Definition: Smith-Lemli-Opitz syndrome (SLO) is characterised by pre- and postnatal growth retardation and microcephaly, severe mental retardation, facial dysmorphic features, hypospadias and syndactyly between toes 2 and 3.

SLO results from cholesterol metabolic impairment with mutation of the 7-dehydro-cholesterol reductase gene (DHCR7, chromosome 11q12-q13).

SLOS patients have decreased cholesterol and increased 7-dehydrocholesterol (7-DHC) levels.

Dietary cholesterol supplementation improves systemic biochemical abnormalities; however, because of the blood-brain barrier, the central nervous system (CNS) is not treated. Simvastatin therapy has been proposed as a means to treat the CNS.

Synopsis

 systemic anomalies

• short stature
• developmental delay
• intrauterine growth retardation (IUGR)
• postnatal growth retardation
• birth weight <2500gm
• failure to thrive
• decreased fetal movement
• breech presentation

 craniofacial anomalies

• microcephaly
• micrognathia
• bitemporal narrowing
• low-set ears
• posteriorly rotated ears
• facial anomalies
• ptosis of eyelids
• inner epicanthal folds
• cataracts
• hypertelorism
• strabismus
• anteverted nares
• broad, flat nasal bridge
• cleft palate (2729358)
• hypoplastic tongue
• broad alveolar margins
• large central front teeth
• dental crowding

 cardiovascular anomalies (12797454)

• ventricular septal defect
• atrial septal defect
• atrioventricular canal defect (AVCD) (12797454)
• anomalous pulmonary venous return (12797454, 2729358)
• coarctation of aorta
• patent ductus arteriosus

 pulmonary anomalies

• hypoplastic lungs
• incomplete lobulation of the lungs

 gastrointestinal anomalies

• digestive malrotation
• pyloric stenosis
• digestive aganglionosis (Hirschsprung disease) (14556255)

 atypical mononuclear giant cells in pancreatic islets

 genital anomalies

• 46,XY intersex (2729358)
  • male pseudohermaphroditism (2729358)
  • perineoscrotal hypospadias
  • ambiguous genitalia (2729358)
  • micropenis
  • hypoplastic scrotum
  • bifid scrotum
  • microurethra
  • cryptorchidism (2729358)
  • cone-shaped cervix (2729358)
  • female external genitalia with testis palpable in each labium majus (2729358)

 urinary anomalies

• renal agenesis (renal aplasia) (12833423)
• renal hypoplasia
• hydronephrosis
• single kidney
• cystic kidneys (cystic renal disease)
• ureteropelvic junction obstruction
• ureteral anomalies

 limb anomalies

• stippled epiphyses
• hip dislocation
• hip subluxation
• limb deficiency (2729358)
  • limb shortening (mesomelic limb shortness) (9475598)
  • short thumbs
  • ectrodactyly (9475598, 2729358)
  • radial aplasia (2729358)
  • monodactyly of the upper limb) (2729358)

• postaxial polydactyly
• hand syndactyly
• proximally placed thumbs
• syndactyly of second and third toes
• talipes calcaneovalgus
• short, broad toes
• overriding toes
• metatarsus adductus

 cutaneous anomalies

• severe photosensitivity
• eczema
• facial capillary hemangioma
• blonde hair

 central nervous system

• hydrocephalus (dilated ventricles)
• microcephaly
• frontal lobe hypoplasia
• cerebellar hypoplasia
• brainstem hypoplasia
• gray matter periventricular heterotopia
• irregular gyral pattern
• irregular neuronal organization
• anomalies of spinal cord development

Biology

 low cholesterol
 elevated 7-dehydrocholesterol

Phenotypic variants

 lethal form of SLOS: Rutledge multiple congenital anomaly syndrome (RMCAS) (SLO2) (Ex-MIM.268670) (12717589)

Etiology

Smith-Lemli-Opitz syndrome is a autosomal recessive malformative syndrome caused by mutations in the sterol delta-7-reductase gene (DHCR7) (MIM.602858), which maps to 11q12-q13.

 mutations in the gene DHCR7 encoding sterol delta-7-reductase at 11q12-q13 (MIM.602858)

See also

 defect of cholesterol biosynthesis

Reviews

 Jira PE, Waterham HR, Wanders RJ, Smeitink JA, Sengers RC, Wevers RA. Smith-Lemli-Opitz syndrome and the DHCR7 gene. Ann Hum Genet. 2003 May;67(Pt 3):269-80. PMID: 12914579

 Herman GE. Disorders of cholesterol biosynthesis : prototypic metabolic malformation syndromes. Hum Mol Genet. 2003 Apr 2 ;12(Suppl 1) :R75-88. PMID : 12668600

 Farese RV Jr, Herz J. Cholesterol metabolism and embryogenesis. Trends Genet. 1998 Mar ;14(3):115-20. PMID : 9540409

 Smith, D. W.; Lemli, L.; Opitz, J. M. : A newly recognized syndrome of multiple congenital anomalies. J. Pediat. 64: 210-217, 1964. PubMed ID : 14119520

 Waterham HR, Wanders RJ. Biochemical and genetic aspects of 7-dehydrocholesterol reductase and Smith-Lemli-Opitz syndrome. Biochim Biophys Acta. 2000 Dec 15;1529(1-3):340-56. PMID: 11111101

 Battaile KP, Steiner RD. Smith-Lemli-Opitz syndrome: the first malformation syndrome associated with defective cholesterol synthesis.Mol Genet Metab. 2000 Sep-Oct;71(1-2):154-62. PMID: 11001806

References

 Digilio MC, Marino B, Giannotti A, Dallapiccola B, Opitz JM. Specific congenital heart defects in RSH/Smith-Lemli-Opitz syndrome: postulated involvement of the sonic hedgehog pathway in syndromes with postaxial polydactyly or heterotaxia. Birth Defects Res A Clin Mol Teratol. 2003 Mar;67(3):149-53. PMID: 12797454

 Singer LP, Marion RW, Li JK. Limb deficiency in an infant with Smith-Lemli-Opitz syndrome. Am J Med Genet. 1989 Mar;32(3):380-3. PMID: 2729358