Smith-Lemli-Opitz syndrome
Smith-Lemli-Opitz syndrome (SLOS) is a genetic developmental disorder characterized by multiple congenital anomalies, intellectual disabilities, and growth deficiencies resulting from mutations in the DHCR7 gene. This gene is crucial for producing the enzyme 7-dehydrocholesterol reductase, which plays a vital role in cholesterol biosynthesis. Individuals with SLOS typically exhibit low cholesterol levels and high levels of cholesterol precursors, leading to a spectrum of developmental challenges. The severity of SLOS varies among affected individuals, often correlating with the level of cholesterol present.
The syndrome primarily affects those of northern or central European descent, with both parents needing to be carriers of the gene mutation to have a child with SLOS. Diagnosis is usually confirmed through blood tests for elevated 7-dehydrocholesterol or genetic sequencing. While there is no cure, treatment may include cholesterol supplementation and targeted therapies to address specific developmental issues. Unfortunately, the prognosis can be severe, with a significant percentage of affected infants facing mortality in the first year of life. Genetic counseling is recommended for families with a history of SLOS to understand risks and implications.
Smith-Lemli-Opitz syndrome
ALSO KNOWN AS: 7-Dehydrocholesterol reductase deficiency; RSH syndrome; SLOS; SLO syndrome
DEFINITION Smith-Lemli-Opitz syndrome (SLOS) is a developmental disorder that affects multiple organ systems, prenatal and postnatal growth, and mental development. It is caused by mutations in the DHCR7 gene that result in deficiency of the enzyme 7-dehydrocholesterol reductase.
Risk Factors
A pregnancy is at risk for SLOS when both parents are carriers of mutations in the DHCR7 gene. SLOS is most common in individuals of northern or central European ancestry and is less common among individuals of African or Asian ancestry.
Etiology and Genetics
SLOS is an autosomal recessive genetic condition. When both parents are carriers of a single mutation in the DHCR7 gene, there is a 25 percent chance in each pregnancy that the child will inherit both mutations and will be affected with SLOS.
The DHCR7 gene is located at 11q12-13. It codes for the 7-dehydrocholesterol (7-DHC) reductase, which normally catalyzes the conversion of 7-DHC to cholesterol. Mutations in the DHCR7 gene result in a loss of function of 7-DHC reductase. This blocks the final step in the cholesterol biosynthesis pathway.
Individuals who have a mutation in one copy of the DHCR7 gene may have slightly increased 7-DHC levels but do not experience any clinical consequences. Individuals who have mutations in both copies of the DHCR7 gene are affected with SLOS. Affected individuals have abnormally low cholesterol levels and elevated levels of the cholesterol precursors 7-DHC and 8-DHC.
Cholesterol deficiency is thought to be the cause of the developmental defects seen in SLOS. During fetal life, very little cholesterol is transported across the placenta from the mother. The fetus relies primarily on biosynthesis of cholesterol. Cholesterol is a major structural component of cell membranes and mitochondrial membranes. It is needed for bile acid, steroid hormone, and vitamin D metabolism. Cholesterol has also been found to bind to hedgehog proteins, a family of signaling proteins that direct embryonic development.
Clinical severity of SLOS can be variable and is inversely associated with cholesterol levels. Mortality is highest in individuals with the lowest cholesterol levels. The variability in severity is partially due to the more than 120 disease-causing mutations that have been described in the DHCR7 gene. The twelve most common mutations account for approximately 69 percent of the alleles found in affected individuals.
Historically, SLOS was classified as type II, which is more severe and often lethal in the neonatal period, and classic type I. However, it is now clear that the difference in severity is related to the genotype. The most severely affected individuals typically have two mutations that result in very little residual 7-DHC reductase activity. Individuals with classic SLOS often have one of these severe mutations and a second that results in higher levels of residual 7-DHC reductase activity. Individuals who have two copies of less severe missense mutations may be mildly affected.
Symptoms
Individuals with SLOS have moderate to severe intellectual disability, developmental delays, multiple congenital anomalies, and behaviors characteristic of autism. Birth defects are often seen involving the heart, lungs, kidneys, gastrointestinal tract, genitalia, palate, fingers, and toes.
Screening and Diagnosis
A diagnosis of SLOS can be made by checking blood or tissues for an elevated concentration of 7-DHC. Most affected individuals have low cholesterol levels as well, but some affected individuals have cholesterol levels that are within the normal range. Sequencing of the DHCR7 gene is able to identify disease-causing mutations in approximately 96 percent of affected individuals. Testing of hair samples for 7-dehydrocholesterol and cholesterol has been investigated as another diagnostic technique.
Prenatal testing for SLOS should be considered when there is a family history of SLOS, ultrasound findings are suggestive of SLOS, or maternal serum unconjugated estriol levels are low. Prenatally, a diagnosis of SLOS can be made by detecting an elevated concentration of 7-DHC in or in tissue obtained from chorionic villus sampling (CVS). Enzyme testing can also be performed on cultured cells from an or CVS to confirm the diagnosis.
Treatment and Therapy
Following an initial diagnosis, evaluations may include a developmental assessment, ophthalmologic evaluation, cardiac evaluation, genitourinary examination, evaluation for functional gastrointestinal problems, nutritional assessment, MRI or other cranial imaging, renal ultrasound, and hearing evaluation. Treatment is directed to the particular problems identified in each child with SLOS. Early intervention and physical, occupational, and speech therapies are often needed.
Cholesterol supplementation has been shown to improve growth and increase nerve conduction velocities. It may improve behavioral problems as well. However, since many of the findings associated with SLOS are due to embryologic developmental defects, cholesterol supplementation cannot cure this condition.
Prevention and Outcomes
Stillbirth is common, and approximately 20 percent of affected children die within the first year of life. Although prenatal screening and diagnosis is available, there is no effective means of preventing SLOS. Genetic counseling should be made available to the families of affected individuals.
Bibliography
Cassidy, Suzanne B., and Judith E. Allanson, eds. Management of Genetic Syndromes. 3rd ed. Hoboken: Wiley, 2011. Print.
Jones, Kenneth Lyons. Smith’s Recognizable Patterns of Human Malformation. 7th ed. Philadelphia: Elsevier, 2013. Print.
Luo, Yitao, et al. "Measurement of 7-Dehydrocholesterol and Cholesterol in Hair Can Be Used in the Diagnosis of Smith-Lemli-Opitz Syndrome." Journal of Lipid Research, vol. 63, no. 6, 2022, doi: 10.1016/j.jlr.2022.100228. Accessed 6 Sept. 2024.
Parker, Philip M. Smith-Lemli-Opitz Syndrome: A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers. San Diego: Icon Group Intl., 2007. Print.
"Smith-Lemli-Opitz/RSH Syndrome Overview." Smith-Lemli-Opitz/RSH Foundation. Smith-Lemli-Opitz/RSH Foundation, 2014. Web. 27 Aug. 2014.
Steiner, Robert D. "Smith-Lemli-Opitz Syndrome." Medscape, 22 July 2024, emedicine.medscape.com/article/949125-overview. Accessed 6 Sept. 2024.