Smith-Lemli-Opitz Syndrome

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In 1964, Smith, Lemli, and Opitz reported three patients with a common distinctive facial appearance, microcephaly, broad alveolar ridges, hypospadias, a characteristic dermatoglyphics pattern, severe feeding disorder, and global developmental delay. The incidence of the Smith-Lemli-Opitz syndrome is esti- mated to be approximately 1 in 10,000 to 1 in 40,000 births based on clinical diagnosis and 1 in 60,000 to 1 in 100,000 births based on biochemical testing. There appears to be strik- ingly different incidences among various ethnic groups.

GENETICS/BASIC DEFECTS

1. Inheritance: autosomal recessive 2. Basic defect

a. Caused by a defect of cholesterol biosynthesis b. Underlying biochemical defect: deficiency of 7-

dehydrocholesterol reductase (DHCR7), an enzyme catalyzing the last step of the Kandutsch-Russell cholesterol biosynthesis pathway, resulting in generalized cholesterol deficiency

c. Mutations of DHCR7 gene lead to deficient activity of 7-dehydrocholesterol reductase (DHCR7), the final enzyme of the cholesterol biosynthesis pathway.

Functional null alleles of the DHCR7 locus results in lethal form of Smith-Lemli-Opitz syndrome.

d. Human DHCR7 gene has been cloned and localized to 11q12-13.

e. An example of metabolic deficiency as a cause of a dysmorphic syndrome

3. Clues pointing to an underlying biochemical defect of cholesterol metabolism

a. Holoprosencephaly, microcephaly, pituitary agenesis, limb defects, and genital anomalies produced by in utero exposure of rat and mouse pups to chemical inhibitors of the cholesterol biosynthetic pathway b. Large adrenal glands with complete absence of lipid

in adrenal cortex of patients with Smith-Lemli-Opitz syndrome

c. Abnormalities of the pituitary-adrenal axis

d. Suppressed fetal estriol production in pregnancies affected with Smith-Lemli-Opitz syndrome

e. Neonatal liver disease in severe Smith-Lemli-Opitz syndrome associated with low serum cholesterol level

f. Male pseudohermaphroditism not caused by dihy- drotestosterone receptor defects

g. Observation of two patients with Smith-Lemli-Opitz syndrome with low plasma cholesterol and elevated levels of 7-dehydrocholesterol (7DHC), the immedi- ate precursor of cholesterol in the Kandutsch-Russell biosynthetic pathway, suggesting that this multiple malformation was caused by a simple Garrodian enzymatic defect

4. Rutledge multiple congenital anomaly syndrome

a. Considered a variant of Smith-Lemli-Opitz syndrome b. Biochemical abnormality of excess 7-dehydrocholesterol

and low cholesterol identified in the liver tissue 5. Five additional related human syndromes resulting from

impaired cholesterol synthesis a. Desmosterolosis

i. Report of a female infant with a lethal syndrome of macrocephaly, thick alveolar ridges, gingival nod- ules, cleft palate, total anomalous pulmonary venous drainage, ambiguous genitalia, short limbs, and generalized osteosclerosis was found to have markedly increased tissue levels of desmosterol ii. Another report of a child with microcephaly, short

stature, and delays in speech and psychomotor development was found to have an increased plasma level of desmosterol and markedly increased levels of desmosterol in cultured lymphoblasts b. X-linked dominant chondrodysplasia punctata type 2

(CDPX2) (Conradi-Hünermann syndrome)

i. Typically in females with a variable combination of bilateral and asymmetric shortening of long bones, punctate calcification of epiphyses, tra- chea, and larynx, segmental cataracts, and patches of ichthyotic skin that typically follow the lines of Blaschko

ii. Caused by function-impairing mutations in the sterol-Δ⁸-isomerase gene, which maps to Xp11.2-3 iii. Lethal to males early in gestation

c. CHILD syndrome (congenital hemidysplasia with ichthyosiform erythroderma/nevus and limb defects)

i. X-linked dominant inheritance

ii. Cutaneous and bony abnormalities similar to CDPX2

iii. Report of a patient with classic CHILD syndrome a) Manifests the characteristic sterol abnormal-

ity of CDPX2

b) Carries a mutation creating a stop codon in the same sterol-Δ⁸-isomerase associated with CDPX2

d. Greenberg dysplasia (hydrops-ectopic calcification- moth-eaten skeletal dysplasia)

i. Autosomal recessive inheritance

ii. A lethal skeletal dysplasia characterized by hydrops fetalis, short-limbed dwarfism, postaxial polydactyly, and abnormal chondro-osseous mineralization

iii. Radiologic abnormalities

a) Moth-eaten appearing long bones b) Ectopic epiphyseal calcification c) Laryngeal and tracheal calcification d) Platyspondyly

iv. Steroid-Δ¹⁴-reductase deficiency 907

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e. Antley-Bixler syndrome

i. A skeletal abnormality syndrome primarily affecting head and limbs

ii. Also known as multi-synostotic osteodysgenesis with long bone fractures

iii. A high incidence of genital ambiguity, an anom- aly unlikely due to the FGFR2 mutation, sug- gesting possible disordered steroidogenesis in early pregnancy

iv. Elevated two primary precursors of steroid hor- mones, pregnenolone and progesterone, as are the classical diagnostic metabolites for 17- and 21-hydroxylase deficiencies, suggesting attenu- ated steroid hydroxylation (including 17,20- lyase activity) at least in the form not associated with FGFR2 mutations

CLINICAL FEATURES

1. General

a. Postnatal growth retardation b. Failure to thrive

c. Feeding difficulties requiring gavage feeding in many cases

d. Abnormal intestinal motility i. Pyloric stenosis ii. Vomiting

iii. Gastoresophageal reflux e. Feeding intolerance

f. Gastrointestinal irritability g. Allergy

h. Initial hypotonia/later hypertonia i. Recurrent otitis media and pneumonias j. Photosensitivity

k. Adrenal insufficiency uncommon 2. Craniofacial features

a. Congenital microcephaly: very common b. Bitemporal narrowing

c. Capillary hemangioma over the glabella d. Eyes

i. Epicanthal folds

ii. Ptosis (more than 50% of patients, often with asymmetrical or unilateral ptosis)

iii. Congenital cataracts iv. Optic nerve hypoplasia

e. Broad nasal bridge and short nasal root with antevert- ed nares

f. Micrognathia g. Oral

i. Cleft lip/palate

ii. High-arched/narrow hard palate iii. Broad/ridged alveolar ridges

iv. Redundant sublingual tissues v. Long philtrum

h. Low-set and posteriorly rotated ears 3. CNS anomalies

a. Global psychomotor retardation

b. Microcephaly (almost universal finding) c. Agenesis/hypoplasia of corpus callosum d. Cellebellar hypoplasia

e. Enlarged ventricles

f. Decreased size of frontal lobes g. Pituitary lipoma

h. Cerebellar hypoplasia with hypoplasia or aplasia of the vermis

i. Holoprosencephaly sequence (5% of cases) j. Seizures

4. Limb anomalies

a. Bilateral or unilateral postaxial polydactyly in the hands or feet

b. Short/proximally placed thumb c. Short first metacarpals

d. Hypoplastic thenar eminences

e. Subtle ‘Zigzag’ alignment of the phalanges of the index finger

f. Characteristic Y-shaped cutaneous syndactyly of the 2nd–3rd toes

5. Genital anomalies

a. Male (range from normal to the appearance of complete sex reversal)

i. External genitalia: normal, hypospadias, female appearing, or ambiguous

ii. Internal genitalia: gonads varying from normal testes to ovotestes to normal ovaries or missing gonads; sex reversal including blind vaginal pouch and rudimentary or bicornuate uterus

b. Female

i. Hypoplasia of labia minora ii. Hypoplasia of labia majora

6. Congenital heart defects (about 50% of cases) a. Endocardial cushion defect (AV canal) b. Septal defect

c. Hypoplastic left heart syndrome d. Patent ductus arteriosus

e. Aortic coarctation

f. Anomalous pulmonary venous return g. Hypertrophic cardiomyopathy 7. Renal anomalies (about 25% of cases)

a. Renal hypoplasia/aplasia with oligohydramnios sequence

b. Horseshoe kidney c. Renal cortical cysts d. Hydronephrosis e. Renal ectopia

f. Ureteral duplication g. Fetal lobation

h. Hypoplastic bladder and ureters 8. Adrenal anomalies

a. Adrenal hyperplasia b. Adrenal hypoplasia 9. Respiratory tract anomalies

a. Laryngomalacia b. Tracheomalacia c. Sleep apnea

d. Abnormal pulmonary lobation e. Pulmonary hypoplasia 10. Gastrointestinal/hepatic anomalies

a. Pyloric stenosis (prominent clinical problem) b. Hirschsprung disease

c. Cholestatic liver disease

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11. Behavioral disorders

a. Hypersensitivity with tactile defensiveness (oral, hands, and feet)

b. Unusual hyperresponsivity to auditory and visual stimuli

c. Aggressiveness and self-injury d. Severe sleep disturbance e. Autistic behavior 12. Prognosis

a. Many survive to adulthood.

b. Many affected children died in the first year from failure to thrive and infections.

13. So-called Smith-Lemli-Opitz syndrome type II, a lethal syndrome resembling the original Smith-Lemli-Opitz syndrome

a. Autosomal recessive disorder

b. Lethal in the newborn period from internal malformations

c. Most 46,XY “males” with severe hypogenitalism or female appearing external genitalia

d. Same sterol pattern in most patients

e. Differences in severity between type I and type II Smith-Lemli-Opitz syndrome: due to severity of the mutations according to subsequent molecular genetic studies

f. Possibility of genetic heterogeneity of the Smith- Lemli-Opitz syndrome

14. Clinical criteria for the revised severity score (revised Bialer score) by Kelly and Hennekam (2000). The severity score is obtained based on categories of cerebral, ocular, oral, skeletal, and genital defects identified.

Based on the severity score, Smith-Lemli-Opitz syndrome phenotype can be divided into three categories:

mild (<20), classical (20–50), and severe (>50). Severity score can be correlated with biochemical parameters and provides a basis for establishing a genotype-phenotype correlation

a. Brain

i. Score 1: Seizures; qualitative MRI abnormality ii. Score 2: Major CNS malformations; gyral

defects b. Oral

i. Score 1: Bifid uvula or submucous cleft ii. Score 2: Cleft hard palate or median cleft lip c. Acral

i. Score 0: Non-Y-shaped minimal toe syndactyly ii. Score 1: Y-shaped 2–3 toe syndactyly; club foot;

upper or lower polydactyly; other syndactyly iii. Score 2: Any two of the above

d. Eye

i. Score 2: Cataract; frank microphthalmia e. Heart

i. Score 0: Functional defects

ii. Score 1: Single chamber or vessel defects iii. Score 2: Complex cardiac malformation f. Kidney

i. Score 0: Functional defect

ii. Score 1: Simple cystic kidney disease

iii. Score 2: Renal agenesis; clinically important cystic disease

g. Liver

i. Score 0: Induced hepatic abnormality ii. Score 1: Simple structural abnormality iii. Score 2: Progressive liver disease h. Lung

i. Score 0: Functional pulmonary disease

ii. Score 1: Abnormal lobation; pulmonary hypoplasia iii. Score 2: Pulmonary cysts; other major malfor-

mations i. Bowel

i. Score 0: Functional GI disease ii. Score 1: Pyloric stenosis iii. Hirschsprung disease j. Genitalia

i. Score 1: Simple hypospadias

ii. Score 2: Ambiguous or female genitalia in a 46,XY; frank genital malformation in a 46,XX

DIAGNOSTIC INVESTIGATIONS

1. Diagnostic biochemical hallmarks of the syndrome a. Low serum cholesterol levels (10% of patients with

DHCR7 deficiency have normal levels of cholesterol) b. Markedly elevated serum levels of 7-dehydrocholesterol (cholesta-5,7-dien-3beta-ol; 7DHC), precursor of cholesterol

2. DHCR7 enzyme assay

3. Analysis of sterol biosynthesis in cultured cells

4. DHCR7 mutation testing: Seven most frequent mutations described to date, representing two thirds of the mutation in analyzed alleles

a. IVS8-1G>C (31.5%) b. T93M (11.2%) c. R404C (10.7%) d. W151X (6.4%) e. V326L (6.3%)

f. R352W (3.2%) g. E448K (3.2%)

GENETIC COUNSELING

1. Recurrence risk a. Patient’s sibs: 25%

b. Patient’s offspring: not increased 2. Prenatal diagnosis

a. Prenatal screening as part of routine triple marker screen for Down syndrome and neural tube defects:

abnormally low maternal serum level of unconjugated estriol observed in pregnancies affected with Smith- Lemli-Opitz syndrome

b. Second trimester ultrasonography i. Nuchal edema

ii. Renal malformation iii. Polydactyly

iv. Ambiguous genitalia v. Cerebral malformation vi. Cardiac malformation

vii. Intrauterine growth retardation c. Amniocentesis or CVS

i. Increased levels of 7DHC in amniotic fluid (typically a more than 500-fold increase in affected pregnancies)

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ii. Relative increase in 7DHC/total sterol ratio in fetal tissues obtained by chorionic villus sam- pling at 11–12 weeks of gestation

iii. Direct DNA mutation analyses for known parental mutations

3. Management

a. Therapeutic trials using dietary supplementation of cholesterol

i. Used to treat complications related to the biochemical disturbance. Clinical benefits of this therapy are limited by presence of developmental problems.

ii. Currently most patients being treated with phar- maceutical-grade cholesterol suspended in either soybean oil or Ora Plus syrup or alternatively with egg yolks

iii. Multiple benefits of dietary cholesterol supplementation

a) Improved nutrition and growth b) Decreased irritability

c) Increased alertness d) Increased sociability

e) Decreased self-abusive and aggressive behavior

f) Decreased tactile defensiveness g) Decreased photosensitivity h) Decreased infections

i) Improved hearing

j) Improved muscle tone and strength iv. Use of bile acids shown no clear benefit b. An alternative therapeutic strategy of treating with

Simvastatin (an oral HMG-CoA reductase inhibitor) for a median period of 2 years with impressive over- all biochemical effect

i. A decrease of 7DHC and 8DHC ii. An increase of cholesterol iii. Promising clinical improvement

c. Fresh frozen plasma, which contains cholesterol rich lipoproteins, used to provide cholesterol supplementation in very sick patients and the fetuses

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Fig. 1. An infant with Smith-Lemli-Opitz syndrome showing failure to thrive, ptosis, cleft palate, thick alveolar ridge, upturned nares, micrognathia, transverse palmar crease, and syndactyly between the second and third toes.

Fig. 2. A boy with Smith-Lemli-Opitz syndrome showing characteris- tic facial features (epicanthal folds, ptosis of the eyelids, broad nose with upturned nares, thick alveolar ridges, ambiguous genitalia (hypospadias), umbilical hernia, transverse palmar crease, and talipes equinovarus.