Personality and Psychopathology in Adults with Noonan Syndrome.

This is the first controlled study regarding personality and psychopathology in adults with Noonan syndrome (NS). Anxiety, depression, alexithymia and symptoms of Attention Deficit-Hyperactivity Disorder and Autism Spectrum Disorder, have been previously described in NS. More information regarding personality and psychopathology in NS could improve mental health care for this population. Therefore, scores on the Minnesota Multiphasic Personality Inventory-2-Restructured Form (MMPI-2-RF), a widely used self-report questionnaire of personality and psychopathology, were compared between patients with NS (n = 18) and matched, healthy controls (n = 18). Furthermore, correlations between MMPI-2-RF scores and alexithymia, measured by the Toronto Alexithymia Scale-20, were investigated. Patients with NS showed significantly higher scores, with medium effect sizes, on MMPI-2-RF scales reflecting infrequent responses (F-r), somatic and cognitive complaints (FBS-r and RBS-r), internalizing problems (EID), demoralization (RCd) and introversion (INTR-r), although the overall profile in both groups was within the non-clinical range. Alexithymia correlated with internalizing problems and negative emotionality in the patient group. In conclusion, patients with NS showed higher levels of introversion, which may predispose them to internalizing problems. These problems were indeed more frequent in patients with NS, especially higher levels of demoralization. Patients may benefit from psychological interventions aimed to decrease internalizing problems, introversion and alexithymia.

The Noonan Syndrome-linked Raf1L613V mutation drives increased glial number in the mouse cortex and enhanced learning.

RASopathies are a family of related syndromes caused by mutations in regulators of the RAS/Extracellular Regulated Kinase 1/2 (ERK1/2) signaling cascade that often result in neurological deficits. RASopathy mutations in upstream regulatory components, such as NF1, PTPN11/SHP2, and RAS have been well-characterized, but mutation-specific differences in the pathogenesis of nervous system abnormalities remain poorly understood, especially those involving mutations downstream of RAS. Here, we assessed cellular and behavioral phenotypes in mice expressing a Raf1L613V gain-of-function mutation associated with the RASopathy, Noonan Syndrome. We report that Raf1L613V/wt mutants do not exhibit a significantly altered number of excitatory or inhibitory neurons in the cortex. However, we observed a significant increase in the number of specific glial subtypes in the forebrain. The density of GFAP+ astrocytes was significantly increased in the adult Raf1L613V/wt cortex and hippocampus relative to controls. OLIG2+ oligodendrocyte progenitor cells were also increased in number in mutant cortices, but we detected no significant change in myelination. Behavioral analyses revealed no significant changes in voluntary locomotor activity, anxiety-like behavior, or sociability. Surprisingly, Raf1L613V/wt mice performed better than controls in select aspects of the water radial-arm maze, Morris water maze, and cued fear conditioning tasks. Overall, these data show that increased astrocyte and oligodendrocyte progenitor cell (OPC) density in the cortex coincides with enhanced cognition in Raf1L613V/wt mutants and further highlight the distinct effects of RASopathy mutations on nervous system development and function.

Social skills in children with RASopathies: a comparison of Noonan syndrome and neurofibromatosis type 1.

BACKGROUND: Gene mutations within the RAS-MAPK signaling cascade result in Noonan syndrome (NS), neurofibromatosis type 1 (NF1), and related disorders. Recent research has documented an increased risk for social difficulties and features of autism spectrum disorder (ASD) among children with these conditions. Despite this emerging evidence, the neuropsychological characteristics associated with social skills deficits are not well understood, particularly for children with NS. METHODS: Parents of children with NS (n = 39), NF1 (n = 39), and unaffected siblings (n = 32) between the ages of 8 and 16 years were administered well-validated caregiver questionnaires assessing their child's social skills, language abilities, attention-deficit hyperactivity disorder (ADHD) symptoms and anxiety. RESULTS: With respect to overall social skills, average ratings of children in both clinical groups were similar, and indicated weaker social skills compared to unaffected siblings. Although ratings of social skills were outside of normal limits for more than four in ten children within the clinical groups, most of the deficits were mild/moderate. Fifteen percent of the children with NS and 5% of the children with NF1 were rated as having severe social skills impairment (< - 2SD). Independent of diagnosis, having fewer ADHD symptoms or better social-pragmatic language skills was predictive of stronger social skills. CONCLUSIONS: Amidst efforts to support social skill development among children and adolescents with RASopathies, neuropsychological correlates such as social language competence, attention, and behavioral self-regulation could be important targets of intervention.

Understanding Treatment Burden for Children Treated for Growth Hormone Deficiency.

OBJECTIVE: Growth hormone deficiency (GHD) treatment for children requires growth hormone injections, typically administered daily until the child reaches adult height. Child GHD treatment burden is not well understood and no disease-specific measures exist to assess this burden. The purpose of the study was to explore GHD treatment burden for children and their parents by conducting concept elicitation interviews supporting a theoretical model of the impact of GHD treatment. METHODS: Four focus groups (in Germany) and 52 telephone interviews (in the UK and USA) were conducted with children/adolescents with GHD aged 8 to <13 years and parents of children with GHD aged ≥4 to <13 years. The purpose of the interviews was to understand the experience of GHD treatment from the child's perspective, and for parents, the impact of their child's treatment on themselves. Interview transcripts were analyzed thematically based on modified grounded theory principles. RESULTS: Interviews with 70 respondents who produced descriptions (n = 73) of patients experiences with GHD treatment (three parents spoke for two children each) were conducted. Analysis identified three major areas of GHD treatment burden for children: physical; emotional well-being; and interference. Parent burdens identified were: emotional well-being and interference. Modifiers such as treatment efficacy and duration, which may impact the degree of treatment burden severity, were identified. CONCLUSIONS: Overall treatment burden of child GHD is considerable for children and their parents. The concept elicitation and theoretical model can be used to develop a disease-specific outcome measure, which adequately reflects the burden of GHD treatment for children and their parents.

Características psicológicas en el síndrome de Noonan: a propósito de un caso / Psychological characteristics of Noonan syndrome: a case report

Se presenta un caso de Síndrome de Noonan (SN). El motivo de consulta es la sospecha de Trastorno por Déficit de Atención e Hiperactividad (TDAH). En el proceso de evaluación, y ante resultados en las pruebas aplicadas que no confirman este diagnóstico, los padres informaron que la paciente padece dicho síndrome. Se discute la importancia de futuras investigaciones que puedan ayudar a identificar un posible fenotipo conductual del síndrome

A case of Noonan Syndrome (NS) is presented. Consulting reason is an Attention deficit hyperactivity disorder (ADHD) suspicion. In the evaluation process and in the face of results in the applied tests, that does not confirm this diagnosis, the parents report that the patient has this syndrome. It is discussed the importance of future research that can help to identify a possible behavioral phenotype of the syndrome

Intellectual development in Noonan syndrome: a longitudinal study.

INTRODUCTION: Although cognitive impairments in adults with Noonan syndrome seem to be limited to a low-average intelligence and slower processing speed, studies in children with Noonan syndrome have demonstrated more extensive cognitive problems. These include deficits in language skills, memory, attention, and executive functioning. This longitudinal study is the first to investigate intellectual development in a group of individuals with Noonan syndrome. METHODS: Sixteen patients with Noonan syndrome underwent intelligence assessment both in childhood and in adulthood, using Wechsler's intelligence scales. IQ scores and Wechsler standard scores achieved in childhood and adulthood were compared. Subsequently, verbal and performance IQ in childhood were used as predictors for adult IQ and index scores. RESULTS: Compared with childhood scores, adult full-scale IQ and performance IQ significantly increased. Adult performance IQ was higher than verbal IQ. Childhood performance IQ and verbal IQ together predicted all adult IQ and index scores, except for the processing speed index. DISCUSSION: Childhood IQ was a significant predictor of adult intelligence in patients with Noonan syndrome. Performance IQ advanced to a normal level in adulthood, while verbal IQ did not develop proportionately, resulting in a discrepancy between adult performance IQ and verbal IQ. This finding could suggest a delay in the development of executive functioning in patients with Noonan syndrome, which seems to be outgrown in adulthood.

Alexithymia, emotion perception, and social assertiveness in adult women with Noonan and Turner syndromes.

Noonan syndrome (NS) and Turner syndrome (TS) are associated with cognitive problems and difficulties in affective information processing. While both phenotypes include short stature, facial dysmorphisms, and a webbed neck, genetic etiology and neuropsychological phenotype differ significantly. The present study examines putative differences in affective information processing and social assertiveness between adult women with NS and TS. Twenty-six women with NS, 40 women with TS, and 40 female controls were matched on age and intelligence, and subsequently compared on (1) alexithymia, measured by the Bermond-Vorst Alexithymia Questionnaire, (2) emotion perception, evaluated by the Emotion Recognition Task, and (3) social assertiveness and social discomfort, assessed by the Scale for Interpersonal Behavior. Women with TS showed higher levels of alexithymia than women with NS and controls (P-values < 0.001), whereas women with NS had more trouble recognizing angry facial expressions in comparison with controls (P = 0.01). No significant group differences were found for the frequency of social assertiveness and the level of social discomfort. Women with NS and TS demonstrated different patterns of impairment in affective information processing, in terms of alexithymia and emotion perception. The present findings suggest neuropsychological phenotyping to be helpful for the diagnosis of specific cognitive-affective deficits in genetic syndromes, for the enhancement of genetic counseling, and for the development of personalized treatment plans.

Learning and memory in children with Noonan syndrome.

Genetic syndromes resulting from molecular alterations of the RAS-MAPK signaling cascade have become the focus of heightened interest among behavioral scientists due to discoveries that proteins within this pathway play an important role in memory formation and consolidation. Individuals with Noonan syndrome (NS), caused by germline mutations in the RAS-MAPK pathway, exhibit wide variability in cognitive and memory skills. The current study aimed to characterize memory deficits that occur in some affected individuals as a key step toward understanding the neurocognitive effects of dysregulated Ras signaling. Learning and memory skills were assessed among 29 children and adolescents with NS using the Wide Range Assessment of Memory and Learning, Second Edition. Performance across subdomains (verbal memory, visual memory and working memory) was compared, as well as the effect of response type (free recall vs. recognition). For immediate memory, children with NS performed significantly better on verbal memory tasks than on visual memory or working memory tasks. For delayed memory, verbal free recall tasks that depend heavily on prefrontal-hippocampal networks were more challenging than recognition tasks that rely on more distributed temporal cortical regions. Additionally, verbal information presented in context was more easily retained than that presented in a rote format. The current study contributes to our knowledge of the effects of dysregulated RAS-MAPK signaling on the brain and behavior. Continued research on neurocognitive skills in NS has the potential to generate a novel conceptualization of how learning disabilities can arise from altered molecular processes within a specific biological pathway.

Cognitive functioning of adults with Noonan syndrome: a case-control study.

Noonan syndrome (NS) is a genetic disorder characterised by short stature, facial dysmorphia, congenital heart defects and mildly lowered intellectual abilities. Research has mainly focused on genetic and somatic aspects, while intellectual and cognitive functioning has been documented scarcely. Also, to date studies have been primarily performed in children. This is the first study in which functioning within the major cognitive domains is systematically evaluated in a group of adults with NS and compared with a control group. Extensive neuropsychological assessment, including the domains intelligence, speed of information processing, memory (working memory, immediate recall and delayed recall), executive function and visuoconstruction, was performed in a sample of 42 patients with NS and 42 healthy controls, matched on age, sex and education level. In addition, subjective cognitive complaints were assessed with self-report questionnaires. On the domain speed of information processing patients performed worse than controls (P < 0.05). Furthermore, except for slightly better results on delayed recall in the patients with NS (P < 0.05), none of the other cognitive domains showed between-group differences. On the questionnaires, patients reported substantially more complaints about their own cognitive abilities than controls (P < 0.05). A lowered speed of information processing and relatively intact functioning in other cognitive domains characterises the cognitive profile of adult patients, in contrast to previous findings in children with NS, who seem to have more generalised cognitive deficits.

The language phenotype of children and adolescents with Noonan syndrome.

PURPOSE: This study presents an analysis of language skills in individuals with Noonan syndrome (NS), an autosomal dominant genetic disorder. We investigated whether the language impairments affecting some individuals arise from deficits specifically within the linguistic system or whether they are associated with cognitive, perceptual, and motor factors. Comparisons of language abilities among the different NS genotypes were also conducted. METHOD: Sixty-six children and adolescents with NS were evaluated using standardized speech, language, and literacy assessments. Additional cognitive, perceptual, and motor tasks were administered to examine the relation of these factors to language development. Genotype was noted for those who underwent genetic testing. RESULTS: Language impairments were more frequent in NS than in the general population and were associated with higher risk for reading and spelling difficulties. Language was significantly correlated with nonverbal cognition, hearing ability, articulation, motor dexterity, and phonological memory. Genotype analyses suggest that the higher performance of SOS1-positive than PTPN11-positive individuals on language tasks was largely mediated by differences in cognitive ability. CONCLUSIONS: Our results indicate that variation in language skill in NS is closely related to cognitive, perceptual, and motor factors. It does not appear that specific aspects of language are selectively affected in this syndrome.

Effects of germline mutations in the Ras/MAPK signaling pathway on adaptive behavior: cardiofaciocutaneous syndrome and Noonan syndrome.

Cardiofaciocutaneous syndrome (CFC) and Noonan syndrome (NS) are two phenotypically overlapping genetic disorders whose underlying molecular etiologies affect a common signaling pathway. Mutations in the BRAF, MEK1, and MEK2 genes cause most cases of CFC and mutations in PTPN11, SOS1, KRAS, and RAF1 typically cause NS. Although both syndromes are associated with developmental delays of varying severity, the extent to which the behavioral profiles differ may shed light on the different roles these respective genes play in development of skills necessary for everyday functioning. In this study, profiles of adaptive behavior of individuals with CFC and NS who had confirmed pathogenic mutations in Ras/mitogen-activated protein kinase (MAPK) pathway genes were investigated. Patterns of strengths and weaknesses, age-related differences, and risk factors for difficulties in adaptive skills were assessed. Although genes acting more downstream in the Ras/MAPK pathway were associated with more difficulties in adaptive functioning than genes more upstream in the pathway, several inconsistencies highlight the wide spectrum of possible developmental courses in CFC and NS. Along with clinical and genetic factors, variables such as chronological age, gestational age at birth, and parental education levels accounted for significant variance in adaptive skills. Results indicate that there is wide heterogeneity in adaptive functioning in CFC and NS, but that these abilities are correlated to some extent with the specific disease-causing genes.

Neuropsychological and behavioral aspects of Noonan syndrome.

The current paper introduces concise neuropsychological assessment as an essential tool for studying the contribution of cognition and behavior in the expression of genetic syndromes, like Noonan syndrome (NS). Cognitive and behavioral findings in NS show intelligence scores across a wide range, with a mildly lowered average level. Language and motor development are often delayed, but no longer dysfunctional in adulthood. Continuing mild problems in selective and sustained attention are noted, as well as suboptimal organization skills and compromised abilities to structure complex information. These problems seem to culminate in learning difficulties, requiring attention for special needs in education. It seems that a complex of psychosocial immaturity, alexithymia and amenable traits is typical of NS patients. Consequently, psychopathology or psychological problems in leading a self-serving life may often remain underreported. This is why the authors advocate the integration of the domain of social cognition and personality in NS assessment.

Genotype differences in cognitive functioning in Noonan syndrome.

Noonan syndrome (NS) is an autosomal-dominant genetic disorder associated with highly variable features, including heart disease, short stature, minor facial anomalies and learning disabilities. Recent gene discoveries have laid the groundwork for exploring whether variability in the NS phenotype is related to differences at the genetic level. In this study, we examine the influence of both genotype and nongenotypic factors on cognitive functioning. Data are presented from 65 individuals with NS (ages 4-18) who were evaluated using standardized measures of intellectual functioning. The cohort included 33 individuals with PTPN11 mutations, 6 individuals with SOS1 mutations, 1 individual with a BRAF mutation and 25 participants with negative, incomplete or no genetic testing. Results indicate that genotype differences may account for some of the variation in cognitive ability in NS. Whereas cognitive impairments were common among individuals with PTPN11 mutations and those with unknown mutations, all of the individuals with SOS1 mutations exhibited verbal and nonverbal cognitive skills in the average range or higher. Participants with N308D and N308S mutations in PTPN11 also showed no (or mild) cognitive delays. Additional influences such as hearing loss, motor dexterity and parental education levels accounted for significant variability in cognitive outcomes. Severity of cardiac disease was not related to cognitive functioning. Our results suggest that some NS-causing mutations have a more marked impact on cognitive skills than others.

Noonan syndrome: psychological and psychiatric aspects.

Although Noonan syndrome (NS) is a disorder with a relatively high prevalence, virtually no information in adult patients is available about the psychological and psychopathological profile. In the present clinical report the first series of 10 NS patients from an ongoing project is presented. The purpose of the study is to investigate the psychopathology, social cognition and adaptation as well as the quality of life in NS patients aged 16 years or more. PTPN11 mutations were present in six patients and KRAS and SOS1 in one patient, respectively. In two patients no known mutation was found. The results demonstrate a variable level of intelligence and suggest moderately impaired social cognition in terms of emotion recognition and alexithymia. In some patients mild signs of anxiety and lowered mood are found that, however, do not meet the criteria for a specific psychiatric disorder. It is concluded that NS in adults is associated with a behavioral phenotype in which deficiencies in social and emotional recognition and expression may be key elements.

Noonan syndrome.

Noonan syndrome is a common autosomal dominant condition caused by multiple genes in the RasMAPK pathway. The adult phenotype can be extremely subtle, and many adults are diagnosed only after the birth of a more obviously affected child. Whether diagnosis is made in childhood or adulthood, initial and ongoing evaluation of many systems can have considerable health benefits.

Psychological profile of children with Noonan syndrome.

A cohort of 48 children with Noonan syndrome, with a mean age of 9 years 10 months (SD 3y 7mo; 28 males, 20 females), was recruited from a national study. Children were assessed using the Wechsler Intelligence Scales and Test of Motor Impairment-Revised (TOMI-R). The Piers-Harris Self-evaluation Questionnaire was also completed in a subgroup of age-appropriate children. Children's parents and teachers completed the Rutter A and B scales to assess of the degree of behavioural and emotional problems respectively. Mean Full-scale IQ score was 84, and one-quarter of the participants had learning disabilities. Verbal IQ tended to be slightly lower than Performance IQ. About half of the group showed evidence of mild to moderate impairment, confirming the impression of 'clumsiness/developmental coordination disorder' on the TOMI-R. Level of self-esteem, as determined by the Piers-Harris Questionnaire, was comparable to that of a standardized population. This research has identified some characteristic psychological features in Noonan syndrome. However, a specific behavioural phenotype could not be identified.

Alexithymia in Noonan syndrome.

Although Noonan syndrome is quite prevalent, there is a general paucity in the description of psychological and psychiatric aspects. In the present paper a 19-year-old female patient with Noonan syndrome is described who presented with anxiety symptoms. Mutation analysis in PTPN11, the NS1 gene on chromosome 12q24, showed no abnormalities. A diagnosis of panic disorder without agoraphobia was established. Treatment with citalopram resulted in a gradual decline of anxiety symptoms. The psychological profile was characterized by a prominent alexithymia. The main conclusion is that patients with Noonan syndrome might have deficits in emotional adaptative functions. It is hypothesized that alexithymia is a key feature of the behavioural phenotype.

Neuropsychological developmental change in a case with Noonan syndrome: longitudinal assessment.

The authors describe the neuropsychological development of a 10-year-old boy with Noonan syndrome. The subject's IQ showed normal intelligence, although there was a discrepancy between verbal and performance IQs. Visual perception was delayed, with clumsiness and inattention affecting his performance. Both visual perception and hyperactivity improved with the subject's general development, but his inattention seemed to increase after the age of 9. The behavioral features and cognitive profile of our case resembled those of attention-deficit/hyperactivity disorder. We recommend that clinicians should evaluate cautiously the specific profile of cognitive development in Noonan syndrome with particular focus on controlling the patient's inattention.