Holoprosencephaly 9

A number sign (#) is used with this entry because of evidence that holoprosencephaly-9 (HPE9) is caused by heterozygous mutation in the GLI2 gene (165230) on chromosome 2q14.

Mutation in the GLI2 gene can also cause Culler-Jones syndrome (CJS; 615849), which is a less severe disorder.

Description

Holoprosencephaly-9 refers to a disorder characterized by a wide phenotypic spectrum of brain developmental defects, with or without overt forebrain cleavage abnormalities. It usually includes midline craniofacial anomalies involving the first branchial arch and/or orbits, pituitary hypoplasia with panhypopituitarism, and postaxial polydactyly. The disorder shows incomplete penetrance and variable expressivity (summary by Roessler et al., 2003 and Bertolacini et al., 2012).

For general phenotypic information and a discussion of genetic heterogeneity of holoprosencephaly, see HPE1 (236100).

Clinical Features

Roessler et al. (2003) reported affected members of 2 families with a distinctive phenotype (within the HPE spectrum) whose primary features included defective anterior pituitary formation and panhypopituitarism, with or without overt forebrain cleavage abnormalities, and HPE-like midfacial hypoplasia, In 1 family, the disorder was transmitted through unaffected mutation carriers. A deceased male in the first generation was reported to have had cleft lip and palate in addition to polydactyly. The proband in the fourth generation had midface hypoplasia, repaired cleft lip and palate, postaxial polydactyly, and absent pituitary on MRI associated with panhypopituitarism. Male twin brothers of the female proband had panhypopituitarism. One died at age 5 months with midline cleft lip and palate, hypotelorism, flat midface, absent pituitary, and partial agenesis of the corpus callosum. The father and paternal aunt of the proband (in the third generation) carried the mutation and had normal intelligence and postaxial polydactyly that may represent a microform. In the other family, the proband had bilateral cleft lip and palate, microcephaly, hypotelorism, single central incisor, postaxial hexadactyly, growth hormone deficiency associated with pituitary hypoplasia, and no other obvious forebrain anomalies. The proband's sister, whose DNA was unavailable for analysis, was found at autopsy to have hypotelorism, single nostril, hypoplastic palate and maxilla, normal digits, absent anterior lobe of the pituitary, alobar HPE, and hydrocephalus.

Rahimov et al. (2006) reported 4 Brazilian patients with GLI2 mutations and a wide phenotypic spectrum. Two girls had lobar HPE and HPE-like phenotype, respectively, but lacked pituitary involvement or polydactyly. Another patient had anophthalmia, branchial arch anomalies, and CNS abnormalities, including asymmetric ventricles, right hemisphere migration defects, and abnormal cerebellar foliation. The fourth patient had heminasal aplasia and orbital anomalies.

Ribeiro et al. (2005) described a Brazilian male infant with macrocephaly, widened cranial sutures, large forehead, hypotelorism, microphthalmia, flat nasal bridge, midline cleft lip/palate, right microtia with meatal atresia and left preauricular skin tag, short and large neck, and mesocardiac systolic/diastolic heart murmur. X-ray examination showed vertebral developmental defects, and echocardiography revealed dextroposition of the aortic arch, ventricular septal defect, patent foramen ovale, and pulmonic stenosis. CT scan showed microphthalmia with colobomatous eyes and semilobar holoprosencephaly. Chromosomal analysis was normal, and no mutations were found in the SHH (600725), TGIF (602630), or SIX3 (603714) genes. Ribeiro et al. (2005) stated that this patient had the same syndrome as that previously reported by Guion-Almeida et al. (1999), who described a Brazilian female infant with holoprosencephaly, bilateral clinical anophthalmia, and agenesis of the eye globes and optic nerves. She presented with severe respiratory distress at birth, required resuscitation, and subsequently died at 9 days of age. She had microcephaly, sloping forehead, hypotelorism, abnormal nares with septal agenesis, absent columella, midline cleft lip/palate with premaxilla agenesis, bilateral preauricular skin tags, abnormal helix, prominent antihelix, and hypoplastic tragus. CT scan showed alobar holoprosencephaly; autopsy confirmed the CNS involvement and also revealed the additional finding of pulmonary hypoplasia. Ribeiro et al. (2005) also suggested that the holoprosencephaly cases with first arch anomalies (cases 14 and 24) reported by Blaas et al. (2002), the features of which included dysmorphic ears, preauricular tags, thoracic hemivertebrae, tetralogy of Fallot, aortic coarctation, and ventricular septal defect, might represent the same syndrome.

Guion-Almeida et al. (2008) reported 3 unrelated Brazilian patients with holoprosencephaly and variable central nervous system involvement, microphthalmia, and first branchial arch anomalies. All were born of nonconsanguineous parents, and G-banded chromosomes in peripheral lymphocytes were normal in all 3 patients. Genetic analysis excluded mutations in the SHH, TGIF, or SIX3 genes in 1 of the patients. Guion-Almeida et al. (2008) concluded that this syndrome represents a recurrent pattern involving the prosencephalon, first branchial arch, and eye primordium, and stated that mutations in the GLI2 and PTCH (601309) genes could not be ruled out.

Bertolacini et al. (2012) reported 6 unrelated Brazilian patients with variable manifestations of HPE9 resulting from a heterozygous mutation in the GLI2 gene (see, e.g., 165230.0004-165230.0007). The patients were identified from a larger cohort of 110 individuals with diverse craniofacial anomalies who were screened specifically for GLI2 mutations. The phenotype in patients with GLI2 mutations ranged from isolated cleft lip/palate with polydactyly, to branchial arch anomalies, to semilobar holoprosencephaly. Some patients had marked involvement of the temporomandibular joint and derivatives of the first branchial arch. Only 1 patient had neurodevelopmental delay. Three of the mutations were inherited from a mother with very mild manifestations, and 1 mutation occurred de novo.

Molecular Genetics

In affected members of 2 families with HPE9, Roessler et al. (2003) identified heterozygous mutations in the GLI2 gene (165230.0001-165230.0002).

Rahimov et al. (2006) reported 4 patients with GLI2 missense mutations, including 1 girl with an HPE-like phenotype who was double heterozygous for mutations in GLI2 (165230.0003) and PTCH1 (601309.0012).