Disorders of cholesterol biosynthesis (Smith-Lemli-Opitz syndrome)

Smith-Lemli-Opitz Syndrome is a Variation of Sex Characteristic (VSC)/Difference of Sex Development (DSD) caused by a defect in cholesterol production secondary to mutations in the gene encoding the enzyme 3 beta-hydroxysteroid-delta 7-reductase. This enzyme is responsible for converting 7-dehydrocholesterol into cholesterol. The lack of cholesterol production leads to congenital alterations affecting various organs. In most cases, the clinical picture is evident from birth, but there are also mild forms identified in childhood or in adulthood.
The syndrome is characterized specifically by microcephaly (reduced head size), cerebral structural defects (for example, reduced or absent corpus callosum), facial dysmorphism (such as, upturned nostrils, drooping upper eyelid), syndactyly (joined fingers) of the 2nd and 3rd toes, decreased muscle tone, delayed growth and weight gain, mental retardation and behavioural disorders (such as hyperactivity, autistic traits, self-harming, sleep disorders). The clinical spectrum also includes atypical external genitalia –generally more frequent in people with 46,XY karyotype– which can range from hypospadias (unusual development of the last portion of the urethra and foreskin) to female external genitalia. Sometimes, derivatives of the Müllerian ducts may also be present (embryonic structures from which the tubes, uterus and upper third of the vagina originate). Adrenal insufficiency can be present at birth or develop over time. In some cases, ocular and visual disturbances (cataract, strabismus, nystagmus), congenital heart disease and congenital anomalies of the gastrointestinal tract (e.g., gastro-oesophageal reflux, pyloric stenosis) have also been described.
This condition has an incidence in central and Northern Europe estimated between 1/20,000 and 1/40,000.

Genetic traits
As already mentioned, Smith-Lemli-Opitz Syndrome is caused by mutations in the DHCR7 gene on chromosome 11 (11q13.4). Over 130 mutations have been identified. Transmission is autosomal recessive. This means that for the gene variation to occur, it must be inherited from both parents. Individuals who have inherited the gene variation from only one parent will not exhibit it in any way, but they may still pass it on to their offspring.

Identification
The reduced enzyme activity determines low cholesterol values and high levels of 7-dehydrocholesterol in the blood.
The diagnostic suspicion can be formulated in the prenatal period during fetal ultrasound. Diagnostic confirmation is obtained through the dosage of 7-dehydrocholesterol in amniotic fluid or chorionic villi, and through molecular analysis for the search for mutations on the DHCR7 gene.
Imaging investigations (CT scan, magnetic resonance, echocardiogram) are important to identify any associated morphological alteration.

Medical options
Treatment of this VSC/DSD is symptomatic. Most people are treated with cholesterol supplements, by including high-cholesterol foods and/or cholesterol-based pharmaceutical preparations in their diet. Observational studies during therapy report benefits in terms of growth, tone and muscle strength, reduction of irritability and aggression. Surgical interventions may be necessary if there are disorders secondary to morphological alterations affecting various organs.

Bibliography
Bianconi SE, Cross JL, Wassif CA, Porter FD. Pathogenesis, Epidemiology, Diagnosis and Clinical Aspects of Smith-Lemli-Opitz Syndrome. Expert opinion on orphan drugs. 2015 Mar;3(3):267-280
Nowaczyk MJ et al. Smith-Lemli-Opitz syndrome: a treatable inherited error of metabolism causing mental retardation. Canadian Medical Association Journal. 1999 Jul 27;161(2):165-70

Further Links
Orphanet. Smith-Lemli-Opitz syndrome
MedlinePlus (NLM). Smith-Lemli-Opitz syndrome