Van der Woude syndrome

AD; IRF6 (Van der Woude type 1). Penetrance is high but incomplete, with highly variable expression that ranges from lip pits alone to full cleft lip and palate.

• Most affected people carry an IRF6 variant, but a substantial minority do not, so a negative test does not exclude the diagnosis.
• GRHL3 causes Van der Woude type 2, a minority of cases and one cause to consider when the IRF6 test is negative.
• IRF6-related disorders are one of the few single-gene conditions in which one relative can have cleft palate alone while another has cleft lip and palate. This mixed clefting within a pedigree is the single most discriminating clue for Van der Woude.

IRF6 is a transcription factor that helps build the periderm, a transient layer covering the embryonic oral epithelium. Think of the periderm as the release liner on a sticker: an anti-adhesive that keeps surfaces from bonding to the wrong thing, so they stick only where and when they should.

Without a working periderm, the underlying basal cells expose E-cadherin and turn sticky, so oral surfaces that should stay separate fuse together and the palatal shelves fail to rise to the midline on time. The lower lip pits reflect the same disrupted lip and palate program on a milder, more localized scale. How much IRF6 function is lost sets the severity: Van der Woude comes from losing one copy (haploinsufficiency), while a stronger hit to the same system, a dominant-negative variant in the DNA-binding domain, produces the more severe popliteal pterygium syndrome.

• Paramedian lower lip pits: the most consistent sign, and the location is the discriminator. Lower lip pits point to Van der Woude; the syndromes in the Differential give upper lip pits instead.
• Cleft lip and/or palate: common, but more variable than the lip pits.
• Cleft palate alone in a subset. The mixed picture within one family is the real clue.
• Hypodontia (often absent second premolars or lateral incisors), sometimes the only sign in a mildly affected relative.
• Most common syndromic cause of cleft lip and palate.

• Clinical recognition of paramedian lower lip pits, with or without cleft lip and/or palate.
• Detailed family history, since variable expression means relatives may have lip pits, hypodontia, or a submucous cleft only.
• Molecular confirmation of an IRF6 (or GRHL3) pathogenic variant. An IRF6 variant also distinguishes Van der Woude from the allelic popliteal pterygium syndrome.

• Popliteal pterygium syndrome (allelic, also IRF6): adds popliteal webbing (pterygia), syndactyly, genital anomalies, and a pyramidal skin fold over the hallux nail that is highly specific. It results from a dominant-negative variant rather than the haploinsufficiency of Van der Woude.
• Kabuki syndrome (KMT2D, KDM6A), TFAP2A-related branchio-oculo-facial syndrome, and RIPK4-related disorders: these give upper lip pits, plus their own systemic features.
• CHD7, MSX1, and TP63-related disorders: mixed clefting without lip pits.
• Nonsyndromic cleft lip and palate: no lip pits, no mixed clefting within the family, and a lower rate of wound complications after repair.

• Multidisciplinary cleft team care: surgical repair of cleft lip and/or palate with staged follow-up.
• Surgical excision of lip pits if symptomatic or for cosmetic concern.
• Speech therapy, dental and orthodontic care (including management of hypodontia), and audiology monitoring for middle-ear disease.
• Counsel about wound healing. In one small study, 47% of people with Van der Woude had wound complications after cleft repair, compared with 19% of those with nonsyndromic cleft lip and palate.
• Examine at-risk relatives (offspring and sibs) for subtle signs: submucous cleft, lip pits or mounds, hypodontia, and the pyramidal hallux fold. Variable expressivity and incomplete penetrance mean an obligate carrier may look unaffected.
• Genetic counseling for autosomal dominant inheritance with high but incomplete penetrance and highly variable expression.