Marni E. Axelrad

Costello syndrome associated with novel germline HRAS mutations: An attenuated phenotype?

Costello syndrome is a rare congenital disorder typically characterized by severe failure‐to‐thrive, cardiac abnormalities including tachyarrhythmia and hypertrophic cardiomyopathy, distinctive facial features, a predisposition to papillomata and malignant tumors, neurologic abnormalities, developmental delay, and mental retardation. Its underlying cause is de novo germline mutations in the oncogene HRAS. Almost all Costello syndrome mutations affect one of the glycine residues in position 12 or 13 of the protein product. More than 80% of patients with Costello syndrome share the same underlying mutation, resulting in a G12S amino acid change. We report on two patients with novel HRAS mutations affecting amino acids 58 (T58I) and 146 (A146V), respectively. Despite facial features that appear less coarse than those typically seen in Costello patients, both patients show many of the physical and developmental problems characteristic for Costello syndrome. These novel HRAS mutations may be less common than the frequently reported G12S change, or patients with these changes may be undiagnosed due to their less coarse facial features. In addition to the findings previously known to occur in Costello syndrome, one of our patients had hypertrophic pyloric stenosis. This led us to review the medical histories on a cohort of proven HRAS mutation positive Costello syndrome patients, and we found a statistically significantly (P < 0.001) increased frequency of pyloric stenosis in Costello syndrome (5/58) compared to the general population frequency of 2–3/1,000. Thus we add hypertrophic pyloric stenosis to the abnormalities seen with increased frequency in Costello syndrome.

Phenotypic analysis of individuals with Costello syndrome due to HRAS p.G13C

Costello syndrome is characterized by severe failure‐to‐thrive, short stature, cardiac abnormalities (heart defects, tachyarrhythmia, and hypertrophic cardiomyopathy (HCM)), distinctive facial features, a predisposition to papillomata and malignant tumors, postnatal cerebellar overgrowth resulting in Chiari 1 malformation, and cognitive disabilities. De novo germline mutations in the proto‐oncogene HRAS cause Costello syndrome. Most mutations affect the glycine residues in position 12 or 13, and more than 80% of patients share p.G12S. To test the hypothesis that subtle genotype–phenotype differences exist, we report the first cohort comparison between 12 Costello syndrome individuals with p.G13C and individuals with p.G12S. The individuals with p.G13C had many typical findings including polyhydramnios, failure‐to‐thrive, HCM, macrocephaly with posterior fossa crowding, and developmental delay. Subjectively, their facial features were less coarse. Statistically significant differences included the absence of multifocal atrial tachycardia (P‐value = 0.033), ulnar deviation of the wrist (P < 0.001) and papillomata (P = 0.003), and fewer neurosurgical procedures (P = 0.024). Fewer individuals with p.G13C had short stature (height below −2 SD) without use of growth hormone (P < 0.001). The noteworthy absence of malignant tumors did not reach statistical significance. Novel ectodermal findings were noted in individuals with p.G13C, including loose anagen hair resulting in easily pluckable hair with a matted appearance, different from the tight curls typical for most Costello syndrome individuals. Unusually long eye lashes requiring trimming are a novel finding we termed dolichocilia. These distinctive ectodermal findings suggest a cell type specific effect of this particular mutation. Additional patients are needed to validate these findings.

Longitudinal assessment of cognitive characteristics in Costello syndrome

Costello syndrome encompasses pre‐ and postnatal medical problems including polyhydramnios, failure to thrive, cardiac complications, and an increased risk for solid tumors. Hypotonia and developmental delay are typical in infancy, and mental retardation can be diagnosed in older patients. Previous studies on the cognitive development in Costello syndrome relied on clinically diagnosed cases. The recent discovery of heterozygous HRAS mutations allows for molecular confirmation of the clinical diagnoses. We report here on cognitive abilities and adaptive behavior in the first cohort of patients with molecularly confirmed diagnoses. Further, this is the first longitudinal assessment of cognitive function in this patient population. Sixteen patients with identified HRAS mutations were tested, and 14 completed the Leiter International Performance Scale—Revised. The mean Full‐Scale IQ score of 57 (range 30–87) was within the range of mild Mental Retardation. Analysis of test component subsets showed a relative strength in Fluid Reasoning with a mean score of 69 (range 48–98), in the mild range of Mental Retardation. Longitudinal analysis was performed for 12 patients by comparison of data obtained at the first evaluation (T1) to results obtained 2 years later (T2). In these patients intellectual and language abilities remained stable, and no deterioration was seen. We have thus shown that Costello syndrome is a static condition regarding intellectual and language abilities. The Leiter‐R Memory Screen indicated functioning in the mildly delayed range for the majority of patients. Adaptive behavior was evaluated using the Vineland tool, and longitudinal data comparison for adaptive behavior showed improvements in Daily Living Skills, Communication, and the Adaptive Behavior Composite. However, these results must be interpreted cautiously as the measuring tool was updated from T1 to T2. Receptive language skills were measured with the Peabody Picture Vocabulary Test‐III, showing a mean receptive vocabulary standard score of 65 (SD 15) in the Extremely Low range. Expressive language skills, as measured by the Expressive Vocabulary Test (EVT), scored a mean of 51 (SD 14), in the Extremely Low range. However, half of the subjects obtained the lowest possible score on the EVT, demonstrating that this is not the ideal tool for use in this patient population.

The Role of Parents

Having a child with a chronic illness places a substantial burden on parents. In early and middle childhood, the parent must shoulder complete responsibility for illness management; as the child enters adolescence, responsibility begins to be shared, and parenting gradually shifts from efforts to gain child compliance to efforts to support the youth’s increasing autonomy. This is a delicate dance, often fraught with the danger of descending into a cycle of parent-child conflict. Yet the research literature is very clear—maintaining positive parent involvement from childhood through even late adolescence is strongly associated with better adherence, better illness control, and better child quality of life. how to maintain involvement in a positive way without devolving into conflict is the focus of this chapter. We discuss important aspects of effective, positive parenting, and the ways parenting can go wrong despite only intending to do well.

Consensus in Guidelines for Evaluation of DSD by the Texas Children's Hospital Multidisciplinary Gender Medicine Team

The Gender Medicine Team (GMT), comprised of members with expertise in endocrinology, ethics, genetics, gynecology, pediatric surgery, psychology, and urology, at Texas Childrens Hospital and Baylor College of Medicine formed a task force to formulate a consensus statement on practice guidelines for managing disorders of sexual differentiation (DSD) and for making sex assignments. The GMT task force reviewed published evidence and incorporated findings from clinical experience. Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) was used to assess the quality of evidence presented in the literature for establishing evidence-based guidelines. The task force presents a consensus statement regarding specific diagnostic and therapeutic issues in the management of individuals who present with DSD. The consensus statement includes recommendations for (1) laboratory workup, (2) acute management, (3) sex assignment in an ethical framework that includes education and involvement of the parents, and (4) surgical management.

Feasibility, Acceptability, and Predictive Validity of a Psychosocial Screening Program for Children and Youth Newly Diagnosed With Type 1 Diabetes

OBJECTIVE Psychosocial screening has been recommended for pediatric patients with newly diagnosed type 1 diabetes and their families. Our objective was to assess a psychosocial screening protocol in its feasibility, acceptability to families, and ability to predict early emerging complications, nonadherent family behavior, and use of preventive psychology services. RESEARCH DESIGN AND METHODS A total of 125 patients and their caregivers were asked to participate in a standardized screening interview after admission at a large urban children’s hospital with a new diagnosis of type 1 diabetes. Medical records were reviewed for subsequent diabetes-related emergency department (ED) admissions, missed diabetes clinic appointments, and psychology follow-up within 9 months of diagnosis. RESULTS Of 125 families, 121 (96.8%) agreed to participate in the screening, and a subsample of 30 surveyed caregivers indicated high levels of satisfaction. Risk factors at diagnosis predicted subsequent ED admissions with a sensitivity of 100% and a specificity of 98.6%. Children from single-parent households with a history of behavior problems were nearly six times more likely to be seen in the ED after diagnosis. Missed appointments were likeliest among African Americans, 65% of whom missed at least one diabetes-related appointment. Psychology services for preventive intervention were underutilized, despite the high acceptability of the psychosocial screening. CONCLUSIONS Psychosocial screening of newly diagnosed patients with type 1 diabetes is feasible, acceptable to families, and able to identify families at risk for early emerging complications and nonadherence. Challenges remain with regards to reimbursement and fostering follow-up for preventive care.

Neurocognitive, Adaptive, and Behavioral Functioning of Individuals With Costello Syndrome: A Review

Costello syndrome is a rare rasopathy resulting from germline mutations of the proto‐oncogene HRAS. Its phenotype includes severe failure‐to‐thrive, cardiac abnormalities, a predisposition to benign and malignant tumors, hypotonia, and developmental delay. Costello syndrome is associated with cognitive impairment, including intellectual functioning generally in the mild to moderate range of disability, commensurate adaptive functioning, and increased anxiety. Relative strengths have been found for nonverbal fluid reasoning (FR). Gender effects have been reported, with females showing better adaptive functioning across domains. Developmentally, nonverbal skills plateau in late childhood/early adolescence, whereas the rate of vocabulary acquisition may increase in adolescence into early adulthood. Here we review the literature assessing cognitive, adaptive, and behavioral functioning in Costello syndrome, and we provide data from an ongoing longitudinal study. Severity of cognitive impairment may depend upon the specific HRAS mutation, as three individuals with the p.G13C change showed average nonverbal FR skills and borderline‐to‐low average overall nonverbal IQ. Further, separation anxiety is more common in Costello syndrome than in the general population, affecting 39% of this cohort, and males are more often overly anxious than females. Interrelations between anxiety and cognitive and adaptive functioning were found, pointing to functional difficulties as a likely source of stress and anxiety. Taking into account data from animal models, cognitive and behavioral changes likely originate from abnormal differentiation of neuronal precursor cells, which result in structural and functional brain differences.

Longitudinal course of cognitive, adaptive, and behavioral characteristics in Costello syndrome†

Costello syndrome is a rare rasopathy caused by germline mutations in the oncogene HRAS resulting in increased signal transduction through the Ras/mitogen‐activated protein kinase pathway. In contrast to the more common rasopathies, such as neurofibromatosis type 1 and Noonan syndrome, limited information is available on standardized cognitive testing in this cohort. Past research indicated a mean average IQ in the mild mental retardation range, with strengths in fluid reasoning (FR) and weakness in expressive language, as well as static skills over time. Here we report on standardized IQ and adaptive functioning in 18 individuals with Costello syndrome, nine males and nine females, and longitudinal development for 11 who had previous testing. The overall IQ, ranging from severe mental retardation to the average range, with a mean in the mildly mentally retarded range, was again found to be stable, but an interesting pattern in the development of nonverbal FR was identified. Participants showed an improvement in nonverbal FR, followed by stable skills thereafter, suggesting a “late bloomer” effect in late childhood/early adolescence. Overall adaptive functioning fell into the range of Intellectual Disability for 70% of subjects, with Socialization as a relative strength and Daily Living Skills an area of relative difficulty. Interestingly, females were found to be higher functioning than males in all domains, including Communication, Daily Living Skills and Socialization. Caregivers reported significantly more behavioral concerns in males, including internalizing, externalizing, and other maladaptive behaviors. In contrast, no gender differences were found in cognitive or visuomotor functioning.

Molecular aspects, clinical aspects and possible treatment modalities for Costello syndrome: Proceedings from the 1st International Costello Syndrome Research Symposium 2007.

Katherine A. Rauen,* Erin Hefner, Kristin Carrillo, Jill Taylor, Laure Messier, Yoko Aoki, Karen W. Gripp, Yoichi Matsubara, Virginia K. Proud, Peter Hammond, Judith E. Allanson, Marie-Ange Delrue, Marni E. Axelrad, Angela E. Lin, Daniel A. Doyle, Bronwyn Kerr, John C. Carey, Frank McCormick, Alcino J. Silva, Mark W. Kieran, Aleksander Hinek, Tan T. Nguyen, and Lisa Schoyer Department of Pediatrics, Division of Medical Genetics, University of California, San Francisco, California UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California Costello Syndrome Family Network, Altadena, California Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan Division of Medical Genetics, Alfred I. DuPont Hospital for Children, Wilmington, Delaware Children’s Hospital of the King’s Daughters, Norfolk, Virginia Molecular Medicine Unit, Institute of Child Health, UCL, London, UK Children’s Hospital of Eastern Ontario, Ontario, Canada Department of Medical Genetics, Centre Hospitalier Pellegrin Enfant, Bordeaux University, Bordeaux, France Learning Support Center for Child Psychology, Department of Pediatrics, Texas Children’s Hospital, Houston, Texas Genetics Unit, MassGeneral Hospital for Children, Boston, Massachusetts Division of Endocrinology, Alfred I. duPont Hospital for Children, Wilmington, Delaware Academic Unit of Medical Genetics, St. Mary’s Hospital, Manchester, UK Department of Pediatrics, Division of Medical Genetics, University of Utah Health Sciences Center, Salt Lake City, Utah Departments of Neurobiology, Psychology, and Psychiatry, Brain Research Institute, UCLA, Los Angeles, California Dana-Farber Cancer Institute, Department of Pediatric Oncology, Boston, Massachusetts Division of Cardiovascular Research, Hospital for Sick Children, Toronto, Canada Office of Orphan Products Development, Food and Drug Administration, Rockville, Maryland

Brief Behavioral Intervention for Young Children with Disruptive Behaviors

Parent reported behavioral difficulties in young children are relatively common. Without adequate intervention, some children will later present with more severe problem behaviors. Parent management training is one of the best methods of treatment for behavior problems; however, existing treatments can be lengthy and difficult to conduct outside of a research setting. The Brief Behavioral Intervention was designed as a briefer version of a manualized parent management training treatment package. Thirty-one parents of children aged 2–6.5 presenting with behavior problems were included in this initial study of treatment effectiveness. Based on parent and teacher report, treatment was effective in a mean of 7.2 sessions.