Smith-Lemli-Opitz Syndrome

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Smith-Lemli-Opitz syndrome

Definition

Smith-Lemli-Opitz syndrome (SLOS) is a syndrome characterized by microcephaly (small head size), mental retardation, short stature, and major and minor malformations. It is caused by an abnormality in cholesterol metabolism.

Description

SLOS was first characterized by David W. Smith, John M. Opitz, and Luc Lemli in 1964. The syndrome has variable characteristics marked mainly by short stature, mental retardation, microcephaly, postaxial polydactyly (an extra digit on the little finger side of the hand or the little toe side of the foot), cleft palate, cardiovascular defects, genital malformations and other abnormalities associated with abnormal cholesterol metabolism. In 1993, scientists discovered that children with SLOS have a metabolic disorder that prevents cholesterol from being made in amounts sufficient for normal growth and development.

Sometimes the severe form of the disease is called SLOS type II. But laboratory testing has shown that type II is not biochemically distinct. Rather it represents the more severe expression of the SLOS phenotype .

SLOS is also known as Smith syndrome, RSH syndrome, and RSH/Smith-Lemli-Opitz (RSH/SLO) syndrome. The designation RSH represents initials of the surnames of the first three patients in whom the syndrome was first observed.

Genetic profile

SLOS is inherited in an autosomal recessive manner. In autosomal recessive inheritance , a single abnormal gene on one of the autosomal chromosomes (one of the first 22 "non-sex" chromosomes) from both parents can cause the disease. Both of the parents must be carriers in order for the child to inherit the disease since recessive genes are expressed only when both copies in the pair have the same recessive instruction. Neither of the parents has the disease (since it is recessive).

A child with both parents who carry the disease has a 25% chance having the disease; a 50% chance of being a carrier of the disease (having both one normal gene and one gene with the mutation for the disorder but not affected by the disease); and a 25% chance of receiving both normal genes, one from each parent, and being genetically normal for that particular trait.

The gene for SLOS, DHCR7, encodes 7-dehydrocholesterol (7-DHC) reductase, the enzyme that is deficient in SLOS. DHCR7 is on the long arm of chromosome 11 at locus 11q12-q13.

Demographics

SLOS occurs in approximately one in 20,000 to 30,000 births in populations of northern and central European background. Evidence suggests that there is a higher frequency of SLOS in people of northern European ancestry and a lower frequency in people of Asian or African background.

Because of the presence of recognizable genital abnormalities, males are more likely than females to be evaluated for a diagnosis of SLOS. Therefore, the occurrence of the disease among females is less certain.

Signs and symptoms

The following are features of the congenital multiple anomaly syndrome.

Nearly 90% of people with SLOS have microcephaly.
Nearly all people with SLOS have moderate to severe mental retardation.
Other neurologic findings are less common. These include seizures and muscle hypotonia.
Characteristic facial features include narrowing at the temples, epicanthal folds (skin fold of the upper eyelid covering the inner corner of the eye), downslanting eyes, drooping upper eyelids, anteverted nares (nostrils that tilt forward), and abnormal smallness of the jaw (micrognathia). Cleft palate is present in 40–50% of people with SLOS, and about 20% have congenital cataracts. Strabismus, poor tracking, opsoclonus (impairment of eye movements), and optic nerve demyelination (deterioration) are other possible ophthalmologic manifestations.
Cardiac abnormalities are present in about 35–40% of patients with SLOS. Increased incidence of atrioventricular canal defects and anomalous pulmonary venous return is seen in people with SLOS.
Urogenital anomalies are frequent. Kidney hypoplasia (smaller than normal) or dysplasia (abnormal development) occurs in about 40% of people with SLOS. Genital anomalies of variable severity may include hypospadias and/or bilateral cryptorchidism, which occur in about half of reported cases, and small penis. Many 46,XY individuals with severe manifestations of SLOS have undermasculinization of the external genitalia, resulting in female external genitalia (sex reversal). Abnormalities in the uterus and vagina have been noted in 46,XX females.
Syndactyly of the second and third toes occurs frequently. Postaxial polydactyly is present in 25–50% of all cases. Other abnormalities affecting the hands and feet may be present.
Short stature is common. Limbs and neck are shorter than normal.

In addition, a child with SLOS will often show failure to thrive, have abnormal sleep patterns, and have photosensitivity. The hair of children with SLOS is blonde.

Growth may be retarded prenatally. Neonates frequently have poor suck, irritability, and failure to thrive.

Diagnosis

The clinical features of SLOS are often distinctive, and a pattern of congenital anomalies suggests the diagnosis. Features that are most commonly seen are microcephaly, postaxial polydactyly, 2–3 syndactyly of the toes, growth and mental retardation, cleft palate, and hypospadias in males.

The diagnosis of SLOS relies on clinical suspicion and detection of abnormally elevated serum concentration of 7-dehydrocholesterol (7-DHC) or an elevated 7-dehydrocholesterol:cholesterol ratio. Serum concentration of cholesterol is usually low, with cholesterol levels less than 50 mg/dl (normal is greater than 100 mg/dl). Cholesterol is an essential building block of all cell membranes and the white matter of the brain, and SLOS appears to be caused by abnormally low levels of the enzyme 7-DHC-reductase, which converts 7-DHC into cholesterol. Children with SLOS with the lowest cholesterol levels tend to have the most severe forms of the disorder and often die at birth or in the first few months. In about 10% of patients, cholesterol is in the normal range, so it is an unreliable marker for screening and diagnosis.

Molecular genetic testing of the DHCR7 gene is not generally available. But since the molecular structure of the DHCR7 has been identified, the possibility now exists for DNA-based testing for diagnosis and genetic counseling . Currently, such testing is available on a research basis only.

Genetic counseling

Carrier detection is problematic using biochemical testing. In carriers, 7-DHC and cholesterol levels are usually normal. Carrier testing is now possible, although not generally available, by measurement of 7DHC or enzyme levels in cultured cells. More accurate DNA testing for DHCR7 mutations is not currently available, but it is anticipated in the near future. Couples who have had one affected child have a 25% risk of having a child with SLOS in each pregnancy.

Prenatal testing

For couples known to be at 25% risk for having a baby with SLOS, testing is available to assist in prenatal diagnosis. Prior testing of family members is usually necessary for prenatal testing.

Either chorionic villus sampling (CVS) or amniocentesis may be performed for prenatal testing. CVS is a procedure to obtain chorionic villi tissue for testing. Abnormal levels of 7-dehydrocholesterol in amniotic fluid or chorionic villus samples is diagnostic of SLOS. Chorionic villus sampling can be performed at 10–12 weeks gestation.

Amniocentesis is a procedure that involves inserting a thin needle into the uterus, into the amniotic sac, and withdrawing a small amount of amniotic fluid. SLOS can be diagnosed from biochemical testing performed on the amniotic fluid. DNA can also be extracted from the fetal cells contained in the amniotic fluid and tested. Amniocentesis is performed at 16–18 weeks gestation.

Abnormal concentration of 7-dehydrocholesterol levels in tissue obtained from CVS or in amniotic fluid is diagnostic.

For low-risk pregnancies, in which there is no family history of SLOS, certain findings in the fetus might prompt consideration of SLOS. The combination of low unconjugated estriol levels, low HCG, and low alphafetoprotein on routine maternal serum testing at 16–18 weeks gestation might suggest the possible diagnosis of SLOS. Findings on ultrasound examination such as cardiac defects, cleft palate, genital abnormalities, or growth retardation might be suggestive, prompting consideration of a 7-dehydrocholesterol assay of amniotic fluid.

Low uE3 levels alone may be an indication of further investigation, especially if it is associated with abnormal ultrasonographic findings suggestive of SLOS.

Treatment and management

It is not known what role the elevated levels of 7-DHC and other sterol precursors—not usually present in significant concentrations in the plasma—play in the pathogenesis of SLOS. Children with SLOS should be under routine health supervision by a physician who is familiar with SLOS, its complications, and its treatment.

Since a common complication of the syndrome is pneumonia, it should be treated with appropriate antibiotics when it occurs.

Special education services and physical therapy may be recommended as needed.

Infant care

A physician familiar with the range of problems seen in infants with SLOS is important for appropriate health supervision and anticipatory guidance. Poor feeding and problems with weight gain are common in infants with SLOS. Many infants have difficulties with suck and/or swallow and may require alternative feeding. A diagnosis of pyloric stenosis (caused by a thickening and spasm of the stomach outlet) should be considered for those with frequent vomiting or apparent gastroesophageal reflux. Particular attention should also be given to the stooling pattern, abdominal distention, or other signs of possible obstruction, particularly in children with more severe phenotype, since these may indicate Hirschsprung disease (absent nerves in colon).

Surgical treatment

Surgical management of congenital anomalies such as cleft palate, congenital heart disease , and genital anomalies for the more severely affected infants need to be considered as they would in any other infant with a severe, usually lethal disorder. Even with vigorous intervention, children with multiple major manifestations of SLOS are believed to have decreased survival. Reassignment of sex of rearing for 46,XY infants with female genitalia may not always be appropriate because most will have early death. The process of gender reassignment can be disruptive to a family already coping with the difficult issues of having a child with a genetic disorder that has life-threatening medical complications.

Dietary supplementation

Because SLOS is a cholesterol deficiency syndrome, research trials have recently included dietary cholesterol supplementation. An increase in total caloric intake and an increase in cholesterol intake hold promise for treatment of SLOS, but the research is still preliminary. Benefits reported in preliminary studies include improved growth in children with SLOS, possible enhanced developmental progress, reduced dermatologic problems (rashes, photosensitivity), and improved behavior. No harmful side effects of cholesterol supplementation have been documented.

Prognosis

Prognosis is variable depending upon the severity of the disease. Children with SLOS who have multiple major malformations are believed to have decreased survival, even with vigorous intervention.

Resources

BOOKS

Jorde, Lynn B., et al., eds. Medical Genetics. 2nd ed. St. Louis: Mosby. 1999.

PERIODICALS

Kelley, R.I., and R.C. Hennekam. "The Smith-Lemli-Opitz Syndrome." Medical Genetics 37 (2000): 321–35.

Porter, F.D. "RSH/Smith-Lemli-Opitz Syndrome: A Multiple Congenital Anomaly/Mental Retardation Syndrome Due to an Inborn Error of Cholesterol Biosynthesis." Molecular Genetics and Metabolism 71 (2000): 163–74.

ORGANIZATIONS

March of Dimes Birth Defects Foundation. 1275 Mamaroneck Ave., White Plains, NY 10605. (888) 663-4637. [email protected]. <http://www.modimes.org>.

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.

Smith-Lemli-Opitz Advocacy and Exchange (RSH/SLO). 2650 Valley Forge Dr., Boothwyn, PA 19061. (610) 485-9663. <http://members.aol.com/slo97/index.html>.