Smith Lemli Opitz Syndrome
What is Smith Lemli Opitz Syndrome?
Autosomal recessive congenital disorder, which causes impaired cholesterol metabolism and resultant of this leads to multiple defective syndromes. Often Smith Lemli Opitz Syndrome affected children have mental retardation, behavioral disorder, and learning darling.
Other distinctive features include facial deformation, including microcephaly (small sized head). Some internal organs like heart, lungs, gastrointestinal system, kidney and genital organs are also malformed1,2.
Smith Lemli Opitz Syndrome Symptoms
In Smith Lemli Opitz Syndrome multiple disorders are characterized.
Craniofacial anomalies, which include microcephaly and resultant of this leads to narrowing of the frontal area of the head.
Facial anomalies, which include wide and flat nasal bridge, small sized nose with an upturned tip or pug nose, anteverted nostrils, undersized jaw (micrognathia), the ear is angulated in the posterior direction with low settings. Upper eyelid drooping (ptosis), typical skin fold at the upper eyelid that covers the inner angle of the eye (epicanthic folds).
In most of the patients have other ocular problems like the abnormal alignment of the eye (strabismus) and cataract. Cleft palate or high-arched palate is also distinct feature present in most of the cases.
Other anatomical anomalies include the indistinct neck, a complete or partial second and third toes are partially or completely joined(syndactyly), some affected individuals have all the toes are united same as web-footed animals.
Genital malformations Autosomal recessive congenital disorder, which causes impaired cholesterol metabolism and resultant of this leads to multiple defective syndromes. Often Smith-Lemli-Opitz affected children have mental retardation, behavioral disorder, and learning darling. Other distinctive features include facial deformation, including microcephaly (small sized head). Some internal organ like heart, gastrointestinal system, lungs, kidney and genital organs also malformed.
Symptoms
In Smith Lemli Opitz Syndrome multiple disorders are characterized.
Craniofacial anomalies, which include microcephaly, which causes a frontal area of the head become narrow.
Facial anomalies, which include wide and flat nasal bridge, small sized nose with an upturned tip or pug nose, anteverted nostrils, undersized jaw (micrognathia), the ear is angulated in the posterior direction with low settings. Upper eyelid drooping (ptosis), typical skin fold at the upper eyelid that covers
The inner angle of the eye (epicanthic folds). Abnormal eye alignment (strabismus) and cataract development are other eyes related problems. Cleft palate or high-arched palate is also distinct in most of the cases.
Other anatomical anomalies include the indistinct neck, a complete or partial second and third toes are partially or completely joined(syndactyly), some affected individuals have all the toes are united same as web-footed animals.
Genital malformations were usually seen in male affected individuals, which include hypospadias, cryptorchidism.
Deficit immune functioning, mainly at early childhood causes increase the susceptibility towards infections.
Mental disorders also prominent in most of the affected patients like delayed mental development, hypotonia, disturbed neuro-psychomotor functioning, hyperactivity, underestimated cognition. Some behavioral disorders like poor eye contact, mania, autism etc also develop in patients with Smith Lemli Opitz Syndrome.
Organ disorders include cardiac anomalies, pyloric stenosis (the junction between the stomach and small intestine become narrower); renal abnormalities, and pulmonary anomalies1,2,3.
Cause
The affected children inherit the abnormal gene from one of their parent, who acts as a carrier of this disease. If both the parents act as a carrier, then both of them can pass the defective gene and risk of Smith Lemli Opitz Syndrome development in each pregnancy will be 25%.
In Smith Lemli Opitz Syndrome, deficiency of 7-dehydrocholesterol-delta 7-reductase (3 beta-hydroxysterol-delta 7-reductase) leads to decrease the concentration of cholesterol in plasma and causing several symptoms. The abnormality in DHCR7 (7-dehydrocholesterol-delta 7-reductase) gene is occurred due to deficiency of 7-dehydrocholesterol-delta 7-reductase enzyme.
The 7-dehydrocholesterol-delta 7-reductase enzyme deficit leads to an abnormal plasma level reduction of cholesterol and elevation of 7DHC (7-dehydrocholesterol – an intermediate in cholesterol synthesis pathway) and other cholesterol precursors.
7-dehydrocholesterol-delta 7-reductase enzyme plays an important role in cholesterol synthesis in the body2,3.
Diagnosis
Diagnosis of Smith Lemli Opitz Syndrome can be conducted at different levels, like laboratory tests, imaging tests etc
Prenatal Test
In presence of family history or previous pregnancy has Smith Lemli Opitz Syndrome, the prenatal test can be conducted to check the fetus condition. Chorionic villous 7DHC content or amniotic fluid measurement can provide confirmatory result in presence of Smith Lemli Opitz Syndrome. Chorionic villi measurement is also important for enzyme activity. The confirmatory test is conducted in very few laboratory.
Research result also showed that exceptional occurrence of equine estriols in the urine sample of pregnant women is an indication of a fetus is affected by Smith-Lemli-Opitz syndrome. This method is an invasive technique4.
Postnatal
It has been considered that low levels of plasma total cholesterol and/or low-density lipoprotein (LDL) cholesterol levels may be a typical finding in Smith-Lemli-Opitz syndrome. However, this finding is not universally obtained for every Smith-Lemli-Opitz syndrome affected individuals.
In the gas-liquid chromatography or gas chromatography/mass spectrometry during sterol analysis, a remarkable increase level of plasma 7DHC is a pathognomonic indicator for Smith-Lemli-Opitz syndrome4.
Imaging Tests
- For identifying the structural deformity in the brain MRI and CT scan may need to perform
- Renal ultrasonography is recommended to detect the severity of the renal abnormality
- Abdominal ultrasonography and Barium swallow are tests, which require performing for detection of pyloric stenosis.
- In the suspicious case of Hirschsprung disease presence, Abdominal radiography assists to detect Hirschsprung disease if it is associated.
- Chest radiography is required to perform to check the congenital cardiac disease, congenital pulmonary disorders.
- Genitourinary ultrasonography may require performing for identifying genitourinary disorders4.
Treatment
The provision of the supportive treatment facility is essential to treat Smith Lemli Opitz Syndrome. The substantial treatment plan is altered depending upon the severity of the deficiency of plasma cholesterol level.
The cholesterol requirement is 30 to 40 mg/kg/day in normal infants and in adults, the requirement is 10 mg/kg/day. This amount of cholesterol requirement is fulfilled by a combination of dietary intake and bodily synthesis of cholesterol.
In Smith Lemli Opitz Syndrome the natural synthesis of cholesterol is hampered, therefore cholesterol supplementation is important. However, routine check up for cholesterol level is important to measure, as it indicates the cholesterol absorption rate in the body of the affected individual.
But practically it has been observed that cholesterol supplementation is not sufficient to treat Smith Lemli Opitz Syndrome affected patients, as the distribution of cholesterol in every cellular structure cannot be possible in this manner. In brain tissue, local biosynthesis is important to maintain the brain functioning because cholesterol supplementation does not cross blood brain barrier.
Therefore, the possibility of cognitive function improvement and normal neurological functioning is rare by cholesterol supplementation. The cholesterol supplement can be given through cholesterol-rich diet like eggs, meats, and meat based formulas, liver, cream or some supplement formulations that contain purified food grade.
Depending upon the patient’s pathophysiology, some experts also recommends cholesterol replacement therapy to avoid 7DHC toxicity. Some affected children show better outcome like improve sleep disorder, behavioral problems with cholesterol replacement therapy.
However, withdrawal of cholesterol supplementation or replacement therapy can cause obsessive disorders. Therefore cholesterol treatment is important for patients with Smith Lemli Opitz Syndrome.
Some experts also recommend a combination therapy of cholesterol supplementation and bile acid for the patients with Smith Lemli Opitz Syndrome to obtain a better result2,3.
Life Expectancy
In Smith Lemli Opitz Syndrome, the intrauterine death or stillbirth can occur due to severe cardiac functioning failure, or renal abnormalities. Research data showed that approximately 27% of children affected with Smith Lemli Opitz Syndrome survive till their second year of life.
The exact data of life expectancy is not known, but most of the death occur due to organ failure or internal malformation. Supportive care can improve patient’s quality life3.
References
- Smith-Lemli-Opitz syndrome; Genetic Home Reference; https://ghr.nlm.nih.gov/condition/smith-lemli-opitz-syndrome
- Smith Lemli Opitz Syndrome; National Organization For Rare Disorders; https://rarediseases.org/rare-diseases/smith-lemli-opitz-syndrome/
- Richard I Kelleya, Raoul C M Hennekamb; The Smith-Lemli-Opitz syndrome; http://jmg.bmj.com/content/37/5/321
- Robert D Steiner; Smith-Lemli-Opitz Syndrome; Medscape; http://emedicine.medscape.com/article/949125-overview
