Smith–Lemli–Opitz syndrome

Overview

Smith–Lemli–Opitz syndrome (SLOS) is a rare autosomal recessive genetic disorder characterized by multiple congenital anomalies, intellectual disability, and metabolic abnormalities. First described in 1964 by Smith, Lemli, and Opitz, the condition is caused by a defect in cholesterol biosynthesis, specifically a deficiency of the enzyme 7-dehydrocholesterol reductase (DHCR7). This enzyme is essential for the final step in producing cholesterol, a crucial component of cell membranes, hormones, and developmental signaling pathways.

Due to its widespread role in embryogenesis, cholesterol deficiency in SLOS results in a broad spectrum of physical and neurodevelopmental abnormalities, ranging from mild to severe. Early diagnosis and management can significantly improve the quality of life and developmental outcomes for affected individuals.

Causes

Smith–Lemli–Opitz syndrome is caused by mutations in the DHCR7 gene located on chromosome 11q13. This gene encodes the enzyme 7-dehydrocholesterol reductase, which is responsible for converting 7-dehydrocholesterol (7-DHC) into cholesterol. Mutations lead to partial or complete loss of enzyme activity, resulting in low cholesterol levels and accumulation of toxic precursors such as 7-DHC.

The condition is inherited in an autosomal recessive manner, meaning a child must inherit two copies of the defective gene (one from each parent) to develop the disorder. Parents who each carry one mutated copy of the gene are typically asymptomatic carriers but have a 25% chance of passing the disorder to their offspring in each pregnancy.

Symptoms

The clinical presentation of SLOS varies significantly depending on the severity of the enzyme deficiency. Common signs and symptoms include:

• Intellectual disability and developmental delay

• Microcephaly (small head size)

• Distinctive facial features such as a broad nasal bridge, upturned nose, and ptosis (drooping eyelids)

• Growth retardation and failure to thrive

• Behavioral problems, including hyperactivity, self-injury, and autism spectrum behaviors

• Polydactyly (extra fingers or toes)

• Syndactyly (fused toes, particularly the second and third)

• Genital abnormalities in males (e.g., hypospadias, micropenis, undescended testes)

• Cleft palate or high-arched palate

• Heart defects (e.g., atrial or ventricular septal defects)

• Gastrointestinal issues such as feeding difficulties, vomiting, and constipation

• Photosensitivity and skin anomalies in some cases

Severity can range from mild developmental issues and subtle physical signs to life-threatening malformations detectable prenatally or at birth.

Diagnosis

Diagnosis of Smith–Lemli–Opitz syndrome involves a combination of clinical evaluation, biochemical testing, and genetic analysis:

• Biochemical tests: Measurement of 7-dehydrocholesterol and cholesterol levels in the blood. Elevated 7-DHC with low cholesterol strongly suggests SLOS.

• Genetic testing: Molecular analysis of the DHCR7 gene to confirm pathogenic mutations.

• Prenatal testing: Available through chorionic villus sampling (CVS) or amniocentesis if there is a known familial mutation.

• Ultrasound imaging: May reveal congenital anomalies such as heart defects or cleft palate during pregnancy.

• Newborn screening: SLOS is not routinely included in newborn screening programs but may be tested in suspected cases.

Treatment

There is no cure for Smith–Lemli–Opitz syndrome, and treatment is primarily supportive and symptomatic. A multidisciplinary approach is essential for addressing the various medical and developmental needs. Common treatment strategies include:

• Cholesterol supplementation: Dietary cholesterol (often in the form of egg yolks or cholesterol-enriched formulas) is given to raise plasma cholesterol levels and improve growth, development, and behavior. Its effectiveness varies.

• Nutritional support: Feeding therapy, nutritional counseling, and gastrostomy tube placement if oral intake is inadequate.

• Developmental therapy: Early intervention with physical, occupational, and speech therapies to support motor and cognitive development.

• Surgical interventions: May be required to correct congenital heart defects, genital anomalies, or cleft palate.

• Behavioral and psychiatric care: Medications and behavioral therapy for managing aggression, anxiety, or autism-like symptoms.

• Regular monitoring: Ongoing care from specialists including pediatricians, cardiologists, neurologists, and geneticists.

Prognosis

The prognosis of Smith–Lemli–Opitz syndrome depends on the severity of the enzyme deficiency and the range of associated anomalies. Children with mild forms can achieve developmental milestones and live into adulthood with appropriate support. In contrast, severe cases involving major organ malformations or failure to thrive may result in early mortality.

With early diagnosis and comprehensive care, many individuals with SLOS can experience improved quality of life. Ongoing research into potential therapies, such as statins and antioxidants, continues to explore ways to modify disease progression and outcomes. Genetic counseling is crucial for families to understand inheritance patterns and reproductive options.