Coloboma, Congenital Heart Disease, Ichthyosiform Dermatosis, Mental Retardation, And Ear Anomalies Syndrome

A number sign (#) is used with this entry because of evidence that CHIME syndrome, also known as Zunich neuroectodermal syndrome, is caused by compound heterozygous mutation in the PIGL gene (605947) on chromosome 17p11.

Description

Zunich neuroectodermal syndrome is an extremely rare autosomal recessive multisystem disorder clinically characterized by colobomas, congenital heart defects, migratory ichthyosiform dermatosis, mental retardation, and ear anomalies (CHIME). Other clinical features include distinctive facial features, abnormal growth, genitourinary abnormalities, seizures, and feeding difficulties (summary by Ng et al., 2012). The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis.

For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).

Clinical Features

Zunich and Kaye (1983, 1984) and Zunich et al. (1985) described 2 unrelated children with a seemingly distinct neuroectodermal syndrome characterized by early-onset migratory ichthyosiform dermatosis, bilateral ocular coloboma, conductive hearing loss, seizures, mental retardation, and remarkably similar facial features. The male patient had cleft palate, and the female patient had tetralogy of Fallot. Zunich et al. (1988) reported that the male patient had a brother born with similar features. Bifid uvula and submucous cleft were present. Transposition of the great vessels was found on cardiac catheterization. Retinal colobomas were present bilaterally on ophthalmologic evaluation, and hearing loss was detected by auditory evoked responses. The skin changes were less severe than in the other 2 patients. Zunich et al. (1988) referred to a fourth patient, an Amish male infant, with similar features.

Shashi et al. (1995) reported a fifth case of the Zunich neuroectodermal syndrome. They suggested the disorder be called CHIME syndrome (for oculo colobomas, congenital heart disease, early-onset ichthyosiform dermatosis, mental retardation and ear anomalies (conductive hearing loss)). Alternatively, the 'E' could stand for seizures (epilepsy). Shashi et al. (1995) stated that ichthyosis and neurologic abnormalities, including seizures and mental retardation, have been described in several genetic syndromes, including Ruds syndrome (308200), Refsum disease (266500), Sjogren-Larsson syndrome (270200), Netherton syndrome (256500), the keratitis, ichthyosis, and deafness (KID) syndrome (148210), and the ichthyosis, brittle hair, impaired intelligence, decreased fertility, and short stature (IBIDS) syndrome (601675). Although there is some overlap in the clinical features, certain characteristics help to distinguish one disorder from another.

Tinschert et al. (1996) reported a 21-month-old girl with symptoms consistent with the Zunich neuroectodermal syndrome. She had characteristic craniofacial dysmorphism, bilateral colobomas of the retina, sparse and fine hair, hearing loss, ichthyosiform erythroderma, mental retardation, ear anomalies, brachydactyly, and broad second toes. Hair, skin, and nail abnormalities were consistent with an ectodermal dysplasia syndrome.

Schnur et al. (1997) reported a child with this syndrome who developed acute lymphoblastic leukemia at age 4.5 years. Her major problems included a migratory ichthyosiform dermatosis, multiple skin infections and infestations, bilateral retinal coloboma, developmental delay, seizures, infantile macrosomia, facial anomalies, a duplicated renal collecting system, and conductive hearing loss.

Molecular Genetics

In 6 unrelated individuals with Zunich neuroectodermal syndrome, Ng et al. (2012) identified compound heterozygosity for 2 mutations in the PIGL gene. All patients carried a founder missense mutation on 1 allele (L167P; 605947.0001). Five patients carried a truncating mutation in the PIGL gene on the other allele (605947.0002-605947.0004), whereas the sixth patient had a 1-Mb deletion of chromosome 17p12-p11.2 including the PIGL gene on the other allele. All of the patients had previously been reported (see, e.g., Zunich and Kaye (1983, 1984); Zunich et al., 1985; Zunich et al., 1988; Schnur et al., 1997; Shashi et al., 1995, and Tinschert et al., 1996). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Cell lines derived from 2 patients showed deficiency of 2 GPI anchor markers, including CD59 (107271), confirming that the disorder is due to a defect in PIGL. Ng et al. (2012) noted that GPI anchor deficiencies cause remarkable clinical diversity.