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Study of Smith-Lemli-Opitz Syndrome

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2, 2016 by National Institutes of Health Clinical Center (CC)
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) ) Identifier:
First received: November 3, 1999
Last updated: April 20, 2017
Last verified: September 2, 2016

Smith-Lemli-Opitz Syndrome (SLOS) is a genetic disorder (autosomal recessive) caused by an abnormality in the production of cholesterol. The disorder can occur in both a "mild" or "severe" form. SLOS is associated with multiple birth defects and mental retardation. Some of the birth defects include; abnormal facial features, poor muscle tone, poor growth, shortened life span, and abnormalities of the heart, lungs, brain, gastrointestinal tract, limbs, genitalia, and kidneys.

There is no known cure for SLOS but recently patients have been treated with increased amounts of cholesterol in their diet. The cholesterol in a persons diet is unable to correct the abnormalities in the patient's organs, but researchers hope it will improve growth failure and mental retardation.

This study was developed to answer questions about the causes and complications of SLOS, as well as the effectiveness of cholesterol treatment. The study will enroll patients diagnosed with SLOS, and their mothers. The objectives of the study will be to address the following questions:

  1. <TAB> What is the prognosis / natural history of the demyelination in the nervous system of patients with SLOS?
  2. <TAB> Do patients with SLOS have other problems concerning the function of their endocrine systems?
  3. <TAB>What are the genetic make-ups of patients with SLOS?
  4. <TAB>Can further studies of cholesterol metabolism and genetic testing, using SLOS fibroblasts, increase the understanding of SLOS?<TAB>

Inborn Errors of Metabolism
Mental Retardation
Muscle Hypotonia
Smith Lemli Opitz Syndrome

Study Type: Observational
Official Title: Clinical and Basic Investigations Into Smith-Lemli-Opitz Syndrome

Resource links provided by NLM:

Further study details as provided by National Institutes of Health Clinical Center (CC):

Estimated Enrollment: 200
Study Start Date: March 19, 1998
Detailed Description:

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive multiple congenital anomaly/mental retardation syndrome. Typical clinical features include a distinctive facial appearance, mental retardation, autistic behavior, hypotonia, failure to feed, poor growth, decreased life span, and variable structural anomalies of the heart, lungs, brain, gastrointestinal tract, limbs, genitalia and kidneys. The SLOS phenotypic spectrum is broad and variable. At the severe end of the spectrum SLOS is a lethal disorder with multiple major congenital anomalies; whereas, mild cases of SLOS present with a combination of minor physical stigmata, behavioral problems, and learning disabilities. SLOS is due to an inborn error of cholesterol biosynthesis. Biochemically, SLOS patients have a deficiency of 3beta-hydroxysterol delta(7)-reductase activity. 3beta-hydroxysterol delta(7)-reductase is an NADPH dependent microsomal enzyme that catalyzes the reduction of the C7(8) double bond of 7-dehydrocholesterol (7-DHC) to yield cholesterol in the last step of cholesterol biosynthesis via the Kandutsch-Russel pathway. This inborn error of cholesterol biosynthesis results in elevated tissue and serum 7-DHC levels and typically decreased serum and tissue cholesterol levels. In 1998 we established that the deficiency in 3beta-hydroxysterol delta(7)-reductase activity is due to mutation of the 3beta-hydroxysterol delta(7)-reductase gene (DHCR7). Once the biochemical defect in SLOS was identified, dietary cholesterol supplementation was proposed and employed as a therapeutic approach. Although developmental malformations remain fixed, dietary cholesterol supplementation appears to improve the overall health of these patients, and initial results have shown that dietary cholesterol supplementation has had a positive impact on some of the behavioral manifestations of this disorder. Although our understanding of this disorder has advanced over the last few years, many questions remain concerning the effectiveness of cholesterol replacement therapy, the long term prognosis for individuals on dietary cholesterol supplementation, and the need for adjunctive measures in the clinical management of SLOS patients. We propose to answer some of these questions by continuing our longitudinal natural history/prognosis study on patients with SLOS.

The objectives of this study are as follows:

  1. To establish the natural history, and thus prognoses, of a cohort of SLOS patients on dietary cholesterol supplementation.<TAB><TAB>


  2. To provide baseline information about SLOS patients on cholesterol supplementation in order to design and interpret future adjunctive therapies.
  3. To function as a screening protocol to recruit patients into other therapeutic or investigative trials. This protocol provides for phenotypic evaluation, obtaining skin fibroblasts, initial laboratory testing, and genotyping. This protocol also provides an alternative for patients who are excluded, or elect not to participate in a future therapeutic trial.
  4. To maintain a large, diverse and well-characterized SLOS cohort to investigate new areas of clinical concern that arise.
  5. To establish a genotype/phenotype correlation for SLOS, to continue to define the SLOS clinical spectrum and to determine other factors that may significantly influence a specific patient s phenotype.
  6. To use in vitro and in vivo studies of cholesterol metabolism to further our understanding of the molecular, biochemical, and cellular processes that underlie the clinical problems encountered in SLOS.
  7. To use newer modalities of magnetic resonance imaging (Quantitative MRS and Diffusion Tensor Imaging) and to correlate findings with both biochemical measures and neurocognitive testing.

Ages Eligible for Study:   Child, Adult, Senior
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
  • Any patient with biochemically confirmed SLOS will be accepted into this study. Patients of any age, either gender, or any ethnicity will be accepted into this study. No exclusions will be made based on race or gender. Historically, more males than females have been diagnosed as having SLOS. This bias was likely a result of the fact that genital hypoplasia is readily apparent in a male, and therefore the clinical diagnosis is easier to make in a male patient. SLOS syndrome appears more commonly in individuals of Northern European ancestry. Out of 150 biochemically proven cases, only one was an African American and no patients of Asian descent were reported. One SLOS mutant allele (R404C) appears to be present in individuals of French Canadian and Creole heritage. This likely represents a founder effect. One puzzling finding is that the carrier rate of the most common SLOS mutant allele in Black Canadians from Ontario and African Americans from Pennsylvania appears to be approximately 0.7%. However, clinical cases appear to be rare. The predominance of Caucasians reported in the literature may represent a bias of ascertainment of the disorder, variable presentation in different ethnic groups, or a founder effect in some ethnic groups. Because we function as a referral center with respect to recruitment, the ethnic background of our population is likely going to reflect the overall population of diagnosed cases.


  • Patients will be excluded if they cannot travel to the NIH because of their medical condition.
  • Pregnant women will be excluded, and a negative urine pregnancy test will be required of menstruating women.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT00001721

Contact: Margarita J Raygada, Ph.D. (301) 451-8822
Contact: Forbes D Porter, M.D. (301) 435-4432

United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL)    800-411-1222 ext TTY8664111010   
Sponsors and Collaborators
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Principal Investigator: Forbes D Porter, M.D. Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
  More Information

Additional Information:
Publications automatically indexed to this study by Identifier (NCT Number):
Responsible Party: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Identifier: NCT00001721     History of Changes
Other Study ID Numbers: 980081
Study First Received: November 3, 1999
Last Updated: April 20, 2017

Keywords provided by National Institutes of Health Clinical Center (CC):
Smith-Lemli-Opitz Syndrome (SLO)

Additional relevant MeSH terms:
Intellectual Disability
Metabolism, Inborn Errors
Cleft Palate
Genetic Diseases, X-Linked
Smith-Lemli-Opitz Syndrome
Muscle Hypotonia
Pathologic Processes
Genetic Diseases, Inborn
Metabolic Diseases
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Neurodevelopmental Disorders
Mental Disorders
Jaw Abnormalities
Jaw Diseases
Musculoskeletal Diseases
Maxillofacial Abnormalities
Craniofacial Abnormalities
Musculoskeletal Abnormalities
Stomatognathic Diseases
Mouth Abnormalities
Mouth Diseases
Stomatognathic System Abnormalities
Congenital Abnormalities processed this record on April 26, 2017