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Smith-Lemli-Opitz Syndrome

Last updated Aug. 14, 2019

Approved by: Maulik P. Purohit MD, MPH

Smith-Lemli-Opitz Syndrome (SLOS) is an inherited developmental disorder, in which the body is unable to produce enough cholesterol, because of shortage of 7-dehydrocholesterol reductase enzyme, which catalyzes the last step in cholesterol synthesis.


What are the other Names for this Condition (Also known as/Synonyms)

  • 7-Dehydrocholesterol Reductase Deficiency Disorder
  • RSH Syndrome
  • SLOS (Smith-Lemli-Opitz Syndrome)

What is Smith-Lemli-Opitz Syndrome? (Definition/Background Information)

  • Smith-Lemli-Opitz Syndrome (SLOS) is an inherited developmental disorder, in which the body is unable to produce enough cholesterol, because of shortage of 7-dehydrocholesterol reductase enzyme, which catalyzes the last step in cholesterol synthesis
  • Since cholesterol is involved in embryonic development, the synthesis of certain hormones and vitamin D3, its deficiency leads to developmental and metabolic disorders
  • Mutation(s) in the DHCR7 gene cause deficiency in 7-dehydrocholesterol reductase enzyme, and lead to Smith-Lemli-Opitz Syndrome. The disorder is inherited in an autosomal recessive manner and is predominantly reported in Caucasian populations with a family history of the disorder
  • The disorder is characterized by multiple congenital anomalies, intellectual abnormalities, and behavioral defects resembling autism spectrum disorders, which can either be mild (type I) or severe (type II)
  • A diagnosis of Smith-Lemli-Opitz Syndrome can be made prenatally, through ultrasound of the developing fetus, followed by amniocentesis, and genetic testing. After birth of the child, blood tests to check cholesterol levels and genetic molecular testing may help in the diagnosis
  • There is no cure for Smith-Lemli-Opitz Syndrome. Use of cholesterol supplements, feeding aids, and surgery to repair certain congenital defects may be recommended
  • The outcome depends on the severity of symptoms. Spontaneous miscarriages are known to occur. Cardiac or renal complications may also lead to fatalities. Those with milder symptoms may be able to lead a near-normal quality of life

Who gets Smith-Lemli-Opitz Syndrome? (Age and Sex Distribution)

  • Smith-Lemli-Opitz Syndrome is rare, with an estimated incidence rate between 1:20,000 and 1:60,000 live births
  • Onset of the disorder may occur prenatally, soon after birth, or during infancy
  • This genetic disorder can affect both male and female genders
  • SLOS is prevalent in Caucasians of northern and central European descent; very few cases are reported in individuals of Asian, South American, and African ancestry

What are the Risk Factors for Smith-Lemli-Opitz Syndrome? (Predisposing Factors)

Smith-Lemli-Opitz Syndrome is a genetic disorder. The following are known risk factors for SLOS:

  • A family history of the disorder
  • Being of Caucasian descent

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider

What are the Causes of Smith-Lemli-Opitz Syndrome? (Etiology)

Smith-Lemli-Opitz Syndrome is caused by mutation(s) in the DHCR7 gene, which codes for the enzyme 7-dehydrocholesterol reductase (DHCR7 enzyme).

  • Under normal circumstances, this enzyme catalyzes the final step in cholesterol synthesis
    • Cholesterol is a fat-like substance that is synthesized by the body, and may be obtained from food sources such as meat and dairy
    • Cholesterol plays crucial roles in the development of embryo, protection of nerve cells, synthesis of certain hormones and digestive acids
  • Mutation(s) in the DHCR7 gene leads to a deficiency in the DHCR7 enzyme, and a consequential reduction of cholesterol in the body. The insufficiency of cholesterol in the body leads to impaired growth and development. Some mutations may cause mild symptoms, while others may cause severe signs and symptoms

Smith-Lemli-Opitz Syndrome is inherited in an autosomal recessive manner. In this type of inheritance, an individual must have both copies of the causative gene to be defective, for the disorder to manifest itself. The affected individual inherits one copy of the defective gene from each parent, who are carriers of the disorder and are typically unaffected.

What are the Signs and Symptoms of Smith-Lemli-Opitz Syndrome?

The signs and symptoms associated with Smith-Lemli-Opitz Syndrome may be mild or severe, depending on the type of mutation in the DHCR7 gene. The following are some common symptoms of SLOS:

  • Distinct facial features that include:
    • Small chin
    • Cleft palate or split upper lip
    • Micrognathia or small size of the jaws
    • Broad nose, flat nasal bridge
    • Nostrils flaring upwards
    • Ptosis or drooping of the upper or lower eyelids
    • Bitemporal narrowing: The size of the head above the eyes are narrow
    • Microcephaly (small head)
  • Feeding problems
  • Difficulty to grow and thrive
  • Syndactyly or fused toes; polydactyly or extra fingers or toes
  • Rhizomelia or disproportionate length of upper arms and thighs
  • Photosensitivity
  • Intellectual disability; learning problems
  • Behavioral issues
    • Hyperactivity
    • Self-injurious behavior
    • Sleep disturbances
    • Multiple autistic traits
  • Difficulties in communication, social interaction
  • Deformities of the following organs:
    • Heart
    • Lungs
    • Kidneys
    • Gastrointestinal tract
    • Genitalia (especially malformed genitals in males)
  • Hypotonia or weak muscle tone
  • Severe structural brain abnormalities such as the following:
    • Hypoplasia (underdevelopment) or absence of the corpus callosum, which connects the two hemispheres of the brain, allowing them to communicate
    • Holoprosencephaly or a single lobe in the brain instead of two hemispheres 
  • Lethargy
  • Hearing and vision loss
  • Eye defects including:
    • Cataract
    • Strabismus: A condition wherein alignment of both eyes is not proper
    • Nystagmus: Involuntary eye movement
  • Respiratory failure
  • Congestive heart failure
  • Coma

How is Smith-Lemli-Opitz Syndrome Diagnosed?

Smith-Lemli-Opitz Syndrome is diagnosed either prenatally, after birth, or in infancy. The diagnostic methods may include:

Prenatal:

  • Ultrasound imaging of the developing fetus
  • Amniocentesis and chorionic villus sampling for mutational analysis of fetal cells

After birth:

  • Complete physical examination and assessment of symptoms
  • Evaluation of family medical history
  • Blood test to check for:
    • Low levels of cholesterol
    • Elevated levels of a precursor of cholesterol (7-dihydrocholesterol), which is converted to cholesterol
  • Electrolyte test to exclude adrenal deficiency
  • Magnetic resonance imaging (MRI) and computed tomography (CT) scan of the brain and other regions, to check for structural malformations
  • Radiological imaging of the chest to check for congenital heart disease and other abnormalities
  • Genitourinary ultrasonography to check for abnormalities
  • Molecular genetic testing to identify the mutation causing SLOS

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Smith-Lemli-Opitz Syndrome?

The following are some potential complications that can arise from Smith-Lemli-Opitz Syndrome:

  • Pneumonia
  • Severe congenital heart defect
  • Hepatic failure
  • Multi-organ failure

Miscarriages are known to occur; death may also result from severe complications such as organ failure.

How is Smith-Lemli-Opitz Syndrome Treated?

Smith-Lemli-Opitz Syndrome is an incurable congenital disorder. Treatment options for the management of SLOS are tailored to address the specific symptoms in each affected child, and may include the following measures: 

  • Dietary cholesterol supplements to increase the child’s growth rate and development. This may be administered in the form of:
    • Purified cholesterol supplement
    • Foods, such as egg yolk and cream
  • Bile acid supplements in conjunction with cholesterol supplementation
  • Feeding through a gastrostomy tube, when chewing food is difficult
  • Surgery to correct cleft palate, heart defects, and genital abnormalities
  • Statin therapy to reduce levels of the cholesterol precursor, 7-dihydrocholesterol. Some studies have shown a combination of statins and cholesterol supplementation decreases the level of the precursor, whose accumulation may be toxic
  • Counseling and behavioral therapy
  • Administration of anti-psychotic and anti-depressant medications

How can Smith-Lemli-Opitz Syndrome be Prevented?

  • Smith-Lemli-Opitz Syndrome is a genetic disorder, and at the present time, no guidelines or methods are available to prevent its occurrence
  • Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
  • If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
  • Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders such as SLOS

Regular medical screening at periodic intervals with tests and physical examinations are strongly recommended.

What is the Prognosis of Smith-Lemli-Opitz Syndrome? (Outcomes/Resolutions)

The prognosis of Smith-Lemli-Opitz Syndrome is determined by the severity of its signs and symptoms.

  • Miscarriages and stillbirths have been reported
  • After birth, children with severe symptoms often succumb to the disorder, owing to extremely low levels of cholesterol resulting in cardiovascular, pulmonary, hepatic, and renal complications
  • With continuing and proper medical care, cholesterol supplementation and diet, affected children may be able to live into adulthood and achieve normal life expectancies

However, because of intellectual disabilities and problems with learning and behavior, the affected individuals may not be able to lead an independent life.

Additional and Relevant Useful Information for Smith-Lemli-Opitz Syndrome:

  • RSH Syndrome is a synonym of Smith-Lemli-Opitz Syndrome. When scientists published the earliest research article on the disorder, it was based on the first letters of the last names of the 3 individuals in whom the disorder was first characterized/identified, and hence the usage of the acronym ‘RSH’
  • Smith-Lemli-Opitz Syndrome is also known as “Polydactyly, Sex Reversal, Renal Hypoplasia, Unilobular Lung”

What are some Useful Resources for Additional Information?


References and Information Sources used for the Article:


Helpful Peer-Reviewed Medical Articles:


Reviewed and Approved by a member of the DoveMed Editorial Board
First uploaded: April 30, 2017
Last updated: Aug. 14, 2019