The Smith-Lemli-Opitz syndrome is a metabolic disorder that encompasses several different symptoms, such as significantly slow growth, characteristic facial features, microcephaly, mild or moderate mental retardation, learning difficulties, and behavior problems.
It is also accompanied by malformations in the lungs, heart, kidneys, intestine and even in the genitals. In addition, they can present syndactyly (fusion of some of the fingers) or polydactyly (more than 5 fingers in a foot or hand).
It seems that the cause of this syndrome is the lack of an enzyme that is important for metabolizing cholesterol that is acquired by genetic inheritance of an autosomal recessive pattern..
However, these presentations seem to vary enormously according to the severity of the disease even in the same family. This syndrome can appear in the literature with names such as 7-dehydrocholesterol reductase deficiency, RSH syndrome or SLO syndrome..
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In 1964, pediatricians David Smith, Luc Lemli, and Opitz John described 3 male patients with microcephaly and hypogenitalism, and defined this condition as RSH by the initials of the original surnames of these patients. Subsequently, the name of the syndrome was changed to the surnames of the discoverers.
Some 30 years later, Tint et al. (1994) found in 5 patients with this condition, significantly low concentrations of cholesterol in the blood, but an increase of more than 1000 times the levels of 7-dehydrocholesterol. They saw that this increase was due to the lack of an enzyme that should transform 7-dehydrocholesterol into cholesterol.
Later, the DHCR7 gene associated with this disease was identified and cloned in 1998..
Smith-Lemli-Opitz syndrome affects approximately 1 in 20,000 to 60,000 live newborns worldwide. It can actually be inherited in 1 in 1590 to 13,500 individuals, but this figure is not used because many fetuses with this condition die before being born (National Organization for Rare Disorders, 2016).
Regarding sex, it affects men and women equally, although it is more easily diagnosed in men since genital malformations are more visible than in women.
Furthermore, it seems to be more common in people of European descent; especially from countries belonging to central Europe such as the Czech Republic or Slovakia. However, it is very rare in the population of Africa or Asia..
Smith-Lemli-Opitz syndrome appears due to mutations in the DHCR7 gene, present on chromosome 11, which is responsible for sending orders to manufacture the enzyme 7-dehydrocholesterol reductase.
This is the enzyme that modulates the production of cholesterol and it would be absent or to a very little extent in this syndrome, which leads to insufficient production of cholesterol that would prevent normal growth..
This has a great impact since cholesterol is important in the body. It consists of a fat-like lipid that is obtained mainly from foods of animal origin, such as egg yolks, dairy, meat, poultry and fish.
It is essential for the embryo to develop without difficulties, having important functions such as contributing to the structure of cell membranes and myelin (a substance that covers brain cells). It also serves to produce hormones and digestive acids.
Lack of the enzyme 7-dehydrocholesterol reductase causes potentially toxic components of cholesterol to build up in the body. So we have, on the one hand, low cholesterol levels, and at the same time accumulation of substances that can be toxic to the body; causing growth failure, mental retardation, physical malformations and internal organ problems.
However, it is not known with complete certainty how these problems associated with cholesterol give rise to the symptoms of Smith-Lemli-Opitz syndrome..
Currently, more than 130 mutations related to the syndrome have been found in the DHCR7 gene, in fact, there is a database that includes all the described cases of Smith-Lemli-Opitz syndrome with their variants, their phenotypes and genotypes..
Although there are so many possible mutations, most of the cases belong to the 5 most frequent and the rest are very rare.
These mutations in the DHCR7 gene are inherited with an autosomal recessive pattern, this means that a person to present the syndrome must have inherited the mutated gene from both parents. If you only receive it from one parent, you will not have the disease; but it could be a carrier and transmit it in the future.
There is a 25% risk that both carrier parents will have an affected child, while the risk that the child is a carrier would also be 50% in each pregnancy.
On the other hand, in 25% of cases it can be born without these genetic mutations or be a carrier; all these data being independent of the sex of the baby.
It should be taken into account that there is a greater probability of having children with any recessive genetic disorder if parents who are close relatives (or consanguineous) than parents who do not have these links.
The symptoms of this syndrome vary depending on the person affected, depending on the amount of cholesterol they can produce. The clinical features cover several aspects and can be very diverse. They are generally found on the face, limbs, and genitals; although they may involve other body systems.
Many of those affected have typical features of autism, affecting social interaction. If the condition is mild, only some learning and behavior problems may be seen; but in the most serious cases, the person can have a great intellectual disability and physical abnormalities that can lead to death.
There are symptoms that may already be present from the birth of the individual, although we are going to include those that occur in all stages of life:
- Lack of physical development observed after birth.
- Mental retardation (100%).
- Microcephaly (90%).
- Syndactyly or fusion of 2 or 3 toes (<95%).
- Eyelid ptosis, that is, having one of the upper eyelids drooping (70%).
- Urinary meatus located in a different place than normal in men, such as in the lower part of the glans, trunk or union between scrotum and penis. It is present in 70% of cases.
- Cleft palate, which manifests as a kind of elongated hole in the palate (50%).
- Very reduced jaw or micrognathia.
- Very small tongue (microglossia).
- Low-set ears.
- Small nose.
- Incomplete descent of one or both testicles.
- Hypotonia or low muscle tone.
- Eating disorders.
- Behavior disorders: antisocial, self-destructive and violent behaviors. Self-stimulating behaviors typical of autism also appear, such as repetitive rocking movements.
- Autism.
- Early cataracts.
- Polydactyly or one more finger after the little finger.
- Growth retardation in the fetal stage.
- Ambiguous genitalia.
- Heart defects.
- Multicystic kidney.
- Absence of one or both kidneys at birth.
- Liver disease.
- Adrenal hyperplasia
- Lung abnormalities.
- Sweating excessively.
- Brain abnormalities in midline structures, such as incomplete development of the corpus callosum, septum, and cerebellar vermis.
- Acrocyanosis: cutaneous vasoconstriction that causes a bluish color in the hands and feet.
- Equinovar feet.
- Pyloric stenosis (15%)
- Hirschprung's disease, causing a lack of intestinal motility (15%)
- Photosensitivity.
- Cloudiness or coma.
- Accumulation of fluid in the body of the fetus.
-Alterations in neurodevelopment.
- Neuropsychiatric problems, which appear more often when they reach adulthood.
- Shortness of breath due to lung problems.
- Hearing loss.
- Vision disturbances, which may be accompanied by strabismus.
- Vomiting.
- Constipation.
- Seizures.
This syndrome appears from conception despite the fact that when the baby is born, the symptoms are not very clear and are more subtle than in late childhood or adulthood; especially if they are milder forms of the disease. For this reason, on several occasions it is detected late.
In any case, the most common is that this condition is already suspected shortly after birth due to the malformations that it usually presents..
According to the National Organization for Rare Disorders, the diagnosis is based on physical exams and a blood test that detects cholesterol levels. It is essential that the child is evaluated for all possible aspects associated with the disease such as the eyes, ears, heart, skeletal muscles, genitals and gastrointestinal disorders.
Regarding blood tests, a subject with Smith-Lemli-Opitz syndrome will have a high concentration of 7-dehydrocholesterol (7-DHC) in the blood (a precursor that must be transformed by the enzyme 7-dehydrocholesterol reductase to obtain cholesterol ), and very low cholesterol levels.
It can also be detected before birth through an ultrasound or ultrasound technique, a device that uses sound waves to examine the inside of the pregnant woman's uterus. With this technique, the physical deformities typical of this syndrome can be observed..
Another test is amniocentesis, which consists of the extraction of a small sample of amniotic fluid (where the fetus develops) to detect genetic defects. The same information can be obtained through chorionic villus sampling (CVS), extracting a tissue sample from the placenta..
On the other hand, molecular genetic tests can be used for prenatal diagnosis in order to observe if there are mutations in the DHCR7 gene, and if the disease is going to present or is only going to be a carrier.
Unfortunately, most of the most serious cases of Smith-Lemli-Opitz syndrome die shortly after birth. If there is severe intellectual disability, it is difficult for these people to develop an independent life.
However, with proper medical care and a good diet, these patients can lead normal lives..
There is currently no specific treatment for Smith-Lemli-Opitz syndrome. This is due to the fact that the biochemical origin of the disease is not known with absolute certainty today since cholesterol has several complex functions in metabolism.
Medical treatment for Smith-Lemli-Opitz syndrome is based on the specific problems found in the affected child and it is best to intervene early.
It can be of great help to receive cholesterol supplements or increase the intake of this through the diet, to improve the level of development and reduce photosensitivity. Sometimes combined with bile acids.
For sun intolerance, it is advisable for these patients to use sunscreen, sunglasses and appropriate clothing when they go outside..
It has been shown that the provision of drugs such as simvastatin can decrease the severity of the disease. Although, as the clinical phenotype occurs during a lack of cholesterol in embryogenesis, it should be administered at that time..
On the other hand, an antagonist drug of the toxic precursor of cholesterol that is in excess (7-dehydrocholesterol) can also be used to prevent its increase. Vitamin E supplements can help..
Other types of specific medications may be helpful for symptoms such as vomiting, gastroesophageal reflux or constipation..
Surgery or braces may be necessary if there are physical deformities or muscle problems related to this syndrome such as cleft palate, heart defects, muscle hypotonia or genital alterations.
In conclusion, it is necessary to continue research in this syndrome so that more effective and specific treatments are developed..
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