Fisiopatologia De Smith Thier Apr 2026

The Pathophysiology of Smith-Lemli-Opitz Syndrome: From Cholesterol Deficiency to Clinical Dysmorphology

| System | Pathophysiology | Clinical Manifestation | | :--- | :--- | :--- | | | Shh deficiency → abnormal ventral patterning; cholesterol lack → poor myelination. | Microcephaly, agenesis of corpus callosum, cerebellar hypoplasia, intellectual disability, autism, self-injurious behavior. | | Craniofacial | Shh deficiency → impaired midline fusion. | Broad nasal tip, ptosis, micrognathia, cleft palate, bifid uvula. | | Limb | Aberrant Shh gradient in zone of polarizing activity (ZPA). | 2-3 toe syndactyly (pathognomonic), postaxial polydactyly, short thumbs. | | Gastrointestinal | Lack of cholesterol → smooth muscle dysmotility; Shh deficiency → abnormal gut looping. | Severe gastroesophageal reflux, pyloric stenosis, Hirschsprung disease (5-7% of cases). | | Genitourinary | Impaired androgen synthesis (cholesterol precursor for all steroids). | Hypospadias, cryptorchidism, ambiguous genitalia in 46,XY males; uterus didelphys in females. | | Skin/Adnexa | Abnormal sterol composition in keratinocyte membranes. | Photosensitivity (due to 7-DHC accumulation), dry skin, syndactyly of toes. | Fisiopatologia De Smith Thier

Cholesterol is not merely a structural lipid; it is a critical and a morphogen . Its deficiency explains the majority of the syndromic features. | Broad nasal tip, ptosis, micrognathia, cleft palate,