SMITH-LEMLI-OPITZ SYNDROME: SYMPTOMS, CAUSES, TREATMENT - GEOGRAFÍA - 2025

The Smith-Lemli-Opitz syndrome is a metabolic disorder that encompasses several different symptoms such as slow growth significantly, characteristic facial features, microcephaly, mild mental retardation or moderate learning difficulties and behavioral problems.

It is also accompanied by malformations in the lungs, heart, kidneys, intestine and even 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).

Symptoms of Smith-Lemli-Opitz syndrome

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.

A little history

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.

Statistics

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.

Causes

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 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 products, meat, poultry and fish.

It is essential for the embryo to develop smoothly, having important functions such as contributing to the structure of cell membranes and myelin (a substance that covers brain cells). It is also used 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 lack of growth, mental retardation, physical malformations and problems in the internal organs.

Mutations in the DHCR7 gene

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 its variants, 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 borne in mind that there is a greater probability of having children with any recessive genetic disorder if parents who are close relatives (or blood) than parents who do not have these links.

Symptoms

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 will include those that occur in all stages of life:

In more than 50% of patients

- 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 the 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.

10 to 50% of cases

- Early cataracts.

- Polydactyly or one more finger after the little finger.

- Delayed growth in the fetal stage.

- Ambiguous genitalia.

- Heart defects.

- Multicystic kidney.

- Absence of one or both kidneys at birth.

- Liver diseases.

- Adrenal hyperplasia

- Pulmonary abnormalities.

- Excessive sweating.

- Brain abnormalities in structures located in the midline, 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, which causes lack of intestinal motility (15%)

- Photosensitivity.

Other symptoms

- Cloudiness or coma.

- Accumulation of fluid in the body of the fetus.

-Alterations in neurological development.

- Neuropsychiatric problems, which appear more frequently when they reach adulthood.

- Shortness of breath due to problems in the lungs.

- Hearing loss.

- Alterations in vision, which may be accompanied by strabismus.

- vomiting

- Constipation.

- Seizures.

Diagnosis

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, it is detected late on several occasions.

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.

Blood test

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.

Ultrasound or ultrasound

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.

Amniocentesis

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), removing 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 be present or if it is only going to be a carrier.

What is the course of the disease?

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.

Treatments

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.

The medical treatment for Smith-Lemli-Opitz syndrome is based on the specific problems encountered in the affected child and it is best to intervene early.

Supplements

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. It is sometimes combined with bile acids.

Protection

For sun intolerance, it is advisable for these patients to use sunscreen, sunglasses and appropriate clothing when going outside.

Drugs

Taking drugs like simvastatin has been shown to decrease the severity of the disease. Although, as the clinical phenotype occurs during a lack of cholesterol in embryogenesis, it must 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 can be helpful for symptoms such as vomiting, gastroesophageal reflux or constipation.

Surgery

Surgery or braces may be necessary if physical deformities or muscle problems related to this syndrome such as cleft palate, heart defects, muscle hypotonia, or genital alterations are present.

In conclusion, it is necessary to continue research in this syndrome so that more effective and specific treatments are developed.

References

1. Jiménez Ramírez, A.; Valdivia Alfaro, R.; Hernández González, L.; León Corrales, L.; Machín Valero, Y. and Torrecilla, L. (2001). Smith Lemli Opitz syndrome. Presentation of a case with a biochemical diagnosis. Espirituana Medical Gazette, 3 (3).
2. Smith Lemli Opitz Syndrome. (sf). Retrieved on July 6, 2016, from the National Organization for Rare Disorders (NORD).
3. Smith-Lemli-Opitz Syndrome. (sf). Retrieved on July 6, 2016, from the University of Utah, Health Sciences.
4. Smith-Lemli-Opitz Syndrome. (sf). Retrieved on July 6, 2016, from Counsyl.
5. Smith-Lemli-Opitz syndrome. (2016, July 5). Obtained from Genetics Home Reference.
6. Steiner, R. (April 1, 2015). Smith-Lemli-Opitz Syndrome. Obtained from Medscape.
7. Tint, GS, Irons, M., Elias, ER, et al. (1994). Defective cholesterol biosynthesis associated with the Smith-Lemli-Opitz syndrome. N Engl J Med, 330: 107–113
8. Witsch-Baumgartner, M., & Lanthaler, B. (2015). Birthday of a syndrome: 50 years anniversary of Smith – Lemli – Opitz Syndrome. European Journal of Human Genetics, 23 (3), 277–278.