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Learn about the biochemical discovery of Smith-Lemli-Opitz syndrome.
Discover what tests physicians use to determine if an individual has SLOS.
Read about the different characteristics associated with this syndrome.
Read about this autosomal recessive disorder and how it occurs.
Find out about common behaviors and attributes of SLOS individuals.
Become aware of the treatments available for this syndrome.
Smith-Lemli-Opitz syndrome is a genetic disorder that affects the development of children both before and after birth.
The syndrome was first described in 1964 in three boys with poor growth, developmental delays, and a common pattern of congenital malformations, including cleft palate, genital malformations, and polydactyly (extra fingers and toes). Initially referred to as the “RSH syndrome” after the initials of the first three patients, the syndrome is now better known by the last names of the three geneticists who first described it – Smith-Lemli-Opitz syndrome (SLOS).
Although SLOS had been known as a genetic disorder, the cause was not determined until 1993, when scientists and clinicians discovered that children with SLOS are unable to produce sufficient amounts of cholesterol, an essential nutrient for proper growth and development.
It is unclear how much cholesterol may be passed from mother to fetus during pregnancy; however, unlike other nutrients or molecules essential for fetal development, the mother cannot supply sufficient cholesterol to the developing baby with SLOS.
The discovery of abnormal cholesterol metabolism in SLOS has been made possible by the development of a laboratory test for diagnosis and served as a rationale for potential treatment.
In 1993, scientists made the important discovery that children with SLOS have an inborn error of metabolism that prevents them from making cholesterol in amounts sufficient for normal growth and development.
At diagnosis, individuals with SLOS typically, but not always, have cholesterol levels below normal (“normal” is typically greater than 100 mg/dl, though this varies with age and may vary from one laboratory to another), and abnormally high levels of a precursor of cholesterol, 7-dehydrocholesterol (7-DHC). Elevated levels of 8-dehydrocholesterol (8-DHC), the isomer to 7-DHC, can also by observed in individuals with SLOS.
The deficiency of cholesterol, an essential building block of all cell membranes and the white matter of the brain, is caused by abnormally low functional levels of the enzyme 7-dehydrocholesterol reductase (DHCR7), which converts 7-DHC into cholesterol.
Children with SLOS who have the lowest cholesterol levels tend to have the most severe forms of the disorder, and those with major internal issues often die at birth or in their early years. However, with proper diagnosis and treatment, many with SLOS live well into adulthood.
Although about 10% of individuals with SLOS have near normal cholesterol levels, essentially all have increased levels of 7-DHC. The few individuals who carry a clinical diagnosis of SLOS, but have normal cholesterol and 7-DHC levels, probably have a genetic disorder that resembles SLOS.
This explainer video was provided by Mirum Pharmaceuticals at the request of the Smith-Lemli-Opitz Foundation. To read more about the syndrome, click the button below.
In most cases, but not all, a standard blood cholesterol test will show low cholesterol levels for individuals with SLOS. However, to confirm the diagnosis of SLOS, another blood test is needed.
This test is called the 7-DHC test or sterol profile.
A sterol profile uses sophisticated instrumentation to measure cholesterol, 7-DHC, 8-DHC, and a number of other sterols. The elevated level of 7-DHC confirms the diagnosis of SLOS.
There are a few conditions associated with 7-DHC elevations, although those conditions generally have different clinical features. In addition, after biochemical testing, molecular testing (a.k.a. DNA mutation testing or sequencing) is indicated to confirm the diagnosis and allow the identification of carriers within a family.
In addition to intellectual disability and developmental delay, many different malformations have been described in SLOS. The most common physical defects are listed below.
Microcephaly is a rare neurological condition in which an infant's head is much smaller than the heads of other children of the same age and sex.
Syndactyly is a condition in which children are born with fused or webbed fingers or toes. In most cases of SLOS, the second and third toes are fused.
Bitemporal narrowing is the reduced distance between the temples of the face (the small flat areas at the edge of the eyebrows, running up to the tip of the ears and back to the hairline).
Ptosis is upper eyelid drooping.
An epicanthal fold is a skin fold of the upper eyelid covering the inner corner of the eye.
An upturned nose is one with a tip that is angled upward. In the case of SLOS, the nose is also short.
The roof of the mouth is known as the palate. The hard palate is the front part of the roof of the mouth, and the soft palate is the back part. In the case of SLOS, the hard palate is high-arched and narrow.
A cleft palate is an opening or split in the roof of the mouth that occurs when the tissue doesn't fuse together during development in the womb.
A cataract is a clouding of the normally clear lens of the eye. An estimated 18% - 20% develop in SLOS cases.
Malformations including agenesis (failure of all or part of an organ to develop during embryonic growth) of the corpus callosum and in very severe cases major
malformation of the front part of the brain
(holoprosencephaly).
The corpus callosum is a large bundle of more than 200 million myelinated nerve fibers that connect the two brain hemispheres, permitting communication between these hemispheres.
Cerebellar hypoplasia is a neurological condition in which the cerebellum is smaller than usual or not completely developed.
Renal, pulmonary, liver, and eye abnormalities are common defects in SLOS cases.
Ears may be low-set and posteriorly rotated (the superior part of the ears is rotated towards the back of the head, and the inferior part of the ears towards the front).
Micrognathia is a term for a lower jaw that is smaller than normal, often manifesting in a small chin.
Polydactyly is a condition in which a person has more than five fingers or toes on one, or on each, hand or foot.
Short, proximally-placed thumb. Proximally means nearest where the thumb is attached.
An abnormality of the creases of the skin of palm of hand. In SLOS cases, the crease is usually a single crease.
Hypospadias is a birth defect in boys in which the opening of the urethra is not located at the tip of the penis.
An undescended testicle (cryptorchidism) is a testicle that hasn't moved into its proper position in the bag of skin hanging below the penis (scrotum) before birth.
Ambiguous or female-like male genitalia is common in males with SLOS.
Differences of the upper lip, a small jaw and large ears, in the number and/or spacing of teeth.
People with SLOS can have a narrowing at the top of the stomach (pyloric stenosis) and blockage (obstruction) of the bowel.
Hirschsprung (HIRSH-sproong) disease is a condition that affects the large intestine (colon) and causes problems with passing stool.
A sensitivity to light (photosensitivity) is also common in individuals with SLOS.
Less common findings include seizures, heart defects and low muscle tone (hypotonia).
Some children will have only one or two minor malformations, such as webbing of the toes and cleft soft palate, whereas others will have almost all of the defects listed above. Because of the possibility of internal malformations, patients with SLOS should be evaluated carefully, especially for heart and kidney defects. Often, children with SLOS resemble one another more than they do others in their families.
Visit the Human Phenotype Ontology (HPO) website to review the different phenotypic abnormalities associated with disorders. Click on the link below to view the HPO Smith-Lemli-Opitz Syndrome page.
Growth and development of children with SLOS can be delayed and affected by the spectrum of disease severity, with decreased weight and final height.
Medical specialists have developed growth charts to improve the care of individuals with SLOS.
With exception to the extremes of growth, there is limited evidence to suggest that failure to attain optimal growth, in mild to moderate degrees, leads to damaging consequences for the individual. Just like with the normal growth curves, a crossing of percentiles can be a sign of an intercurrent illness.
Many of our families download and bring the SLOS growth charts to their pediatricians to help them understand the decreased growth of our children.
Smith-Lemli-Opitz syndrome of all degrees of severity is inherited as an autosomal recessive disorder, like cystic fibrosis and sickle cell disease.
In autosomal recessive diseases, each parent is a carrier of one abnormal gene but shows no physical evidence of the disorder, because the paired normal gene is protective. However, if a child inherits the abnormal SLOS gene from each parent, then SLOS will occur. There is a 1 in 4 chance that a child will inherit only the abnormal SLOS gene from each parent.
Following the discovery of the gene mutation on the long arm of chromosome 11, molecular testing or DNA testing is now available to aid in carrier determination and future pregnancy testing.
SLOS is one of the most common autosomal recessive disorders. Estimates of the incidence vary, but most studies in Europe, the United States, and Canada have found an incidence of 1 in 20,000 births. In some regions, the disorder may occur as often as 1 in 10,000 births.
Certain behaviors and attributes are common in SLOS patients. Read about these in the drop-down table.
Common feeding problems include trouble sucking and swallowing because of weakness, cleft palate, reflux, persistent vomiting, and pyloric stenosis.
Other causes of poor growth may be internal malformations such as heart and kidney defects, Hirschsprung disease, or, more rarely, chronic liver disease.
However, even children who are vigorous and feed well do not grow normally and tend to be small as children and adults.
Many SLOS children have severe sleep disorders, some requiring medication. Lack of sleep can increase irritability, lack of focus and behavioral issues; therefore, it may be necessary for families to consult with a sleep specialist to help improve the child’s quality of sleep.
For those with severely delayed speech, frustration comes easily, and screaming or tantrums are often an outlet. Many patients show aggressiveness and self-injurious behaviors, including biting, hitting, scratching, or more seriously, head banging. In up to 75% of cases, a secondary diagnosis of autism is made. Given the frequency of behavior issues and overall hypersensitivity, it is highly recommended that families consult with a behavioral specialist on an ongoing basis.
Almost all SLOS children are born with minor anatomical variations in brain structure and have various degrees of slow development and intellectual disability. Although not all children with SLOS learn to walk and talk, many acquire good communication (often with the help of electronic devices) and can learn daily living skills. Independent living as adults, however, is unlikely.
Recurrent infections, including ear infections and pneumonia, are common.
The major medical problems of children with SLOS are in the areas of feeding, growth, and development. In addition, there may be other serious medical problems caused by one or more malformations, such as heart or kidney defects. The care of these problems often requires the combined efforts of geneticists and specialists.
Even for more mildly affected children, feeding problems are common and require careful management. Special attention must be paid to the frequent problem of limited formula tolerance because of the prevalence of functionally small stomachs and poor gastrointestinal motility in children with SLOS. Some patients with SLOS have feeding problems severe enough to require the placement of feeding tubes.
Consultation with a registered dietician may be necessary, and the use of special formulas is often helpful. It is also important to recognize that children with SLOS have a limited potential for growth.
A special SLOS growth chart has been developed and can be downloaded here: SLOS Growth Charts
Pyloric stenosis, caused by a thickening and spasm of the stomach outlet, is also common in the first weeks or months and often requires surgical correction.
Severe liver disease is a rare problem in some of the most severely affected children and may require treatment with special medications.
There is no cure for SLOS and treatment is mostly symptomatic.
Three potential treatment options have been or are currently being investigated:
• cholesterol supplementation • antioxidant supplementation • cholic acid supplementation
Click the tabs below to read about these treatments.
With the discovery that SLOS is caused by a metabolic error in cholesterol production, dietary cholesterol supplementation has been proposed as an intervention since the 1990s.
With the more recent discovery that the accumulation of the cholesterol precursors 7-DHC and 8-DHC can also lead to medical concerns, cholesterol treatment which is given both to raise cholesterol levels as well as lower production of precursors, may prove to be important. This may be particularly relevant in more severely affected patients who have very low cholesterol levels. However, dietary cholesterol does not cross the blood-brain-barrier and there is no good evidence that dietary cholesterol will improve behavior or developmental outcomes.
However, most specialists believe that cholesterol supplementation may result in better growth and overall health of individuals with SLOS. Cholesterol supplementation is either achieved by consuming foods that are naturally high in cholesterol (such as egg yolks), or in the form of a synthetic cholesterol compounded by a pharmacy. Any cholesterol supplementation should be recommended and monitored by a physician.
More clinical studies are needed to determine the benefits and possible risks of cholesterol supplementation as an intervention.
A trial using antioxidant supplementation was started in 2008, following studies in an SLOS animal model which showed that abnormalities in eye function could be improved with antioxidant treatment.
It was then discovered that the precursors 7-DHC and 8-DHC are “oxidized” and turned into substances called oxysterols which are toxic to the brain and the eye. A research protocol was developed to give antioxidants in the form of vitamins, in hopes of reducing the formation of oxysterols and thus protecting the brain and eye from oxysterol toxic side effects.
So far there have been no negative side effects of the vitamins and some improvements in special vision tests have been noted, but further studies are needed to determine the overall efficacy of this treatment as a therapy.
Bile acids are made from cholesterol, so a patient with very low cholesterol levels cannot make a sufficient amount of bile acids. Therefore, patients with severe SLOS have a bile acid deficiency.
Bile acids are essential for the absorption of nutrients in the intestines, particularly fats and fat-soluble vitamins. Without sufficient bile acids present in the gut, patients cannot properly absorb cholesterol and other nutrients.
Bile acids (including one called cholic acid) were used in the early 1990s to treat patients with SLOS. The bile acids were tolerated well and seemed to help cholesterol levels improve on treatment. But in the late 1990s, cholic acid stopped being manufactured and was not available until recently.
A new pharmaceutical company is manufacturing cholic acid again, called Cholbam, making it available for patients with SLOS. A pilot study was conducted at Children’s Hospital Colorado, and cholic acid was well tolerated and had minimal side effects. There was a modest improvement in cholesterol and precursor levels in the short study time.
By Ellen R Elias, MD and William B. Rizzo, MD
A private forum for Parents (only) of individuals with Smith-Lemli-Opitz syndrome to provide support and information for other parents. We review each request to join the group and reserve the right to deny entry into the group.
We work worldwide to improve the quality of life for people with Smith-Lemli-Opitz syndrome through educating and supporting families, spreading SLOS awareness, and funding research into the disorder.
The Smith-Lemli-Opitz Foundation is a registered charitable organization. Donations are tax-exempt under IRS 501(c)(3), ID #23-2635206.
