What is Smith-Lemli-Opitz Syndrome?
Smith-Lemli-Opitz syndrome (SLOS) is a rare genetic disorder that affects the body’s ability to correctly produce cholesterol, leading to unusually low amounts of cholesterol in the bloodstream and increased levels of a substance called 7-dehydrocholesterol (7-DHC). This condition results from a deficiency in an enzyme known as 7-dehydrocholesterol reductase (DHCR-7). It was first identified in 1964 by Dr. Smith, Dr. Lemli, and Dr. Opitz, who noticed a similar pattern of abnormal physical signs in three young boys.
SLOS is inherited in an autosomal recessive pattern, meaning both copies of the gene in each cell must have mutations for the individual to be affected. It comes with a variety of symptoms including the merging of two or more fingers or toes (syndactyly), a head size that is smaller than normal (microcephaly), growth problems, intellectual disability, abnormalities in the urinary opening in males (hypospadias), internal changes in most organs, and other unique physical features. People of white descent are the most likely to be carriers of this disorder, with about 1 to 2 percent carrying the gene for it. The difference between the actual number of cases and the expected number of cases is most likely due to undiagnosed mild cases, or severe cases leading to death before birth.
What Causes Smith-Lemli-Opitz Syndrome?
SLOS, also known as Smith-Lemli-Opitz Syndrome, is a genetic disorder that someone is born with. It is passed down through families in a way known as autosomal recessive inheritance. This means that both parents must carry and pass on the faulty gene for the child to have the condition. This disorder happens due to a change, or mutation, in a specific gene that controls a substance called DHCR-7. This gene is found at a particular place on chromosome 11 (referred to as 11q13).
There are different kinds of mutations, and the most commonly seen type in 87.6% of SLOS cases is called missense mutations. In total, there are 12 mutations that are known to be responsible for SLOS. Among these, the mutation named ‘c.964-1G>C’ is frequently seen in the United States. However, scientists have found that there can be as many as 218 different variations of the mutation that can potentially cause SLOS.
Risk Factors and Frequency for Smith-Lemli-Opitz Syndrome
SLOS, or Smith-Lemli-Opitz Syndrome, is a condition that’s been found within several ethnic groups around the world, though it’s most commonly reported in Europeans. People from Afro-Caribbean, Japanese, East Asian, Korean, or Arabic cultures have also been diagnosed with SLOS. When it comes to how often the syndrome occurs, the estimates vary, but it’s thought to affect between 1 in 10,000 to 70,000 newborns.
- SLOS is most commonly reported in European populations.
- People of Afro-Caribbean, Japanese, East Asian, Korean, and Arabic descent can also have SLOS.
- The incidence of SLOS is estimated at 1 in 10,000 to 70,000 newborns.
- The higher prevalence in European populations is thought to be due to a phenomenon called the founder effect.
- Between 1% and 2% of white populations are thought to be carriers of SLOS.
However, the actual number of people with SLOS might be lower than what these numbers suggest. That’s because the most severe cases can result in mortality before or shortly after birth, and the milder cases are often not diagnosed.
Signs and Symptoms of Smith-Lemli-Opitz Syndrome
Smith-Lemli-Opitz Syndrome (SLOS) is a disease that presents itself in various physical and mental features. It may lead to death in the womb, noticeable abnormal physical features at birth, or carry on into later stages of life affecting cognitive abilities. Doctors often diagnose this condition during pregnancy through increased nuchal translucency and ultrasound findings.
Postnatal features of SLOS can affect multiple systems in the body, including:
- Craniofacial Features: Microcephaly (smaller head), Micrognathia (smaller jaw), Bilateral ptosis (drooping of both eyelids), Bitemporal narrowing (narrowing of the skull), Cleft palate (an opening in the roof of the mouth), Short upturned nose.
- Central Nervous System: Hypotonia (decreased muscle tone), Absence or underdevelopment of corpus callosum (a part of the brain), Hypoplastic frontal lobes (underdeveloped front part of the brain), Enlarged ventricles, Pituitary lipomas (fat tissue tumors in the pituitary gland), Global developmental delay, Learning disability, Holoprosencephaly (a disorder in which the brain does not divide into two hemispheres).
- Growth and Skeletal: Delay in growth, Restricted growth in utero (in the womb), Abnormal fingerprints, Extra digits (Postaxial polydactyl), Fused fingers or toes (Syndactyl).
- Genital: Ambiguous genitalia, Hypospadias (misplaced opening of the penis or urethra), Sex reversal.
- Cardiovascular: Ostium primum (a kind of atrial septal defect), Atrial septal defect (a hole in the wall of the heart), Ventricular septal defects (holes in the heart), Patent ductus arteriosus (persistent opening between two major blood vessels leading from the heart), Atrioventricular canal (a big, single open chamber in the heart instead of four separate ones).
- Renal and Adrenal: Adrenal hypo/hyperplasia (either under or over-development of the adrenal glands), Renal ectopia (misplaced kidneys), Renal aplasia/hypoplasia (small or absent kidneys), Renal cortical cysts (fluid-filled sacs on the kidneys), Duplication of the ureter, Underdeveloped external genitalia and hypospadias (misplaced opening of the penis) in males.
- Respiratory: Abnormalities of the cartilage in trachea and larynx, Pulmonary hypoplasia (underdeveloped lungs), Abnormal division of the lung.
- Gastroenterology: Gastroesophageal reflux disease (GERD), Pyloric stenosis (narrowing of the opening between the stomach and intestines), Hirschprung’s disease (blockage of the large intestine), problems with the movement of the intestines (intestinal dysmotility), Cholestatic liver disease (a condition that slows down or stops the flow of bile).
Testing for Smith-Lemli-Opitz Syndrome
If doctors suspect a baby might be born with Smith-Lemli-Opitz Syndrome (SLOS), they can start checks while the mother is still pregnant. Ultrasound scans can provide early clues by indicating possible physical abnormalities in the fetus. There are also certain tests, known as multimarker screening tests, that can suggest if there might be a problem based on specific hormone levels in the mother’s blood.
One of these signs can be low levels of unconjugated estriol, a hormone produced by the fetus and the placenta, mildly depressed levels of alpha-fetoprotein, a protein made by the baby’s liver, and low levels of human chorionic gonadotropin, another hormone produced in the placenta. A special technique called gas chromatography-mass spectrometry can be used on a sample of the mother’s urine to reliably diagnose SLOS. This test is noninvasive and avoids the need for drawing fluid from the amniotic sac.
Scan findings may show things such as increased fluid at the back of the fetus’s neck (nuchal translucency) or other alterations in the baby’s growth. After birth, if the baby has certain physical features that are not typical, doctors might consider SLOS as a possible cause.
It’s important to note that the levels of cholesterol in the blood can’t be used to diagnose SLOS. This is because about 10% of people with SLOS have normal cholesterol levels and tests can sometimes mistakenly measure another similar substance as cholesterol, leading to incorrect readings. Instead, doctors use levels of two different compounds (7-DHC and 8-DHC) to make an initial assessment. To confirm the diagnosis, a test is done to identify any mutations in a specific gene known as DHCR-7.
To understand the severity of the syndrome, a scoring system known as the modified Bialer scoring system is used. It involves assessing the health condition of several organs and parts of the body, such as the brain, mouth, extremities (acral), eyes, heart, kidneys, liver, lungs, intestines (bowel), and genitalia. The score for each area is between 0 and 2, with higher scores indicating a more severe condition.
Treatment Options for Smith-Lemli-Opitz Syndrome
Smith-Lemli-Opitz Syndrome (SLOS) is a condition that lacks standard treatment guidelines. The main focus of treatment typically includes the increased provision of cholesterol and oral therapy for bile acid. These are used to raise cholesterol levels in the blood, which can alleviate some signs and symptoms of SLOS. The goal of these treatments is to enhance growth and development, and to address behavioral challenges associated with SLOS, such as poor sleep and serious symptoms of autism spectrum disorder, although there is still ongoing research about its effectiveness.
An unfortunate downside to cholesterol supplementation is that it can’t cross the blood-brain barrier, a protective shield that prevents potentially harmful substances in the bloodstream from entering the brain. In order to support the patient, additional care may be required. This can include nasogastric feeding, a process where a thin plastic tube, inserted through the nose, carries food and medicine to the stomach or gastrostomy, where an opening is made in the stomach for feeding directly.
Another part of managing SLOS is regular monitoring of the patient’s condition, as certain types of abnormalities common in SLOS might necessitate surgical intervention. The specifics of these surgeries will depend on the patient’s individual symptoms and are primarily aimed at improving the patient’s quality of life.
Planning a surgery for a patient with SLOS has its own challenges, as these patients may face problems during the process of intubation, that is, inserting a tube through the mouth or nose into the airway, due to malformed structures in the region of the larynx and windpipe. There’s also an elevated risk of a severe reaction called malignant hyperthermia that could occur in response to particular medications used during general anesthesia.
Additionally, psychological support for the families of individuals with SLOS is highly encouraged. Services like genetic counseling should be offered to these families to help them understand the risks and implications for future pregnancies.
What else can Smith-Lemli-Opitz Syndrome be?
When diagnosing Smith-Lemli-Opitz Syndrome (SLOS), a rare and genetic disorder, physicians may also consider other complex conditions that can have similar symptoms:
- Gardner-Silengo-Wachtel syndrome (also known as Genito-Palato-Cardiac syndrome)
- Young Madders syndrome (also known as Pseudotrisomy 13 or Holoprosencephaly–Polydactyly syndrome)
- Patau syndrome (also known as trisomy 13)
- Noonan syndrome
- Opitz G syndrome (also known as BBB syndrome)
- Edwards syndrome (also known as trisomy 18)
- Zellweger syndrome
- Pierre Robin sequence
These conditions can cause similar signs and symptoms, making it more challenging to accurately diagnose SLOS.
What to expect with Smith-Lemli-Opitz Syndrome
The outlook for a patient varies based on how severe the disease is. In the most serious cases, the disease can cause the death of a baby before it is born, while milder cases may see the individual live into adulthood with only minor effects. Of the babies that do survive beyond the newborn period, around 20% unfortunately don’t make it past their first year of life. Generally, this disease often results in a shorter life span.
The most common cause of death during infancy in individuals with this disease is gastric problems that lead to poor nutrition, but other factors like infections, low blood sugar (known as hypoglycemia) and adrenal insufficiency (a condition in which the adrenal glands do not produce enough hormones) can also cause sudden death.
Most patients will likely need ongoing assistance throughout their lives because of delayed development and intellectual disability.
Possible Complications When Diagnosed with Smith-Lemli-Opitz Syndrome
SLOS, or Smith-Lemli-Opitz Syndrome, can lead to different complications throughout the body. For instance, problems in the digestive system can occur due to issues like gastroesophageal reflux disease and muscle weakness, causing slow digestion and movement of food. These issues may lead to difficulties with eating, difficulties coordinating sucking or swallowing, or a need for artificial feeding methods or surgery.
Another complication linked with SLOS is intellectual disability, with most children affected showing low IQ levels. However, it is important to note that individuals with normal or slightly lower than average IQ levels have been recorded too. Furthermore, there is a strong association between SLOS and autism spectrum disorder (ASD). Typical characteristics can differ by age – infants may be hard to soothe, whereas older children may display specific behaviors like arching their back, acting aggressively, disturbing their sleep, or harming themselves (e.g., headbanging). It is estimated that about 75% of people with SLOS also have ASD.
Another area that is commonly impacted in SLOS are the kidneys and heart. Conditions like kidney agenesis (absence of one or both kidneys), hypoplasia (underdevelopment of an organ), and hydronephrosis (accumulation of urine in the kidneys) are common, with 43% of patients experiencing such issues. Equally, 44% of patients have reported cardiovascular defects, mostly atrial septal defects (holes in the wall between the two top chambers of the heart) and atrioventricular septal defects (holes in the heart and incorrectly formed heart valves). These defects can result in complications such as heart failure and chronic kidney disease.
- Common complications of SLOS:
- Gastrointestinal complications related to gastroesophageal reflux disease and hypotonia
- Issues with eating due to poor sucking and swallowing reflexes
- Need for artificial feeding methods or surgical interventions
- Development of intellectual disabilities, including Autism Spectrum Disorder
- Renal and cardiovascular abnormalities leading to kidney and heart diseases
Preventing Smith-Lemli-Opitz Syndrome
It’s crucial for parents who have children with SLOS, or Smith-Lemli-Opitz Syndrome, to receive genetic counseling. This counseling can provide explanation about how SLOS is passed down through families. Understanding this can be of great relief to parents while they weigh the decision of having their child genetically tested or the impact of the condition on future family planning.
Additionally, counseling can offer valuable information about the potential outcomes of a pregnancy where SLOS is suspected. This can include preparing parents for the possibility of a newborn not surviving or needing immediate medical attention after birth. Educating parents properly about this condition is key – the more information parents have about SLOS, the better they’ll be able to make informed decisions on behalf of their children affected by this disorder.
