Cardio-Facio-Cutaneous Syndrome: Clinical Features, Diagnosis, and Management Guidelines

Cardio-facio-cutaneous syndrome (CFC) is one of the RASopathies that bears many clinical features in common with the other syndromes in this group, most notably Noonan syndrome and Costello syndrome. CFC is genetically heterogeneous and caused by gene mutations in the Ras/mitogen-activated protein kinase pathway. the major features of CFC include characteristic craniofacial dysmorphology, congenital heart disease, dermatologic abnormalities, growth retardation, and intellectual disability. It is essential that this condition be differentiated from other RASopathies, as a correct diagnosis is important for appropriate medical management and determining recurrence risk. Children and adults with CFC require multidisciplinary care from specialists, and the need for comprehensive management has been apparent to families and health care professionals caring for affected individuals. To address this need, CFC International, a nonprofit family support organization that provides a forum for information, support, and facilitation of research in basic medical and social issues affecting individuals with CFC, organized a consensus conference. Experts in multiple medical specialties provided clinical management guidelines for pediatricians and other care providers. These guidelines will assist in an accurate diagnosis of individuals with CFC, provide best practice recommendations, and facilitate long-term medical care.CFC International, Vestal, New YorkNational Institutes of HealthNational Institutes of Health (NIH)Univ Minnesota, Dept Pediat & Ophthalmol, Div Genet & Metab, Minneapolis, MN 55454 USAUniv Minnesota, Dept Pediat, Div Clin Behav Neuroscience, Minneapolis, MN 55454 USAChildrens Hosp & Clin Minnesota, St Paul, MN USATexas Childrens Hosp, Dept Mol & Human Genet, Houston, TX 77030 USABaylor Coll Med, Houston, TX 77030 USABenioff Childrens Hosp, Madison Clin Pediat Diabet, San Francisco, CA USAUniv Calif San Francisco, San Francisco, CA 94143 USAUniversidade Federal de São Paulo, Med Genet Ctr, São Paulo, BrazilCatholic Univ, A Gemelli Sch Med, Inst Med Genet, Rome, ItalyUniv Kentucky, Dept Pediat, Lexington, KY USAUniv Texas Hlth Sci Ctr San Antonio, Dept Orthoped, San Antonio, TX 78229 USABoston Childrens Hosp, Dept Cardiol, Boston, MA USABoston Childrens Hosp, Div Genet, Boston, MA USAHarvard Univ, Sch Med, Boston, MA USAEmory Univ, Sch Med, Dept Human Genet, Atlanta, GA USAEmory Univ, Sch Med, Dept Ophthalmol, Atlanta, GA 30322 USAUniv Calif San Francisco, Dept Neurol, San Francisco, CA USAYoungstown State Univ, Special Educ & Sch Psychol, Dept Counseling, Youngstown, OH 44555 USACFC Int, Vestal, NY USAUniv Calif Davis, UC Davis MIND Inst, Dept Pediat, Div Genom Med, Sacramento, CA 95817 USAUniversidade Federal de São Paulo, Med Genet Ctr, São Paulo, BrazilNational Institutes of Health: R01-AR062165Web of Scienc

Expanding the clinical and genetic spectrum of ALPK3 variants: Phenotypes identified in pediatric cardiomyopathy patients and adults with heterozygous variants

Introduction: Biallelic damaging variants in ALPK3, encoding alpha-protein kinase 3, cause pediatric-onset cardiomyopathy with manifestations that are incompletely defined. Methods and Results: We analyzed clinical manifestations of damaging biallelic ALPK3 variants in 19 pediatric patients, including nine previously published cases. Among these, 11 loss-of-function (LoF) variants, seven compound LoF and deleterious missense variants, and one homozygous deleterious missense variant were identified. Among 18 live-born patients, 8 exhibited neonatal dilated cardiomyopathy (44.4%; 95% CI: 21.5%-69.2%) that subsequently transitioned into ventricular hypertrophy. The majority of patients had extracardiac phenotypes, including contractures, scoliosis, cleft palate, and facial dysmorphisms. We observed no association between variant type or location, disease severity, and/or extracardiac manifestations. Myocardial histopathology showed focal cardiomyocyte hypertrophy, subendocardial fibroelastosis in patients under 4 years of age, and myofibrillar disarray in adults. Rare heterozygous ALPK3 variants were also assessed in adult-onset cardiomyopathy patients. Among 1548 Dutch patients referred for initial genetic analyses, we identified 39 individuals with rare heterozygous ALPK3 variants (2.5%; 95% CI: 1.8%-3.4%), including 26 missense and 10 LoF variants. Among 149 U.S. patients without pathogenic variants in 83 cardiomyopathy-related genes, we identified six missense and nine LoF ALPK3 variants (10.1%; 95% CI: 5.7%-16.1%). LoF ALPK3 variants were increased in comparison to matched controls (Dutch cohort, P = 1.6×10−5; U.S. cohort, P = 2.2×10−13). Conclusion: Biallelic damaging ALPK3 variants cause pediatric cardiomyopathy manifested by DCM transitioning to hypertrophy, often with poor contractile function. Additional extracardiac features occur in most patients, including musculoskeletal abnormalities and cleft palate. Heterozygous LoF ALPK3 variants are enriched in adults with cardiomyopathy and may contribute to their cardiomyopathy. Adults with ALPK3 LoF variants therefore warrant evaluations for cardiomyopathy

Correction: Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype–phenotype correlation

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CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum

Purpose: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD). Methods: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function. Results: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits. Conclusion: We significantly broaden the mutational and clinical spectrum of CTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila.Peer reviewe

Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype–phenotype correlation

Purpose: Neurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors. Methods: A total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study. Results: None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_297

Variability in neuropsychological functioning in patients with downstream RAS pathway mutations. Poster presented at the 47th Annual Meeting of the International Neuropsychological Society. New York, NY.

Objective: Gene mutations within the Ras-mitogen-activated protein kinase (RAS-MAPK) signaling cascade have been associated with multiple genetic syndromes with varying degrees of neurocognitive impairment. Current research has focused on how specific molecular alterations in RAS pathway genes may predict the presence and severity of neurocognitive sequelae. Results from cohort studies suggest greater frequency of neurocognitive and adaptive impairment with more downstream mutations (i.e., Cesarini et al., 2009; Pierpont et al., 2010), with a high degree of variability noted across individuals with the mutations in the same gene (e.g., Pierpont et al., 2016). The aim of the current study was to examine the neurocognitive profiles of individuals with downstream RAS pathway mutations. Participants and Methods: Participants (ages 3-24) with MEK2 (n=3), BRAF (n=4), and KRAS (n=6) mutations were administered neurocognitive evaluations, including measures of nonverbal intellectual ability, receptive vocabulary, and adaptive functioning. Nonverbal reasoning (DAS-II & KBIT-2) and receptive vocabulary (PPVT-IV) scores were compared alongside overall parent-rated adaptive skills (Vineland-3). Results: More than half of the sample (54%) met criteria for intellectual disability, with significant neurocognitive variability among the remaining participants. Parent-rated adaptive functioning was generally higher in those patients whose verbal skills were relatively strong compared to nonverbal abilities. Further exploration of adaptive functioning skills indicated relative strengths in social skills for the majority of the current sample. Conclusions: While there was a high degree of variability across participants, patterns of cognitive and adaptive functioning emerged based on the specific gene mutation. The BRAF mutation was associated with a greater degree of neurocognitive impairment. Study findings may assist with guiding treatment planning and family-based interventions