🧬 Chapter 25: Dysmorphology

Nelson's Pediatric Symptom-Based Diagnosis | Malformation · Deformation · Disruption · Sequence · Syndrome · Association · Teratogens · Chromosomal Microarray

🔍 Dysmorphology: Key Concepts

📊 Key Definitions
Malformation: primary structural defect from abnormal development (e.g., cleft lip). Deformation: alteration from mechanical forces (e.g., clubfoot from oligohydramnios). Disruption: destruction of normally formed tissue (e.g., amniotic band). Dysplasia: abnormal organization of cells (e.g., skeletal dysplasia).
🔄 Syndromes, Sequences, Associations
Syndrome: multiple anomalies from single cause (Down syndrome). Sequence: cascade from single anomaly (Pierre Robin → micrognathia → cleft palate → glossoptosis). Association: non-random co-occurrence, no known cause (VACTERL).
⚠️ Minor Anomalies & Major Malformations
≥3 minor anomalies → 20-30% risk of major malformation. Minor anomalies: ear pits, single palmar crease, clinodactyly. Major: congenital heart disease, neural tube defects, cleft lip/palate.
💧 Common Teratogens
Alcohol (FAS: smooth philtrum, thin vermilion, microcephaly), Valproate (neural tube defects), Phenytoin, Lithium (Ebstein anomaly), Warfarin, Isotretinoin, Thalidomide. Timing of exposure determines outcome.
🧬 Genetic Testing in Dysmorphology
First-tier: Chromosomal microarray (CMA) – detects microdeletions/duplications (15-20% yield). Karyotype for translocations. Targeted: FISH (22q11.2), Fragile X, RASopathy panels. Whole exome sequencing (30% yield).
🚩 Red Flags for Genetic Syndrome
≥3 minor anomalies, major malformation, dysmorphic facies, developmental delay, family history of similar findings, consanguinity, stillbirths/recurrent pregnancy loss, abnormal growth (microcephaly/macrocephaly, short stature).

💡 Key Takeaway: Dysmorphology is the study of abnormal morphology. Differentiate malformation (intrinsic) from deformation (extrinsic). ≥3 minor anomalies warrant genetic evaluation. Chromosomal microarray is first-line testing.

🩺 Clinical Approach to Dysmorphology: Step-by-Step

🔹 Step 1: Distinguish malformation, deformation, disruption, dysplasia
• Malformation: intrinsic abnormality of development (e.g., cleft lip, heart defect).
• Deformation: extrinsic mechanical force (e.g., clubfoot, plagiocephaly from intrauterine constraint).
• Disruption: destruction of normally formed tissue (e.g., amniotic band, gastroschisis).
• Dysplasia: abnormal organization of cells (e.g., achondroplasia, osteogenesis imperfecta).
🔹 Step 2: Determine if it is a syndrome, sequence, or association
• Syndrome: multiple anomalies from a single cause (e.g., Down, Noonan).
• Sequence: cascade from a single anomaly (e.g., Pierre Robin sequence: micrognathia → glossoptosis → cleft palate).
• Association: non-random co-occurrence (VACTERL: vertebral, anal, cardiac, TE fistula, renal, limb).
🔹 Step 3: Count minor anomalies
• 0-1 minor anomaly: usually normal variant.
• ≥3 minor anomalies: 20-30% risk of major malformation → genetic referral.
• Minor anomalies: preauricular pits/tags, single palmar crease, clinodactyly, sandal gap, epicanthal folds.
🔹 Step 4: Teratogen exposure history
• Alcohol (FAS): smooth philtrum, thin vermilion, microcephaly, short palpebral fissures.
• Valproate: neural tube defects, facial dysmorphism.
• Phenytoin: nail hypoplasia, hypertelorism.
• Isotretinoin: conotruncal defects, microtia.
• Timing: critical period weeks 3-8 (organogenesis).
🔹 Step 5: Diagnostic testing strategy
• First-line: Chromosomal microarray (CMA) – detects microdeletions/duplications.
• Targeted: 22q11.2 FISH (conotruncal defects, cleft palate), Fragile X, RASopathy panel, MECP2 (Rett).
• Whole exome sequencing if CMA negative and strong suspicion of genetic syndrome.