Smith-Lemli-Opitz Syndrome Treatment & Management

Updated: May 26, 2017
  • Author: Robert D Steiner, MD; Chief Editor: Luis O Rohena, MD  more...
  • Print
Treatment

Medical Care

Currently, no treatment has proven effective long-term for patients with Smith-Lemli-Opitz syndrome (SLOS). [27] In March 2015, cholic acid (Cholbam) was approved by the US Food and Drug Administration (FDA) for bile acid synthesis disorders caused by a single-enzyme defect. Bile acids are important in fat digestion and absorption, as well as in the absorption of fat-soluble vitamins in the intestine. Cholic acid's efficacy in the treatment of bile acid synthesis disorders was evaluated in a single-arm trial in which 50 patients were treated over an 18-year period, as well as an extension trial involving 21 of these patients along with an additional 12 subjects. Treatment response was measured in relation to improvements in baseline liver function tests and weight. Cholic acid's mechanism of action is not yet fully understood. [28, 29, 30]

Potentially, cholesterol supplementation is a logical treatment because it may be expected to raise plasma and tissue cholesterol levels. By feedback inhibition of hydroxymethylglutaryl-coenzyme-A-reductase, cholesterol supplementation may reduce levels of 7DHC and related cholesterol intermediates that may be toxic. Dosing guidelines, optimal form of cholesterol to be administered, and whether supplemental bile acids are needed are some of the questions remaining in development of therapy. The major question is whether cholesterol supplementation makes a difference. Therapeutic trials are underway.

Cholesterol supplementation leads to increased plasma cholesterol levels and variable decreases in 7DHC. Kelley et al anecdotally reported that cholesterol suspension has allowed some patients to sleep through the night for the first time and others to overcome aberrant behaviors, to learn to walk, to speak for the first time, and to become responsive sociable family members. [8] Well-controlled clinical trials of cholesterol supplementation showing clear clinical benefit have not yet been published. Short-term cholesterol supplementation in a placebo-controlled clinical trial did not improve behavior. [31]

Doses of cholesterol used in therapeutic trials have varied from 20-300 mg/kg/d; in some studies of treatment in Smith-Lemli-Opitz syndrome, supplemental bile acids were incorporated as well. Pharmacologic crystalline cholesterol in oil or aqueous suspension was used in early studies. Other options for cholesterol supplementation include use of egg yolk, whipping cream, and butterfat.

The early promising results of clinical trials in patients with Smith-Lemli-Opitz syndrome, the known severity of the untreated condition, and the ability to confirm the diagnosis prenatally have drawn attention toward preconceptional and prenatal therapy.

Fetal therapy, like the therapeutic trials for adults and children, should be recognized to be possibly palliative and not curative. The findings that cholesterol is essential in early embryonic development and that the yolk sac is the source of cholesterol at this time suggest a critical period or therapeutic window in the periconceptional period. Most prenatal diagnoses are made during the second trimester. Cholesterol delivery across the placenta and the blood-brain barrier pose significant future challenges.

Antenatal therapeutic intervention for Smith-Lemli-Opitz syndrome was recently reported. Supplementation of cholesterol was provided by fetal intravenous and intraperitoneal transfusions of fresh frozen plasma during the third trimester. Fetal cholesterol levels and fetal red cell mean corpuscular volume rose, which further indicated that the exogenous cholesterol was incorporated into the fetal erythrocytes.

Irons et al concluded that antenatal treatment of Smith-Lemli-Opitz syndrome by cholesterol supplementation is possible and may be beneficial in elevating cholesterol levels. [32] No positive or negative effects on the baby were obvious postnatally, but follow-up is ongoing. To speculate that the sooner the sterol derangements can be addressed therapeutically the greater the potential decrease in severity is reasonable. Therefore, antenatal therapy may lead to improvement in Smith-Lemli-Opitz syndrome clinical expression.

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have recently been studied as potential therapy for Smith-Lemli-Opitz syndrome. Statins would be expected to lower 7DHC concentrations. Interestingly, in contrast to the effects in healthy individuals, statins do not appear to lower plasma cholesterol levels in many of those with Smith-Lemli-Opitz syndrome. Some statins cross the blood-brain barrier. Whether statins will emerge as a useful therapy for Smith-Lemli-Opitz syndrome has yet to be determined. A retrospective study of simvastatin did not lead to clinical improvements in one series. [33]

Hormone supplementation may be needed for some patients with Smith-Lemli-Opitz syndrome.

Hearing aids may be of great benefit for those with hearing loss.

Gastrostomy feeding may be indicated.

Patients should limit exposure to the sun and use liberal amounts of sunscreen.

Next:

Surgical Care

See the list below:

  • Consider repair of congenital heart defects in cases of Smith-Lemli-Opitz syndrome type I.
  • Repair of polydactyly is best performed early.
  • Consider cleft palate repair as well as pyloromyotomy in a timely fashion in cases of pyloric stenosis.
  • Rectal biopsy for evaluation of ganglion cells may be useful when Hirschsprung disease is suspected and surgical management for Hirschsprung disease may be needed.
  • Gastrostomy placement, with or without fundoplication, may be necessary when feeding difficulties or gastrointestinal reflux is present.
Previous
Next:

Consultations

Medical geneticists and/or metabolic-disease specialists should be consulted.

Depending on the extent of congenital malformations, the following consultations are often needed:

  • Pediatric gastroenterologist
  • Pediatric surgeon
  • Ophthalmologist
  • Cardiologist
  • Developmental/behavioral pediatrician
  • Occupational therapist
  • Physical therapist
  • Speech/language pathologist
  • Audiologist
  • Child psychologist and/or psychiatrist
  • Pediatric otorhinolaryngologists
  • Facial and plastic reconstructive surgeon
  • Pediatric urologist
Previous
Next:

Diet

See the list below:

  • A high-cholesterol diet may be useful (see Medical Care). Cholesterol should not be considered as a specific treatment of Smith-Lemli-Opitz syndrome until efficacy is proven in controlled trials.
Previous