Management Recommendations for CFC

Clinical SpecialtyRecommendations
GeneticsAt risk for CFC based upon physical examination, developmental history, and medical history.
At diagnosis:
• Genetics consultation.
• Genetic testing directed by a geneticist/genetics provider using multigene Ras/MAPK pathway panel testing (if available). Approximately 80% mutation detection rate for CFC.
• Consider sequential gene testing if panel testing is not available: (1) BRAF, (2) MEK1 and MEK2, and (3) KRAS
• Parental testing if variant of uncertain significance is detected.
• Consider high-resolution chromosome microarray if gene testing is negative.
• If the above testing is negative, the geneticist/genetics provider can determine if exome sequencing is appropriate.
Ongoing management:
• Annual follow-up with geneticist/genetics provider or specialty Ras pathway clinic.
CardiovascularAt risk for pulmonary stenosis, HCM, septal defects.
At diagnosis:
• Echocardiogram, electrocardiogram.
• Consultation with a cardiologist if murmur present or if clinical features suggest CFC or other RASopathy.
Ongoing management:
• Cardiology follow-up if cardiac disease found at diagnosis or at each of the age intervals below. Cardiologist will decide on necessity for cardiac catheterization, interventional procedures, or surgical procedures depending on the individual cardiac abnormalities of each patient.
• Infancy up to 1 y: If arrhythmias present, 24-h Holter evaluation.
• Childhood and adolescence (up to 20 y): If no cardiac disease found initially, repeat echocardiogram every 2–3 y. Measurement of blood pressure at each visit.
• Adulthood (>20 y): Echocardiogram every 3–5 y if no previous heart disease found. Measurement of blood pressure at each visit.
DermatologicAt risk for keratosis pilaris, ulerythema ophryogenes, eczema, progressive multiple pigmented nevi, dystrophic nails, lymphedema, hemangiomas, hyperkeratosis, and generalized hyperpigmentation.
At diagnosis:
• Consultation with a dermatologist.
• Evaluation of hemangiomas.
• Evaluation of pigmented nevi.
• If lymphedema present, referral to vascular specialist/clinic.
Ongoing management:
• Frequent dermatology visits for management of xerosis, hyperkeratosis, and eczema.
• Annual evaluation of pigmented nevi.
• Referral to a podiatrist for dystrophic nails or hyperkeratosis if needed.
• Monitor for lymphedema.
• Meticulous skin care and early treatment of skin infection in the context of lymphedema.
• Sun protection as recommended for the general population (ie, sunscreen; hats).
NeurologicAt risk for infantile spasms, seizures, hydrocephalus, type I Chiari malformation, and other structural brain anomalies.
At diagnosis:
• Referral to neurologist for a baseline evaluation.
• Families should receive anticipatory guidance about the risk of seizures (infantile spasms, other seizure types) and other neurologic issues.
• Brain MRI should be obtained in cases of rapid increase in head growth, infantile spasms, changes in neurologic examination, and regression of skills.
• EEG if there is a suspicion of seizure activity.
• Accurate seizure classification with clinical history and EEG to help guide medical management.
Ongoing management:
• Continued follow-up with neurologist for seizure management (if present).
• In child with infantile spasms, consult with cardiologist for possible steroid management due to risk of cardiomyopathy.
• If peripheral neuropathy suspected, consult with neurologist for nerve conduction velocities and electromyogram.
Cognitive and behavioralAt risk for intellectual disability, delayed fine and gross motor skills, emotional and behavioral problems, atypical sensory processing, and speech/language impairments.
At diagnosis:
• Referral to early childhood services or local school system for needs assessment and intervention.
• Speech and language evaluation including assessment of oral-motor functioning, articulation, and expressive/receptive language ability. Speech and language therapy as indicated based on evaluation. For severe delays, consideration of alternative or augmentative communication systems.
• Physical therapy (specific attention to hypotonia and gross motor delay).
• Occupational therapy (specific attention to hypotonia, sensory integration, and vision concerns).
• Behavioral therapy, mental health services, and/or alternative therapies may be considered to address behavioral, sensory, motor, social, emotional, and/or communication concerns.
Ongoing management:
• Continued evaluation and services by early childhood intervention programs in early childhood.
• Upon school entry, physician referral for a full neuropsychological evaluation.
• Upon school entry, school professionals and families should collaboratively develop an Individualized Education Plan (IEP) and/or other accommodation plan. Clarity should be established regarding medical diagnosis and eligibility for special education services.
• If behavioral concerns exist, a functional behavior assessment may be indicated to assist in development of a behavior intervention plan (specific attention to sensory concerns, communication skills, and attentional ability).
GastrointestinalAt risk for feeding and/or swallowing difficulties, FTT, constipation, gastroesophageal reflux, and intestinal malrotation.
At diagnosis:
• Nutrition assessment/growth measurements by primary physician.
• Refer to gastroenterologist in early infancy for feeding difficulties, gastroesophageal reflux, and poor growth.
• If feeding difficulties are present, referral for feeding therapy evaluation and recommendations.
• Evaluate for gastroesophageal reflux and swallowing dysfunction by swallowing studies, pH studies, upper gastrointestinal series, and endoscopy studies as recommended by gastroenterologist.
• Consider treatment with proton pump inhibitors for gastroesophageal reflux.
• Consider assisted feeding for FTT (nasogastric or gastrostomy tube), found to be necessary in 40% to 50% with CFC. Surgical recommendations to be assisted by gastroenterologist.
• If feeding difficulties are present, then refer for feeding therapy evaluation.
Ongoing management:
• Regular follow-up to monitor growth and nutrition.
• Continued feeding therapy if there are persistent feeding difficulties.
• Treatment of gastroesophageal reflux and constipation as needed as children get older
Growth/endocrineAt risk for failure to thrive, short stature, GH deficiency, GH resistance, and delayed puberty.
At diagnosis:
• Refer to endocrinologist between ages 2 and 3 y for growth monitoring or earlier if there are concerns about growth.
• Obtain thyrotropin, free thyroxine, IGF-1, and IGF-BP3 levels because thyroid and GH abnormalities are seen in other RASopathies.
• Nutritional assessment/growth measurements by primary physician.
Ongoing management:
• Monitor growth carefully (height, weight, and head circumference at each visit) and refer to appropriate specialists if significant change in growth curves (eg, endocrinologist, gastroenterologist, neurologist, or neurosurgeon).
• Regular follow-up by endocrinologist if growth failure, GH deficiency, or thyroid hormone abnormality.
• If growth failure: thyroid function studies, celiac disease screening, GH stimulation studies to be directed by endocrinologist.
• Monitor pubertal development beginning around age 10 y.
MusculoskeletalAt risk for hypotonia with decreased muscle, scoliosis, pes planus, joint contractures, hip dysplasia, and pectus deformities.
At diagnosis:
• Referral to a pediatric orthopedist.
Ongoing management:
• Radiograph of thoracolumbar spine, pelvis and lateral radiograph of cervical spine depending on clinical findings of child.
• For those who are not ambulatory: AP radiographs of pelvis every 2 y to monitor for hip dysplasia.
• Monitor for scoliosis.
• Spine MRI before any spinal surgery.
• Long-term follow-up with orthopedist as appropriate.
• Before orthopedic surgery, see hematologic recommendations.
• Bone density scan in young adults.
OphthalmologyAt risk for ptosis, amblyopia, refractive errors, strabismus, cataracts, optic nerve hypoplasia, optic atrophy, cortical visual impairment, delayed visual maturation, and abnormal depth perception.
At diagnosis:
• Referral to a pediatric ophthalmologist.
• Early intervention as appropriate (ie, correction of ptosis, prescription glasses for refractive errors or strabismus, patching for amblyopia).
Ongoing management:
• Follow-up every 6–12 mo or more frequently as recommended by ophthalmologist.
• Visual functional assessment by early childhood programs and vision resources for poor vision and abnormal depth perception.
• In those with optic nerve abnormalities, MRI of brain should be obtained to screen for malformations that could cause optic atrophy.
Otolaryngology/audiologyAt risk for narrow ear canals, impacted cerumen, hearing loss, and laryngomalacia.
At diagnosis:
• Audiologic evaluation.
• Refer to otolaryngologist for airway evaluation/management in the case of neonatal or early respiratory issues.
• Referral to otolaryngologist for hearing loss management.
Ongoing management:
• Audiologic assessment every 2–3 y, or more frequently if necessary. Hearing aids as needed.
• Refer to otolaryngologist for impacted cerumen, abnormal audiologic testing, and hearing loss.
• Prompt treatment of ear infections to minimize hearing loss.
• Otolaryngology follow-up for management of airway.
Renal/genitourinaryAt risk for kidney malformation, vesicoureteral reflux, and cryptorchidism.
At diagnosis:
• Renal ultrasound to evaluate for structural renal anomalies.
• Refer to urologist and endocrinologist if cryptorchidism present.
Ongoing management:
• As indicated by urologist.
Hematology/oncologyAt risk for easy bruising, von Willebrand disease, and thrombocytopenia.
At diagnosis:
• Obtain history regarding easy bruising or bleeding problems.
• If easy bruising or bleeding problems are present, screen with CBC, platelet count, platelet function study, and von Willebrand screen.
• Refer to a hematologist for an abnormal CBC.
Ongoing management:
• If evidence of easy bruising or bleeding appears with time, then screen with CBC, platelet count, platelet function study, and von Willebrand screen.
• If patient requires surgery, screen with the above testing before surgery if not already done.
• For those on divalproex sodium for seizures, obtain platelet count every 6 mo.
DentalAt risk for malocclusion, posterior crossbite, and bruxism.
At diagnosis:
• Dental evaluation.
Ongoing management:
• Appropriate hygiene.
• Restorative care.
• Orthodontic treatment as needed.
  • CBC, complete blood cell; FTT, failure to thrive.