ocular manifestations of autosomal recessive Alport syndrome are probably identical to those for the X-linked form. Although the mutations in these diseases affect genes for different type IV collagen chains, these chains occur together in the basement membranes of the kidney, eye and ear, and abnormalities in any one may result in the same clinical phenotype.     

Clinical characteristics of hereditary pancreatitis in a large family, based on high-risk haplotype. The Midwest Multicenter Pancreatic Study Group (MMPSG)

OBJECTIVES: Because there are no markers for hereditary pancreatitis (HP), diagnosis has relied on clinical features and inferences. Identification of the HP disease gene locus on chromosome 7q35 provides the first genetic marker for HP, allowing an accurate comparison of the clinical diagnosis of HP with the presence of a high-risk HP haplotype. Our objectives were to compare the clinical diagnosis of HP with inheritance of the HP gene and to characterize the common clinical features. METHODS: A detailed questionnaire was administered to 102 study participants of a large HP kindred. Blood samples were taken for DNA extraction and high-risk haplotype determination. Clinical findings were compared with the presence of a high-risk haplotype. RESULTS: A family tree of more than 500 members and eight generations was constructed, and clinical features of the 102 participants were determined. HP occurred before the age of 5 yr in 58% of subjects, who presented with common symptoms of abdominal pain, nausea/vomiting, and frequent attacks. Thirty-five probands, of whom 80% had clinical symptoms, carried the high-risk haplotype, confirming previous estimates of 80% penetrance. Thirty-two of the study participants had been clinically diagnosed with HP, whereas 70 were clinically unaffected. With regard to the presence of the high-risk haplotype, 87.5% of the clinically diagnosed patients were affected by HP (true positive), whereas 12.5% did not carry the high-risk haplotype (false positive). Seven obligate carriers were identified through DNA analysis; three had previously been unrecognized because of lack of affected offspring. CONCLUSIONS: The diagnosis of hereditary pancreatitis on clinical grounds alone may be inaccurate in less severe cases, as is the exclusion of carrier status through family tree analysis. Therefore, a definitive diagnosis of hereditary pancreatitis in equivocal cases or exclusion of a carrier state should include analysis of genetic markers.     

HIV-1 viral load: comparative evaluation of three commercially available assays in Argentina

Autosomal recessive nonsyndromic hearing loss (ARNSHL) is the most common form of hereditary hearing impairment (HHI). To date, 16 different loci have been reported, making ARNSHL an extremely heterogeneous disorder. One of these loci, DFNB4, was mapped to a 5-cM interval of 7q31 in a large Middle-Eastern Druze family. This interval also includes the gene for Pendred syndrome. We report on three new families with HHI from the Madras region of southern India that demonstrate linkage to 7q. Their pedigrees are compatible with autosomal recessive inheritance. Furthermore, the largest family identifies a novel locus (DFNB17) telomeric to the DFNB4 and Pendred intervals. A 3-cM region of homozygosity by descent between markers D7S486 and D7S2529 is present in all affected individuals in this family and generates a multipoint LOD score of 4.24. The two other families map to the previously reported DFNB4 region but have insufficient power to attain significant LOD scores. However, mutations in the Pendred syndrome gene are present in one of these families.     

A family segregating a Friedreich ataxia phenotype that is not linked to the FRDA locus

Friedreich ataxia is an autosomal recessive neurodegenerative disorder. The genetic homogeneity to the FRDA locus on chromosome 9q13-21.1 has been observed in families from different ancestries. We report a Spanish family with two affected and three unaffected children. The segregated classical Friedreich ataxia did not show the expected linkage. The analysis focusses on flanking markers FR1, FR2, FR7 and FR5, excluding linkage 1 cM around the FRDA locus. The unique clinical hallmark in this family was the absence of cardiomyopathy after a long-term follow-up in the two affected children. In both patients serum vitamin E levels were normal. The present observations support the existence of a second locus in Friedreich ataxia, and we suggest that this form could be clinically characterized by the absence of muscular heart disease.     

Autosomal dominant postaxial polydactyly, nail dystrophy, and dental abnormalities map to chromosome 4p16, in the region containing the Ellis-van Creveld syndrome locus

We have studied a four-generation family with features of Weyers acrofacial dysostosis, in which the proband has a more severe phenotype, resembling Ellis-van Creveld syndrome. Weyers acrofacial dysostosis is an autosomal dominant condition with dental anomalies, nail dystrophy, postaxial polydactyly, and mild short stature. Ellis-van Creveld syndrome is a similar condition, with autosomal recessive inheritance and the additional features of disproportionate dwarfism, thoracic dysplasia, and congenital heart disease. Linkage and haplotype analysis determined that the disease locus in this pedigree resides on chromosome 4p16, distal to the genetic marker D4S3007 and within a 17-cM region flanking the genetic locus D4S2366. This region includes the Ellis-van Creveld syndrome locus, which previously was reported to map within a 3-cM region between genetic markers D4S2957 and D4S827. Either the genes for the condition in our family and for Ellis-van Creveld syndrome are near one another or these two conditions are allelic with mutations in the same gene. These data also raise the possibility that Weyers acrofacial dysostosis is the heterozygous expression of a mutation that, in homozygous form, causes the autosomal recessive disorder Ellis-van Creveld syndrome.     

Exposure to chlorine gas: effects on pulmonary function and morphology in anaesthetised and mechanically ventilated pigs

We report on a child with a 'new' syndrome characterized by multiple congenital anomalies, mental retardation, sensorineural deafness, talon cusps of upper central incisors, growth retardation, bilateral symmetrical digital anomalies mainly in the form of preaxial brachydactyly and hyperphalangism of digits I-III. Because he had a similarly affected brother and his parents were cousins we suggest autosomal recessive inheritance, X-linked recessive inheritance cannot be excluded. Differential diagnosis from other syndromes with preaxial brachydactyly and hyperphalangism is presented.     

The genetics of vitiligo in Korean patients

BACKGROUND: Vitiligo is a common disorder whose exact cause is unknown, but genetic factors are thought to be involved. We analyzed 120 Korean proband families to clarify which genetic factors are involved in the pathogenesis of vitiligo in Korean patients. METHODS: The genetics of vitiligo were analyzed in 120 Korean proband families out of 1030 vitiligo patients. Each family was analyzed through a proband afflicted with vitiligo. RESULTS: In 51 (42.5%) of 120 proband families, at least one first-degree relative of the proband had vitiligo. The incidence of those affected among 1755 relatives (first-, second-, and third-degree) was found to be 8.0+/-0.6%. There was a statistically significant departure for segregation analysis which was inconsistent with inheritance as an autosomal or X-linked locus model. On the basis of our results, the inheritance pattern of vitiligo is more likely to tend toward the model of multifactorial inheritance. The threshold trait among first-degree relatives (7.2%) appeared to tend more toward the square root of the frequency in the general population (10%) than towards those of dominant (50%) or recessive (25%) models. CONCLUSIONS: These results indicate that there are certain genetic factors involved in the etiology of vitiligo, and that vitiligo seems to have a polygenic nature.     

Two Japanese siblings with Bloom syndrome gene mutation and B-cell lymphoma

Bloom syndrome (BS) is a rare autosomal recessive genetic disorder characterized by lupus-like erythematous telangiectasia of the face, sun sensitivity, infertility and stunted growth. Upper respiratory tract and gastrointestinal infections are commonly associated with the decreased immunoglobulin levels found in BS patients. Chromosomal abnormalities are hallmarks of the disorder, and high frequencies of sister chromatid exchanges and quadriradial configurations in lymphocytes and fibroblasts are virtually diagnostic. Recently, the causative gene for BS (BLM) has been identified. We encountered and defined a family with a nonsense mutation in BLM. The brother and sister were homozygous for the mutation and both developed B-cell malignant lymphoma in their twenties. These findings indicate the importance of prenatal diagnosis and the detection of BS carriers based on molecular genetic analysis.     

Distribution of type II diabetes in nuclear families

Type II diabetes has a substantial genetic component, but the mode of inheritance and the molecular basis of this inheritance are uncertain. This study documents the familial distribution of the disease in the parents and siblings of a consecutive series of type II diabetic subjects. We studied 66 first-degree relatives of 20 white subjects with type II diabetes and both parents alive. They were tested with a continuous infusion of glucose (5 mg.kg IBW-1.min-1) (n = 49) or FPG and hemoglobin A1c (n = 17). Seven probands had neither parent affected with diabetes or IGT, 10 had one parent affected (6 with diabetes and 4 with IGT), and 3 had both parents affected. The probands with affected and those with unaffected parents were phenotypically similar. These findings indicate that a sizable subgroup of type II diabetic subjects may have neither parent affected with a demonstrable abnormality of glucose tolerance. The assumption of autosomal dominance with complete penetrance is not supported, although it remains possible that a dominant gene of low penetrance may play a role in some pedigrees. Polygenic inheritance would appear likely, and genetic heterogeneity may occur. The inheritance of diabetic traits from phenotypically normal parents needs to be considered in the analysis of genetic linkage with type II diabetes.     

A new Rett syndrome family consistent with X-linked inheritance expands the X chromosome exclusion map

Although familial recurrences of Rett syndrome (RTT) comprise only approximately 1% of the reported cases, it is these cases that hold the key for the understanding of the genetic basis of the disorder. Families in which RTT occurs in mother and daughter, aunt and niece, and half sisters are consistent with dominant inheritance and variable expressivity of the phenotype. Recurrence of RTT in sisters is likely due to germ-line mosaicism in one of the parents, rather than to recessive inheritance. The exclusive occurrence of classic RTT in females led to the hypothesis that it is X-linked and may be lethal in males. In an X-linked dominant disorder, unaffected obligate-carrier females would be expected to show nonrandom or skewed inactivation of the X chromosome bearing the mutant allele. We investigated the X chromosome inactivation (XCI) patterns in the female members of a newly identified family with recurrence of RTT in a maternal aunt and a niece. Skewing of XCI is present in the obligate carrier in this family, supporting the hypothesis that RTT is an X-linked disorder. However, evaluation of the XCI pattern in the mother of affected half sisters shows random XCI, suggesting germ-line mosaicism as the cause of repeated transmission in this family. To determine which regions of the X chromosome were inherited concordantly/discordantly by the probands, we genotyped the individuals in the aunt-niece family and two previously reported pairs of half sisters. These combined exclusion-mapping data allow us to exclude the RTT locus from the interval between DXS1053 in Xp22.2 and DXS1222 in Xq22.3. This represents an extension of the previous exclusion map.     

Role of neutrophil elastase in compression-induced spinal cord injury in rats

Myeloperoxidase (MPO) is an essential component of the oxygen-dependent microbicidal system of neutrophils and monocytes. Hereditary deficiency of MPO occurs in 1 in 2,000 to 4,000 individuals in the general population and has been generally considered an autosomal recessive trait. Previous studies have used the peroxidase activity of blood leukocytes to assess the phenotype of affected family members. Eosinophil peroxidase (EPO) also contributes to the peroxidase activity of blood leukocytes. Because EPO expression is normal in MPO-deficient subjects, eosinophil contamination can significantly contribute to peroxidase activity in leukocytes from family members of an MPO-deficient subject and thereby undermine correct interpretation of the inheritance pattern. To avoid this potential problem, we used cytochemical, immunochemical, and genetic techniques to assess the inheritance pattern of MPO deficiency in sixteen individuals from five unrelated kindreds. Each kindred had an index case with MPO deficiency and the R569W missense mutation, a genotype that causes MPO deficiency. Our analysis demonstrated that MPO deficiency was not inherited as a simple autosomal recessive trait. Most subjects were compound heterozygotes with respect to the R569W mutation and demonstrated a spectrum of phenotypes. Our data demonstrate the broad phenotypic impact of compound heterozygosity on the expression and function of a multimeric protein such as MPO.     

Segregation analysis of NIDDM in Caucasian families

Non-insulin-dependent diabetes mellitus (NIDDM) has a substantial genetic component, but the mode of inheritance and the molecular basis are unknown. We have undertaken segregation analysis of NIDDM after studying 247 subjects in 59 Caucasian nuclear pedigrees ascertained without regard to family history of the disorder. The analyses were performed using POINTER and COMDS, which are computer programs which apply statistical models to the data. POINTER analysis was performed defining the phenotype as a presence or absence of hyperglycaemia. Among single locus hypothesis, the analyses rejected a recessive model and favoured a dominant model, but could not statistically show that this fitted better than a mixed model (a single locus against a polygenic background) or a polygenic model. COMDS analysis assumed a continuum of hyperglycaemia from normality to NIDDM, classified family members into a series of diathesis classes with increasing plasma glucose levels and compared the distribution with that found by screening the normal population. This analysis improved the likelihood of a dominant single locus model and suggested a gene frequency of 7.4%. It raised the possibility of a second locus, but cannot identify or exclude a polygenic model. In conclusion, two types of segregation analyses rejected a recessive model and favoured a dominant model of inheritance, although they could not statistically show that this fitted better than the polygenic model. The results raised the possibility of a common dominant gene with incomplete penetrance, but genetic analysis of NIDDM needs to take into account the likelihood of polygenic inheritance with genetic heterogeneity.     

Evidence for a single gene effect causing polycystic ovaries and male pattern baldness

OBJECTIVE: Polycystic ovary syndrome is one of the most common endocrine disorders but its aetiology remains unknown. It is highly prevalent within families, suggesting a genetic basic for the syndrome, but the mode of inheritance is unclear. The purpose of this study was to determine the mode of inheritance of polycystic ovary syndrome, within the families of affected individuals, by classic segregation analysis. DESIGN: All first degree relatives of affected individuals were screened for the presence or absence of polycystic ovaries in post-menarchal-premenopausal women and early onset male pattern baldness (MPB) in the males. In extended pedigrees, assignment of affected status in post-menopausal women was made by consideration of the clinical history alone. PATIENTS: Fourteen women (probands), presenting with a variety of clinical symptoms, were identified sequentially as having polycystic ovaries (PCO) by ultrasound scan. They were examined in detail to determine their family structure, clinical and endocrine status. Ten families were found to have sufficient members for further study. MEASUREMENTS: All family members had their body mass index calculated, their degree of hirsutism assessed using the Ferriman and Gallwey score and serum levels of gonadotrophins (FSH and LH), testosterone, prolactin and 17 alpha-hydroxyprogesterone measured by radioimmunoassay. A careful reproductive history was taken for each woman and any menstrual disturbance was noted. Obese probands had their glucose and insulin response to a standard 75-g oral glucose tolerance test determined. Each male family member was also assessed for the degree and time of onset of balding. RESULTS: First degree female relatives of affected individuals had a 51% chance of being affected. Early onset male pattern baldness (MPB) was found to be an accurate phenotype for obligate male carriers. Each family showed autosomal dominant inheritance for PCO with greater than 90% penetrance. CONCLUSIONS: We postulate that PCO and male pattern baldness are caused by alleles of the same gene which affect androgen production or action. The different frequencies of PCO and male pattern baldness arise from differing thresholds for phenotypic expression in females and males respectively. The modifying effects of other genes is the most likely explanation of the somewhat variable phenotype.