2nd–3rd toe syndactyly with hypospadias
1. Smith-Lemli-Opitz syndrome
• 2nd–3rd toe syndactyly
• Hypospadias
• Ambiguous genitalia/undervirilization
• IUGR
• Microcephaly
• Intellectual disability
• Postaxial polydactyly (occasionally)
• Congenital heart disease
• Cleft palate
Gene: DHCR7
Inheritance: Autosomal recessive
Pathophysiology:
• Defective cholesterol synthesis
• Cholesterol is required for steroid hormone synthesis and Sonic Hedgehog signaling
• Leads to genital anomalies and limb abnormalities
Prenatal clues:
• Bilateral 2/3 toe syndactyly
• Hypospadias or ambiguous genitalia
• IUGR
• Cardiac defects
• Brain anomalies
A male fetus with hypospadias and 2/3 toe syndactyly should always prompt consideration of SLOS.
2. Aarskog-Scott syndrome
• Shawl scrotum
• Hypospadias
• Cryptorchidism
• Mild syndactyly
• Brachydactyly
• Hypertelorism
• Short stature
Gene: FGD1
Inheritance: X-linked
Toe syndactyly can occur but is less characteristic than in SLOS.
3. Opitz G/BBB syndrome
• Hypospadias
• Laryngotracheoesophageal defects
• Hypertelorism
• Imperforate anus
• Cleft lip/palate
Gene: MID1
Toe syndactyly may occur but is not a defining feature.
4. Hand-Foot-Genital syndrome
• Hypospadias
• Urogenital malformations
• Distal limb anomalies
• Short thumbs
• Clinodactyly
• Syndactyly
Gene: HOXA13
Inheritance: Autosomal dominant
5. Disorders of androgen synthesis/action
5-alpha reductase deficiency
• Hypospadias
• Undervirilized external genitalia
Usually:
• No characteristic 2/3 toe syndactyly
Gene: SRD5A2
Androgen Insensitivity Syndrome
Features:
• Hypospadias
• Ambiguous genitalia
Syndactyly is generally absent.
6. Ciliopathies
Bardet-Biedl syndrome
• Hypospadias
• Postaxial polydactyly
• Renal abnormalities
• Developmental delay
Toe syndactyly can occur.
Genes:
• Numerous BBS genes
7. Pallister-Hall syndrome
• Hypospadias
• Polydactyly
• Syndactyly
• Hypothalamic hamartoma
Gene: GLI3
8. Townes-Brocks syndrome
Features:
• Hypospadias
• Ear anomalies
• Anal anomalies
• Limb anomalies including syndactyly
Gene: SALL1
Specific significance of isolated 2nd–3rd toe syndactyly
2/3 toe syndactyly alone is relatively common and may be:
• Familial
• Isolated
• Non-syndromic
However, when combined with:
• Hypospadias
• Ambiguous genitalia
• IUGR
• Postaxial polydactyly
• Cleft palate
• Congenital heart disease
the likelihood of an underlying syndrome rises substantially.
