Smith-Lemli-Opitz syndrome is a rare hereditary disease that is associated with a genetic defect in cholesterol metabolism. Occurs when the DHCR7 gene is mutated on the 11th chromosome, at the 11q12-q13 locus. Pathology is manifested by stunting, mental retardation, numerous bone anomalies and congenital malformations of internal organs. Diagnosis of the syndrome involves biochemical analyses, genetic testing, instrumental visualization methods, according to the prevailing symptoms. Supportive treatment: neurorehabilitation measures, the help of plastic surgeons, cardiac surgeons, maxillofacial surgeons.
Q87.1 Syndromes of congenital anomalies, manifested mainly by dwarfism
The syndrome is named after American pediatricians D. Smith, L. Lemley and geneticist J. Opica, who in 1964 described its clinical signs. The genetic mechanisms of the development of the disease were established in 1998. The frequency of occurrence of the syndrome is on average 1:29000, Europeans are more often ill (1:22000). At the same time, the carriage of the mutant gene is widespread: up to 1.2% in the light-skinned population and up to 0.8% in dark-skinned people. The condition is characterized by severe course, frequent disability, high mortality, which determines its relevance in modern genetics.
Smith-Lemley-Opitz syndrome is associated with an anomaly (missense and nonsense mutation) of the DHCR7 gene, which is located on the long arm of chromosome 11 (11q12-q13). It encodes the enzyme 7-dehydrocholesterol reductase, involved in the final stage of cholesterol synthesis. The disease has an autosomal recessive type of inheritance. The risk of the syndrome in a child whose both parents are carriers of the damaged gene is 25%.
The main mechanism that provokes the appearance of pathognomonic phenotypic signs of the syndrome is considered to be cholesterol deficiency. In this disease, the final molecule is not formed, instead, low-density lipoproteins and other intermediate metabolites accumulate in the body. These substances in excessive amounts have a toxic effect on cells.
Neurological disorders are caused by insufficient formation of lipids, which are necessary for the myelination of nerve fibers, and the specific signaling protein sonic hedgehog provokes disorders of intrauterine formation of brain tissue. Cholesterol deficiency correlates with a lack of hormones (testosterone, estrogens), which explains the disorders of the formation of external genitalia in boys.
Microcephaly, cleft palate, and micrognathia are specific for Smith-Lemli-Opitz disease. Less common is the Pierre-Robin syndrome in combination with protruding incisors, which creates difficulties when chewing food, conducting anesthesia. 95% of children have Y-shaped syndactyly of 2-3 toes, in half of the cases there is postaxial syndactyly. Dislocation of the hip joints, shortening of the limbs are also characteristic.
With a genetic defect of DHCR7, a lag in growth and physical development is typical. From birth, babies gain weight poorly, their body length is below normal. As the child grows older, the growth retardation becomes more noticeable, in adulthood the body parameters are below the 3rd percentile. Puberty is disrupted: hypospadias, cryptorchidism are detected in boys, and clitoral hypertrophy in girls.
In most patients, pronounced neurological symptoms are determined. It is manifested by sleep disorders (70% of patients): frequent night awakenings, inability to sleep, lack of a clear daily routine. Mental symptoms include increased aggressiveness, including autoaggression, a tendency to obsessive behavior, autism spectrum disorders. Most children suffering from Smith-Lemley-Opitz syndrome are mentally retarded.
36-38% of cases of the syndrome are complicated by congenital heart defects. Gastrointestinal tract abnormalities occur in 25-29% of patients. They include gastroesophageal reflux, Hirschsprung’s disease, intestinal malrotation. Defects of the genitourinary system are common: cystic dysplasia of the kidneys (29%), kidney dystopia (19%), hydronephrosis (16%) and obstruction of the pelvic-ureteral junction (13%). About 12-18% of patients suffer from decreased vision.
Most patients are diagnosed with disability due to severe mental retardation, lagging rates of physical development. Smith-Lemli-Opitz syndrome is associated with a high mortality rate both in the perinatal period and after the birth of a child due to gross congenital anomalies. Although many patients live to adulthood, they require constant care and medical supervision.
During a physical examination of the child, it is possible to identify pathognomonic changes in the phenotype, which, together with signs of growth retardation and psychomotor development, allows a preliminary diagnosis to be made. To confirm the Smith-Lemli-Opitz syndrome, an examination by a geneticist is prescribed, a number of diagnostic measures:
- Biochemical analysis. The content of lipids in the blood plasma and body tissues is checked. In this genetic disease, an increase in the level of 7-dehydrocholesterol is observed simultaneously with a decrease in the amount of cholesterol.
- Genetic research. Exon sequencing is performed to detect a specific mutation. When the DHCR7 anomaly is detected, the diagnosis of Smith-Lemli-Opitz syndrome is confirmed with 100% accuracy. The same diagnosis is shown to the patient’s relatives.
- Prenatal diagnosis. Couples with burdened heredity are recommended to study during pregnancy by measuring the concentration of 7-dehydrocholesterol, genetic analysis of amniotic fluid or chorionic villi.
- Instrumental methods. Patients undergo a comprehensive examination of the cardiovascular (echocardiography, ECG), genitourinary (excretory urography, ultrasound of the pelvic organs), nervous system (EEG, neurosonography, CT or MRI of the brain).
In the presence of Smith-Lemli-Opitz syndrome, symptomatic therapy is performed, which is selected individually based on the leading clinical signs. Patients need the help of a multidisciplinary team of doctors, since one patient combines various lesions of internal organs, disorders of the musculoskeletal system, neuropsychiatric disorders. There are the following areas of treatment of genetic syndrome:
- Diet therapy. To normalize the lipid profile of blood plasma, dietary supplements with crystalline cholesterol are used, the diet is enriched with egg yolks, animal fats.
- Rehabilitation. To improve motor functions, a comprehensive exercise therapy program, massage, kinesitherapy is prescribed. In order to correct the neuropsychiatric deficit, long-term classes with correctional teachers, speech therapists, psychologists are shown.
- Qualified care. Due to mental retardation, patients cannot live independently. They are cared for by parents with the participation of medical personnel, and the option of patients staying in specialized boarding schools is also being considered.
- Dispensary observation. Patients with Smith-Lemli-Opitz syndrome should regularly undergo medical examinations by an orthopedic traumatologist, neurologist, urologist and other specialists. The frequency of examinations is determined by the severity of clinical symptoms.
Plastic and maxillofacial interventions are performed to eliminate facial skull anomalies, syndactyly, hypospadias. The volume and timing of the operation are selected taking into account the severity of phenotypic changes. Correction of congenital heart defects is performed according to standard protocols, depending on the nature of the anomaly, the presence of circulatory disorders. Complex defects require the intervention of cardiac surgeons already in the first year of a child’s life.
Prognosis and prevention
With timely diagnosis of the syndrome and early initiation of complex therapy, the prognosis is relatively favorable. Doctors manage to accelerate psychomotor development, eliminate skeletal abnormalities, correct somatic pathologies. However, low growth, mental retardation, fertility problems remain for life. Prevention involves genetic counseling of carriers of the mutated gene before planning pregnancy.