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

Mental Retardation and Abnormal Skeletal Development (Dyggve-Melchior-Clausen Dysplasia) Due to Mutations in a Novel, Evolutionarily Conserved Gene

Dyggve-Melchior-Clausen dysplasia (DMC) and Smith-McCort dysplasia (SMC) are similar, rare autosomal recessive osteochondrodysplasias. The radiographic features and cartilage histology in DMC and SMC are identical. However, patients with DMC exhibit significant developmental delay and mental retardation, the major features that distinguish the two conditions. Linkage studies localized the SMC and DMC disease genes to chromosome 18q12-21.1, providing evidence suggesting that they are allelic disorders. Sequence analysis of the coding exons of the FLJ90130 gene, a highly evolutionarily conserved gene within the recombination interval defined in the linkage study, identified mutations in SMC and DMC patients. The affected individuals in two consanguinous DMC families were homozygous for a stop codon mutation and a frameshift mutation, respectively, demonstrating that DMC represents the FLJ90130-null phenotype. The data confirm the hypothesis that SMC and DMC are allelic disorders and identify a gene necessary for normal skeletal development and brain function

Bone Resorption in Syndromes of the Ras/MAPK Pathway

BACKGROUND: Disorders of the Ras/MAPK pathway have an overlapping skeletal phenotype (eg. scoliosis, osteopenia). The Ras proteins regulate cell proliferation and differentiation and NF1 individuals have osteoclast hyperactivity and increased bone resorption as measured by urine pyridinium crosslinks [pyridinoline (Pyd) and deoxypyridinoline (Dpd)]. Pyd and Dpd are hydroxylysine derived cross-links of collagen found in bone and cartilage and excreted in the urine. Dpd is most abundant in bone. The aim of this study was to evaluate if other syndromes of the Ras/MAPK pathway have increased bone resorption, which may impact the skeletal phenotype. METHODS AND RESULTS: Participants: [Noonan syndrome (n=14), Costello syndrome (n=21), and cardiofaciocutaneous (CFC) syndrome (n=14)]. Pyridinium cross-links from two consecutive first morning urines were extracted after acid hydrolysis and analyzed by High Performance Liquid Chromotography. Three separate analyses of covariance (ANCOVA) were performed to compare Pyd, Dpd, and Dpd/Pyd ratio of each group to controls after controlling for age. Data were compared to 99 healthy controls. CONCLUSIONS: The Dpd and the Dpd/Pyd ratio were elevated (p<0.0001) in all 3 conditions compared to controls suggesting that collagen degradation was predominantly from bone. The data suggest that the Ras/MAPK signal transduction pathway is important in bone homeostasis