Review Question - QID 219545

Smith-Lemli-Opitz syndrome is an autosomal recessive disorder associated with microcephaly, cleft palate, cardiac defects, post-axial polydactyly, and 2-to-3 syndactyly of the toes.

Syndactyly of the toes is a congenital condition characterized by the fusion of the bones or skin of the foot digits. Patients with Smith-Lemli-Opitz syndrome have a disorder caused by an abnormality in cholesterol metabolism resulting from deficiency of the enzyme 7-dehydrocholesterol reductase. The associated toe syndactyly most commonly occurs between digits two and three and represents a pure cosmetic deformity that causes no delay in motor milestones. It is treated conservatively with observation and does not require operative separation in the early years of life or the use of toe spacers later in life.

Nowaczyk et al. reviewed Smith-Lemli-Opitz syndrome (SLOS). The authors note that the external malformations include distinctive facial features, cleft palate, postaxial polydactyly, 2–3 syndactyly of the toes, and underdeveloped external genitalia in males. The syndactyly is typically Y-shaped cutaneous syndactyly of the second and third toes, which may be a subtle finding and only noticeable from the plantar aspect of the foot. They recommend that, although considered a normal variant, given the wide phenotypic spectrum for SLOS, syndactyly of the second and third toes in combination with other malformations, behavioral disturbances, or cognitive problems should prompt consideration of SLOS.

Sánchez-Soler et al. published a review of 4 cases of Smith-Lemli-Opitz syndrome. The authors noted the extremely variable expressivity of the condition's physical manifestations. The classical phenotype is characterized by prenatal and postnatal growth restriction, microcephaly, multiple major and minor malformations (mainly cardiac defects, cleft palate, and ambiguous genitalia), moderate-to-severe intellectual disability, and second-toe and third-toe syndactyly. They concluded that clinical exome sequencing is clearly useful for the diagnosis of SLOS in the case of atypical phenotypes or classic but mild phenotypes, which has important repercussions not only for the patients, as it allows consideration of preventive and therapeutic interventions and adequate reproductive genetic counseling, but also for their families.

Figure A is a clinical photograph of a forefoot demonstrating 2-to-3 syndactyly of the toes.

Incorrect Answers:
Answer 1: Beckwith-Wiedemann Syndrome is a congenital condition caused by a mutation in 11p15.5 that presents with hemihypertrophy, macroglossia, abdominal wall defects, and clinical hypoglycemia, but is not associated with toe syndactyly.
Answer 2: Facioscapulohumeral Muscular Dystrophy involves progressive muscle weakness involving the face, scapular stabilizers, upper arm, lower leg (peroneal muscles), and hip girdle, but is not associated with toe syndactyly.
Answer 3: Prader-Willi Syndrome is a congenital condition caused by a partial chromosome 15 deletion that presents with obesity, failure to thrive, mental retardation, hip dysplasia, scoliosis, genu valgum, and pes planus, but is not associated with toe syndactyly.
Answer 4: Rett Syndrome is a congenital condition caused by an X-linked dominant mutation in the MECP2 gene that affects girls between 6 and 18 months of age, presenting with progressive impairment, developmental delays, and spinal abnormalities, but not toe syndactyly.