Smith-Lemli-Opitz syndrome

Smith-Lemli-Opitz syndrome is a congenital condition characterized by multiple physical anomalies, intellectual challenges, and behavioral difficulties. It is caused by pathogenic variants in the DHCR7 gene, which plays an essential role in cholesterol synthesis. The condition is inherited in an autosomal recessive manner and typically presents in infancy with a range of distinguishing features. Because precise prevalence estimates are not available, the condition is understood to be uncommon, with severity and specific manifestations varying widely between individuals.

Individuals with Smith-Lemli-Opitz syndrome exhibit a broad range of clinical features that affect multiple organ systems. Cardiac findings such as atrial septal defects, hypertrophic cardiomyopathy, and episodes of ventricular fibrillation are consistently observed. Craniofacial and skeletal anomalies include hypertelorism, depressed nasal bridge, posteriorly rotated and low-set ears, microretrognathia, and distinctive features of the hands and feet such as 2-3 toe cutaneous syndactyly and postaxial polydactyly, sometimes accompanied by penoscrotal hypospadias. Gastrointestinal and other systemic issues, including abdominal distention, feeding difficulties, pyloric stenosis, hepatic steatosis, splenomegaly, hypotonia, sacral dimpling, hypoalbuminemia, and elevated circulating 7-dehydrocholesterol levels, contribute to the complex clinical picture. Not all individuals experience every feature, and severity varies considerably.

Smith-Lemli-Opitz syndrome results from pathogenic variants in the DHCR7 gene, which is critical for the final step of cholesterol biosynthesis. Disruption of this gene interferes with normal cholesterol production, which in turn affects the development of multiple organ systems. The condition is inherited in an autosomal recessive pattern, meaning that both parents must carry a variant for the risk of having an affected child, who then has a 25% chance of inheriting the condition. Individual expression of symptoms varies, and genetic counseling is recommended to help families understand recurrence risks and family planning options.

Currently, management of Smith-Lemli-Opitz syndrome focuses on supportive care and symptom management since there are no FDA-approved treatments specifically for this condition. Treatment is highly individualized and typically involves a multidisciplinary team to address the many affected organ systems. Regular surveillance is an essential part of long-term care, helping to detect complications early through scheduled monitoring of cardiac, gastrointestinal, and other systemic issues. Families are encouraged to discuss treatment options with their healthcare team and to consider genetic counseling to help navigate the complexities of this condition.

The course of Smith-Lemli-Opitz syndrome is highly variable, with outcomes depending on the severity of symptoms, age at diagnosis, and access to specialized, multidisciplinary care. With current standards of care, many individuals experience improvements in quality of life and an extended lifespan, although the condition remains challenging due to its multisystem involvement. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with specialists experienced in managing this condition as well as genetic counselors to discuss long-term management and support options.

There are clinical trials underway exploring new treatment approaches for Smith-Lemli-Opitz syndrome, reflecting an active research area. Individuals interested in clinical trials can search ClinicalTrials.gov or consult their healthcare team about potential eligibility for these investigational therapies.