Smith-Lemli-Opitz syndrome

Table of Contents

Alternative Terminology for This Medical Condition

  • Deficiency of 7-dehydrocholesterol reductase
  • RSH Syndrome
  • Smith-Lemli-Opitz Syndrome
  • SLOS Condition

In vitro fertilization (IVF) and preimplantation genetic testing (PGT) are significant advancements in the realm of reproductive medicine and genetics, particularly for individuals at risk of transmitting genetic disorders like Smith-Lemli-Opitz syndrome. For couples with a known risk of passing on Smith-Lemli-Opitz syndrome to their offspring, IVF coupled with PGT offers a proactive approach. In this process, eggs are fertilized in a lab setting, and the resulting embryos are screened for the specific genetic mutations associated with Smith-Lemli-Opitz syndrome. This enables the selection of embryos without the disorder for implantation, significantly reducing the likelihood of the child inheriting Smith-Lemli-Opitz syndrome. Thus, IVF and PGT provide a powerful combination for family planning, particularly for those with a genetic predisposition to this condition, allowing them to minimize the risk of genetic transmission while achieving pregnancy.

Introduction of Smith-Lemli-Opitz Syndrome

What is Smith-Lemli-Opitz syndrome and what are its main characteristics?

Smith-Lemli-Opitz syndrome is a complex developmental disorder impacting multiple body systems. Key characteristics include unique facial traits, reduced head size (microcephaly), cognitive impairments or learning challenges, and behavioral issues. Many children with this syndrome display traits of autism, affecting communication and social interactions. Common physical malformations include those of the heart, lungs, kidneys, gastrointestinal tract, and genitalia. Infants often exhibit low muscle tone (hypotonia), face difficulties in feeding, and have slower growth rates compared to their peers. A notable physical feature is the fusion of the second and third toes (syndactyly), and in some cases, there may be additional fingers or toes (polydactyly).

The severity of Smith-Lemli-Opitz syndrome varies significantly among individuals. Mild cases may involve slight physical abnormalities with learning and behavioral difficulties, while severe instances can pose life-threatening risks, including profound intellectual disability and major physical anomalies. The condition stems from genetic alterations in the DHCR7 gene and follows an autosomal recessive inheritance pattern. Diagnosis is typically based on clinical features combined with laboratory and genetic testing results.

Genetic Transmission of Smith-Lemli-Opitz Syndrome

What is the inheritance pattern of Smith-Lemli-Opitz syndrome, and what are its primary manifestations?

Smith-Lemli-Opitz syndrome is a genetic disorder that impacts various body systems. It’s marked by unique facial characteristics, a small head size (microcephaly), cognitive impairments or learning difficulties, and behavioral challenges. Many children with this syndrome exhibit autism-like traits affecting communication and social interaction. Common physical abnormalities include malformations in the heart, lungs, kidneys, gastrointestinal system, and genitalia. Infants with this condition often have low muscle tone (hypotonia), struggle with feeding, and grow at a slower pace than their peers. A distinctive physical sign is the fusion of the second and third toes (syndactyly), with some cases also presenting extra digits (polydactyly).

The spectrum of Smith-Lemli-Opitz syndrome’s symptoms can range significantly. While some individuals may experience only minor physical irregularities alongside learning and behavioral issues, others may face life-threatening challenges, including severe intellectual disability and extensive physical anomalies.

Incidence Rates and Demographic Distribution of Smith-Lemli-Opitz Syndrome

What is the estimated frequency of Smith-Lemli-Opitz syndrome in newborns, and how does it vary among different ethnic groups?

Smith-Lemli-Opitz syndrome is estimated to affect approximately 1 in every 20,000 to 60,000 newborns. The syndrome is notably more prevalent among individuals of European descent, particularly in Central European nations like Slovakia and the Czech Republic, while it’s considerably rarer in African and Asian populations. Among Caucasians, its prevalence is estimated within the same range. The syndrome is also found among Hispanic populations, though its exact prevalence in various ethnic groups remains not fully determined. Documented cases of Smith-Lemli-Opitz syndrome span across diverse regions, including the United States, many Northern European countries, Japan, South America, and others.

In North America specifically, the birth prevalence is approximated at 1 in 40,000 live births, with a carrier frequency estimated to be around 1%. As an autosomal recessive condition, Smith-Lemli-Opitz syndrome occurs with equal frequency in both males and females.

Genetic Origins of Smith-Lemli-Opitz Syndrome

What genetic factors lead to the development of Smith-Lemli-Opitz syndrome?

Smith-Lemli-Opitz syndrome is primarily caused by mutations in the DHCR7 gene. This gene is responsible for encoding the enzyme 7-dehydrocholesterol reductase, which plays a crucial role in the final stage of cholesterol production. Cholesterol, a vital fat-like substance, is synthesized in the body and also sourced from animal-based foods like egg yolks, meat, poultry, fish, and dairy products. It’s essential for normal embryonic development and serves several important functions, both pre- and post-birth, including being a key component of cell membranes and myelin, and aiding in hormone and digestive acid production.

The mutations in the DHCR7 gene lead to reduced or completely absent activity of the 7-dehydrocholesterol reductase enzyme. This deficiency hinders adequate cholesterol production in cells and results in the accumulation of harmful byproducts of cholesterol synthesis in the blood, nervous system, and other tissues. The combination of depleted cholesterol levels and the buildup of these substances likely interferes with the growth and development of various body systems. However, the exact mechanisms through which these genetic abnormalities manifest as the specific characteristics of Smith-Lemli-Opitz syndrome are not fully understood.

Genetic Transmission of Autosomal Recessive Conditions like Smith-Lemli-Opitz Syndrome

How is an autosomal recessive condition like Smith-Lemli-Opitz syndrome inherited?

Smith-Lemli-Opitz syndrome follows an autosomal recessive inheritance pattern. This means that for an individual to be affected by the condition, they must inherit mutated versions of the gene associated with the disorder from both parents. In this context, ‘autosomal’ indicates that the gene is located on a non-sex chromosome, as genes and chromosomes typically exist in pairs. The term ‘recessive’ denotes that the disease manifests only when both copies of the relevant gene carry a pathogenic variant, previously referred to as a mutation.

An individual with an autosomal recessive disorder inherits one pathogenic variant of the gene from each parent. Parents carrying only one pathogenic variant of the gene are carriers and usually do not show symptoms of the disease. When two carriers of such a condition conceive a child, there is a 25% chance (1 in 4) that their child will be affected by the disease.

Signs and symptoms

Symptoms of this disease may start to appear as a Newborn and as an Infant.

The age symptoms may begin to appear differs between diseases. Symptoms may begin in a single age range, or during several age ranges. The symptoms from some diseases may begin at any age. Knowing when symptoms began to appear can help medical providers find the correct diagnosis.

The following signs and symptoms may be noted in Smith-Lemli-Opitz syndrome:

  • Lethargy
  • Obtundation or coma
  • Respiratory failure
  • Hearing loss
  • Visual loss
  • Vomiting
  • Feeding difficulties
  • Failure to thrive
  • Constipation
  • Cyanosis
  • Congestive heart failure
  • Photosensitivity

Neuropsychiatric and neurodevelopmental abnormalities are common and include variable intellectual disability (ID), aberrant behavior, and autism.

There are many symptoms and signs which include:

  • CNS
    • intellectual disability
    • hyperexcitability
    • microcephaly
    • hypotonia
    • holoprosencephaly
  • craniofacial
    • blepharophimosis
    • epicanthus
    • micrognathia
    • low set ears
  • limb
    • postaxial polydactyly
    • syndactyly: usually 2ndand 3rd toes
  • congenital cardiac anomalies
  • congenital urogenital anomalies
    • hypospadias
    • cryptorchidism
  • intrauterine growth restriction (IUGR)

Manifestations and Onset of Smith-Lemli-Opitz Syndrome

What are the typical signs and symptoms of Smith-Lemli-Opitz syndrome, and at what age do they usually present?

Symptoms of Smith-Lemli-Opitz syndrome can emerge at different stages, often starting in the newborn and infant phases. The onset age varies, with some diseases showing symptoms in a specific age range, while others may manifest at any age. Recognizing the timing of symptom onset can aid in accurate diagnosis.

In Smith-Lemli-Opitz syndrome, the following signs and symptoms may be observed:

– Lethargy

– Reduced consciousness or coma

– Respiratory distress

– Loss of hearing

– Vision impairment

– Vomiting

– Difficulties in feeding

– Poor growth or failure to thrive

– Constipation

– Cyanosis (bluish skin)

– Congestive heart failure

– Sensitivity to light

Neuropsychiatric and neurodevelopmental issues are common, including varying degrees of intellectual disability (ID), unusual behaviors, and autism spectrum disorders.

Other notable symptoms and signs include:

– Central Nervous System (CNS): Intellectual disability, heightened excitability, small head size (microcephaly), low muscle tone (hypotonia), and holoprosencephaly (a brain development disorder).

– Craniofacial Features: Narrowing of the eye opening (blepharophimosis), fold of skin on the upper eyelid (epicanthus), small lower jaw (micrognathia), and low-set ears.

– Limb Abnormalities: Extra fingers (postaxial polydactyly) and webbing or fusion of the second and third toes.

– Congenital Cardiac Anomalies

– Congenital Urogenital Anomalies: Such as underdeveloped urethra opening (hypospadias) and undescended testes (cryptorchidism).

– Intrauterine Growth Restriction (IUGR): Restricted growth and development inside the uterus.

Table 1 Features of Smith-Lemli-Opitz Syndrome.


% of Persons w/Feature


2-3 toe syndactyly



Growth restriction







Common 1

UVA mediated

Congenital heart defect



Hypospadias &/or bilateral cryptorchidism


In males

Cleft palate






Postaxial polydactyly



Renal anomalies



External female genitalia w/a 46,XY karyotype





May be congenital or develop acutely

Conditions to Consider in the Differential Diagnosis of Smith-Lemli-Opitz Syndrome

What are some of the differential diagnoses to consider when evaluating for Smith-Lemli-Opitz syndrome?

In the process of diagnosing Smith-Lemli-Opitz syndrome, several other conditions should be considered, including:

– Abetalipoproteinemia

– Adrenal Hypoplasia

– Androgen Insensitivity Syndrome

– Autism Spectrum Disorder

– Cerebrotendinous Xanthomatosis (CTX)

– Cholestasis

– Chromosomal abnormalities

– Cognitive Impairments

– Congenital Adrenal Hyperplasia

– Delayed growth and development

– Denys-Drash Syndrome

– Disorders of Sex Development (DSDs)

– Expressive language disorder

– Extremely Low Birth Weight Infant

– Gastroesophageal Reflux Disease (GERD) Imaging

– Growth Failure

– Hearing Impairment

– Hydrolethalus syndrome

– Hydrops Fetalis Imaging

– Hypobetalipoproteinemia

– Hypospadias

– Malnutrition

– Meckel syndrome

– Microphallus

– Mixed language disorder

– Neonatal Jaundice

– Neonatal Sepsis

– Nutritional Issues in Failure to Thrive

– Pallister-Hall syndrome

– Pediatric Adrenal Insufficiency (Addison Disease)

– Pediatric Cleft Lip and Palate

– Pediatric Fulminant Hepatic Failure

– Pediatric Hirschsprung Disease

– Pervasive Developmental Disorder

– Pierre Robin Sequence

– Receptive language disorder

– Short Stature

– Steroid sulfatase deficiency

– Trisomy 18

– Ullrich-Feichtiger syndrome

– Undescended testes (Cryptorchidism)

Assessment and Diagnostic Methods for Identifying Congenital Anomalies

What are the physical signs and diagnostic imaging studies used to diagnose congenital anomalies?

When diagnosing congenital anomalies, the following physical signs may be evident upon examination:

– Small head size (Microcephaly)

– Intracranial germinoma

– Broad nasal tip with forward-facing nostrils

– Small lower jaw (Micrognathia)

– Drooping of eyelids (Ptosis)

– Skin folds of the upper eyelid (Epicanthal folds)

– Eye misalignment (Strabismus)

– Cataracts, potentially developing after birth

– Wide maxillary alveolar ridges

– Slanted or low-set ears

– Webbing or fusion of the second and third toes (Syndactyly)

– Extra digits (Postaxial polydactyly)

– Underdeveloped urethra opening or undescended testes in males, occasionally complete sex reversal

– Cleft palate

– Heart murmurs, cyanosis, or respiratory issues due to cardiac defects

– Respiratory distress caused by pulmonary anomalies

Imaging and Diagnostic Studies include:

– Brain MRI or CT scans to detect structural brain malformations.

– Renal ultrasonography for identifying kidney anomalies.

– Abdominal ultrasound for pyloric stenosis detection or exclusion.

– Barium swallow for assessing or excluding pyloric stenosis.

– Abdominal X-rays when Hirschsprung disease is suspected.

– Barium enema for Hirschsprung disease evaluation.

– Chest X-rays to check for congenital heart and lung abnormalities.

– Genitourinary ultrasound for identifying anomalies in the genitourinary system.

– Slit lamp examination to detect strabismus, cataracts, ptosis, and optic nerve issues.

– Developmental or IQ testing to assess intellectual or learning disabilities.

Management and Therapeutic Approaches for Smith-Lemli-Opitz Syndrome

What are the current treatment strategies and clinical trial developments for managing Smith-Lemli-Opitz syndrome (SLOS)?

At present, there is no long-term effective treatment for Smith-Lemli-Opitz syndrome. Cholesterol supplementation is considered a potential therapy, aiming to increase plasma and tissue cholesterol levels. Dietary sources for cholesterol supplementation might include egg yolk, whipping cream, and butterfat. Additionally, hormone therapy may be necessary for some individuals with this syndrome.

For those experiencing hearing loss, the use of hearing aids can be significantly beneficial. Gastrostomy feeding might also be indicated in certain cases. It is recommended for patients to limit sun exposure and use sunscreen liberally.

In terms of clinical trials, early encouraging results in treating Smith-Lemli-Opitz syndrome have sparked interest in both preconceptional and prenatal therapies. While these approaches are often more palliative than curative, cholesterol’s critical role in early embryonic development suggests a potential therapeutic window around the time of conception. Prenatal diagnoses are usually made in the second trimester, but effective cholesterol delivery across the placenta and blood-brain barrier remains a significant challenge.

There have been reports of antenatal therapeutic interventions for the syndrome, including fetal intravenous and intraperitoneal transfusions of fresh frozen plasma in the third trimester, which resulted in increased fetal cholesterol levels and erythrocyte mean corpuscular volume.

Consultations with various specialists are often essential, including:

– Pediatric gastroenterologists and surgeons

– Ophthalmologists

– Cardiologists

– Developmental/behavioral pediatricians

– Occupational, physical, and speech/language therapists

– Audiologists

– Child psychologists and psychiatrists

– Pediatric otorhinolaryngologists

– Facial and plastic reconstructive surgeons

– Pediatric urologists

Prenatal diagnosis of Smith-Lemli-Opitz syndrome can be suspected through fetal ultrasonography and confirmed by analyzing amniotic fluid or chorionic villous samples, measuring 7DHC content, and conducting mutation analysis if DHCR7 mutations are known in the family.

Potential Health Challenges in Smith-Lemli-Opitz Syndrome

What are the various complications associated with Smith-Lemli-Opitz syndrome, and how can they impact the body?

Smith-Lemli-Opitz syndrome can lead to numerous complications, as cholesterol is essential for the normal functioning of every cell in the body. Consequently, the cholesterol deficiency seen in patients with this syndrome can potentially affect every organ system.

The most severely affected individuals with Smith-Lemli-Opitz syndrome often experience fatal outcomes either through spontaneous abortion or neonatal death, even with extensive medical intervention.

Commonly, those with the condition present with multiple congenital anomalies. Life-threatening conditions such as congenital heart disease and brain malformations are common. For those who survive, there may be ongoing health challenges including renal disease, adrenal insufficiency, seizures, growth failure, and liver dysfunction.

Outlook for Individuals with Smith-Lemli-Opitz Syndrome

What factors influence the prognosis of Smith-Lemli-Opitz syndrome, and what are the potential outcomes for affected individuals?

The outlook for individuals with Smith-Lemli-Opitz syndrome varies depending on the disease’s severity and the presence of associated malformations. Life-threatening complications can arise from heart disease and brain abnormalities. However, some individuals with the condition do reach adulthood. Those with milder forms of the syndrome may have the capacity to live and work in supervised group home environments.

The survival rate tends to be lower for those with plasma cholesterol levels below approximately 20 mg/dL, as determined by gas chromatography measurements.

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