Developmental and behavioural phenotype in Noonan syndrome?

Developmental and behavioural phenotype in Noonan syndrome? Noonan syndrome is characteristic by facial dysmorphology, congenital heart defects, short stature, developmental retardation and severe early feeding disorders in many cases. Data from a postal survey on physical development, feeding difficulties, developmental problems and behavioural aspects in 26 children are reported. The findings suggest developmental and behavioural difficulties in 46 per cent, but do not support the notion of a behavioural phenotype specific to Noonan syndrome. Having to cope with early surgery, feeding, developmental and behavioural problems establishes a need for psychological counseling for families receiving a diagnosis of Noonan syndrome.     

A strong genetic correlation underlying a behavioural syndrome disappears during development because of genotype–age interactions

In animal populations, as in humans, behavioural differences between individuals that are consistent over time and across contexts are considered to reflect personality, and suites of correlated behaviours expressed by individuals are known as behavioural syndromes. Lifelong stability of behavioural syndromes is often assumed, either implicitly or explicitly. Here, we use a quantitative genetic approach to study the developmental stability of a behavioural syndrome in a wild population of blue tits. We find that a behavioural syndrome formed by a strong genetic correlation of two personality traits in nestlings disappears in adults, and we demonstrate that genotype–age interaction is the likely mechanism underlying this change during development. A behavioural syndrome may hence change during organismal development, even when personality traits seem to be strongly physiologically or functionally linked in one age group. We outline how such developmental plasticity has important ramifications for understanding the mechanistic basis as well as the evolutionary consequences of behavioural syndromes.     

Wolf-Hirschhorn (4P-) syndrome in adults

Wolf-Hirschhorn syndrome (WHS) or 4p-deletion syndrome has been extensively described in children. Knowledge on adult WHS patients is still limited due to the small number of published cases. We present 4 adults and review the literature. The phenotype of adult WHS is in general similar to that of childhood WHS. Growth retardation, microcephaly and mental retardation are the rule in both adults and children. Facial dysmorphism also remains similar. The main difference lies in the absence of serious internal (cardiac) abnormalities in adult WHS. Mental retardation ranges from moderate to severe. The nosological overlap between WHS and Pitt-Rogers-Danks syndrome (PRDS) is discussed. More extensive data on adult WHS are needed for appropriate counselling of families with affected young children.     

Correlational selection does not explain the evolution of a behavioural syndrome

Correlated suites of behaviours, or behavioural syndromes, appear to be widespread, and yet few studies have explored how they arise and are maintained. One possibility holds that correlational selection can generate and maintain behavioural syndrome if certain behavioural combinations enjoy greater fitness than other combinations. Here we test this correlational selection hypothesis by comparing behavioural syndrome structure with a multivariate fitness surface based on reproductive success of male water striders. We measured the structure of a behavioural syndrome including dispersal ability, exploration behaviour, latency to remount and sex recognition sensitivity in males. We then measured the relationship between these behaviours and mating success in a range of sex ratio environments. Despite the presence of some significant correlational selection, behavioural syndrome structure was not associated with correlational selection on behaviours. Although we cannot conclusively reject the correlational selection hypothesis, our evidence suggests that correlational selection and resulting linkage disequilibrium might not be responsible for maintaining the strong correlations between behaviours. Instead, we suggest alternative ways in which this behavioural syndrome may have arisen and outline the need for physiological and quantitative genetic tests of these suggestions.     

Neural mechanisms in Williams syndrome: a unique window to genetic influences on cognition and behaviour

Williams syndrome, a rare disorder caused by hemizygous microdeletion of about 28 genes on chromosome 7q11.23, has long intrigued neuroscientists with its unique combination of striking behavioural abnormalities, such as hypersociability, and characteristic neurocognitive profile. Williams syndrome, therefore, raises fundamental questions about the neural mechanisms of social behaviour, the modularity of mind and brain development, and provides a privileged setting to understand genetic influences on complex brain functions in a 'bottom-up' way. We review recent advances in uncovering the functional and structural neural substrates of Williams syndrome that provide an emerging understanding of how these are related to dissociable genetic contributions characterized both in special participant populations and animal models.     

Prospects of TAT-Mediated Protein Therapy for Fragile X Syndrome

Fragile X syndrome is due to the absence of the fragile X mental retardation protein (FMRP). Patients are mentally retarded and show physical as well as behavioural abnormalities. Loss of protein in the neurons results in changes of dendrite architecture, and impairment of the pruning process has been indicated. Apart from some minor differences, no severe morphological changes have been observed in the brain. Until now, no therapy is available for fragile X patients. Recently it has been reported, that a protein transduction domain (TAT) is able to deliver macromolecules into cells and even into the brain when fused to the protein in question. Upon production of a TAT-FMRP fusion protein in a baculovirus-expression system, we used immunohistochemistry to verify TAT-mediated uptake of FMRP in fibroblasts. However, uptake efficiency and velocity was lower than expected. Neuronal uptake was highly inefficient and the fusion protein demonstrated toxicity.     

Chromosome abnormalities found among 34910 newborn children: results from a 13-year incidence study in Århus,Denmark

Summary As part of a larger prospective study of the influence of environmental factors on pregnancy, birth and the fetus, chromosome examinations have been made in 34910 newborn children in Århus over a 13-year period. Klinefelter's syndrome was found in 1 per 576 boys, XYY in 1 per 851 boys, triple-X in 1 per 947 girls and Turner's syndrome in 1 per 1893 girls. Other sex chromosome aberrations were found in 1 per 11637 children. The total incidence of sex chromosome abnormalities was 1 per 426 children or 2.34 per 1000. The most frequent autosomal abnormalities were that of Down's syndrome with 1 per 592 children, and reciprocal translocations with 1 per 712 children. The total incidence of autosomal abnormalities was 1 per 164 children. Chromosome abnormalities were found in 276 liveborn children and in 19 fetuses, who were aborted after prenatal chromosome examination. The combined incidence of sex chromosomal and autosomal abnormalities was 1 per 118 children or 8.45 per 1000 children.     

Anxiety as an enhancing phenomenon in origin of stress, CAN and PTSD in disabled children. Contribution to the ICD-10 re-classification

This paper studies the contribution of anxiety in origin of functional behavioural disorders of children. The intense sensing of anxiety attributes to the shaping of one's personality. Adaptation and adjustment, accommodation and assimilation to stressful conditions producing anxiety are analyzed. There are diagnosed reactions of organism to the circumstances of the CAN syndrome and trauma. In these circumstances, a primary perception of reality is at stake that consequently leads to sociopathological features. This paper also provides the authors' opinions of psychoanalytical and behavioural schools on origin of personal decompensation and neurotic disorders. Causes of panic disorder and other diseases, in which a stress trauma plays a role, are considered. For these reasons the authors suggest classifying the CAN syndrome as a separate nosologic unit in the future ICD-11.     

Pure distal monosomy 10q26 in a patient displaying clinical features of Prader-Willi syndrome during infancy and distinct behavioural phenotype in adolescence

A male patient is reported with terminal 10q26 deletion and clinical findings suggesting Prader-Willi syndrome during the infancy. These findings included decreased fetal movements, neonatal hypotonia, need for tube feeding, characteristic facial dysmorphism with dolichocephaly, narrow bifrontal diameter, almond-shaped eyes and epicanthus, hypogenitalism and developmental retardation. However, during the further evolution there was neither hyperphagia nor obesity and chromosomal and molecular investigations failed to confirm the diagnosis of Prader-Willi syndrome. Special behavioural abnormalities became evident with notably hyperactivity, hyperkinesis and destructive tendency. Finally, at the age of 17 years high resolution chromosome studies revealed a terminal 10q26.3 deletion. A review of the literature is made on previously reported patients with either a Prader-Willi-like syndrome or a terminal 10q deletion with behavioural problems.     

Lemierre's syndrome: case report in a pediatric patient

Lemierre's syndrome was described in 1936 as a severe oropharyngeal infection followed by septic thrombophlebitis of the internal jugular vein and disseminated metastatic infections. Cases occur typically in previously healthy young adults and children. Fusobacterium necrophorum is the main anaerobic bacterium implicated. We present a septic 2-month-old infant with mastoiditis, multiple sites of osteoarthritis and multiple subcutaneous abscesses. No underlying anatomic or immunologic abnormalities were identified. Fusobacterium necrophorum was recovered from blood and bone samples obtained intraoperatively. Treatment included anaerobic coverage and drainage of septic foci. The patient was discharged home on 35th hospital day with oral amoxicillin-clavulanic acid and he recovered without sequelae. This was the first case of Lemierre's syndrome in our hospital. We want to highlight the absence of jugular vein thrombophlebitis, the presence of mastoiditis as previous infection and the surprising appearance of this infection in an edentulous 2-month-old infant.     

Absence of PTPN11 mutations in 28 cases of cardiofaciocutaneous (CFC) syndrome

CFC (cardiofaciocutaneous) syndrome (MIM 115150) has been considered by several authors to be a more severe expression of Noonan syndrome. Affected patients present with congenital heart defects, cutaneous abnormalities, Noonan-like facial features and severe psychomotor developmental delay. We have recently demonstrated that Noonan syndrome can be caused by missense mutations in PTPN11(MIM 176876), a gene that encodes the non-receptor protein tyrosine phosphatase SHP-2. In this report, we have evaluated the possible involvement of mutations in PTPN11 in CFC syndrome. A cohort of 28 CFC subjects rigorously assessed as having CFC based on OMIM diagnostic criteria was examined for mutations in the PTPN11 coding sequence by using DHPLC analysis. The results showed no abnormalities in the coding region of the PTPN11 gene in any CFC patient, nor any evidence of major deletions within the gene suggesting that mutations in other gene(s) are responsible for this syndrome.     

Étude de la cohorte nord-finlandaise de 1966: facteurs prédictifs et conséquences de la schizophrénie

Subtle motor, emotional, cognitive and behavioural abnormalities are often present in apparently healthy children and adolescents who later develop schizophrenia. This suggests that some aspects of causation are established long before psychosis becomes manifest. We aim to assess the factors contributing to the development of schizophrenia focusing mainly on genetic factors, pregnancy and delivery complications, early development and scholastic performance, as well as later educational, social and health consequences. This is done by reviewing the Northern Finland 1966 Birth Cohort, its scientific activities, publications and work in progress.     

Tetraphocomelia and bilateral femorotibial synostosis. A severe variant of the thrombocytopenia-absent radii (TAR) syndrome?

In this report we describe severe tetraphocomelia with complete femorotibial fusion in a second trimester male fetus. The association of severe tetraphocomelia-femorotibial synostosis has previously been reported in three patients as examples of a severe variant of the thrombocytopenia-absent radii (TAR) syndrome. In the present fetus no morphological abnormalities of the megakaryocytes were detected. This observation is not in favour of the hypothesis that abnormalities of the primordial megakaryocytes may be causally related with the pathogenesis of the limb malformations as present in this syndrome.     

An additional manifestation in acrocallosal syndrome: temporal lobe hypoplasia

Acrocallosal Syndrome is a rare genetic disorder which is characterized by moderate to severe mental retardation, agenesis or hypoplasia of the corpus callosum and polydactyly of fingers and toes. The spectrum of this syndrome is very variable. Prominent forehead, broad nasal bridge, short nose and mandible, hypertelorism, epicanthic folds, large anterior fontanelle and tapered fingers, omphalocele and inguinal hernia are some other common findings in this syndrome. Twenty percent of the patients have associated brain abnormalities such as cerebral atrophy, hypothalamic dysfunction, small cerebrum, micropolygyria, hypoplasia of pons, hypoplasia of cerebellar hemispheres, hypoplasia of medulla oblongata, agenesis or hypoplasia of cerebellar vermis and corpus callosum abnormalities. Here we present a 10-month-old female infant with clinical and radiological findings indicative of acrocallosal syndrome. She was noted to have craniofacial abnormalities suggestive of acrocallosal syndrome, optic atrophy and polydactyly. MRI revealed cerebral atrophy, corpus callosum agenesis, dilated lateral ventricules and unilateral right temporal lobe hypoplasia, the latter not previously reported in the spectrum of this syndrome. Based on this observation we conclude the importance of screening brain abnormalities and present temporal lobe hypoplasia as a new additional anomaly in this syndrome.     

Measuring social-cognitive functions in children with somatotropic axis dysfunction

Growth hormone (GH) and insulin-like growth factor I (IGF-I) are expressed in specific regions of the central nervous system during early human development. They may consequently influence aspects of cognition, or emotional and behavioural adjustment from childhood to adulthood, in conditions associated with abnormalities of the somatotropic axis. GH receptors are relatively common within hippocampal and perihippocampal regions that are primarily involved in declarative memory for facts and events. They are also located in structures (e.g. the putamen) that are involved in the processing of social perceptions. IGF-I receptors have been discovered in the amygdala and prefrontal cortex, which contribute to the neural circuits known as the 'social brain'. The evaluation of emotional, social and behavioural adjustment among children who have deficiencies in GH or IGF-I functional integrity requires the objective assessment of their social-cognitive competence. We describe a computerized test battery, the Schedules for the Assessment of Social Intelligence (SASI), which has been shown to possess excellent psychometric properties in terms of reliability and validity. The SASI, which can be used by both children and adults, may provide new evidence for deficits and treatment effects of GH/IGF-I on emotional, behavioural and cognitive functions.     

Elevated rates of testosterone-related disorders in women with autism spectrum conditions

The androgen theory of autism proposes that autism spectrum conditions (ASC) are in part due to elevated fetal testosterone (FT) levels, which are positively correlated with a number of autistic traits and inversely correlated with social development and empathy. A medical questionnaire was completed by n=54 women with ASC, n=74 mothers of children with ASC, and n=183 mothers of typically developing children to test whether women with ASC have an increased rate of testosterone-related medical conditions, and to see whether mothers of children with ASC show similar abnormalities, as part of the 'broader autism phenotype'. Compared to controls, significantly more women with ASC reported (a) hirsutism, (b) bisexuality or asexuality, (c) irregular menstrual cycle, (d) dysmenorrhea, (e) polycystic ovary syndrome, (f) severe acne, (g) epilepsy, (h) tomboyism, and (i) family history of ovarian, uterine, and prostate cancers, tumors, or growths. Compared to controls, significantly more mothers of ASC children reported (a) severe acne, (b) breast and uterine cancers, tumors, or growths, and (c) family history of ovarian and uterine cancers, tumors, or growths. These results suggest current hormone abnormalities in women with ASC and their mothers. Direct investigations of serum testosterone levels and genetic susceptibility to high testosterone production or sensitivity in women with ASC would illuminate the origin of these conditions. The relationship between FT and current testosterone levels also needs to be clarified. The present results may be relevant to understanding the increased male risk to developing autism.     

Open-label add-on treatment trial of minocycline in fragile X syndrome

Background  

Fragile X syndrome (FXS) is a disorder characterized by a variety of disabilities, including cognitive deficits, attention-deficit/hyperactivity disorder, autism, and other socio-emotional problems. It is hypothesized that the absence of the fragile X mental retardation protein (FMRP) leads to higher levels of matrix metallo-proteinase-9 activity (MMP-9) in the brain. Minocycline inhibits MMP-9 activity, and alleviates behavioural and synapse abnormalities in fmr1 knockout mice, an established model for FXS. This open-label add-on pilot trial was conducted to evaluate safety and efficacy of minocycline in treating behavioural abnormalities that occur in humans with FXS.     

Ovarian dysgenesis in individuals with chromosomal abnormalities

Summary To understand better the pathogenesis of ovarian dysgenesis in individuals with abnormalities such as 45,X Turner syndrome, trisomy 13, and trisomy 18, we have examined microscopically the ovaries of 36 infants with a number of chromosomal abnormalities confirmed by karyotype analysis. All infants with trisomy 13, trisomy 18, triploidy, and 45,X were found to have severe ovarian dysgenesis characterized by a virtual absence of primary oocytes. The ovaries of individuals with 21 trisomy and of those with partial deletion or duplication of an autosome demonstrated variable findings, which ranged from complete absence of oocytes to a mild diminution of oocyte numbers. The results of this study suggest that the attrition of germ cells in these infants is a result of faulty meiotic pairing and that ovarian dysgenesis is a more frequent finding in children with karyotypic abnormalities than has been realized previously.Presented, in part, at the 1989 David W. Smith Morphogenesis and Malformations Conference, Madrid, 1989, and at the 1990 Southern Society for Pediatric Research Meeting, New Orleans, 1990     

Applying a quantitative genetics framework to behavioural syndrome research

Current interest in behavioural syndromes, or 'animal personalities', reinforces a need for behavioural ecologists to adopt a multivariate view of phenotypes. Fortunately, many of the methodological and theoretical issues currently being dealt with by behavioural ecologists within the context of behavioural syndromes have previously been investigated by researchers in other areas of evolutionary ecology. As a result of these previous efforts, behavioural syndrome researchers have considerable theory and a wide range of tools already available to them. Here, we discuss aspects of quantitative genetics useful for understanding the multivariate phenotype as well as the relevance of quantitative genetics to behavioural syndrome research. These methods not only allow the proper characterization of the multivariate behavioural phenotype and genotype-including behaviours within, among and independent of behavioural syndrome structures-but also allow predictions as to how populations may respond to selection on behaviours within syndromes. An application of a quantitative genetics framework to behavioural syndrome research also clarifies and refines the questions that should be asked.