Summary
Zellweger syndrome is a rare peroxisome biogenesis disorder characterized by dysmorphic craniofacial features, profound hypotonia, seizures, and liver and renal dysfunction. It occurs in between 1 in 50,000 and 100,000 births. Infants with Zellweger syndrome present with flattened facies, large anterior fontanel, split sutures, a prominent high forehead, a flattened occiput, upslanting palpebral fissures, a broad nasal bridge, epicanthal folds, and hypoplastic supraorbital ridges. Macrocephaly or microcephaly, a high-arched palate, protruding tongue or micrognathia, and redundant neck skin folds may be present. Cataracts, glaucoma, pigmentary retinopathy, nystagmus and optic nerve atrophy may be seen. Visual changes and vision loss are progressive. Sensorineural hearing loss may be present. Hepatomegaly, jaundice, pyloric hypertrophy, and severe hydronephrosis are common manifestations. Cryptorchidism and hypospadias in males, and clitoromegaly females, may also occur. Skeletal abnormalities are frequent. Central nervous system function is severely affected (profound muscular hypotonia, hyporeflexia or areflexia, severe intellectual deficit). A genetic defect in the PEX1 gene is the most common cause of Zellweger syndrome but mutations in several different genes (involved in peroxisome biogenesis have also been implicated. Impaired metabolism results in the accumulation of toxic metabolites and damages developing neural cells. The disease is transmitted in an autosomal recessive manner. Zellweger syndrome is often suspected on the basis of clinical findings during physical examination and definitively confirmed with biochemical evaluation. Magnetic resonance imaging can be used as an adjunct method (revealing polymicrogyria). Hydronephrosis may have been suspected on prenatal ultrasounds. The main differential diagnoses include neonatal adrenoleukodystrophy and infantile Refsum's disease; other disorders to be excluded are Usher syndrome, and disorders with severe hypotonia (see these terms). Genetic counseling allows parents to understand the natural history and progression of the disease and to determine the risk for future pregnancies. Prenatal screening for very-long-chain fatty acids (VLCFAs) and plasmalogen synthesis can be performed on cultured amniocytes and chorionic villus sampling in suspected or high-risk pregnancies. Management is supportive and should be multidisciplinary. Most infants with Zellweger syndrome die within the first year of life, secondary to progressive apnea or respiratory compromise related to infection or intractable epilepsy. *Author: Orphanet (January 2008)*.
