Smith-Lemli-Opitz Syndrome
Smith-Lemli-Opitz Syndrome
Smith-Lemli-Opitz Syndrome (SLOS) is a rare autosomal recessive disorder characterized by multiple congenital anomalies and intellectual disability. It is caused by a deficiency in 7-dehydrocholesterol reductase, an enzyme crucial for cholesterol biosynthesis. The syndrome was first described in 1964 by David Smith, Luc Lemli, and John Opitz.
Key Points:
- Incidence: Approximately 1 in 20,000 to 60,000 births
- Inheritance: Autosomal recessive
- Genetic basis: Mutations in the DHCR7 gene on chromosome 11q13.4
- Characterized by distinctive facial features, limb anomalies, and developmental delays
- Associated with low cholesterol levels and elevated 7-dehydrocholesterol
Clinical Features
Smith-Lemli-Opitz Syndrome presents with a wide spectrum of clinical features, varying from mild to severe:
Craniofacial Features:
- Microcephaly
- Broad, upturned nose
- Ptosis (drooping eyelids)
- Micrognathia (small jaw)
- Cleft palate
- Low-set, posteriorly rotated ears
Limb Abnormalities:
- Syndactyly (fused toes), typically of the second and third toes
- Postaxial polydactyly (extra digits)
- Short or proximally placed thumbs
Genital Abnormalities:
- In males: Hypospadias, cryptorchidism, micropenis
- In females: Hypoplastic external genitalia
Other Features:
- Intellectual disability (ranging from mild to severe)
- Growth retardation and failure to thrive
- Feeding difficulties
- Hypotonia
- Congenital heart defects
- Renal anomalies
- Photosensitivity
- Behavioral issues (autism spectrum disorders, ADHD, self-injurious behaviors)
Diagnosis
Diagnosis of Smith-Lemli-Opitz Syndrome is based on clinical features, biochemical testing, and genetic analysis:
Clinical Diagnosis:
- Presence of characteristic facial features
- Syndactyly of toes
- Genital abnormalities
- Developmental delays
Biochemical Testing:
- Serum cholesterol levels (typically low)
- Elevated 7-dehydrocholesterol (7-DHC) levels in blood and tissues
- 7-DHC/cholesterol ratio > 0.01
Genetic Testing:
- Molecular genetic testing for mutations in the DHCR7 gene
- Sequence analysis and deletion/duplication analysis
Prenatal Diagnosis:
- Measurement of 7-DHC in amniotic fluid or chorionic villus sampling
- Molecular genetic testing if familial mutations are known
Management
Management of Smith-Lemli-Opitz Syndrome is multidisciplinary and focuses on addressing specific symptoms:
Dietary Management:
- Cholesterol supplementation (150-300 mg/kg/day)
- High-cholesterol diet
- Monitoring of serum cholesterol and 7-DHC levels
Surgical Interventions:
- Repair of congenital heart defects
- Correction of cleft palate
- Management of genital abnormalities (e.g., hypospadias repair)
- Correction of polydactyly or syndactyly
Developmental Support:
- Early intervention programs
- Special education services
- Speech and language therapy
- Occupational and physical therapy
Other Management Strategies:
- Gastrostomy tube placement for severe feeding difficulties
- Management of behavioral issues (e.g., ABA therapy for autism)
- Antioxidant therapy (under investigation)
- Regular follow-up with multidisciplinary team (genetics, neurology, cardiology, etc.)
Genetics
Genetic Basis:
- Caused by mutations in the DHCR7 gene located on chromosome 11q13.4
- DHCR7 gene encodes 7-dehydrocholesterol reductase, the final enzyme in cholesterol biosynthesis
- Over 160 different mutations have been identified
Inheritance Pattern:
- Autosomal recessive inheritance
- Parents are typically asymptomatic carriers
- 25% chance of affected offspring when both parents are carriers
Genotype-Phenotype Correlation:
- Severity of symptoms generally correlates with the degree of enzyme deficiency
- Null mutations typically result in more severe phenotypes
- Some mutations allow residual enzyme activity, leading to milder phenotypes
Genetic Counseling:
- Offer carrier testing for at-risk relatives
- Discuss prenatal testing options for future pregnancies
- Preimplantation genetic diagnosis may be available
