Smith-Lemli-Opitz Syndrome 

Updated: Apr 11, 2019
Author: Robert D Steiner, MD; Chief Editor: Luis O Rohena, MD, FAAP, FACMG 

Overview

Background

Smith-Lemli-Opitz syndrome (SLOS) is a multiple congenital anomaly (MCA)/intellectual disability (ID) syndrome caused by a defect in cholesterol synthesis.[1] Smith-Lemli-Opitz syndrome is an autosomal recessive genetic condition caused by a deficiency of the enzyme 3 beta-hydroxysterol-delta 7-reductase (7-dehydrocholesterol-delta 7-reductase [DHCR7] EC 1.3.1.21), the final enzyme in the sterol synthetic pathway that converts 7-dehydrocholesterol (7DHC) to cholesterol.

Affected individuals usually have low plasma cholesterol levels and invariably have elevated levels of cholesterol precursors, including 7DHC. The most severely affected individuals (those with the condition formerly referred to as Smith-Lemli-Opitz syndrome type II) have multiple congenital malformations and are often miscarried or stillborn or die in the first weeks of life. Dysmorphic facial features, microcephaly, second-toe and third-toe syndactyly, other malformations, and mental retardation (MR) are typical. Mildly affected individuals may have only subtle dysmorphic features and learning and behavioral disabilities.

See the image below.

Child with Smith-Lemli-Opitz syndrome. Child with Smith-Lemli-Opitz syndrome.

Pathophysiology

The classic paradigm for the pathogenesis of an inborn error of metabolism includes the accumulation of a toxic precursor and/or deficiency of an essential product as a result of an enzyme deficiency. In the case of Smith-Lemli-Opitz syndrome, the precursor 7DHC is potentially toxic in large concentrations, and cholesterol deficiency is almost certainly detrimental.

Smith, Lemli, and Opitz initially described Smith-Lemli-Opitz syndrome as a genetic MCA/MR syndrome in 1964.[2] They named the condition RSH after the first initial of the last names of the first 3 patients ascertained.[3] The clinical characteristics of Smith-Lemli-Opitz syndrome have been well established over the past 4 decades.

The etiology of Smith-Lemli-Opitz syndrome was unknown until 1993, when Irons et al discovered that patients with Smith-Lemli-Opitz syndrome had low plasma cholesterol levels and accumulated sterol precursors such as 7DHC.[4] A deficiency of the microsomal enzyme DHCR7, which reduces the 7-8 double bond of 7DHC to form cholesterol in the final step of the cholesterol synthetic pathway, was hypothesized and later proven to cause Smith-Lemli-Opitz syndrome. Mutations in the DHCR7 gene are responsible for Smith-Lemli-Opitz syndrome. Therefore, Smith-Lemli-Opitz syndrome can now be considered a classic inborn error of metabolism.

Currently, the reason defects in cholesterol synthesis cause congenital malformations is not known. Several disparate lines of research have led to recent understanding of the critical and somewhat unexpected role of cholesterol in early human development. Cholesterol is important in cell membranes, serves as the precursor for steroid hormones and bile acids, and is a major component in myelin. Cholesterol is covalently bound to the embryonic signaling protein sonic hedgehog (Shh) in a necessary step of the autoprocessing of the precursor to active form, occurring about age gestational day 0-7 in humans.

Shh plays a critical role in several embryologic fields relevant to Smith-Lemli-Opitz syndrome (eg, brain, face, heart, limbs). Therefore, cholesterol is an essential triggering agent in the early developmental program of the human. Because 7DHC can also activate Shh, cholesterol deficiency that leads to decreased activation of Shh is probably not the sole explanation for congenital malformations in this syndrome.

Abnormalities in the Shh-patched signaling cascade presumably play a role. Membrane instability and dysmyelination from cholesterol deficiency and accumulation of 7DHC and other potentially toxic cholesterol precursors are also likely to contribute to the Smith-Lemli-Opitz syndrome phenotype.

Increased isoprenoids were reported in Smith-Lemli-Opitz syndrome, but the role these nonsterol isoprenoids play in the pathophysiology of this disorder is unclear.[5]

A study by Merkens et al indicated that high 7DHC plasma levels correlate with feeding difficulties in patients with Smith-Lemli-Opitz syndrome. In the report, which involved 26 patients (aged 0.4-19 years) with the syndrome, the investigators found that patients with a plasma level of more than 0.24 mmol/L or a cholesterol concentration of less than 1.95 mmol/L were more likely to require use of a gastrostomy tube.[6]

A study by Sparks et al found reduced levels of the neurotransmitter metabolites 5-hydroxyindoleacetic acid (from serotonin) and homovanillic acid (from dopamine) in the cerebrospinal fluid of patients with Smith-Lemli-Opitz syndrome. The investigators suggested that this may result from a sterol-associated defect in synaptic vesicle development.[7]

Epidemiology

Frequency

United States

Prevalence of Smith-Lemli-Opitz syndrome has been estimated to be 1 in 20,000-60,000 births among whites. Smith-Lemli-Opitz syndrome is also not uncommon in Hispanics. Its specific prevalence in different populations has not been precisely determined. The higher-than-expected prevalence of Smith-Lemli-Opitz syndrome suggests a heterozygote advantage.

Only one description of an African-American patient has been published, although no biochemical or molecular confirmation of Smith-Lemli-Opitz syndrome was available.[8] In a study of 150 biochemically diagnosed patients with Smith-Lemli-Opitz syndrome, only one individual was of African descent.[9] In 2000, Yu and colleagues did not detect the mutation among 121 Africans from Sierra Leone.[10] In 2001, Nowaczyk and colleagues reported an IVS8-1G>C (common Smith-Lemli-Opitz syndrome mutation) carrier frequency of 1.09% (17 per 1559 population) in Canadian whites and 0.79% (4 per 504 population) in Canadians of African descent; however, no African Canadian patients were identified.[11]

The results of Wright et al's 2003 study indicate an IVS8-1G>C carrier frequency of 0.73% (10 per 1378 population) in African Americans.[12] This predicts the prevalence of Smith-Lemli-Opitz syndrome due to IVS8-1G>C homozygosity to be 1 case per 75,061 persons in the African American population. Although the African American carrier frequency of the IVS8-1G>C allele was determined to be 0.73%, few African American patients with Smith-Lemli-Opitz syndrome have been identified.

Carrier frequency for Smith-Lemli-Opitz syndrome is approximately 1 in 30 persons of northern European descent, suggesting a disease frequency of 1 per 5000-18,000 people. The actual disease prevalence may be lower because of fetal losses.

International

Smith-Lemli-Opitz syndrome has been described in patients from the United States, many northern European countries, Japan, South America, and other countries. Smith-Lemli-Opitz syndrome appears to be uncommon in Japan. The frequency of Smith-Lemli-Opitz syndrome appears to be similar in northern Europe and the United States, but additional studies are needed to determine the frequency of Smith-Lemli-Opitz syndrome in other regions. The European origin of some of the major mutations found in Smith-Lemli-Opitz syndrome has been explored.[13]

Mortality/Morbidity

Spontaneous abortion of fetuses with Smith-Lemli-Opitz syndrome is not unusual. Stillbirths have also been reported, although a prospective study by Gibbins et al found that homozygous DHCR7 mutations (indicative of Smith-Lemli-Opitz syndrome) were present in only one out of 139 unexplained stillbirths (0.7%), suggesting that unrecognized DHCR7 mutations are not strongly associated with stillbirth.[14]

Death from multiorgan system failure during the first weeks of life is typical in the most severely affected individuals with Smith-Lemli-Opitz syndrome. Cause of death can include pneumonia, lethal congenital heart defect, or hepatic failure. Survival is unlikely if the plasma cholesterol level is less than approximately 20 mg/dL as measured by gas chromatography, which is used because routine methods of cholesterol measurement include precursor sterols.

Congenital heart disease is not uncommon in Smith-Lemli-Opitz syndrome and can cause cyanosis or congestive heart failure. Pulmonary hypertension has been noted in at least one patient.[15] Vomiting, feeding difficulties, constipation, toxic megacolon, electrolyte disturbances, and failure to thrive are common and, in some cases, related to GI anomalies. Liver disease has been commonly described.[16] Visual loss may occur because of cataracts, optic nerve abnormalities, or other ophthalmologic problems,[17] and subclinical retinal abnormalities may be noted on electroretinography.[18] Cataracts may occur acutely in the postnatal period.[19] Hearing loss is fairly common.

Race

See Frequency.

Sex

As an autosomal recessive genetic condition, Smith-Lemli-Opitz syndrome is equally prevalent among males and females.

Age

Smith-Lemli-Opitz syndrome is a genetic condition that is present from conception, but signs may occasionally be so subtle that patients avoid detection until later childhood or even adulthood. Some have postulated that the mildest cases may completely escape detection in some instances. More commonly, Smith-Lemli-Opitz syndrome is suspected at birth or shortly thereafter because of birth defects.

 

Presentation

History

The following signs and symptoms may be noted:

  • Lethargy

  • Obtundation or coma

  • Respiratory failure

  • Hearing loss

  • Visual loss

  • Vomiting

  • Feeding difficulties

  • Failure to thrive

  • Constipation

  • Cyanosis

  • Congestive heart failure

  • Photosensitivity

Neuropsychiatric and neurodevelopmental abnormalities are common and include variable mental retardation, aberrant behavior, and autism. The aberrant behavior of the older child can include antisocial, self-destructive, and violent acts or withdrawal, self-stimulation, and frank autism. Indeed, autism is quite common in Smith-Lemli-Opitz syndrome (SLOS).[20]

The risk for neuropsychiatric disorders also appears to be increased in adults with Smith-Lemli-Opitz syndrome.

A study by Eroglu et al indicated that it is possible for persons with Smith-Lemli-Opitz syndrome to have a normal intelligence quotient (IQ). The investigators found that out of 145 children with the syndrome, nine of them (six girls and three boys) had a normal or low-normal IQ.[21]

Physical

Intrauterine growth retardation (IUGR) is common, as is short stature or abnormally low weight for height, altered muscle tone (hypotonia), and often a distinctive shrill cry.

Growth charts for SLOS have been published.[22] Rarely, hydrops fetalis occurs.

Congenital anomalies evident upon physical examination may include the following:

  • Microcephaly

  • Intracranial germinoma[23]

  • Broad nasal tip with anteverted nostrils

  • Micrognathia

  • Ptosis of eyelids

  • Epicanthal folds

  • Strabismus

  • Cataracts (may also develop postnatally[24] )

  • Broad maxillary alveolar ridges

  • Slanted or low-set ears

  • Syndactyly of second and third toes

  • Postaxial polydactyly

  • Hypospadias or cryptorchidism in males and, occasionally, complete sex reversal (ie, 46,XY females)

  • Cleft palate

  • Heart murmur or cyanosis or respiratory distress secondary to congenital cardiac defects

  • Respiratory distress secondary to pulmonary anomalies

Considerable phenotypic variance may be present within affected families, between individuals, and over time in the neonate, infant, child, and adult with Smith-Lemli-Opitz syndrome. Mildly affected individuals may exhibit only subtle dysmorphic facies and learning disabilities, whereas severely affected individuals may have complete sex reversal, lethal cardiac and brain malformations, microcephaly, cleft palate, and multiorgan system failure.

Causes

Analysis of family pedigrees has revealed that Smith-Lemli-Opitz syndrome is transmitted in an autosomal recessive fashion as an multiple congenital anomaly (MCA)/intellectual disability (ID) syndrome. Three different groups reported the molecular genetic basis for Smith-Lemli-Opitz syndrome simultaneously.

Smith-Lemli-Opitz syndrome is caused by mutations in the DHCR7 gene, the gene that codes for the enzyme DHCR7 that normally converts 7DHC to cholesterol in the final step of the cholesterol synthetic pathway. Mapping of the DHCR7 gene established the chromosomal position on band 11q12.13. Subsequent mutational analyses by several groups have identified a wide variety of different mutations within the DHCR7 gene, with several common mutations.[25]

Most patients with Smith-Lemli-Opitz syndrome have proven to be compound heterozygotes. This genetic heterogeneity points to possible phenotype-genotype corollaries.

The cause of the intellectual disability, behavioral abnormalities, and malformations is unclear, but cholesterol deficiency, accumulation of potentially toxic precursors, and/or oxysterols or esterified oxysterols may be implicated.[26]

 

DDx

 

Workup

Laboratory Studies

Prenatal

Fetal ultrasonography may reveal anomalies suggestive of Smith-Lemli-Opitz syndrome (SLOS). When clinical suspicion arises, or if Smith-Lemli-Opitz syndrome was present in a previous pregnancy, confirmation of diagnosis is available with measurements of amniotic fluid or chorionic villous 7DHC content. In addition, enzyme activity can be measured in chorionic villi. Mutation analysis for prenatal diagnosis could also be considered, but this is most likely to be helpful if a proband in the family has had previously identified DHCR7 gene mutations.

Confirmatory prenatal diagnostic testing is currently available in only a few laboratories.

Low maternal serum unconjugated estriol levels or a pattern of maternal serum triple or quadruple screen markers suggestive of trisomy but with normal karyotype is a marker for Smith-Lemli-Opitz syndrome or steroid sulfatase deficiency. Shackleton reported the unique presence of equine estriols in the maternal urine during pregnancy of a fetus affected by Smith-Lemli-Opitz syndrome, potentially allowing noninvasive prenatal screening for Smith-Lemli-Opitz syndrome.[27]

Postnatal

Smith-Lemli-Opitz syndrome is usually suspected clinically, but biochemical studies are necessary for diagnosis. Plasma total cholesterol and/or low-density lipoprotein (LDL) cholesterol levels may be low but are not universally low. Measurement of plasma sterols, including, at a minimum, cholesterol and 7DHC, is the diagnostic test for Smith-Lemli-Opitz syndrome.

The striking elevation of plasma 7DHC on sterol analysis by gas-liquid chromatography or gas chromatography/mass spectrometry is pathognomonic. The characteristic pattern of low plasma cholesterol levels and the extremely high 7DHC levels define Smith-Lemli-Opitz syndrome. 7DHC is present in plasma in healthy individuals in trace quantities. Cholesterol levels are not always below the reference range; screening by plasma cholesterol measurement alone should be discouraged.

Sterol analysis has proven useful for diagnosing patients with the classical phenotype, prenatal cases identified through maternal serum screening, and patients with more subtle physical findings and intellectual disability. In the United States, a handful of laboratories perform this analysis, and a timely query to GeneTests is extremely useful in identifying laboratories performing this analysis.

Mutational analyses/molecular genetic testing are useful confirmatory tests and important for prenatal diagnosis in a family with a known mutation.

Reserve enzyme analysis for atypical cases or cases yielding equivocal results by other methods.

Electrolytes and, possibly, cortisol and adrenocorticotropic hormone (ACTH) may be useful in ruling out adrenal insufficiency.

Imaging Studies

See the list below:

  • Brain MRI or CT scanning may reveal structural brain malformations.

  • Renal ultrasonography may be useful in identifying renal anomalies.

  • Abdominal ultrasonography may help identify or rule out pyloric stenosis.

  • Barium swallow may help identify or rule out pyloric stenosis.

  • Abdominal radiography may be useful when Hirschsprung disease is suspected.

  • Barium enema may be useful when Hirschsprung disease is suspected.

  • Chest radiography is important in looking for congenital heart disease and/or congenital pulmonary abnormalities.

  • Genitourinary ultrasonography may be important in identifying genitourinary anomalies.

Other Tests

See the list below:

  • Slit lamp examination may reveal strabismus, cataracts, ptosis, and/or optic nerve abnormalities.

  • Developmental or intelligence quotient (IQ) testing may reveal intellectual disability or learning disabilities.

Procedures

See the list below:

  • Rectal biopsy may be useful when Hirschsprung disease is suspected.

  • Echocardiography and ECG are indicated in every newborn with Smith-Lemli-Opitz syndrome because the incidence of congenital heart disease is quite high.

  • Obtaining a brainstem-evoked response or audiogram is important in Smith-Lemli-Opitz syndrome because hearing loss is not uncommon.

  • Cultured fibroblasts can be used for enzymatic testing to provide diagnostic confirmation in atypical cases. Skin biopsy and enzyme analysis are not normally required when clinical features of Smith-Lemli-Opitz syndrome are present in a patient with elevated levels of 7DHC in the blood.

Histologic Findings

See the list below:

  • Histologic findings have not generally been useful in the diagnosis of Smith-Lemli-Opitz syndrome, and little literature is available that describes histologic findings in Smith-Lemli-Opitz syndrome. The gross anatomic findings and biochemical findings are of much greater importance.

  • In one case reported by Ness et al, the liver showed severe cholestasis of the hepatocytes, distorted hepatic architecture, septal fibrosis, and extramedullary hematopoiesis.[28] Iron and bilirubin deposition were observed in the hepatocytes. Thymic sections showed marked depletion of thymocytes. The brain was small, weighed 250 g, and showed marked yellow bile staining of the meninges. The gyral pattern was strikingly abnormal. Coronal sections showed mild hydrocephalus with porencephaly, absence of the corpus callosum, and a small hypoplastic cerebellum. Bile staining was present in the basal ganglia and dentate nucleus of the cerebellum, consistent with kernicterus. The cortex corresponding to the grossly abnormal gyral pattern showed abnormal neuronal migration with 4 instead of 6 cortical layers. A severe lack of myelination was also evident using anti-LDL receptor sera.

  • The pancreas in Smith-Lemli-Opitz syndrome may be enlarged and have hyperchromatic nuclei in the islet cells. Severely affected infants have defective or absent pulmonary lobation.

 

Treatment

Medical Care

Currently, no treatment has proven effective long-term for patients with Smith-Lemli-Opitz syndrome (SLOS).[29] 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.[9] 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.[30]

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, including ursodeoxycholic and chenodeoxycholic 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 has been 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.[31] 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 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, research has suggested that statins do not 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.[32]  However, another study, by Wassif et al, reported that simvastatin improved the serum dehydrocholesterol-to-total sterol ratio and significantly reduced irritability symptoms, in patients with mild to typical Smith-Lemli-Opitz syndrome.[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.

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.

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

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.

 

Follow-up

Further Outpatient Care

See the list below:

  • Early intervention is often useful. In addition, children affected by Smith-Lemli-Opitz syndrome may benefit from receiving follow-up care from a geneticist, metabolic-disease specialist, and/or behavioral/developmental pediatrician familiar with the complications and long-term needs of patients with Smith-Lemli-Opitz syndrome.

Further Inpatient Care

See the list below:

  • The condition of patients with the most severe type of Smith-Lemli-Opitz syndrome (SLOS), sometimes referred to as Smith-Lemli-Opitz syndrome type II, is characterized by very low plasma cholesterol levels (usually, approximately < 20 mg/dL [as measured by gas chromatography methods to separate sterols]), obtundation or coma, respiratory failure necessitating mechanical ventilation, and multiple malformations manifesting at birth. This condition is almost invariably lethal. The clinician should strongly consider offering palliative care only.

Inpatient & Outpatient Medications

See the list below:

  • Supplemental cholesterol may be helpful. Clinical trials are ongoing. Fresh frozen plasma and bile acids have sometimes been administered to patients with Smith-Lemli-Opitz syndrome who have very low plasma cholesterol levels or when mildly to moderately affected patients are unable to take their oral cholesterol supplement, often as a result of illness or surgery.

Transfer

See the list below:

  • In the newly diagnosed fetus, newborn, or young infant, transfer to a tertiary care academic facility where a medical geneticist or metabolic-disease specialist is immediately available and pediatric general surgeons and appropriate pediatric surgical subspecialists are available may be required. In some cases, the infant may be too ill and unstable to transport.

  • Transfer or intermittent visits to a facility where active clinical research in Smith-Lemli-Opitz syndrome is ongoing may be considered in any age group.

Deterrence/Prevention

See the list below:

  • Photosensitivity may occur; instruct patient to avoid prolonged exposure to sunlight and to judiciously use sunscreens and clothing. Supplemental cholesterol, or even fresh frozen plasma (as a source of cholesterol), may be useful in the short term for patients with Smith-Lemli-Opitz syndrome who require surgery or who are very ill for any reason. Adrenal insufficiency may occur, and glucocorticoid and/or mineralocorticoid supplementation may be needed.[34]

Complications

See the list below:

  • Many possible complications are recognized. Virtually every cell in the body is dependent on cholesterol to maintain normal function; therefore, the cholesterol deficiency in patients with Smith-Lemli-Opitz syndrome can affect every organ.

  • Those most severely affected with Smith-Lemli-Opitz syndrome are either spontaneously aborted or die in the neonatal period despite maximal therapy.

  • Many individuals have multiple malformations. Congenital heart disease and brain malformations may be lethal.

  • Affected individuals who survive may have renal disease, adrenal insufficiency, seizures, failure to thrive, and hepatic dysfunction.

Prognosis

Survival is less likely when the plasma cholesterol level is less than approximately 20 mg/dL as measured by gas chromatography.

Some individuals with Smith-Lemli-Opitz syndrome live into adulthood.

Long-term survival may be more common in the era of cholesterol supplementation. Pauli et al reported a 30-year follow-up of 1 of the 3 original patients described by Smith et al and described the following:[35]

  • Phenotypic manifestation persisted, although the patient's general health had been excellent.

  • He has severe mental retardation (MR) and expresses violent behavioral outbursts.

  • He is medicated for a seizure disorder and behavior control.

  • His diet analysis showed poor cholesterol intake, which was increased dramatically because of possible benefit of dietary cholesterol supplementation.

  • Two months following initiation of this diet, caregivers described him as calmer, happier, and more verbal.

  • Repeat assessment of plasma cholesterol levels did not demonstrate impressive improvement.

  • Although published data concerning long-term prognosis of patients with Smith-Lemli-Opitz syndrome is scarce, this case report is illustrative.

Patient Education

See the list below:

  • The Web site maintained by the Smith-Lemli-Opitz syndrome support group The SLOS Advocacy and Exchange provides much useful information for families and health care professionals who wish to learn more about the condition or to contact families who also have a child or children with Smith-Lemli-Opitz syndrome .

  • For excellent patient education resources, visit eMedicineHealth's Cholesterol Center. Also, see eMedicineHealth's patient education article Understanding Your Cholesterol Level.