CHIME syndrome is a rare autosomal recessive neuroectodermal syndrome recently identified as a disorder of glycosylation secondary to mutations in PIGL (Ng et al, Am J Hum Genet 90:685-688, 2012).  Also known as Zunich Neuroectodermal syndrome, CHIME syndrome was initially reported in 1983 (Zunich and Kaye, Am J Med Genet 15:331-333, 1983) and is characterized by Coloboma, Heart defects, Ichthyosiform dermatosis, Mental retardation and Ear anomalies with hearing loss. Subsequent case reports established genitourinary malformations as a cardinal feature.

The ichthyosiform dermatosis is migratory and present at birth or within the first 4-6 weeks. Biopsies of affected areas show disordered keratinization, deep rete pegs in the dermis and demyelination in the deep dermis which, once the rash moves elsewhere, become normal. Nearly all affected individuals have bilateral retinal coloboma with less frequent ophthalmologic abnormalities including myopia, hyperopia, ptosis, heterochromia irides, corneal clouding, and strabismus. Significant desquamation of the auditory canal appears to be the cause of mild to moderate conductive hearing loss in all cases.

By age 1, nearly all will develop seizures which are difficult to control and exacerbated by fever and high environmental temperatures. Moderate to severe psychomotor retardation and especially speech delay are common as are behavior problems, including autistic mannerisms and violent behavior towards oneself and others which worsens after puberty and correlates with the degree of discomfort resulting from the rash. Wide-based gait has been reported in all cases and hypotonia in some.

Congenital heart defects are reported in 70% (tetralogy, transposition, VSD, peripheral pulmonic stenosis, subaortic stenosis, and dilated aortic root) and genitourinary malformations in all cases (hydronephrosis, renal agenesis, duplication of the collecting system, bicornuate uterus, and cryptorchidism). Brachydactyly, clinodactyly and deviation of fingers and toes are frequent with less common skeletal anomalies including pectus, club foot and joint contractures. Broad second toe has been noted in 70%, resulting from soft tissue enlargement and not some bony abnormality. Additional complications include feeding difficulties, both swallowing and chewing solids, reflux, and recurrent respiratory infections.

Slightly less than half of cases have had birth weights and lengths greater than the 90th percentile. Though head circumference is normal at birth, microcephaly is usually present before age 1. Characteristic facial features include brachycephaly; fine, sparse hair; hypertelorism; epicanthal folds; small, low set or cupped ears; flat, broad nasal root and tip; short philtrum; and wide mouth with full lips. Teeth are small and irregularly shaped with increased spacing. Cleft palate and bifid uvula have been reported.

Of six CHIME cases studies by Ng, all demonstrated the missense mutation c.500T>C which may represent a founder mutation. The other mutations identified included frameshift, nonsense, essential splice site and entire gene deletions, all of which are predicted to be highly damaging. Mutation analysis of PIGL is now available at the University of Chicago Genetic Services Laboratory. It will be interesting to see if other cases also have the c.500T>C mutation present.