Smith-Lemli-Opitz syndrome (SLOS) is a developmental disorder that impacts multiple body systems. It is a metabolic condition caused by an impaired ability to produce cholesterol, a substance necessary for embryonic development and functions both before and after birth. The effects of SLOS vary significantly, with severity ranging from minor physical differences and learning problems to life-threatening abnormalities.
Genetic Causes and Inheritance
Smith-Lemli-Opitz syndrome results from a mutation in the DHCR7 gene, which provides instructions for making the enzyme 7-dehydrocholesterol reductase. This enzyme performs the final step in cholesterol production, converting a precursor molecule called 7-dehydrocholesterol (7-DHC) into cholesterol. A mutated gene leads to a deficient enzyme, causing both a shortage of cholesterol and a toxic buildup of 7-DHC in body tissues. This combination disrupts the growth and development of many body systems.
The wide variability in the syndrome’s severity is explained by more than 130 different identified mutations in the DHCR7 gene.
SLOS is inherited in an autosomal recessive pattern, meaning an individual must inherit two copies of the mutated gene—one from each parent—to be affected. Parents who each carry one copy of the mutated gene are known as carriers and do not show signs of the condition. When two carriers have a child, there is a 25% chance in each pregnancy that the child will have SLOS.
Signs and Characteristics
Common physical features include a smaller than average head size (microcephaly), a short nose with upturned nostrils, and drooping eyelids. A common characteristic is the webbing or fusion of the second and third toes, known as syndactyly. Other physical signs can include extra fingers or toes (polydactyly), a cleft palate, and underdeveloped external genitalia in males.
Developmental and neurological issues are prevalent. Intellectual disability ranges from mild learning problems to profound cognitive impairment. Many infants with SLOS have weak muscle tone (hypotonia), which contributes to feeding difficulties and slower growth. These feeding problems, along with potential gastrointestinal abnormalities like pyloric stenosis or Hirschsprung disease, can further impact development.
Behavioral traits are a significant aspect of SLOS. These can include characteristics associated with autism spectrum disorder, such as challenges with communication and social interaction. Other common behaviors may include hyperactivity, sleep disturbances, and self-injurious actions. A notable trait is photosensitivity, where sunlight exposure can cause a rapid sunburn-like reaction.
Diagnosis Process
The diagnosis of Smith-Lemli-Opitz syndrome can occur before and after birth, relying on clinical observations and specific laboratory tests. Postnatally, a physician may suspect the syndrome based on characteristic physical features, such as distinctive facial traits or syndactyly of the toes. While clinical signs raise suspicion, a definitive diagnosis requires biochemical confirmation.
The primary diagnostic test is a blood analysis that measures sterol levels. In individuals with SLOS, this test will reveal elevated levels of 7-dehydrocholesterol (7-DHC). While blood cholesterol levels are often low, this finding is not universal, making the measurement of 7-DHC the most reliable biochemical marker.
Prenatal diagnosis is also possible if a routine fetal ultrasound reveals abnormalities associated with SLOS. To confirm, a sample of amniotic fluid or placental tissue can be analyzed to measure 7-DHC levels. The diagnosis is definitively confirmed through molecular genetic testing that identifies mutations in both copies of the DHCR7 gene.
Management and Therapeutic Approaches
There is no cure for Smith-Lemli-Opitz syndrome, so management focuses on addressing symptoms and improving quality of life through a multidisciplinary approach. A primary strategy is dietary cholesterol supplementation, administered through purified products or by increasing the intake of high-cholesterol foods like egg yolks and cream. This supplementation can improve growth and may lessen photosensitivity, though its impact on developmental outcomes is not fully established.
Physical, occupational, and speech therapies are utilized to help address developmental delays, improve muscle tone, and assist with feeding difficulties. For infants who struggle with feeding, a gastrostomy tube may be necessary to ensure adequate nutrition.
Surgical interventions may be required to correct physical abnormalities like a cleft palate or heart defects. Other supportive measures are tailored to the individual’s needs, including educational support for learning disabilities and medications for behavioral issues.
Due to photosensitivity, protective measures such as using sunscreen and appropriate clothing are recommended for sun exposure.