Smith-Lemli-Opitz syndrome

Page most recently updated 7 September 2026

This page focuses on the reported psychiatric associations, which may be the initial presenting manifestation, and on other clinical features that may assist the psychiatrist or primary care physician in identifying the underlying diagnosis, considered through the lenses of the diagnostic lenses framework.

Smith-Lemli-Opitz syndrome is a rare genetic disorder caused by impaired cholesterol synthesis due to deficiency of 7-dehydrocholesterol reductase, resulting from pathogenic variants affecting both copies of the relevant gene. It is inherited in an autosomal recessive manner, so absence of a relevant family history does not exclude the diagnosis. The clinical spectrum is broad, ranging from severe congenital malformations and intellectual disability to milder presentations with relatively preserved cognition. A distinctive presentation may include the combination of 2nd–3rd toe syndactyly, characteristic facial features, and — in males — hypospadias and cryptorchidism.

It can present with psychiatric features such as autism spectrum disorder (ASD), stereotypic behaviors, sensory hyperreactivity, irritability, sleep disturbance, self-injurious behavior, and behavioral dysregulation. Social and communication difficulties are also common, and depression and other psychiatric disorders have been reported in older individuals. Cognitive impairment and developmental delay are common, although intellectual function ranges from normal or borderline to severe intellectual disability, particularly across the broad clinical spectrum.

From a morphologic lens perspective, other features include (but are not limited to):

  • Microcephaly

  • Micrognathia

  • Epicanthus

  • Ptosis

  • Low-set ears

  • Submucous cleft palate

  • Polydactyly

  • Syndactyly (2nd and 3rd toes)

  • Single transverse palmar crease

Other characteristic features include hypotonia, growth restriction, and multisystem congenital abnormalities. Neurologic manifestations may include seizures/epilepsy, abnormal myelination, and structural brain abnormalities, including abnormalities of the corpus callosum and cerebellum. Ophthalmologic abnormalities may include cataracts, ptosis, and strabismus, while photosensitivity may also occur. Additional reported features include congenital heart defects, renal abnormalities, respiratory abnormalities and recurrent respiratory infections, gastrointestinal and feeding difficulties, constipation, gastroesophageal reflux, dental abnormalities, and genital abnormalities, particularly hypospadias and cryptorchidism in males.

Early diagnosis is important to identify and monitor potentially serious neurologic, cardiac, renal, gastrointestinal, ophthalmologic, and developmental complications, recognize neuropsychiatric needs early, and institute tailored multidisciplinary surveillance and treatment. Diagnosis is particularly important because it can be confirmed by demonstrating elevated levels of 7-dehydrocholesterol and/or identifying disease-causing variants affecting both copies of the relevant gene, while cholesterol levels themselves may occasionally be normal.

Selected references and further reading — Morphologic lens

Jones KL, Jones MC, del Campo M. Smith's recognizable patterns of human malformation. 8th ed. Philadelphia: Elsevier; 2021.

Reardon W. The bedside dysmorphologist: a guide to identifying and assessing congenital malformations. 2nd ed. Oxford: Oxford University Press; 2016.

Allanson JE, Biesecker LG, Carey JC, Hennekam RCM. Elements of morphology: introduction. Am J Med Genet A. 2009;149A(1):2-5. doi:10.1002/ajmg.a.32601.

Hennekam RCM, Biesecker LG, Allanson JE, Hall JG, Opitz JM, Temple IK, Carey JC; Elements of Morphology Consortium. Elements of morphology: general terms for congenital anomalies. Am J Med Genet A. 2013;161A(11):2726-2733. doi:10.1002/ajmg.a.36249.