The dysmorphic newborn

A newborn whose face, body proportions, or minor anomalies don't fit the family or the population norm. Three or more minor anomalies in a single infant is the operational threshold for concern (each minor anomaly individually is common, but the combination has cumulative diagnostic weight). The bedside task is to organize the findings into a recognizable pattern, decide which testing to send first, and counsel the family about what the work-up can and can't answer.

Dysmorphology is pattern recognition built on a disciplined exam. Walk the checklist before you reach for a panel.

1. Look at the parents. Family resemblance accounts for many "dysmorphic" features. Take a photo or measure the mother's intercanthal distance before deciding the baby's is wide.
2. Plot growth. Microcephaly, macrocephaly, IUGR, postnatal growth failure each open different differentials.
3. Inventory minor anomalies systematically. Head shape, fontanelles, hair pattern, ear position and shape, palpebral fissure length and slant, philtrum, mouth, jaw, neck, hands (palmar creases, finger length, clinodactyly), feet (sandal gap, 2-3 toe syndactyly), genitalia, skin (café-au-lait, hypopigmented macules), nipple position.
4. Catalog major anomalies. Cardiac murmur or cyanosis, abdominal wall defects, ambiguous genitalia, neural tube defect, anal atresia.
5. Prenatal history. Polyhydramnios (swallowing problem, congenital myotonic), oligohydramnios (renal, premature rupture), maternal exposures (alcohol, valproate, warfarin, retinoic acid, untreated PKU, diabetes).
6. Family photos. Look at the baby's parents at the same age. Compare siblings.

The first split is the cause category:

• Chromosomal aneuploidy (gross numerical or structural anomaly): trisomy 21, 18, 13, 45,X, 47,XXY, 47,XYY.
• Submicroscopic chromosomal (microdeletion/duplication): 22q11.2, 1p36, Williams (7q11.23), Wolf-Hirschhorn (4p-), cri-du-chat (5p-).
• Single-gene syndromes: RASopathies (Noonan, Costello, CFC), BAFopathies (Coffin-Siris), Kabuki, CHARGE.
• Imprinting disorders: Beckwith-Wiedemann, Prader-Willi, Angelman, Russell-Silver.
• Teratogenic embryopathies: fetal alcohol, valproate, warfarin, retinoic acid, maternal diabetes, maternal PKU.

Trisomies and sex chromosome aneuploidies

• Trisomy 21 (Down syndrome): upslanting palpebral fissures + epicanthal folds + flat nasal bridge + brachycephaly + small ears + protruding tongue + single transverse palmar crease + hypotonia + AV canal defect or VSD.
• Trisomy 18 (Edwards): clenched fists with overlapping fingers + rocker-bottom feet + small chin + IUGR + cardiac (VSD) + horseshoe kidney. Severely shortened lifespan.
• Trisomy 13 (Patau): midline defects (holoprosencephaly, cleft lip/palate, cyclopia at the severe end) + postaxial polydactyly + cardiac + scalp defects (cutis aplasia).
• Turner syndrome (45,X): can present in the newborn with cystic hygroma, lymphedema of hands/feet, coarctation, webbed neck.

Microdeletion syndromes

• 22q11.2 deletion syndrome: cardiac (interrupted arch, TOF, truncus) + cleft palate or VPI + hypocalcemia + thymic hypoplasia + immune deficiency + characteristic face. The single most common microdeletion; CMA or 22q-specific FISH.
• Monosomy 1p36: most common pure terminal deletion; microcephaly + straight eyebrows + deep-set eyes + pointed chin + hypotonia + ID + seizures + cardiomyopathy.
• Williams syndrome (7q11.23): "elfin" face + supravalvular AS + transient infantile hypercalcemia + cocktail-party personality + ID (visible later).
• Wolf-Hirschhorn syndrome (4p-): "Greek warrior helmet" face + IUGR + microcephaly + cardiac + seizures.
• Cri-du-chat (5p-): high-pitched cat-like cry + microcephaly + round face + hypotonia.

Single-gene syndromes recognizable in the newborn

• Noonan syndrome (PTPN11, SOS1, RAF1, others): pulmonic stenosis or HCM + ptosis + low-set posteriorly rotated ears + webbed neck + lymphedema in newborn.
• Costello (HRAS) and cardiofaciocutaneous (BRAF, MAP2K1, MAP2K2): RASopathies with coarse facies, severe feeding difficulties, redundant skin (Costello), sparse curly hair (CFC).
• Coffin-Siris syndrome (ARID1B et al.; BAFopathy): hypoplastic 5th fingernails + coarse facies + ID + hypertrichosis.
• Kabuki syndrome (KMT2D, KDM6A): everted lower eyelids + arched sparse eyebrows + persistent fetal fingertip pads + cleft palate.
• CHARGE syndrome (CHD7): coloboma + heart + choanal atresia + retardation + genital + ear.

Imprinting and overgrowth

• Beckwith-Wiedemann (11p15.5): macroglossia + omphalocele + macrosomia + hemihyperplasia + ear creases + neonatal hypoglycemia + Wilms risk.
• Russell-Silver (11p15 hypomethylation, mUPD7): IUGR + relative macrocephaly + triangular face + clinodactyly + hemihypotrophy.

Teratogenic embryopathies

• Fetal alcohol spectrum: smooth philtrum + thin upper lip + small palpebral fissures + microcephaly + growth failure + CNS involvement.
• Valproate embryopathy: spina bifida + cardiac + facial features (epicanthus, trigonocephaly).
• Warfarin embryopathy: stippled epiphyses + nasal hypoplasia (first-trimester exposure).
• Retinoic acid embryopathy: ear anomalies + cardiac + CNS.
• Maternal diabetes: caudal regression + cardiac + sacral agenesis + macrosomia + transient hyperinsulinism.
• Maternal PKU: microcephaly + cardiac + ID (if maternal phenylalanine uncontrolled).

The diagnostic yield of each test depends on the phenotype. A reasonable opening sequence:

1. Chromosomal microarray (CMA) is the first-line genetic test for any infant with multiple congenital anomalies or unexplained dysmorphism. Yield is ~15-20% in dysmorphic newborns. Higher resolution than karyotype; catches microdeletions and duplications karyotype misses.
2. Karyotype if a balanced rearrangement is suspected (familial translocation, recurrent miscarriages) or if mosaic aneuploidy is on the differential (CMA can miss low-level mosaicism).
3. Targeted testing when a syndrome is strongly suspected: FISH or MLPA for 22q11.2 (now usually picked up on CMA), methylation studies for Beckwith-Wiedemann / Russell-Silver / Prader-Willi / Angelman.
4. Echocardiogram in any dysmorphic newborn with a murmur, cyanosis, or syndrome with high cardiac yield (22q11, Noonan, Williams, trisomies).
5. Renal ultrasound for syndromes with renal involvement (22q11, BWS, CHARGE, Williams).
6. Brain MRI if microcephaly, macrocephaly, seizures, or midline defects.
7. Exome or genome sequencing if CMA is negative and a syndrome remains likely: yield of 25-40% additional in CMA-negative dysmorphic infants, higher with deep phenotyping.
8. Photographic documentation for serial comparison and dysmorphology consultation, with consent.