Clinical Guidance

A strict genotype-phenotype correlation is difficult because most affected individuals are compound heterozygotes.

• In general, individuals who are homozygous for two null alleles, such as the common or variants, have a severe phenotype.

• A detailed evaluation of 207 individuals with SLOS showed that the most severe phenotypes were observed in individuals with two null variants or with two variants in loop 8-9 (amino acids 352-411), while those with one or two pathogenic variants in loop 1-2 (amino acids 59-94 and amino acids 119-151 respectively) or one pathogenic variant in the N-terminus (amino acids 1-37) have milder phenotypes .

Source: GeneReviews — "Smith-Lemli-Opitz Syndrome"

Diagnostic Criteria

Clinical diagnostic criteria for Smith-Lemli-Opitz syndrome (SLOS) have not been established.

Suggestive Findings

Smith-Lemli-Opitz syndrome should be suspected in individuals with the following clinical features and laboratory findings.

Clinical features

• Characteristic facial features (narrow forehead, epicanthal folds, ptosis, short mandible with preservation of jaw width, short nose, anteverted nares, and low-set ears)

• 2-3 syndactyly of the toes (minimal to Y-shaped)

• Microcephaly

• Growth restriction / short stature

• Intellectual disability

• Hypospadias in males

• Cleft palate

• Postaxial polydactyly

Laboratory findings

• Elevated serum concentration of 7-dehydrocholesterol (7-DHC) as defined by the laboratory

Source: GeneReviews — "Smith-Lemli-Opitz Syndrome"

Differential Diagnosis

Clinical features. Although many malformation syndromes share at least some of the clinical features of Smith-Lemli-Opitz syndrome (SLOS) (e.g., polydactyly, hypospadias, cleft palate), with the exception of squalene synthase deficiency they rarely have more than two of these features in common. In particular, the Y-shaped 2-3 toe syndactyly, present in most individuals with SLOS, is rarely seen in other disorders. Biochemical findings. The biochemical findings should allow for ready differentiation between individuals with SLOS and those with conditions that are clinically and biochemically similar. Biochemically, only SLOS presents with elevated 7DHC and low or low-normal plasma cholesterol. Other sterol metabolic disorders present with distinct patterns of sterol abnormalities and are unlikely to be confused with SLOS. See for genes associated with disorders that share some clinical features of SLOS. Table 3. Genes and Disorders of Interest in the Differential Diagnosis of Smith-Lemli-Opitz Syndrome

Management Guidelines

No consensus clinical management guidelines have been published.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Smith-Lemli-Opitz syndrome (SLOS), the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

Recommended Evaluations Following Initial Diagnosis in Individuals with Smith-Lemli-Opitz Syndrome

System/Concern | Evaluation | Comment

Constitutional

| Assessment of growth, incl weight, length/height, head circumference |

Gastrointestinal/

Feeding

| Gastroenterology / nutrition / feeding team eval | • Consider assessment for pyloric stenosis or gastroesophageal reflux in those w/suggestive symptoms.

• Particular attention should be given to stooling pattern, abdominal distention, or other signs of possible bowel obstruction because of risk for Hirschsprung disease.

AST, ALT, and bilirubin concentrations | To assess for cholestatic liver disease

Development

| Developmental assessment | • To incl motor, adaptive, cognitive, speech-language evaluation

• Evaluation for early intervention / special education

Psychiatric/

Behavioral

| Neuropsychiatric eval | For persons age 12 mos: screening for behavior concerns incl sleep disturbances, ADHD, anxiety, /or traits suggestive of ASD

Neurologic

| Neurologic eval | To incl brain MRI EEG if seizures are a concern

Genitourinary

| Physical exam of external genitalia | • To assess for genital anomalies

Source: GeneReviews — "Smith-Lemli-Opitz Syndrome"

Clinical Guidance

Treatment with haloperidol, which has a high affinity for the DHCR7 substrate binding site, may exacerbate the biochemical sterol abnormalities in individuals with SLOS and cause an increase in symptoms. It is likely that other drugs in this class will cause the same change in sterol levels . Other psychotropic drugs shown to elevate 7-DHC are trazodone and aripiprazole (Abilify®) . Thus, one must weigh the benefit of such medications against the potential negative side effects. As many individuals with SLOS do require psychotropic medications, close monitoring of clinical signs/symptoms and serum concentration of 7-DHC is recommended. Photosensitivity can be severe and extended periods of sun exposure should be avoided, as severe sunburn can occur with only limited exposure; however, limited sun exposure is possible for some affected individuals as long as protective clothing is worn and a sunscreen with UVA and UVB properties is used.

Source: GeneReviews — "Smith-Lemli-Opitz Syndrome"

Therapies Under Investigation

A study assessing the safety and therapeutic benefits of cholesterol supplementation and antioxidant medications is underway in Colorado (see Cholesterol and Antioxidant Treatment in Patients with Smith-Lemli-Opitz Syndrome). Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Source: GeneReviews — "Smith-Lemli-Opitz Syndrome"

Surveillance Guidelines

Routine health supervision by a physician familiar with SLOS, its complications, and its treatment includes the following. Table 7. Recommended Surveillance for Individuals with Smith-Lemli-Opitz Syndrome

Source: GeneReviews — "Smith-Lemli-Opitz Syndrome"