In an adolescent girl with frontal bossing, down‑slanting (antimongoloid) palpebral fissures, brachydactyly of the third toe, and mild intellectual impairment, what are the differential diagnoses?

Differential Diagnoses

The primary differential diagnosis for this adolescent girl with frontal bossing, downslanting (antimongoloid) palpebral fissures, third toe brachydactyly, and mild intellectual impairment is Cardio-Facio-Cutaneous (CFC) syndrome, followed by other RASopathies including Noonan syndrome (NS), Costello syndrome (CS), and NS with multiple lentigines. 1

Primary Consideration: RASopathies

Cardio-Facio-Cutaneous (CFC) Syndrome

This is the most likely diagnosis given the constellation of features. CFC characteristically presents with:

• Craniofacial features: Frontal bossing (tall forehead with bitemporal narrowing), downslanting palpebral fissures, hypertelorism, ptosis, and epicanthal folds 1
• Cognitive impairment: Mild to moderate intellectual disability is typical, with mutations in BRAF and MEK genes associated with greater cognitive impairment 1
• Digital anomalies: While third toe brachydactyly is not the most common finding in CFC, digital abnormalities do occur in this syndrome 1
• Ophthalmologic findings: Antimongoloid (downslanting) palpebral fissures are prominent features, with 9 of 21 patients having strabismus 2

Key distinguishing features of CFC include sparse, curly, friable hair with absent eyebrows and ulerythema ophryogenes (follicular hyperkeratosis), which occur more frequently than in other RASopathies 1. The facial features may become coarser with age 1.

Noonan Syndrome (NS)

NS shares multiple features with CFC but has important differences:

• Common features: Hypertelorism, downslanting palpebral fissures, ptosis, short stature, relative macrocephaly 1
• Key differences: Facial features are less coarse, lower incidence of severe feeding problems, fewer cutaneous features (less follicular hyperkeratosis, sparse eyebrows), and less marked cognitive delay compared to CFC 1

Costello Syndrome (CS)

CS overlaps significantly but differs in:

• Common features: Coarse facial features, curly hair, broad nasal bridge, downslanting palpebral fissures, short stature, intellectual disability 1
• Key differences: Papillomata of face or perianal regions, multifocal atrial tachycardia, ulnar deviation of wrist and fingers, and loose skin 1

NS with Multiple Lentigines (formerly LEOPARD syndrome)

• Common features: Short stature, hypertelorism, pulmonary valve stenosis, hypertrophic cardiomyopathy 1
• Key differences: Multiple skin lentigines, frequent sensorineural deafness, cardiac conduction abnormalities, and less marked cognitive delay 1

Secondary Considerations

Baraitser-Winter Syndrome

• Common features: Hypertelorism, ptosis, short stature, cognitive delay 1
• Key differences: Iris coloboma, lissencephaly, pachygyria, aortic valve anomalies, and less coarse facial features 1

22q11.2 Deletion Syndrome

While this patient has some overlapping features, 22q11.2DS typically presents with:

• Different facial pattern: Malar flatness, upslanting (not downslanting) palpebral fissures, hooded eyelids, bulbous nasal tip 3
• The upslanting palpebral fissures in 22q11.2DS are opposite to this patient's antimongoloid slant, making this diagnosis less likely

Pycnodysostosis

Less likely given normal development, but consider if:

• Frontal bossing, beaked nose, micrognathia, brachydactyly are present 4
• Key distinguishing features: Generalized osteosclerosis, acro-osteolysis, open sutures/fontanelles, and normal cognitive development (unlike this patient) 5, 4

Diagnostic Approach

Immediate next step: Refer to medical genetics for molecular testing. 1

1. Multigene panel testing for RASopathy genes (BRAF, MEK1, MEK2, KRAS) is the preferred initial test, detecting mutations in 70-90% of CFC cases 1

2. If panel testing unavailable, sequential gene testing starting with BRAF, then MEK1/MEK2, then KRAS 1

3. If RASopathy genes are negative, consider:

   • Testing other RASopathy genes
   • Chromosome microarray for microdeletions/microduplications
   • Whole exome or genome sequencing 1

4. Concurrent evaluations while awaiting genetic results:

   • Pediatric cardiology with echocardiography (75% of CFC patients have cardiac involvement, most commonly pulmonary valve stenosis) 1
   • Ophthalmology assessment for strabismus and other ocular abnormalities
   • Developmental assessment and early intervention services

Critical Pitfalls to Avoid

• Do not rely solely on clinical diagnosis: No pathognomonic features uniquely identify CFC, and molecular confirmation is essential for appropriate medical management and genetic counseling 1
• Do not delay cardiac evaluation: Hypertrophic cardiomyopathy in CFC can be rapidly progressive and life-threatening 1
• Do not assume static phenotype: Facial features may become more or less pronounced with age, and cardiac abnormalities like myocardial thickening can develop later 1