A failure of fusion of the lip, alveolus, and/or palate during the 5th-12th weeks of gestation. Three operational categories matter clinically and genetically:
- Cleft lip with or without cleft palate (CL ± P): failure of fusion of the maxillary and medial nasal prominences.
- Cleft palate only (CPO): failure of fusion of the palatal shelves.
- Submucosal cleft palate: occult, the muscle is non-fused under intact mucosa; presents with hypernasal speech or VPI.
CL ± P and CPO are embryologically and epidemiologically distinct. They have different recurrence risks, different syndrome associations, and rarely segregate in the same family. A pedigree with both forms is unusual unless the underlying gene is one of the few (e.g. IRF6 in Van der Woude) that can produce either.
The first question is syndromic versus non-syndromic. About 30% of orofacial clefts are syndromic, often presenting with one or more of: an associated cardiac defect, dysmorphic features, growth failure, developmental delay, or specific findings such as lip pits or limb anomalies. The remaining 70% are non-syndromic, multifactorial, and follow empirical recurrence risks.
The next question is CL ± P vs CPO: each has its own list of syndromes.
The third question, if syndromic, is which syndrome: examine for lip pits (Van der Woude), small jaw with airway compromise (Pierre Robin / Stickler / 22q11), midline forebrain defects (holoprosencephaly), midface and limb (Treacher Collins, EEC), and add cardiac/immune/parathyroid (22q11.2 deletion).
Syndromic CL ± P or CPO
- Van der Woude syndrome (IRF6, AD): the most common syndromic cause of cleft lip/palate. Look for lower-lip pits in the patient or a parent; presence is essentially pathognomonic and shifts the recurrence risk from ~3% (non-syndromic) to 50% (autosomal dominant).
- 22q11.2 deletion syndrome: cleft palate (especially submucosal or velopharyngeal insufficiency) + conotruncal cardiac defects + hypocalcemia + immune deficiency + characteristic face. The most common syndromic cause of CPO. FISH or CMA finds it.
- Pierre Robin sequence: triad of micrognathia + glossoptosis + cleft palate (U-shaped). Most commonly part of Stickler syndrome (COL2A1, COL11A1, COL11A2; AD; myopia + retinal detachment + sensorineural hearing loss + arthropathy). Also occurs in 22q11.2 deletion, Treacher Collins, and as an isolated sequence.
- Treacher Collins syndrome (TCOF1; AD): mandibulofacial dysostosis with downslanting palpebral fissures, malar hypoplasia, microtia, conductive hearing loss, coloboma of lower eyelid. Cleft palate in ~30%.
- Holoprosencephaly spectrum: midline cleft of upper lip (true median cleft), single central incisor, hypotelorism, midface hypoplasia. SHH pathway and trisomy 13 are the main causes.
- CHARGE syndrome (CHD7): coloboma + heart defect + atresia choanae + retardation of growth/development + genital anomalies + ear anomalies. Cleft lip/palate in a subset.
- Trisomy 13 (Patau) and trisomy 18 (Edwards): cleft is part of a polymalformed picture.
- Smith-Lemli-Opitz (DHCR7): cleft palate + 2-3 toe syndactyly + microcephaly + hypospadias + low cholesterol.
- Kabuki syndrome (KMT2D, KDM6A): cleft palate + everted lower eyelids + arched eyebrows + persistent fetal fingertip pads + intellectual disability.
- Apert, Crouzon, Pfeiffer (FGFR2): cleft palate plus craniosynostosis.
Teratogenic and prenatal exposures
- Maternal anticonvulsants: phenytoin, valproate (CL ± P), topiramate.
- Maternal smoking, alcohol (smooth philtrum + thin upper lip in fetal alcohol spectrum), maternal folate deficiency.
- Maternal diabetes raises baseline malformation risk.
Non-syndromic (multifactorial)
70% of all orofacial clefts. Empirical recurrence risk for an unaffected couple after one affected child: ~3-5% (CL ± P) and ~2-3% (CPO), modified by sex of the affected child and severity (bilateral > unilateral). Recurrence rises further with an affected parent. Folate periconceptionally reduces risk.
- Lower-lip pits in patient or parent → Van der Woude (IRF6).
- Cleft palate + conotruncal heart defect → 22q11.2 deletion.
- Pierre Robin + myopia or family history of retinal detachment → Stickler.
- Midline cleft lip + hypotelorism + single central incisor → holoprosencephaly spectrum (look for SHH, ZIC2, SIX3, TGIF, and trisomy 13).
- Bilateral cleft lip + polydactyly + microcephaly + cardiac → trisomy 13.
- Cleft palate + coloboma + choanal atresia + ear anomaly → CHARGE.
- Cleft palate + 2-3 toe syndactyly + low cholesterol → Smith-Lemli-Opitz.
The work-up depends on whether features beyond the cleft suggest a syndrome.
- Careful exam. Inspect the lower lip (pits = Van der Woude). Measure intercanthal distance (hypotelorism in holoprosencephaly). Look at the eyes (coloboma in CHARGE), ears (microtia in Treacher Collins, ear creases/pits in BWS), hands (limb anomalies in EEC, polydactyly in trisomy 13), heart (echo if conotruncal suspicion).
- Family history. Three-generation pedigree. Ask specifically about lip pits, hearing loss, joint problems (Stickler).
- Echocardiogram in any cleft palate (especially if submucosal or VPI) to exclude conotruncal anomaly suggesting 22q11.2.
- Chromosomal microarray if multiple anomalies or developmental concern; CMA is first-tier in syndromic CL/P.
- Targeted molecular testing when a specific syndrome is recognized: IRF6 (Van der Woude), 22q11.2 FISH/MLPA, COL2A1/COL11A1 (Stickler), TCOF1 (Treacher Collins), SHH pathway (holoprosencephaly), CHD7 (CHARGE), DHCR7 + cholesterol panel (SLO).
- Renal US if 22q11.2 confirmed (renal anomalies are common).
- Multidisciplinary cleft team referral for surgical planning, feeding support, speech, dental, ENT, and genetics; coordination matters for outcomes.
- Look at the lower lip on every cleft patient AND on both parents. Lip pits are subtle, easy to miss, and pivot the family's recurrence risk from ~3% to 50%.
- Cleft palate is the high-yield phenotype for 22q11.2. Cleft palate alone (especially submucosal) without an obvious face still earns FISH/MLPA or CMA.
- CL ± P ≠ CPO genetically. Same family rarely has both. If they do, think AD syndrome (Van der Woude).
- Pierre Robin is a sequence, not a syndrome: identify the underlying cause (Stickler is the most common).
- Folate periconceptionally reduces non-syndromic CL/P risk; this should be counseled to any future pregnancies in affected families.