Fragile X syndrome

Fragile X syndrome is the most common familial form of mental retardation. This X-linked disorder affects one in every 1000 males and one in every 2000 females. The female carrier rate in the general population is estimated to be 1/600. A fragile site at the distal long arm of the X chromosome (Xq 27.3) is the hallmark cytogenetic feature of the syndrome. Clinical features include physical as well as cognitive and neuropsychological deficits. Although fragile X syndrome follows an X-linked pattern of inherltance (which explains the predominance of affected males), females can also beaffected,Many inconsistencies exist between the genetic inheritance pattern of fragile X and traditional Mendelian inheritance tenets of most X-linked diseases. Due to recent molecular advances, our understanding of the perplexing genetic issues surrounding fragile X syndrome has grown and diagnostic techniques have become both reliable and readily available.     

Abnormalities-retardation syndrome caused by incomplete triploidy

We report on a four year old boy with multiple congenital anomalies and mental retardation due to incomplete triploidy (diploid triploid mixoploidy). Initially, we had thought of the Silver-Russell syndrome. The main characteristics in the patient are short stature, body asymmetry, hypogenitalism, and considerable mental retardation. In addition, there are several minor anomalies of the hands and feet. The diagnosis was verified by microscopic detection of a triploid cell line in cultivated skin fibroblasts and by supplementary studies using flow cytometry. The characteristics of this recognizable multiple congenital anomalies/mental retardation syndrome are discussed with reference to the pertinent literature. As differential diagnosis, in particular the Silver-Russell syndrome has to be taken into account.     

Alpha-Thalassämie-Retardierungs-Syndrom

Alpha-thalassemia X-linked mental retardation (ATRX, MIM#301040) syndrome is associated with severe mental retardation, muscular hypotonia, facial dysmorphism, and genital anomalies in males. We present the case of a family with two affected boys. The diagnosis was made by maternal X-chromosome inactivation studies which showed marked skewing of maternal X-chromosome inactivation and ATRX analysis revealed a novel mutation in exon 34.     

染色体异常在儿童遗传咨询中的分析及8种新核型报道

目的 探讨广西地区儿童遗传咨询患儿中异常核型和临床表型的关系。方法 采用细胞培养及G 显带的方法,对2009 年1 月至2012 年7 月进行儿童遗传咨询的601 例患儿行细胞遗传学及临床分析。结果 在601 例受检者中检出329 例异常核型,包括8 种人类染色体新核型,检出率为54.7%。329 例异常染色体核型中,数目异常317 例（96.4%）,结构异常12 例（3.6%）。异常染色体核型在临床上多以唐氏综合征（245/329,74.5%）、发育迟缓（36/329,10.9%）、智力低下（10/329,3.0%）等表现为主。结论 发现了8 例罕见的染色体异常核型,为分析儿童遗传学研究及病因学分析提供了新的资源。     

Studies of malformation syndromes of man XXXIII: The FG syndrome. An X-linked recessive syndrome of multiple congenital anomalies and mental retardation

Three brothers and two of their male first cousins were affected with a previously apparently undefined multiple congenital anomaly, mental retardation syndrome which was designated the FG syndrome and which consists of variable growth problems with a disproportionately large head, characteristic appearance and minor anomalies, imperforate anus, mild to severe mental retardation and congenital hypotonia; pyloric stenosis, hypoplastic left heart, generalized dilatation of the urinary tract, cutaneous syndactyly of third and fourth fingers, and severe craniosynostosis were seen each in 1 patient. Partial agenesis of the corpus callosum seen in 1 patient is suspected in another on the basis of EEG abnormalities. 1 boy died neonatally with congenital heart disease, and 2 others of pneumonia at 20 and 23 months. The FG syndrome is an X-linked recessive condition; heterozygotes appear grossly normal.Paper No. 1705 from the University of Wisconsin Genetics Laboratory     

Brachmann-de Lange syndrome in 16 of our patients

The Brachmann-de Lange-syndrome (Cornelia de Lange-syndrome) belongs to the group of well established multiple congenital anomalies/mental retardation syndromes. The main features are a characteristic dysmorphic face, short stature, defects mainly of the upper limbs and severe psychomotor retardation. A variety of internal anomalies belongs to the non obligatory features of the syndrome. Based on 16 own observations (7 females, 9 males) aged between 1 day and 16 years, we describe the clinical variability of the Brachmann-de Lange-syndrome. Relatively poor prognosis is shown by the fact that up to now 6 of the patients have died.     

Editorial: Early Discharge in Febrile Neutropenia

Noonan's syndrome (NS) is a syndrome with multiple congenital anomalies, characterized by craniofacial anomalies, congenital heart disease, skeletal and genital abnormalities, and mild mental retardation. Chromosomal abnormalities have been found in only a few cases. The combination of NS and acute leukemia has been reported in only three cases. Two additional cases are described here.     

Neurodevelopmental disorders in males related to the gene causing Rett syndrome in females (MECP2).

Mutations in the MECP2 (methyl-CpG-binding protein 2) gene are known to cause Rett syndrome, a well-known and clinically defined neurodevelopmental disorder. Rett syndrome occurs almost exclusively in females and for a long time was thought to be an X-linked dominant condition lethal in hemizygous males. Since the discovery of the MECP2 gene as the cause of Rett syndrome in 1999, MECP2 mutations have, however, also been reported in males. These males phenotypically have classical Rett syndrome when the mutation arises as somatic mosaicism or when they have an extra X chromosome. In all other cases, males with MECP2 mutations show diverse phenotypes different from classical Rett syndrome. The spectrum ranges from severe congenital encephalopathy, mental retardation with various neurological symptoms, occasionally in association with psychiatric illness, to mild mental retardation only. We present a 21-year-old male with severe mental retardation, spastic tetraplegia, dystonia, apraxia and neurogenic scoliosis. A history of early hypotonia evolving into severe spasticity, slowing of head growth, breathing irregularities and good visual interactive behaviour were highly suggestive of Rett syndrome. He has a de novo missense mutation in exon 3 of the MECP2 gene (P225L). The clinical spectrum and molecular findings in males with MECP2 mutations are reviewed.     

Noonan's Syndrome in Association with Acute Leukemia

Noonan's syndrome (NS) is a syndrome with multiple congenital anomalies, characterized by craniofacial anomalies, congenital heart disease, skeletal and genital abnormalities, and mild mental retardation. Chromosomal abnormalities have been found in only a few cases. The combination of NS and acute leukemia has been reported in only three cases. Two additional cases are described here.     

Unbalanced X; autosome translocation

Unbalanced X; autosome translocation can result in multiple congenital abnormalities/mental retardation syndrome due to chromosomal imbalance. Here is described a patient with developmental delay, microcephaly, agenesis of corpus callosum spasticity, seizures and dysmorphism as a result of meiotic malsegregation of balanced X; autosome translocation in mother. Present case signifies the importance of chromosomal analysis in a patient with developmental delay/ mental retardation and discuss lyonization in cases with X; autosome translocation.     

Smith-Lemli-Opitz syndrome: Review and report of two affected siblings

This paper reports two siblings with the Smith-Lemli-Opitz syndrome and reviews the literature on the subject. SLOS is a syndrome of multiple congenital anomalies with mental and growth retardation, unusual facies, genito-urinary and hand and foot abnormalities inherited as an autosomal recessive trait.     

Fragile X syndrome

The fragile X syndrome is the most common inherited form of mental retardation known. Its phenotype includes large or prominent ears, macroorchidism, and characteristic behavioral problems. It has attracted the interest of cytogeneticists and molecular biologists because of its characteristic fragile site on the X chromosome. It has puzzled geneticists because of its unusual inheritance pattern involving nonpenetrant males. This syndrome has also spearheaded an appreciation of cytogenetic abnormalities in the etiology of all degrees of developmental delay.     

Advances in X-linked mental retardation

PURPOSE OF REVIEW: Mutations in genes on the X chromosome rival chromosome aberrations as a cause of mental retardation. Progress in the clinical and molecular delineation of X-linked mental retardation has outpaced progress in understanding autosomal mental retardation. This is a result in large part of the identification of large families in which mental retardation has segregated in an X-linked pattern and the greater ease with which molecular technologies can be applied to hemizygosity in males. RECENT FINDINGS: About one-third of the estimated 165 genes associated with syndromal mutations of genes on the X chromosome and one-fourth of the estimated 100 genes associated with nonsyndromal mutations of genes on the X chromosome have been identified. In a number of instances, the same gene is responsible for syndromal and nonsyndromal mutations of genes on the X chromosome. The molecular delineation of mutations of genes on the X chromosome has allowed certain conditions to be lumped together on the basis of allelism and has caused others that appear clinical similar to remain separate. SUMMARY: The clinical and molecular advances have allowed X-linked mental retardation to be more clearly delineated, have provided the means of confirmatory laboratory testing, and have ushered in an era of carrier testing, prenatal diagnosis, and prevention strategies.     

Prepubertal XX male with profound physical and mental deficiency, retinitis pigmentosa and multiple congenital anomalies

A unique case of a prepubertal XX male with profound mental and physical retardation, retinitis pigmentosa, ambiguous genitalia and multiple congenital anomalies is reported. His clinical, genetic, dermatoglyphic and histological findings are presented. This case could represent a new multiple congenital malformation syndrome. Theories on XX male aetiology are briefly discussed.     

Incidence and Etiology of Mental Retardation in Patients with Congenital Heart Disease

Of 1,235 patients (609 male; 626 female) with congenital heart disease for whom types, etiology and associated congenital anomalies were determinable, 129 patients (10.4%) had mental retardatin. Patients with congenital heart disease complicated by mental retardation included 70 (54.3%) with chromosome aberrations, three(2.3%) with single gene disorders, two (1.6%) caused by environmental insult, and two (1.6%) with other recognized syndromes. Among the remaining 52 patients, asphyxia at birt was noted in 16, including 12 complicated by multiple malformations, and 4 in whom mental retardedation was presumed to be due to the asphyxia. In the remaining 36 patients, the incidence of the complication of mental retardation in cyanotic congenital heart disese was significantly higher than that in acyanotic congenital heart disease was signicantly higher than that in acyanotic congenital heart disease. Patients with congenital heart disease of unknown etiology associated with mental retardation included those from two families considered to have new pedigree syndromes.     

Molecular analysis of X-linked agammaglobulinemia with growth hormone deficiency

To address the relationship between the gene (or genes) that causes the syndrome of X-linked hypogammaglobulinemia with isolated growth hormone deficiency and the gene responsible for typical X-linked agammaglobulinemia (XLA), we have used cytogenetics, examination of X chromosome inactivation patterns in potential carriers of the defect, and linkage analysis to study two unrelated families in which the affected males had isolated growth hormone deficiency and immunologic findings indistinguishable from those of typical XLA. A deletion could not be demonstrated in either family by G-banded karyotypes or flow cytometric analysis of metaphase chromosomes. Studies of X inactivation showed that mothers of affected boys from both families exhibited selective use of a single X chromosome as the active X chromosome in B cells but not T cells. This pattern is the same as that seen in obligate carriers of typical XLA. Linkage analysis demonstrated the most likely location for this gene (or genes) to be the midportion of the long arm of the X chromosome between DXS3 and DXS94. This segment of the X chromosome, which constitutes approximately 5% of the total X chromosome, encompasses the gene for XLA. These findings are consistent with the combination of XLA and growth hormone deficiency being caused by a small, contiguous, gene deletion syndrome involving the gene for XLA or an allelic variant of the gene for typical XLA.     

A characteristic EEG pattern in 4p-syndrome: case report and review of the literature

Deletions on the short arm of chromosome 4 cause Wolf-Hirschhorn syndrome (WHS) and Pitt-Rogers-Danks syndrome (PRDS). WHS is associated with severe growth and mental retardation, microcephaly, a characteristic facies and congenital malformations. The PRDS phenotype is similar to WHS but generally less severe. Seizures occur in the majority of WHS and PRDS patients. Sgrò et al. [17] described a stereotypic electroclinical pattern in four unrelated WHS patients, consisting of intermittent bursts of 2–3 Hz high voltage slow waves with spike wave activity in the parietal areas during drowsiness and sleep associated with myoclonic jerks. We report a patient with PRDS and the typical EEG pattern and review 14 WHS patients with similar EEG findings reported in the literature. Conclusion Awareness and recognition of the characteristic electroclinical findings in Wolf-Hirschhorn syndrome and Pitt-Rogers-Danks syndrome might help in the early diagnosis of such patients. Received: 2 June 2000 and in revised form: 15 September 2000 / Accepted: 18 September 2000     

Is it possible to make a clinical diagnosis of the fragile X syndrome in a boy?

Clinical observations were made on a series of 156 boys with severe mental retardation, before cytogenetic results were known. The clinical features that helped to distinguish the 14 boys with the fragile X chromosome from those without were: head circumference over the 50th centile, postpubertal testicular volume over the 50th centile, and an IQ between 35 and 70. If the above clinical features were all present, then the chance of finding the fragile X chromosome was 1 in 3.6, whereas the chance of finding this abnormality in any boy with severe idiopathic mental retardation, regardless of his clinical features, was 1 in 9. Two boys with fragile X syndrome did not, however, possess any of the above clinical features. Moreover, some of the other retarded boys had clinical features of the syndrome, or an X linked pedigree, but lacked the chromosome abnormality.     

Partial tetrasomy 9 in an infant with clinical and radiological evidence of multiple joint dislocations

We report on an infant with partial tetrasomy of chromosome 9 due to the presence in her peripheral lymphocytes and in 55% of skin fibroblasts of an isochromosome 9 comprised of the p arm and of a portion of the q arm extending to band q21.1. The phenotype is comparable to that of other cases with a similar chromosome aberration, with multiple joint dislocations as a prominent manifestation.Abbreviations MCA/MR multiple congenital anomalies/mental retardation - OFC occipito-frontal head circumference     

Studies of malformation syndromes of man XXIV B: The Dubowitz syndrome. Further observations

This paper reports observations on 6 new patients with the Dubowitz syndrome which was first defined by Grosse et al., in 1971 and which is a recessively inherited, pleiotropic malformation syndrome including variable degrees of intrauterine growth retardation and primordial shortness of stature, microcephaly, mental retardation, eczema, and a characteristic appearance, voice and combination of minor anomalies. Data in the present report show that eczema can be absent, and patients can be of normal height, and of normal intelligence in spite of a head circumference which has so far always fallen below the third percentile. So far 11 patients (8 females and 3 males) are known with the Dubowitz syndrome; in one family the parents were first cousins.Paper No. 1617 from the University of Wisconsin Genetics Laboratory.