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.     

Neurological manifestation and genetic diagnosis of Angelman, Rett and Fragile-X syndromes

OBJECTIVE: To discuss clinical and electroencephalographic aspects and the genetic mechanisms of three neurogenic syndromes that can be related to nosologic entities in the heterogenic pathological group presenting symptoms of mental retardation and autism. SOURCES: The authors carried out a bibliographic review on each syndrome involved, correlating and characterizing the neurological manifestations, as well as describing genetic mechanisms and identifying biological markers. SUMMARY OF THE FINDINGS: The authors were able to confirm that Rett Sydrome is a genetic disease resulting from the mutation of the MECP2 gene and clinical variations can be explained by different mutations in this gene. Angelman syndrome has four genetic mechanisms responsible for phenotypic variations and different risks of recurrence. In Fragile-X syndrome, the degree of cognitive impairment is related to the number of trinucleotide repeats. CONCLUSIONS: Different genetic mechanisms of the three syndromes are responsible for clinical variability. By identifying the biological markers, the diagnosis will be performed earlier and it will be possible to identify new subtle expressions of the disease.     

X-linked hydrocephalus: Clinical heterogeneity at a single gene locus

X-linked hydrocephalus-stenosis of the aqueduct of Sylvius sequence (H-SAS, MIM number 30007) is a rare genetic disorder characterized by hydrocephalus, macrocephaly, adducted thumbs, spasticity, agenesis of corpus callosum and mental retardation. We confirm here the localisation of the mutant gene on Xq (Xq 2.8) by linkage analysis in a 5-generation pedigree (maximum lod score of Z=4.57 at theta =0.04 with probe St14 at locus DXS52) and emphasise the phenotypic variability of the disease. Ventricular dilatation in affected males was either severe and diagnosed antenatally or moderate and consistent with a long survival with little or no macrocephaly. Since other X-linked syndromes of mental retardation with spasticity and flexion deformities of the thumbs have previously been shown to map to the Xq 2.8 region as well (e.g. MASA syndrome and spastic paraplegia), the present results raise the question of whether H-SAS syndrome, MASA syndrome and spastic paraplegia with mental retardation might represent different phenotypic expression of various mutations at the same locus.     

Mental Retardation: Genetic Findings, Clinical Implications and Research Agenda

The most important genetic advances in the field of mental retardation include the discovery of the novel genetic mechanism responsible for the Fragile X syndrome, and the imprinting involved in the Prader-Willi and Angelman syndromes, hut there have also been advances in our understanding of the pathogenesis of Down syndrome and phenylketonuria. Genetic detects (both single gene Mendelizing disorders and cytogenetic abnormalities) are involved in a substantial proportion of cases of mild as well as severe mental retardation, indicating that the previous equaling of severe mental retardation with pathology, and of mild retardation with normal variation, is a misleading over–simplication. Within the group in which no pathological cause can be detected, behaviour genetic studies indicate that genetic influences are important, but that their interplay with environmental factors, which are also important, is at present poorly understood. Research into the joint action of genetic and environmental influences in this group will be an important research area in the future.     

Clinical genetic evaluation of the child with mental retardation or developmental delays

This clinical report describes the clinical genetic evaluation of the child with developmental delays or mental retardation. The purpose of this report is to describe the optimal clinical genetics diagnostic evaluation to assist pediatricians in providing a medical home for children with developmental delays or mental retardation and their families. The literature supports the benefit of expert clinical judgment by a consulting clinical geneticist in the diagnostic evaluation. However, it is recognized that local factors may preclude this particular option. No single approach to the diagnostic process is supported by the literature. This report addresses the diagnostic importance of clinical history, 3-generation family history, dysmorphologic examination, neurologic examination, chromosome analysis (> or =650 bands), fragile X molecular genetic testing, fluorescence in situ hybridization studies for subtelomere chromosome rearrangements, molecular genetic testing for typical and atypical presentations of known syndromes, computed tomography and/or magnetic resonance brain imaging, and targeted studies for metabolic disorders.     

Genetics of mental retardation

Aim of this review is to present the latest advances in the identification of the genetic determinants of intellectual deficiency. Mental retardation (MR) is often associated with other neurologic symptoms, metabolic disorders, or malformation syndromes. The purpose of the review is to subdivide the large field of MR into categories that may help professionals in making a diagnosis. Nonspecific MR can also segregate in families and the mapping and cloning of corresponding mutant genes will eventually advance our understanding of normal and abnormal brain functioning. Several genes responsible for nonspecific X-linked mental retardation have been identified in the last 12 to 24 months and are being intensively investigated. This will hopefully lead to new possibilities of either genetic or pharmacological therapy.     

Genetic counseling in acrocallosal syndrome

This article reports two families with children having acrocallosal syndrome, an autosomal recessive disorder characterized by agenesis of corpus callosum, facial dysmorphism and polydactyly along with psychomotor retardation. Both families sought genetic counseling in subsequent pregnancies. Although the gene for the disorder is not yet identified, prenatal diagnosis was attempted by ultrasound studies. In both families, an affected fetus was diagnosed in the presence of postaxial polydactyly of hands and absence of corpus callosum. It is emphasized that pediatricians should make precise diagnosis in cases of dysmorphism and mental retardation, as this enable prenatal diagnosis in future pregnancies.     

IDENTICAL SYNDROMES OF CEREBRAL PALSY IN THE SAME FAMILY

Familial cases of cerebral palsy were traced all over Sweden. Fortythree families were collected, in 30 of which the patients were siblings. The families were divided into three groups: (1) 16 families with cases of identical syndromes and a history of normal pregnancy, delivery and perinatal period; (2) 3 families with cases of identical syndromes but an abnormal perinatal period; (3) 24 families with non-identical syndromes. Within the first group, which is of main genetic importance, 10 families were found with 2-3 siblings affected with congenital non-progressive ataxia and mental retardation, the mode of inheritance with all probability being autosomal recessive. Three families showed ataxic diplegia, two of them only in siblings, the third with affected members of both sexes represented in three generations. Surprisingly enough, pure spastic diplegia was only revealed in one family, viz. a grandfather and his grandson. Spastic tetraplegia was found in two mentally retarded siblings in an otherwise healthy sibship of 11 members. True microcephaly combined with a dystonic tetraplegic cerebral palsy was seen in one family and was thought to have an autosomal recessive inheritance as in similar cases reported in the literature. Chromosome studies and laboratory screening tests revealed no abnormalities indicating particular aetiological mechanisms.     

ISSUES IN THE CLASSIFICATION OF MENTAL RETARDATION: DIFFERENTIATING AMONG ORGANIC ETIOLOGIES

Many researchers of mental retardation fail to take etiological differences into account, although the value of distinguishing between organic and familial mental retardation has long been discussed. The argument is made that even the two-group approach needs to be extended so that groups with different organic etiologies are studied separately. Taking etiological distinctions into account will allow for more precise research and a better understanding of mental retardation. Evidence for the utility of differentiating retarded persons by etiology is provided by a research review showing examples of behavioral differences between organically retarded groups. It is concluded that such differentiation also has clear implications for intervention.     

Mentale Retardierung

Mental retardation is defined as an IQ<70, and affects approximately 2% of the general population. Between 40% and 50% of these patients have a genetic defect. While databases currently list 1600 genetic syndromes with mental retardation, the number of defects without specific syndromology is assumed to be much higher. This article aims to present the differential diagnosis of the more frequent genetic syndromes and help with the clarification of syndromologic and non-syndromoligic forms.     

Expanding the phenotype of alopecia–contractures–dwarfism mental retardation syndrome (ACD syndrome): description of an additional case and review of the literature

Alopecia-contractures-dwarfism mental retardation syndrome (ACD syndrome; OMIM 203550) is a very rare genetic disorder with distinct features. To our knowledge, there have been four cases documented to date. In addition, another three patients, previously described as having IFAP syndrome (OMIM %308205), may also have ACD syndrome. We report on one patient with short stature, total alopecia, ichthyosis, photophobia, seizures, ectrodactyly, vertebral anomalies, scoliosis, multiple contractures, mental retardation, and striking facial and other features (e.g. microdolichocephaly, missing eyebrows and eyelashes, long nose, large ears) consistent with ACD syndrome. Results of laboratory testing in the literature case reports were normal, although in none of them, array-CGH (microarray-based comparative genomic hybridization) analysis was performed. In conclusion, the combination of specific features, including total alopecia, ichthyosis, mental retardation, and skeletal anomalies are suggestive of ACD syndrome. We propose that children with this syndrome undergo a certain social pediatric protocol including EEG diagnostics, ophthalmological investigation, psychological testing, management of dermatologic and orthopedic problems, and genetic counseling.     

Etiologic and Pathogenetic Study of Mental Retardation with Multiple Congenital Anomalies

Etiology and pathogenesis of MCA/MR in 1,023 patients (618 male; 405 female) with mental retardation were studied. Of 1,023 patients, there were 563 cases (317 male; 246 female) with MCA (55%). Among the MCA patients, there were 303 (156 male; 147 female) whose primary etiology was clarified (53.8%). Among the 260 patients with MCA/MR of unknown etiology, there were 23 with recognizable syndromes of unknown etiology and 7 previously reported by us as possibly having a new malformation syndrome. We had 569 patients with mental retardation of unknown etiology including 236 (41.5%) who were involved with MCA.     

Recent advances in understanding the genetic etiology of congenital heart disease.

The genetic etiologies of multiple cardiovascular disorders have been identified recently. For the most part, familial cardiomyopathic, vascular, or arrhythmogenic disorders have been studied given the opportunity to identify the disease gene by linkage analyses, positional cloning, and analysis of candidate genes. Given that structural congenital heart disease rarely occurs in the context of large families, alternative approaches to understand the possible genetic etiologies have been taken. In particular, molecular evaluations of genetic syndromes in which cardiac defects are a cardinal feature are providing new insights into disease-related genes and developmental pathways. The identification of rare families with multiple affected members also has provided some insight into the genetic contribution to structural congenital heart defects. This review highlights the newest findings on the genetic etiology or implications in each of the subcategories of congenital cardiovascular disorders, and will provide the reader with both a brief overview and update. Particular note will be made of the genotype/phenotype analyses of hypertrophic cardiomyopathy and the long QT syndromes, as well as the identification of new disease-related genes for dilated cardiomyopathy, idiopathic ventricular fibrillation, and structural heart disease.     

The child with developmental delay: An approach to etiology

OBJECTIVE:

To describe an approach to history, physical examination and investigation for the developmentally delayed child.

METHODS:

A review of electronic databases from 1997 to 2001 was done searching for articles relating to the approach to or investigations of children with developmental delay. Five studies, including a review of a consensus conference on evaluation of mental retardation, were chosen because of their general approaches to developmental delay and/or mental retardation, or specific evaluations of a particular laboratory investigation.

CONCLUSIONS:

A diagnosis or cause of mental retardation can be identified in 20% to 60% of cases. Evaluation of the developmentally delayed child should include a detailed history and physical examination, taking special care to record a three-generation pedigree, as well as to look for dysmorphic features. If no other cause is apparent, routine investigations should include a chromosome study and fragile X studies. Further investigations are warranted depending on the clinical features.     

Non-progressive congenital ataxia with cerebellar hypoplasia in three families

AIM: Non-progressive ataxias with cerebellar hypoplasia are a rarely seen heterogeneous group of hereditary cerebellar ataxias. METHOD: Three sib pairs from three different families with this entity have been reviewed, and differential diagnosis has been discussed. RESULTS: In two of the families, the parents were consanguineous. Walking was delayed in all the children. Truncal and extremity ataxia were then noticed. Ataxia was severe in one child, moderate in two children, and mild in the remaining three. Neurological examination revealed horizontal, horizonto-rotatory and/or vertical nystagmus, variable degrees of mental retardation, and pyramidal signs besides truncal and extremity ataxia. In all the cases, cerebellar hemisphere and vermis hypoplasia were detected in MRI. During the follow-up period, a gradual clinical improvement was achieved in all the children. CONCLUSION: Inheritance should be considered as autosomal recessive in some of the non-progressive ataxic syndromes. Congenital non-progressive ataxias are still being investigated due to the rarity of large pedigrees for genetic studies. If further information on the aetiopathogenesis and clinical progression of childhood ataxias associated with cerebellar hypoplasia is to be acquired, a combined evaluation of metabolic screening, long-term follow-up and radiological analyses is essential.     

Body fluids and salt metabolism - Part II

Mental retardation is a heterogeneous condition, affecting 1-3% of general population. In the last few years, several emerging clinical entities have been described, due to the advent of newest genetic techniques, such as array Comparative Genomic Hybridization. The detection of cryptic microdeletion/microduplication abnormalities has allowed genotype-phenotype correlations, delineating recognizable syndromic conditions that are herein reviewed. With the aim to provide to Paediatricians a combined clinical and genetic approach to the child with cognitive impairment, a practical diagnostic algorithm is also illustrated. The use of microarray platforms has further reduced the percentage of "idiopathic" forms of mental retardation, previously accounted for about half of total cases. We discussed the putative pathways at the basis of remaining "pure idiopathic" forms of mental retardation, highlighting possible environmental and epigenetic mechanisms as causes of altered cognition.     

Case of subtelomeric aberration as a cause of familial intellectual disability with congenital defects and dysmorphic features--problems of diagnosis and genetic counseling

Intellectual disability, defined as an IQ less than 70, occurs in 2-3% of the population and is both a medical and social problem of outstanding importance. Establishing its aetiology is not always easy, but it is a necessary condition in providing genetic counseling for families. Until now, the aetiology of mental retardation remains unknown in about half of the cases. Chromosomal aberrations are found in about 30-40% of moderately and profoundly intellectually impaired. Submicroscopic chromosomal aberrations involving the telomeric regions of chromosomes discovered in the recent years, are responsible for 4-9% cases of idiopathic mental retardation. Identification of very small structural rearrangements in the telomeric regions of the chromosomes requires another strategy than those applied in routine classic methods of chromosomal analysis (fluorescence in situ hybridisation in situ FISH). We present several cases of mental retardation with congenital defects and dysmorphic features which occurred in one family. Submicroscopic aberration in the telomeric regions of chromosomes 7 and 10 was revealed as a cause of mental retardation in this family. That aberration was a result of familial reciprocal translocation which had been not previously identified by routine cytogenetic methods. Detailed retrospective clinical characteristics of the proband and his affected relatives is presented. Variable clinical expression in presented cases in relation to difficulties in diagnosis and genetic counseling is discussed.     

Pitt-Hopkins syndrome: report of a case with a TCF4 gene mutation

Aims

We will discuss the clinical and genetic diagnosis of a child with severe psychomotor delay, who at 3 years of age presented with paroxysms of hyperpnea-apnea and seizures unrelated to breathing anomalies.

Methods

The child underwent genetic (karyotype, FISH telomeres) and neuroradiological (cranial CT and MRI) tests, which proved to be normal. He came under our clinical observation at 3 years and 5 months of age. Due to severe psychomotor delay and facial dysmorphisms we completed the genetic investigations based on his clinical feature and analysis of the available literature.

Results

The presence of severe mental retardation associated with anomalous breathing pattern may suggest the Joubert and Rett syndrome, however these were excluded on the basis of clinical and genetic examination. Angelman syndrome, suspected for facial dysmorphisms and absent language, was also excluded because of the presence of a normal pattern of methylation at SNRPN locus. Another possible diagnosis was the Pitt-Hopkins Syndrome (PHS), characterized by severe mental retardation, breathing anomalies (paroxisms of hyperpnea-apnea), dysmorphisms and sometimes epilepsy. Haploinsufficiency of TCF4 gene located at 18q21.2 region has been recently identified as causative of this syndrome. In our patient the research of TCF4 mutation by the Institute of Human Genetics, University Hospital Erlangen (Germany), showed a de novo mutation.

Conclusions

The diagnosis of Pitt-Hopkins syndrome, an underdiagnosed cause of mental retardation, was based on clinical and genetic findings. Searching for TCF4 mutations is highly recommended when others overlapping syndromes was excluded. At our knowledge our patient is the first italian case of PHS diagnosed at molecular level.

     

Genetic syndromes predisposing to paediatric brain tumours: the chicken or the egg?

Cancer in childhood is a disorder of growth and development. Up to 10% of patients diagnosed with cancer during childhood have a known underlying genetic predisposition syndrome. Affected individuals usually have multisystem involvement from the underlying syndrome and certain syndromes are associated with development of characteristic tumours with sites of predilection within the neuraxis. For the healthcare professionals involved with paediatric patients it is important to have basic knowledge of the cancer susceptibility syndromes. A holistic multidisciplinary approach is required for the overall management of the syndrome itself with specific recommendations for imaging surveillance and genetic counselling based on the pattern of inheritance and the relative risk of developing a tumour. Appropriate knowledge of these syndromes will help paediatricians manage and refer patients at risk to specialist neuro-oncology centres. A typical brain tumour diagnosis can also indicate certain underlying genetic disorders and examples of such tumours include optic pathway glioma, choroid plexus carcinoma and subependymal giant cell astrocytoma. A detailed family history can be helpful in identifying at risk patients and families as the typical clinical signs associated with the genetic condition are often not fully apparent in young children. This article focuses on well-known genetic diagnoses associated with or predisposing to childhood brain tumours. In some instances, the brain tumour diagnosis subsequently leads to the diagnosis of an underlying genetic syndrome.