Holoprosencephaly 7

A number sign (#) is used with this entry because of evidence that holoprosencephaly-7 (HPE7) is caused by heterozygous mutation in the PTCH1 gene (601309) on chromosome 9q22.

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


Holoprosencephaly (HPE) is the most commonly occurring congenital structural forebrain anomaly in humans. HPE is associated with mental retardation and craniofacial malformations. Considerable heterogeneity in the genetic causes of HPE has been demonstrated (Ming et al., 2002).

Clinical Features

Ming et al. (2002) described 5 probands from 5 families affected with HPE7. One female proband had semilobar HPE, absence of the corpus callosum, and fusion of the thalami. Her brother had a single central maxillary incisor, bilateral cleft lip/palate, and developmental delay. In a second pedigree, a female proband had HPE and partial agenesis of the corpus callosum, panhypopituitarism, midline cleft lip and palate, a small omphalocele, and mild to moderate developmental delay. In the report by Ming et al. (2002), 3 families studied had an asymptomatic parent with normal cognitive function who carried the same mutation as the offspring with holoprosencephaly. Ming et al. (2002) quoted Cohen (1989), who estimated that approximately one-third of obligate carriers of autosomal dominant forms of HPE are asymptomatic with normal cognitive function.

In a 5-year-old Brazilian girl with holoprosencephaly-like phenotype, Rahimov et al. (2006) identified double heterozygosity for a T728M mutation in the PTCH1 gene (601309.0012) and an R151G mutation in the GLI2 gene (165230.0003). Clinical features included large ears, hypoplastic anterior nasal spine, diminished frontonasal angle, hypotelorism, hypoplastic premaxilla, hypoplastic nose with flattened alae and nasal tip, poorly developed philtrum, bilateral cleft lip/palate, malocclusion, and normal neuropsychologic development. MRI demonstrated mild gyral asymmetry in the perisylvian areas.

Ribeiro et al. (2006) described 5 Brazilian probands, 4 with holoprosencephaly and 1 with holoprosencephaly-like facial features with normal MRI. In 2 probands with the same PTCH1 mutation (601309.0015), the phenotypic presentation was different: alobar HPE, absent nasal septum, and midline cleft lip-palate in 1 patient, and lobar HPE, macrocephaly, hypertelorism, clefting of the nose, severe microphthalmia, and a single maxillary central incisor in the other.

Derwinska et al. (2009) reported a mother and son with microcephaly and mild developmental delay and a 364-kb duplication encompassing the entire PTCH1 gene on chromosome 9q22.32. The 21-month-old boy had mild dysmorphic features, including flat occiput, broad facies with frontal and biparietal bossing, arched eyebrows, inner epicanthal folds, short, prominent and upturned nose, broad nasal root, long flat philtrum, and thin upper lip. He also had brachydactyly and loose joints. The mother had a broad forehead, protruding ears, prominent nose, arched eyebrows, malar flatness, and a high palate. The mother had 7 previous miscarriages. Derwinska et al. (2009) postulated that a gain of function of PTCH1 may be involved in a holoprosencephaly-like phenotype, which includes microcephaly.

Molecular Genetics

Ming et al. (2002) hypothesized that mutations in genes encoding other components of the SHH (600725) signaling pathway could also be associated with HPE. PTCH1, the receptor for SHH, normally acts to repress SHH signaling. This repression is relieved when SHH binds to PTCH1. Ming et al. (2002) identified 4 different mutations in PTCH1 (601309.0011-601309.0014) in 5 unrelated affected individuals. They predicted that by enhancing the repressive activity of PTCH on the SHH pathway, these mutations caused decreased SHH signaling, with resulting HPE. The mutations could affect the ability of PTCH to bind SHH or perturb the intracellular interactions of PTCH with other proteins involved in SHH signaling. The findings demonstrated further genetic heterogeneity associated with the HPE phenotype, as well as showing that mutations in different components of a single signaling pathway can result in the same clinical disorder.

Ribeiro et al. (2006) identified 4 different PTCH1 mutations (see, e.g., 601309.0015) in 4 Brazilian probands with HPE7 and 1 proband with a holoprosencephaly-like facial phenotype but normal MRI (601309.0014). One of the patients with holoprosencephaly described by Ribeiro et al. (2006) was considered by Guion-Almeida et al. (2007) to have cerebrooculonasal syndrome (CONS; 605627); see 601309.0015.