Smith-Lemli-Opitz Syndrome (SLOS) is a rare genetic disorder that affects multiple systems in the body. It is caused by the body’s inability to properly make cholesterol. While cholesterol often gets a bad reputation in discussions about adult heart health, it is, in fact, a substance that is absolutely essential for normal human development and function. Cholesterol is a vital building block for:

• Healthy Cell Membranes: Every cell in our body requires cholesterol to build and maintain its outer wall.
• Brain Development: The brain is particularly rich in cholesterol, which is a key component of the myelin sheath that insulates nerve cells.
• Hormone Production: Cholesterol is the precursor molecule used to create essential steroid hormones, including cortisol (the stress hormone) and sex hormones (like testosterone and estrogen).
• Vitamin D Synthesis: The body uses cholesterol to produce vitamin D in response to sunlight.
• Digestion: Cholesterol is used to produce the bile acids needed to digest fats.

In SLOS, a specific step in the body’s cholesterol production pathway is blocked. To understand this, it is helpful to use an analogy. Think of cholesterol production as a critical assembly line in the body’s factory. The line takes a starting material and, through a series of steps, converts it into the final, essential product: cholesterol. A specific “worker,” which is an enzyme, performs each step. In SLOS, the very last worker on the assembly line is missing or broken. This causes two major problems throughout the body:

1. Cholesterol Deficiency: The factory can’t produce enough of the finished product, cholesterol, leading to a critical shortage of this vital building block.
2. Toxic Buildup: The raw material just before that final step, a substance called 7-dehydrocholesterol (7-DHC), piles up to toxic levels.

This combination of a severe cholesterol shortage and a toxic buildup of its precursor, 7-DHC, is what disrupts fetal development and causes the widespread signs and symptoms of SLOS.

In my experience, SLOS can present with such a broad range of symptoms that it’s often first suspected during newborn exams, especially when multiple congenital anomalies are present.

SLOS is caused by mutations in the DHCR7 gene. This gene contains the precise genetic instructions for making the enzyme 7-dehydrocholesterol reductase. This is the “last worker on the assembly line” in the cholesterol synthesis pathway. Its specific job is to perform the final chemical reaction that converts 7-DHC into cholesterol.

A mutated gene leads to a deficient or non-functional enzyme, causing the buildup of 7-DHC and the shortage of cholesterol.

Clinically, I’ve found that understanding SLOS hinges on remembering one core issue: the body is starved of cholesterol at a time when it needs it most during fetal development.

SLOS is inherited in an autosomal recessive pattern. This has several important implications:

• It means that for a child to have SLOS, they must inherit two copies of the mutated DHCR7 gene, one from their mother and one from their father.
• Parents are almost always unaffected carriers. A carrier is a person who has one normal copy of the DHCR7 gene and one mutated copy. Their one normal gene produces enough of the enzyme for them to be perfectly healthy and show no signs of the disorder. Most carriers are completely unaware of their genetic status.

When two carriers have a child together, there are three possible outcomes for each pregnancy:

• There is a 25% chance that the child will inherit a mutated gene from both parents and will be affected with SLOS.
• There is a 50% chance that the child will inherit one mutated gene and one normal gene, and will be an unaffected carrier like the parents.
• There is a 25% chance that the child will be unaffected and not a carrier.

Because both parents must carry the same faulty gene, the chances of having a child with an autosomal recessive condition like SLOS are higher in communities where it is common for close relatives, such as first cousins, to marry. This is because related individuals are more likely to have inherited the same rare, faulty gene from a common ancestor.

Many parents are shocked by the diagnosis, as there’s no family history. I explain that carrier parents are healthy and often unaware they carry the gene.

SLOS is a spectrum disorder, meaning the signs and symptoms can vary dramatically in number and severity from one person to another. Individuals with some residual enzyme function may have a milder form of the disease, while those with no enzyme function have the most severe form.

The characteristic features of SLOS affect many parts of the body and are typically present at birth.

Growth and Physical Features

• Intrauterine Growth Restriction (IUGR): The baby is born unusually small and light for their gestational age.
• Poor Postnatal Growth: Infants often have significant feeding difficulties, low muscle tone (hypotonia), and poor growth after birth, a condition known as “failure to thrive.”
• Microcephaly: An abnormally small head size is very common.
• Distinctive Facial Features: These can include a small jaw (micrognathia), a broad nasal bridge with upturned nostrils, and drooping eyelids (ptosis).
• Limb Abnormalities: A characteristic sign is syndactyly, the webbing or fusion of the second and third toes is a hallmark sign. Some infants may also have polydactyly, or extra fingers or toes.
• Genital Abnormalities (in males): Underdeveloped or ambiguous genitalia is common.

Neurological and Developmental Features

• Intellectual Disability: This is a feature of almost all SLOS cases and ranges from mild to profound.
• Behavioral Issues: Many children with SLOS exhibit behavioral challenges, including features of autism, hyperactivity, and self-injurious behavior.
• Low Muscle Tone (Hypotonia): This can contribute to feeding problems and delays in achieving motor milestones like sitting and walking.

Other Common Medical Problems

• Photosensitivity: The accumulation of 7-DHC in the skin makes individuals with SLOS extremely sensitive to sunlight, leading to easy and severe sunburns.
• Gastrointestinal Issues: Chronic constipation, vomiting, and gastroesophageal reflux are common.
• Congenital Malformations: In more severe cases, individuals may be born with structural defects of the heart, lungs, kidneys, or gastrointestinal tract. A cleft palate is also common.

Clinically, I’ve found that the toe webbing between the second and third digits often raises suspicion during newborn exams, leading to earlier testing for SLOS.

A diagnosis of SLOS may be suspected before birth if a prenatal ultrasound shows signs like growth restriction and other physical abnormalities. It is often suspected at birth when a newborn presents with the characteristic combination of features.

The diagnostic process involves several steps:

1. Biochemical Testing (The Definitive Test): The diagnosis of SLOS is confirmed with a simple blood test that measures the amount of cholesterol and its precursor, 7-dehydrocholesterol (7-DHC). In an individual with SLOS, the test will show abnormally high levels of 7-DHC and low to low-normal levels of cholesterol. This biochemical signature is the hallmark of the disease.
2. Genetic Testing: A diagnosis can also be confirmed by molecular genetic testing. This involves sequencing the DHCR7 gene from a blood sample to identify the specific mutations responsible for the condition. This is particularly useful for carrier testing in family members and for prenatal diagnosis in future pregnancies.
3. Evaluation for Associated Conditions: Once a diagnosis of SLOS is made, a comprehensive evaluation is performed to check for any internal malformations. This typically includes an echocardiogram of the heart and an ultrasound of the kidneys.

In my practice, early genetic confirmation helps guide a multidisciplinary approach, from nutrition and endocrine support to speech and physical therapy.

There is no cure for Smith-Lemli-Opitz syndrome. Therefore, treatment is supportive, lifelong, and focused on managing the specific symptoms and medical problems to improve the individual’s health and quality of life. This requires a coordinated, multidisciplinary team of specialists, including a pediatrician, a clinical geneticist, an endocrinologist, a neurologist, developmental therapists, and a nutritionist.

The key management strategies include:

• Cholesterol Supplementation: This is a cornerstone of therapy. Since the body cannot produce its own cholesterol, providing it through the diet can help to alleviate the deficiency. This may involve supplementation with purified cholesterol, or more commonly, by increasing the intake of cholesterol-rich foods like egg yolks (NORD, 2023). While this can improve some symptoms, it does not correct the underlying neurological issues.
• Nutritional and Feeding Support: This is the most critical intervention in infancy. Due to feeding difficulties and low muscle tone, many infants require a high-calorie diet and support from a feeding therapist. In many cases, a gastrostomy tube (G-tube) , a tube placed directly into the stomach, is necessary to ensure the child receives adequate nutrition and calories to grow and to prevent low blood sugar.
• Sun Protection: Due to severe photosensitivity, individuals with SLOS must practice rigorous sun protection. This includes using high-SPF sunscreen, hats, and protective clothing, and avoiding peak sun exposure.
• Surgical Interventions: Surgery may be required to correct physical abnormalities, such as a cleft palate, heart defects, or genital abnormalities.
• Developmental Therapies: Early and intensive intervention with physical, occupational, and speech therapy is crucial to help a child reach their maximum developmental potential.
• Medication: For managing behavioral issues or seizures if they occur.

I’ve seen that children with early cholesterol therapy and structured developmental support often make meaningful gains, even if they continue to need lifelong care.

Smith-Lemli-Opitz syndrome is a rare and complex genetic disorder that presents profound challenges for affected individuals and their families from the moment of birth. Caused by a fundamental error in the body’s ability to produce cholesterol, this multi-system condition affects growth, physical development, and neurological function. While the diagnosis can be overwhelming and there is no cure, a proactive and comprehensive management plan can significantly improve a child’s health and well-being. What I always tell families is this: with care, structure, and love, children with SLOS can thrive beyond what the diagnosis suggests.

National Institutes of Health, Genetic and Rare Diseases Information Center (GARD). (2021). Smith-Lemli-Opitz syndrome. Retrieved from https://rarediseases.info.nih.gov/diseases/7674/smith-lemli-opitz-syndrome

National Organization for Rare Disorders (NORD). (2023). Smith-Lemli-Opitz Syndrome. Retrieved from https://rarediseases.org/rare-diseases/smith-lemli-opitz-syndrome/

The MAGIC Foundation. (n.d.). Smith-Lemli-Opitz Syndrome (SLOS). Retrieved from https://www.magicfoundation.org/growth-disorders/smith-lemli-opitz-syndrome-slos/