A Systematic Review of Evidence-Based Treatments for Adolescent and Adult Sexual Assault Victims.

BACKGROUND: Sexual assault (SA) is a serious crime that is a prevalent mental and public health problem. AIMS: Addressing the needs of SA victims and providing appropriate treatment are essential to reduce potential adverse short- and long-term outcomes. METHODS: Our team undertook an extensive systematic literature review (published between January 2006 and July 2021) to provide evidence-based mental health intervention recommendations for adolescent and adult victims of SA. Where SA-specific research was limited, the literature and clinical practice guidelines on treatments for trauma-induced post-traumatic stress disorder (PTSD) were reviewed to provide additional information to formulate recommendations. RESULTS: Findings strongly support several primary psychotherapy treatments: cognitive behavioral therapy, cognitive processing therapy, eye movement desensitization and reprocessing, narrative exposure therapy, and prolonged exposure therapy. Complementary (aerobic exercise, art, drama, and music therapy) and pharmacological treatments were explored. CONCLUSIONS: Mental health nurses who provide services for victims of SA can utilize this overview to guide recommendations for treatment of SA trauma and related PTSD symptoms to mitigate the short- and long-term negative impacts after a traumatic event. When victims of SA receive optimal mental health treatments, our communities benefit as victims heal and recover.

Treatment Delays in Nonsyndromic Craniosynostosis: A 30-Year Retrospective Case-Control Analysis of the Impact of Socioeconomic and Family Status on Access to Care.

BACKGROUND: Patients with nonsyndromic craniosynostosis (NSC) generally undergo corrective surgery before 1 year of age to the mitigate morbidities and risks of delayed repair. The cohort of patients who receive primary corrective surgery after 1 year and factors associated with their gaps to care is poorly characterized in literature. METHODS: A nested case-control study was conducted for NSC patients who underwent primary corrective surgery at our institution and affiliates between 1992 and 2022. Patients whose surgery occurred after 1 year of age were identified and matched 1:1 by surgical date to standard-care control subjects. Chart review was conducted to gather patient data regarding care timeline and sociodemographic characteristics. RESULTS: Odds of surgery after 1 year of age were increased in Black patients (odds ratio, 3.94; P < 0.001) and those insured by Medicaid (2.57, P = 0.018), with single caregivers (4.96, P = 0.002), and from lower-income areas (+1% per $1000 income decrease, P = 0.001). Delays associated with socioeconomic status primarily impacted timely access to a craniofacial provider, whereas caregiver status was associated with subspecialty level delays. These disparities were exacerbated in patients with sagittal and metopic synostosis, respectively. Patients with multisuture synostosis were susceptible to significant delays related to familial strain (foster status, insurer, and English proficiency). CONCLUSIONS: Patients from socioeconomically strained households face systemic barriers to accessing optimal NSC care; disparities may be exacerbated by the diagnostic/treatment complexities of specific types of craniosynostosis. Interventions at primary care and craniofacial specialist levels can decrease health care gaps and optimize outcomes for vulnerable patients.

Pediatric Orthognathic Surgery: A NSQIP-P Comparison of Peri-Operative Factors and Outcome Differences Between Cleft and Noncleft Patients.

OBJECTIVE: The present study aimed to investigate the risk factors, complication profiles, and clinical outcomes of cleft and noncleft patients undergoing single jaw (mandibular or LeFort 1) and bimaxillary (BSSO + LeFort 1). DESIGN: Retrospective Cross-sectional Study Setting: National Surgical Quality Improvement Program database 2018-2019. PATIENTS: Pediatric patients. INTERVENTIONS: Outcomes for mandibular, LeFort 1, and bimaxillary osteotomy were retrospectively evaluated for cleft and noncleft patients. MAIN OUTCOME MEASURES: Multivariate logistic regression was used to determine the odds of complications and length of stay for cleft and noncleft patients undergoing single jaw and double jaw surgery. RESULTS: 669 pediatric patient underwent orthognathic surgery in the study period; the majority received LF1 only (n = 385; 58.3%), followed by mandible only (n = 179; 27.1%), and bimaxillary (n = 105; 15.9%%). Cleft differences were present in 56% of LFI patients, 32% of mandibular patients, and 22% of bimaxillary patients. After multivariate adjustment, ASA class III was associated with nearly 400% increased odds of any complication including readmission and reoperation (OR = 5.99; CI [[1.54-23.32]], p < 0.01, and 65% increased LOS (ß-coefficient = 1.65, CI [1.37-1.99], p < 0.01). Presence of cleft was not significantly associated with odds of any complication (p = 0.69) nor increased LOS (p = 0.46) in this population. CONCLUSION: Complications remained low between surgery types among cleft and noncleft patients. The most significant risk factor in pediatric orthognathic surgery was not the presence of cleft but rather increased ASA class. Though common in patients seeking orthognathic surgery, cleft differences did not cause additional risk after adjustment for other variables.

New nurses apply only basic source evaluation criteria but realize their skills are lacking: More sophisticated approaches to teaching evaluation skills are required.

BACKGROUND: While information evaluation is an essential component of evidence based practice, it remains unclear how nurses perceive their own source evaluation skills and what evaluation criteria they typically apply. OBJECTIVES: This study aims to determine nurses' self-reported confidence in their evaluation skills and their actual source evaluation ability. The findings will guide information literacy instruction. METHODS: A questionnaire asked recently graduated nurses from four institutions in the Intermountain West (USA) to rate their confidence in evaluating information and to provide examples of evaluation criteria they typically applied. The quality of these criteria was rated by nursing librarians, then compared with reported confidence in evaluation, years employed as a nurse and highest degree level. RESULTS: While nurses' self-reported confidence levels about source evaluation largely matched their ability, their evaluation criteria showed a low level of sophistication and did not match the recommended criteria by professional organizations. Graduate education, not years of work experience, was predictive of the quality of criteria used by nurses, suggesting the importance of more instruction on source evaluation for nursing students. CONCLUSIONS: Nursing educators, including librarians, need to teach evaluation skills at the undergraduate level. Further investigation into building evaluation skills in nurses is warranted.

Preclinical Development of EBI-005: An IL-1 Receptor-1 Inhibitor for the Topical Ocular Treatment of Ocular Surface Inflammatory Diseases.

OBJECTIVE: Topical interleukin (IL)-1 receptor (R)1 blockade is therapeutically active in reducing signs and symptoms of dry eye disease. Herein, we describe in vitro and in vivo nonclinical Investigational New Drug (IND)-enabling studies of EBI-005, a novel protein chimera of IL-1ß and IL-1 receptor antagonist (IL-1Ra or anakinra) that potently binds IL-1R1 and blocks signaling. These studies provide an assessment of receptor affinity, drug bioavailability, immunogenic response, safety, and tolerability in mice and rabbits. METHODS: In vitro and in silico along with Good Laboratory Practices (GLP) and non-GLP in vivo studies in mice and rabbits assessed the topical ocular and systemic immunogenicity and toxicology of EBI-005. Animals were treated with EBI-005 once daily subcutaneously or four times daily by topical ocular administration for up to 6 weeks (with 2-week recovery phase). RESULTS: EBI-005 has 500 times higher affinity than anakinra to IL-1R1. Predictive immunogenicity testing suggested that EBI-005 is not more immunogenic. Systemic bioavailability of EBI-005 is low (1.4% in mice and 0.2% in rabbits) after topical ocular administration. EBI-005 penetrated into the anterior ocular tissues within 15 min of topical ocular administration. However, it is low or undetectable after 4 hr and does not form a depot after repeated topical ocular administration. EBI-005 was safe and well tolerated, and exposure to drug was maintained despite an antidrug antibody response after systemic administration, based on IND-enabling toxicology and safety pharmacology studies. CONCLUSIONS: Ocular doses of EBI-005 at 50 mg/mL in mice and rabbits totaling 0.15 mg/eye in mice and 1.5 mg/eye in rabbits, administered 4 times daily, did not produce adverse effects, and demonstrated excellent bioavailability in target tissues with low systemic exposure. In addition, immunogenic response to the drug did not cause adverse effects or diminish the drug's activity in most cases. The results support drug administration of the highest anticipated human clinical study dose of a 20 mg/mL solution (40 µL 3 times daily in each eye).

Exonic deletions in AUTS2 cause a syndromic form of intellectual disability and suggest a critical role for the C terminus.

Genomic rearrangements involving AUTS2 (7q11.22) are associated with autism and intellectual disability (ID), although evidence for causality is limited. By combining the results of diagnostic testing of 49,684 individuals, we identified 24 microdeletions that affect at least one exon of AUTS2, as well as one translocation and one inversion each with a breakpoint within the AUTS2 locus. Comparison of 17 well-characterized individuals enabled identification of a variable syndromic phenotype including ID, autism, short stature, microcephaly, cerebral palsy, and facial dysmorphisms. The dysmorphic features were more pronounced in persons with 3'AUTS2 deletions. This part of the gene is shown to encode a C-terminal isoform (with an alternative transcription start site) expressed in the human brain. Consistent with our genetic data, suppression of auts2 in zebrafish embryos caused microcephaly that could be rescued by either the full-length or the C-terminal isoform of AUTS2. Our observations demonstrate a causal role of AUTS2 in neurocognitive disorders, establish a hitherto unappreciated syndromic phenotype at this locus, and show how transcriptional complexity can underpin human pathology. The zebrafish model provides a valuable tool for investigating the etiology of AUTS2 syndrome and facilitating gene-function analysis in the future.

The Gene Pool: The Ethics of Genetics in Primary Care.

AIM: The purpose of this integrative review is to critically analyze the research literature regarding ethical principles that surround the integration of genetics and genomics in primary care clinical practice. BACKGROUND: Advanced practice nurses (APRNs) play an important role in the provision of primary care services, in the areas of obstetrics, pediatrics, family practice, and internal medicine. Advances in genetic and genomic science are infiltrating these day-to-day health-care systems and becoming an integral part of health-care delivery. It is imperative for primary care providers to understand the ethical, legal, and social implications of genetics and genomics. METHODS: A comprehensive multistep search of CINAHL, MEDLINE, Academic Search Premier, PsycINFO, Web of Science, and Scopus databases was conducted to identify primary research articles published from 2003 to 2015 that evaluated ethical issues related to genetics and genomics in U. S. primary care practice. A sample of 26 primary research articles met the inclusion criteria. Whittemore and Knafl's (2005) revised framework for integrative reviews was used to guide the analysis and assess the quality of the studies. Key findings from the studies are discussed according to Beauchamp and Childress's (2009) ethical principles of autonomy, beneficence, nonmaleficence, and justice. RESULTS: Research conducted to date is mainly qualitative and descriptive and the analysis revealed several ethical challenges to implementing genetics and genomics in primary care settings. CONCLUSION: The review suggests that there are several implications for research, education, and the development of primary care practice that support APRNs delivering genetic and genomic care while incorporating knowledge of ethical principles. More research needs to be conducted that evaluates the actual genetic/genomic ethical issues encountered by primary care providers.

Health literacy and obesity among native Hawaiian and Pacific Islanders in the United States.

OBJECTIVES: Our purpose was to describe relationships between demographic characteristics, body mass index (BMI), and health literacy among Native Hawaiians and other Pacific Islanders (NHPIs). DESIGN AND SAMPLE: In this cross-sectional survey, we interviewed 364 NHPI adults. MEASURES: We used Newest Vital Sign (NVS), a health literacy tool; measured heights and weights; and demographic questions. RESULTS: According to participants' NVS scores, 45.3% had at least a possibility of low health literacy. Lower NVS scores were associated with increased BMI (r = -0.12, p = .027) and increased age (r = -0.26, p < .001). Higher NVS scores were associated with higher incomes (r = 0.21, p = .001) and higher education (r = 0.27, p < .001). Women scored significantly better than men (t = -2.0, p = .05). Participants' NVS scores in Hawaii versus Utah were not significantly different (t = .26, p = .80). CONCLUSIONS: Pathways to health literacy are complex; however, age, income, education, and BMI explained a modest 19.95% of the combined variance in NVS scores. Public health nurses working to improve health literacy could include review of critical information on nutrition facts labels, frequently used calculations, and application of this information when making food choices.

Assessing genotype-phenotype correlation in Costello syndrome using a severity score.

PURPOSE: Costello syndrome, a rare genetic disorder with multisystemic involvement, is caused by germline HRAS mutations. Because several different missense mutations have been reported, a severity scoring system was developed to assess a possible genotype-phenotype correlation. METHODS: Records of 78 individuals with Costello syndrome were scored in early childhood, childhood, and young adulthood by a reviewer blinded to the individuals' specific mutations. These scores were based on certain medically relevant feeding, neurologic, orthopedic, endocrine, cardiac, malignancy, and mortality manifestations. Individuals' severity scores were then grouped by the particular HRAS mutation. The mixed-model approach for repeated-measures analysis of variance with unstructured within-subject correlation, pairwise comparisons, and contrast were used to determine whether the severity scores differed by mutation. RESULTS: Although the sample size was small, individuals with the p.G12A or p.G12C HRAS change were more severely affected than those with other HRAS mutations. Regardless of the mutation, severity did not increase significantly over time. CONCLUSION: Despite its limitations, including the small number of individuals with rare mutations and possibly incomplete medical records, this work providing the first quantitative assessment of phenotypic severity in a Costello syndrome cohort supports a medically relevant genotype-phenotype correlation.

Cardiac anomalies in Axenfeld-Rieger syndrome due to a novel FOXC1 mutation.

Axenfeld-Rieger syndrome (ARS) is an autosomal dominant condition characterized by ophthalmologic anterior segment abnormalities and extraocular findings including dental anomalies and redundant periumbilical skin. Intragenic mutations in the homeobox gene PITX2 or the transcription factor encoding FOXC1 were identified, and genomic rearrangements encompassing either gene also cause ARS. A molecular etiology is identified in 40-60%. Extraocular anomalies occur more often with intragenic PITX2 than FOXC1 mutations. We report on a patient with infantile glaucoma presenting at age 21 months with congestive heart failure due to a dysplastic arcade mitral valve necessitating valve replacement, and mildly hypoplastic left ventricular outflow tract and aortic arch. Family history included early onset glaucoma in four relatives; congenital hip dysplasia requiring surgery in three; and an atrial septal defect in the affected maternal grandmother. Despite the absence of dental or umbilical abnormalities, anterior chamber abnormalities consistent with ARS were present in affected individuals. Molecular testing revealed a novel FOXC1 mutation (c.508C>T; p.Arg170Trp) in the proband and his affected mother; other family members were unavailable. A literature review revealed four reports of congenital heart disease associated with intragenic FOXC1 mutations, and none with intragenic PITX2 mutations. Previously, mouse studies showed Foxc1 (Mf1) expression in the developing valves and atrial septum, supporting a causal relationship of FOXC1 mutations for valvar anomalies and ASD. Hip dysplasia in three family members suggests a role for FOXC1 in the femoral head dysplasia of de Hauwere syndrome with 6p25 deletions. Further reports of clinical and molecular diagnoses will clarify genotype-phenotype correlation.

Orthopedic manifestations and implications for individuals with Costello syndrome.

Costello syndrome is a rare genetic condition caused by heterozygous alterations in HRAS and characterized by multi-system abnormalities. Individuals with Costello syndrome usually present with severe feeding difficulties in infancy, short stature, coarse facial features, increased tumor risks, cardiac and neurological complications, intellectual disability and orthopedic complications. This study further defines the orthopedic manifestations affecting individuals with Costello syndrome. We studied 43 participants and performed medical records review, clinical examinations and orthopedic inquiry forms. In 23 participants, hip and or spinal imaging assessments were completed. Serial radiographs were analyzed when available. A total of 25 orthopedic manifestations were identified. Ten manifestations were seen in the majority of the participants: hypotonia (87%), ligamentous laxity (85%), scoliosis (63%), kyphosis (58%), characteristic hand deformities (85%), ulnar deviation of the wrist (63%), elbow (55%) and shoulder contractures (65%), tight Achilles tendon (73%), and pes planus (53%). Other characteristics of special note were hip dysplasia (45%), foot deformities requiring surgical intervention (38%) and osteopenia/osteoporosis (47%). We also studied the development of the hips and spine. Uni- or bilateral hip dysplasia was congenital in some, while it developed throughout childhood in others. Spinal involvement included scoliosis, kyphosis, lordosis, and curvature reversal (thoracic lordosis and lumbar kyphosis). Based on these findings, we recommend routine referral to an orthopedic surgeon as well as instituting screening protocols for hips and spine for individuals with Costello syndrome.

The duplication 17p13.3 phenotype: analysis of 21 families delineates developmental, behavioral and brain abnormalities, and rare variant phenotypes.

Chromosome 17p13.3 is a gene rich region that when deleted is associated with the well-known Miller-Dieker syndrome. A recently described duplication syndrome involving this region has been associated with intellectual impairment, autism and occasional brain MRI abnormalities. We report 34 additional patients from 21 families to further delineate the clinical, neurological, behavioral, and brain imaging findings. We found a highly diverse phenotype with inter- and intrafamilial variability, especially in cognitive development. The most specific phenotype occurred in individuals with large duplications that include both the YWHAE and LIS1 genes. These patients had a relatively distinct facial phenotype and frequent structural brain abnormalities involving the corpus callosum, cerebellar vermis, and cranial base. Autism spectrum disorders were seen in a third of duplication probands, most commonly in those with duplications of YWHAE and flanking genes such as CRK. The typical neurobehavioral phenotype was usually seen in those with the larger duplications. We did not confirm the association of early overgrowth with involvement of YWHAE and CRK, or growth failure with duplications of LIS1. Older patients were often overweight. Three variant phenotypes included cleft lip/palate (CLP), split hand/foot with long bone deficiency (SHFLD), and a connective tissue phenotype resembling Marfan syndrome. The duplications in patients with clefts appear to disrupt ABR, while the SHFLD phenotype was associated with duplication of BHLHA9 as noted in two recent reports. The connective tissue phenotype did not have a convincing critical region. Our experience with this large cohort expands knowledge of this diverse duplication syndrome.

Epidemiology and Etiology of Facial Injuries in Children.

Pediatric Trauma results in over 8 million emergency department visits and 11,000 deaths annually. Unintentional injuries continue to be the leader in morbidity and mortality in pediatric and adolescent populations in the United States. More than 10% of all visits to pediatric emergency rooms (ER) present with craniofacial injuries. The most common etiologies for facial injuries in children and adolescence are motor vehicle accidents, assault, accidental injuries, sports injuries, nonaccidental injuries (eg, child abuse) and penetrating injuries. In the United States, head trauma secondary to abuse is the leading cause of mortality among non-accidental trauma in this population.

Determining the affinities of high-affinity antibodies using KinExA and surface plasmon resonance.

Accurate and efficient affinity measurement techniques are essential for the biophysical characterization of therapeutic monoclonal antibodies, one of the fastest growing drug classes. Surface plasmon resonance (SPR) is widely used for determining antibody affinity, but does not perform well with extremely high affinity (low picomolar to femtomolar range) molecules. In this study, we compare the SPR-based Carterra LSA and the kinetic exclusion assay (KinExA) for measuring the affinities of 48 antibodies generated against the SARS-CoV-2 receptor-binding domain. These data reveal that high-affinity antibodies can be generated straight from selections using high-quality in vitro library platforms with 54% correspondence between affinities measured using LSA and KinExA. Generally, where there was a 2-fold or greater difference between LSA and KinExA, KinExA reported that affinities were tighter. We highlight the differences between LSA and KinExA, identifying the benefits and pitfalls of each in terms of dynamic range and throughput. Furthermore, we demonstrate for the first time that single-point screening with KinExA can significantly improve throughput while maintaining a strong correlation with full binding curve equilibrium measurements, enabling the accurate rank-ordering of clones with exceptionally tight binding properties.

Transmission of the rare HRAS mutation (c. 173C > T; p.T58I) further illustrates its attenuated phenotype.

Costello syndrome was delineated based on its distinctive phenotype including severe failure-to-thrive with macrocephaly, characteristic facial features, hypertrophic cardiomyopathy, papillomata, malignant tumors, and cognitive impairment. Heterozygous germline mutations in the proto-oncogene HRAS cause Costello syndrome, and its inheritance pattern would thus be autosomal dominant. With exception of two instances of parental mosaicism, one presumed gonadal and the other proven somatic mosaicism for the p.G12S change, all published cases resulted from de novo mutations, typically arising in the paternal germline. More than 90% of these mutations affect the glycine residues in position 12 or 13, and result in a gain-of-function of the altered protein. A rare heterozygous HRAS alteration (c.173C > T; p.T58I) associated with an attenuated phenotype was previously reported in one patient. We identified two additional individuals with this mutation, father and son. Further studies supported origin of the alteration in the grand-paternal germline. Transmission of the mutation underscores its attenuated phenotype compatible with reproduction. We reviewed the phenotype in the newly identified individuals (Patient 1, 2) and include updated information on the first previously reported individual with HRAS p.T58I (Patient 3). Macrocephaly was present in all three. Cardiac findings included hypertrophic cardiomyopathy with double-chambered right ventricle; or mitral valve prolapse in one patient each. While subtle neurologic abnormalities or developmental delay were present in all, only one showed significant cognitive and functional impairment. None developed papillomata or a malignant tumor. Genetic counseling for Costello syndrome needs to take into consideration the particular HRAS mutation.

A novel HRAS substitution (c.266C>G; p.S89C) resulting in decreased downstream signaling suggests a new dimension of RAS pathway dysregulation in human development.

Costello syndrome is caused by HRAS germline mutations affecting Gly(12) or Gly(13) in >90% of cases and these are associated with a relatively homogeneous phenotype. Rarer mutations in other HRAS codons were reported in patients with an attenuated or mild phenotype. Disease-associated HRAS missense mutations result in constitutive HRAS activation and increased RAF-MEK-ERK and PI3K-AKT signal flow. Here we report on a novel heterozygous HRAS germline alteration, c.266C>G (p.S89C), in a girl presenting with severe fetal hydrops and pleural effusion, followed by a more benign postnatal course. A sibling with the same mutation and fetal polyhydramnios showed a Dandy-Walker malformation; his postnatal course was complicated by severe feeding difficulties. Their apparently asymptomatic father is heterozygous for the c.266C>G change. By functional analyses we identified reduced levels of active HRAS(S89C) and diminished MEK, ERK and AKT phosphorylation in cells overexpressing HRAS(S89C) , which represent novel consequences of disease-associated HRAS mutations. Given our patients' difficult neonatal course and presence of this change in their asymptomatic father, we hypothesize that its harmful consequences may be time limited, with the late fetal stage being most sensitive. Alternatively, the phenotype may develop only in the presence of an additional as-yet-unknown genetic modifier. While the pathogenicity of the HRAS c.266C>G change remains unproven, our data may illustrate wide functional and phenotypic variability of germline HRAS mutations.

Megalencephaly-capillary malformation (MCAP) and megalencephaly-polydactyly-polymicrogyria-hydrocephalus (MPPH) syndromes: two closely related disorders of brain overgrowth and abnormal brain and body morphogenesis.

The macrocephaly-capillary malformation syndrome (M-CM), which we here propose to rename the megalencephaly-capillary malformation syndrome (MCAP; alternatively the megalencephaly-capillary malformation-polymicrogyria syndrome), and the more recently described megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH) are two megalencephaly (MEG) disorders that involve a unique constellation of physical and neuroimaging anomalies. We compare the features in 42 patients evaluated for physical and neuroimaging characteristics of MCAP and MPPH and propose a more global view of these syndromes based on classes of developmental abnormalities that include primary MEG and growth dysregulation, developmental vascular anomalies (primarily capillary malformations), distal limb anomalies (such as syndactyly and polydactyly), cortical brain malformations (most distinctively polymicrogyria, PMG), and variable connective tissue dysplasia. Based on these classes of developmental abnormalities, we propose that MCAP diagnostic criteria include progressive MEG with either vascular anomalies or syndactyly. In parallel, we propose that MPPH diagnostic criteria include progressive MEG and PMG, absence of the vascular anomalies and syndactyly characteristic of MCAP, and absence of brain heterotopia.

Normative growth charts for individuals with Costello syndrome.

Costello syndrome is a rare condition due to heterozygous germline mutations in the proto-oncogene HRAS. It affects multiple organ systems and includes severe failure-to-thrive, short stature, and macrocephaly. The goal of this study was to develop Costello syndrome-specific growth curves. We collected height, weight, and head circumference (OFC) measurements from 94 individuals (45 males and 49 females). Their HRAS mutation spectrum reflects previously published cohorts, with p.G12S in 77.7%. Participants received medical care, therefore our data does not reflect natural history per se, but rather growth with nutritional support. Due to limited cohort size, we analyzed data from males and females together. Weight-for-age data included 417 separate measurements from 80 individuals age 0-36 months, and 585 measurements from 82 individuals for age 0-10 years. Height-for-age data were derived from 391 measurements from 77 individuals age 0-36 months, and 591 measurements from 90 individuals age 0-10 years. Measurements obtained after growth hormone exposure in 15 individuals were excluded in this analysis. The OFC curve was derived from 221 measurements from 55 individuals age 0-36 months. Centiles (5th, 50th, and 95th) were estimated across the age continuum for each growth parameter, and compared to gender-specific curves for average stature individuals. The resulting curves demonstrate very slow weight gain in the first 2 years. Short stature is seen in many, but after age 4 years the 95th centile for height falls within the low normal range for average stature children. Head circumference curves largely overlap those for average stature, reflecting relative macrocephaly.

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.

Molecular confirmation of HRAS p.G12S in siblings with Costello syndrome.

Costello syndrome was first reported based on its characteristic phenotype. Its presentation affects multiple organ systems, including severe failure-to-thrive with macrocephaly, characteristic facial features, hypertrophic cardiomyopathy, papillomata, malignant tumors, and cognitive impairment. Heterozygous germline mutations in the proto-oncogene HRAS have been recognized to cause Costello syndrome, and its inheritance pattern would thus be autosomal dominant. Here, we report on the identification of an HRAS mutation c.34G>A, predicting a p.G12S amino acid substitution, in the surviving brother of a previously reported sibling pair, and documentation of the same change in autopsy material from his deceased sister. This represents, to our knowledge, the first molecularly confirmed Costello syndrome in siblings. We did not detect the mutation in a heterozygous state or mosaicism in peripheral white blood cell or cheek swab-derived DNA samples from either parent. Using single nucleotide polymorphic markers and allele-specific amplification, we clearly identified the mutation in the surviving sibling to be of maternal origin. While we cannot exclude two independently occurring de novo mutations, the complete sharing of polymorphic markers around the mutation site in both siblings supports maternal germ cell mosaicism. Recurrence risk counseling for families with apparently de novo occurring autosomal dominant conditions includes discussion of germ cell mosaicism, and this report underscores the applicability of this concern to Costello syndrome.