The pattern of inheritance of X-linked traits is not dominant or recessive, just X-linked

Our modern concepts of genetic inheritance originated nearly a century ago. Early concepts of dominant and recessive inheritance were developed in insects and were subsequently applied to sex-linked inheritance in mammals. Years of clinical experience, however, suggest that the modern-day rules for X-linked dominant and recessive diseases do not explain why so many female carriers of X-linked 'recessive' disorders have an abnormal phenotype. In a review of 32 X-linked diseases we revealed an unexpectedly high degree of intermediate disease penetrance in females that cannot be explained by existing concepts. We recommend that the terms 'dominant' and recessive' be abandoned and that these disorders be referred to as X-linked. In this review we will present modified rules for X-linked inheritance and propose hypotheses related to the potential mechanisms that may explain differences in disease expression in females.Conclusion: Past assumptions regarding factors that may affect phenotype in heterozygous females do not capture the extraordinarily variable expressivity of X-linked disorders in females and need to be revisited.     

The pattern of inheritance of X-linked traits is not dominant or recessive, just X-linked

Our modern concepts of genetic inheritance originated nearly a century ago. Early concepts of dominant and recessive inheritance were developed in insects and were subsequently applied to sex-linked inheritance in mammals. Years of clinical experience, however, suggest that the modern-day rules for X-linked dominant and recessive diseases do not explain why so many female carriers of X-linked 'recessive' disorders have an abnormal phenotype. In a review of 32 X-linked diseases we revealed an unexpectedly high degree of intermediate disease penetrance in females that cannot be explained by existing concepts. We recommend that the terms 'dominant' and recessive' be abandoned and that these disorders be referred to as X-linked. In this review we will present modified rules for X-linked inheritance and propose hypotheses related to the potential mechanisms that may explain differences in disease expression in females.
Conclusion : Past assumptions regarding factors that may affect phenotype in heterozygous females do not capture the extraordinarily variable expressivity of X-linked disorders in females and need to be revisited.     

Genochondromatosis II

We report a new disorder which we have called genochondromatosis II. The disorder is similar in mode of inheritance and long bone changes to that named genochondromatosis but shows some distinctive features, namely involvement of short tubular bones and normal clavicles. The disorder has a benign clinical course and may be discovered incidentally. Accurate diagnosis is important for proper genetic counselling.     

Hereditary thyroglossal duct cysts

Thyroglossal duct cysts are one of the most commonly encountered benign neck lumps found in the paediatric population. Despite their relative frequency, reports of familial inheritance are rare. A total of 21 patients with hereditary thyroglossal duct cysts from seven families worldwide have been reported. The most common inheritance pattern is dominant, with a minority possibly representing a recessive aetiology. We describe a further instance of dominantly inherited thyroglossal duct cysts in two generations.     

Update on inborn errors of metabolism: primary lactic acidemia.

Initially thought to be rare, primary lactic acidemia is diagnosed with increasing frequency. Elevations in lactate and pyruvate are markers for a variety of metabolic blocks. Although there have been great strides made in the diagnosis and treatment of lactic acidemia, much remains to be learned. As laboratory techniques improve, clinicians will be able to make an exact enzymatic diagnosis on an increasing percentage of patients. Specific enzymatic diagnosis also will help clinicians determine inheritance patterns, recurrence risks, and methods of prenatal diagnosis.     

CUTIS LAXA ASSOCIATED WITH SEVERE INTRAUTERINE GROWTH RETARDATION AND CONGENITAL DISLOCATION OF THE HIP

Two female siblings with cutis laxa are reported. Both these infants showed marked intrauterine growth retardation, hyperlaxity of the joints, with congenital dislocation of the hip. Four similar female infants have been reported in the literature. The mode of inheritance appears to be as an autosomal recessive gene. The marked degree of intrauterine growth retardation may be indicative of a more severe form of the disease, which might be lethal in the male foetus.     

Aspects génétiques de la surdité

Hearing loss is the most common sensory disability with an incidence of one over 1000 newborns. Hearing loss may be caused by environmental and genetic factors; inherited causes are assumed in two thirds of cases. There is a great clinical and genetic heterogenicity. All inheritance modes have been described. Mutations in the GJB2 gene, which encodes connexin 26, are mainly responsible for sensorineural deafness resulting in prelingual non syndromic autosomal recessive phenotypes DFNB1. The 35delG mutation of this gene is very frequent (70% of the cases). Thus, 35delG is, with the delta F508 mutation of the CFTR gene, the most frequent human pathogenic mutation known. Hearing loss might also be associated with other clinical features. Some of these syndromes, including hearing loss, have to be looked for systematically because of their frequency, of their possible clinical presentation as an isolated hearing loss and of the possibility of a medical treatment.     

Genetic counseling and the pediatrician.

The assistance of the pediatrician, following diagnosis of a child with a genetic disorder, towards his family consists today in giving genetic counseling for prevention of recurrence in future pregnancies. The process of genetic counseling, once the right diagnosis is made, should not be difficult as concerns Mendelian inheritance. It is well known that several chromosomal disorders follow the rules of Mendelian inheritance. The theory of polygenic or multifactorial inheritance may create problems in the accurate estimation of risks. An effort is made to discover the mechanisms of genetic "predisposition" or the adverse environmental factors, in order to minimize the occurrence of such disorders. An important tool in prevention of several genetic disorders, which should be mentioned in genetic counseling, is prenatal diagnosis.     

G-6-PD缺乏症和新生儿高胆红素血症

葡萄糖-6-磷酸脱氢酶缺乏症是一种常见的单基因遗传性疾病,在全球范围内分布非常广泛,而且人群中携带者频率很高。患者突然出现的急性溶血会导致血清总胆红素升高,引起高胆红素血症,甚至胆红素脑病。新生儿高胆红素血症是儿科医生经常遇到的问题,需要及时发现和处理。     

Familial occurrence of Elfin's face (Williams-Beurens Syndrome =wbs) and supravalvular aortic stenosis (= svas) (author's transl)

Three siblings out of two families -- the mothers being sisters -- have signs of WBS: a girl shows the complete picture of elfin's face syndrome; a boy who needed surgical treatment for severe supravalvular aortic stenosis, presents only with minimal signs of the peculiar facies like his mother. His brother has slight supravalvular aortic stenosis. The three children described show trivial peripheral pulmonary stenosis. It is known that SVAS and WBS may show a dominant mode of inheritance with variable expressivity. The purpose of this study was to find signs which would prove a dominant inheritance in this kinship. Dental malpositions and coarse upperlip with shallow philtrum where the only symptomes found in the patients and their mothers. If we accept this traits as markers for the syndrome than we could assume a dominant way of inheritance.     

Miller-Dieker syndrome: lissencephaly and monosomy 17p

Miller-Dieker syndrome, which includes lissencephaly and a characteristic phenotypic appearance, has been reported to have an autosomal recessive pattern of inheritance. However, we have found abnormalities of chromosome 17 in two of three unrelated patients with this syndrome, one with a ring chromosome 17 and the other with an unbalanced translocation resulting in partial monosomy of 17p13. A review of the literature revealed five additional patients in three families, who had Miller-Dieker syndrome and an abnormality of 17p. Thus, we propose that monosomy of distal 17p may be the cause of Miller-Dieker syndrome in some patients.     

Congenital chylothorax in siblings

We describe two cases of congenital chylothorax in siblings with important differences from previously described familial cases. Our findings support the likelihood of an autosomal recessive inheritance in some cases of this condition, rather than X-linked recessive inheritance, which has also been suggested. Autopsy findings from one of these cases and others previously described suggest that the pathophysiological mechanisms involved may be variable.     

Familial distal foregut atresia in a family with likely autosomal dominant inheritance pattern

Familial occurrence of distal foregut atresia (DFA) (Type 1) is rare. Diagnosis is based upon the clinical symptomatology and confirmed by radiological studies, surgery and histology. A number of reports have described families in which several family members have been involved and suggested an autosomal recessive mode of inheritance. Little is known about the underlying genetic causes or indeed the likely pathogenic mechanism. We report a family in which there are five affected cases including three siblings where the DFA appears to be inherited in an autosomal dominant inheritance pattern with reduced penetrance.     

非典型溶血尿毒综合征分子遗传学研究进展

非典型溶血尿毒综合征是一种罕见的有遗传倾向的疾病,易患基因主要是补体旁路途径活化的调控基因:补体因子H基因、膜辅助蛋白基因和补体因子Ⅰ基因.但其总突变率约为50%,突变类型包括错义突变、无义突变、缺失突变、插入突变和剪切位点突变.遗传方式有常染色体隐性遗传和常染色体显性遗传,显性遗传的三个突变基因均为不完全外显.     

Cardiac malformations in relatives of infants with hypoplastic left-heart syndrome

In a pilot study of relatives of infants with hypoplastic left-heart syndrome (HLHS), we obtained a medical history, cardiovascular examination, and echocardiogram in 48 first-degree relatives of 11 probands with isolated HLHS and 3 with HLHS and noncardiac malformations. Echocardiography confirmed heart defects in 5 of 41 relatives of patients with isolated HLHS. In four instances, the cardiac abnormality was unrecognized. Among 7 relatives of infants with HLHS and extracardiac anomalies, no heart defects were detected. Cardiac defects occurred in first-degree relatives of probands at a frequency higher than previously predicted by an additive multifactorial model of inheritance. These findings suggest that first-degree relatives of HLHS probands may have an increased risk for subclinical cardiac defects and that genetic factors likely contribute to the cause of left-heart blood-flow lesions.     

CHRONIC GRANULOMATOUS DISEASE IN THREE RELATED PATIENTS

Three related patients with chronic granulomatous disease are described. Two are brothers and one a half-brother; all have the same mother. The purpose of this paper is to stress that an X-linked genetic defect is probably involved in this condition, although there may be other modes of inheritance. This is thought to be the first report of chronic granulomatous disease in Australian children.     

Familial hypogammaglobulinemia with variable serum immunoglobulins. Concordance with lymphocyte ecto-5'-nucleotidase deficiency

Four male subjects from two generations of a black family were found to have variable expression of hypogammaglobulinemia (IgG, IgM, and IgA deficiency in two, IgA deficiency in one, and IgM and IgA deficiency in another) and also to be moderately deficient in the lymphocyte plasma membrane enzyme, 5'-nucleotidase. The inheritance pattern of the immune abnormality is compatible with X linkage. The affected patients had normal numbers of complement receptor-bearing lymphocytes, variably depressed proportions of IgM- and IgD-bearing lymphocytes, and impaired ability to synthesize antibody after specific antigenic stimulation. In this family, the 5'-nucleotidase deficiency and the pattern of inheritance suggest that the different types of hypogammaglobulinemia may represent a variable expression of a common underlying genetic abnormality.     

Genetics of the nephrotic syndrome

There are a large number of glomerular diseases that may be responsible for a nephrotic syndrome, the most frequent in childhood being minimal change disease. In the past few years, the molecular genetic basis of several conditions that may cause a nephrotic syndrome have been identified. Denys-Drash syndrome and Frasier syndrome are related diseases caused by mutations in the WT1 gene. Familial forms of idiopathic nephrotic syndrome with focal and segmental glomerular sclerosis/hyalinosis have been identified with an autosomal dominant or recessive mode of inheritance and linkage analysis have allowed to localize several genes on chromosomes 1, 11 and 17. The gene responsible for the Finnish type congenital nephrotic syndrome has been identified. This gene, named NPHS1, codes for nephrin, which is located at the slit diaphragm of the glomerular podocytes and is thought to play an essential role in the normal glomerular filtration barrier.     

Autosomal recessive type I lissencephaly

Lissencephaly (LIS) is a brain malformation manifested by a smooth cerebral surface, thickened cortical mantle and microscopic evidence of incomplete neuronal migration, excluding polymicrogyria and other cortical dysplasias. It is important to consider LIS in the diagnosis of developmental delay as many patients may be diagnosed as cerebral palsy. It may have familial occurrence and can occur in sibs of same family often leading to a diagnostic problem. Several lissencephaly syndromes have been described. Here a familial syndrome of lissencephaly is reported. Autosomal recessive inheritance is suggested by recurrence in sibs within the same family, but germ cell mosaicism for a dominant mutation cannot be excluded.     

Wilms tumor in five cousins

Wilms tumor developed in five cousins in a family. Two with bilateral tumors have died, but three with unilateral lesions have survived. None of the patients had associated chromosome defects, aniridia, hemihypertrophy, or other anomalies. The pattern of Wilms tumor in the family is consistent with several postulated mechanisms of inheritance of the neoplasm, and shows that relatives within affected families may be at risk.