Smith-Lemli-Opitz Syndrome (SLOS) 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). Although the name “RSH syndrome” (after the first initials of the first three patients) was first used for the disorder, the syndrome is now better known by the names of the three geneticists who first described it, Smith, Lemli, and Opitz. Although SLO/RSH Syndrome has always been known as a genetic disorder, the cause was not known for the first 30 years after its description.

In 1993 scientists discovered that children with SLO/RSH Syndrome are unable to make cholesterol, an essential nutrient that is not provided by the mother to the baby before birth. Because the body also makes most of its own cholesterol after birth, children with SLO/RSH Syndrome continue to have trouble with development and general health after birth. The discovery of abnormal cholesterol metabolism in SLO/RSH Syndrome has made possible not only a laboratory test for more precise diagnosis of SLO/RSH Syndrome, but also provided a rationale for treatment of affected children. Given the advances of medical treatment, often the children can now live to adulthood.

In addition to growth retardation and developmental delay, many different malformations have been described in SLO/RSH Syndrome. The most common defects are:

  • Heart Defects
  • Cleft Palate
  • Microcephaly (small head)
  • Extra fingers or toes
  • Low-set ears
  • Small, upturned nose
  • Webbing between 2nd and 3rd toes (syndactyly)
  • Abnormal palmar creases (usually single)
  • Hypospadias (genital malformation in boys)
  • Cataracts
  • Undescended testicles
  • Blepharoptosis (drooping eyelids)
  • Micrognathia (small chin)
  • Pyloric stenosis
  • Short thumbs
  • Hirschsprung disease (absent nerves in colon)

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 such as heart or kidney defects or liver disease, patients with SLO/RSH Syndrome should be evaluated carefully at birth. Often, children with SLO/RSH Syndrome resemble one another more than others in their families. Prior to 1993 the diagnosis of SLO/RSH Syndrome rested entirely on the clinical judgment of a geneticist or other specialist. Now, a biochemical test (mass spectrometry) for abnormal cholesterol metabolism is used to confirm a suspected diagnosis of SLO/RSH Syndrome.

Although lifespan can be limited by serious internal malformations, with good nutrition and medical care a normal lifespan is possible.

At diagnosis, children with SLO/RSH Syndrome typically have cholesterol levels less than 50 mg/dl (normal is greater than 100 mg/dl) and abnormally high levels of a precursor of cholesterol, 7-dehydrocholesterol (7DHC). Cholesterol is an essential nutrient used as a building block in all cell membranes and the white matter of the brain. The deficiency of cholesterol appears to be caused by abnormally low levels of the enzyme “7DHC-reductase,” which converts 7DHC into cholesterol. SLO/RSH children with the lowest cholesterol levels tend to have the most severe forms of the disorder, some of which die at birth or in the first few months. Although about 10% of children with SLO/RSH have normal or near normal cholesterol levels, essentially all have increased levels of 7DHC. With the discovery that SLO/RSH Syndrome children cannot make adequate amounts of cholesterol, there is now a treatment using dietary cholesterol, either in natural form such as egg yolks and cream or in the form of purified cholesterol (given as part of several research protocols) that in many cases helps with growth and development. Although breast milk is rich in cholesterol, unlike commercial formulas, which have almost no cholesterol, even breast milk contains insufficient cholesterol to supply a growing baby’s need.

SLO/RSH Syndrome is inherited as an autosomal recessive Mendelian disorder, like cystic fibrosis and sickle cell disease. In autosomal recessive diseases, both parents are carriers of an abnormal gene but show no physical evidence of the disorder because the paired normal gene takes precedence. If a child inherits two copies of the same abnormal SLO/RSH gene, one from each parent, then SLO/RSH Syndrome will occur. With each pregnancy, there is a 1 in 4 chance that a child will inherit only the abnormal genes from both parents who each carry the SLO/RSH Syndrome gene.

SLO/RSH Syndrome 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. The incidence of SLO/RSH Syndrome appears to be much lower in Asian and African populations. An autosomal recessive disease with an incidence of 1 in 20,000 births necessarily has a relatively high carrier frequency of about 1 in 70. As a result, families in which there are cousins or other relatives with SLO/RSH are not uncommon. Carrier testing is now possible by a DNA (a.k.a. molecular) test.

Feeding problems and “failure-to-thrive” occur in most children with SLO/RSH Syndrome. Common feeding problems include weak or non-existent sucking and swallowing reflex, cleft palate, microgastria (abnormally small stomach), reflux and/or persistent vomiting, and pyloric stenosis. 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 caused by congenitally small stomachs and poor gastrointestinal motility in children with SLO/RSH. Children with SLO/RSH Syndrome also have a limited potential for growth which is important to recognize. Otherwise, the children are often overfed in an attempt to make them grow faster. 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.

Other causes of failure-to-thrive may be internal malformations such as heart and kidney defects, Hirschsprung disease or, more rarely, chronic liver disease. Even children with SLO/RSH Syndrome who feed well do not grow normally and tend to be small as children and adults. Almost all SLO/RSH Syndrome children are born with small brains and have various degrees of slow development and mental retardation. Although not all children with SLO/RSH learn to walk and talk, many acquire good language and can learn skills, but independent living as adults is unlikely.

Source: SmithLemliOpitz.org