Alternative titles; symbols
SNOMEDCT: 205798005, 253137003, 30915001; ICD10CM: Q04.1, Q04.2, Q87.0; ORPHA: 2162; DO: 0110881;
Cytogenetic location: 21q22.3 Genomic coordinates (GRCh38): 21:41,200,001-46,709,983
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 21q22.3 | Holoprosencephaly 1 | 236100 | Autosomal dominant; Isolated cases | 2 |
Holoprosencephaly (HPE) is the most common structural malformation of the human forebrain and occurs after failed or abbreviated midline cleavage of the developing brain during the third and fourth weeks of gestation. HPE occurs in up to 1 in 250 gestations, but only 1 in 8,000 live births (Lacbawan et al., 2009). Classically, 3 degrees of severity defined by the extent of brain malformation have been described. In the most severe form, 'alobar HPE,' there is a single ventricle and no interhemispheric fissure. The olfactory bulbs and tracts and the corpus callosum are typically absent. In 'semilobar HPE,' the most common type of HPE in neonates who survive, there is partial cortical separation with rudimentary cerebral hemispheres and a single ventricle. In 'lobar HPE,' the ventricles are separated, but there is incomplete frontal cortical separation (Corsello et al., 1990). An additional milder form, called 'middle interhemispheric variant' (MIHV) has also been delineated, in which the posterior frontal and parietal lobes are incompletely separated and the corpus callosum may be hypoplastic (Lacbawan et al., 2009). Finally, microforms of HPE include a single maxillary median incisor or hypotelorism without the typical brain malformations (summary by Mercier et al., 2011). Cohen (2001) discussed problems in the definition of holoprosencephaly, which can be viewed from 2 different perspectives: anatomic (fixed) and genetic (broad). When the main interest is description, the anatomic perspective is appropriate. In genetic perspective, a fixed definition of holoprosencephaly is not appropriate because the same mutational cause may result in either holoprosencephaly or some microform of holoprosencephaly. Cohen (2001) concluded that both fixed and broad definitions are equally valid and depend on context.
Munke (1989) provided an extensive review of the etiology and pathogenesis of holoprosencephaly, emphasizing heterogeneity.
See also schizencephaly (269160), which may be part of the phenotypic spectrum of HPE.
Genetic Heterogeneity of Holoprosencephaly
Several loci for holoprosencephaly have been mapped to specific chromosomal sites and the molecular defects in some cases of HPE have been identified. Holoprosencephaly-1 (HPE1) maps to chromosome 21q22. See also HPE2 (157170), caused by mutation in the SIX3 gene (603714) on 2p21; HPE3 (142945), caused by mutation in the SHH gene (600725) on 7q36; HPE4 (142946), caused by mutation in the TGIF gene (602630) on 18p11; HPE5 (609637), caused by mutation in the ZIC2 gene (603073) on 13q32; HPE6 (605934), mapped to 2q37; HPE7 (610828), caused by mutation in the PTCH1 gene (601309) on 9q22; HPE8 (609408), mapped to 14q13; HPE9 (610829), caused by mutation in the GLI2 gene (165230) on 2q14; HPE10 (612530), mapped to 1q41-q42; HPE11 (614226), caused by mutation in the CDON gene (608707) on 11q24; HPE12 (618500), caused by mutation in the CNOT1 gene (604917) on 16q21; HPE13 (301043), caused by mutation in the STAG2 gene (300826) on Xq25; and HPE14 (619895), caused by mutation in the PLCH1 gene (612835) on 3q25.
Wallis and Muenke (2000) gave an overview of mutations in holoprosencephaly. They indicated that at least 12 different loci had been associated with HPE.
Mutations in genes involved in the multiprotein cohesin complex, including STAG2, have been shown to be involved in midline brain defects such as HPE. Mutations in some of those genes cause Cornelia de Lange syndrome (CDLS; see 122470), and some patients with severe forms of CDLS may have midline brain defects. See, for example, CDLS2 (300590), CDLS3 (610759), and CDLS4 (614701).
Ellis (1865) reported twins with cyclopia. Dominok and Kirchmair (1961) reported a family in which 3 children were affected: 1 had cyclopia and 2 had premaxillary agenesis.
DeMyer et al. (1963) noted that there is a spectrum of holoprosencephalic disorders representing impaired midline cleavage of the embryonic forebrain. Cyclopia, the most extreme form, is characterized by a single eye globe with varying degrees of doubling of intrinsic ocular structures, arhinia, and a blind-ending proboscis located above the median eye. In ethmocephaly, the features are extreme orbital hypotelorism, arhinia, and a blind-ended proboscis located between the eyes. In cebocephaly, orbital hypotelorism is associated with single-nostril nose. Premaxillary agenesis is characterized by a median pseudocleft, agenesis of nasal bones and primary palate, and ocular hypotelorism. DeMyer et al. (1963) described 2 sisters with alobar holoprosencephaly of the premaxillary agenesis type, i.e., associated with median cleft lip and palate. A paternal aunt may have been identically affected. Chromosomes were normal.
Hintz et al. (1968) reported 2 sisters with premaxillary agenesis. The sisters had 12 sibs, 5 of whom died between 1 and 3 days of unknown causes but without observable malformations; 6 were normal and 1 male had growth hormone deficiency, perhaps on a hypothalamic basis without overt evidence of the holoprosencephaly complex (Romshe and Sotos, 1973). Dallaire et al. (1971) described multiple infants with premaxillary agenesis in several different sibships of a French-Canadian kindred. James and Van Leeuwen (1970) described sibs with cebocephaly.
Begleiter and Harris (1980) reported 2 brothers with holoprosencephaly, facial clefts, and endocrine dysgenesis, including absence of pituitary gland, hypoplastic adrenals, and micropenis. The first-born infant lived 4 months with a seizure disorder and severe hypoglycemia. The second sib lived 1 day. Autopsy showed holoprosencephaly, complex brain malformations, no pituitary tissue, and hypoplastic adrenal glands with no fetal cortex.
Seidlitz et al. (1983) described a brother and sister with full-blown holoprosencephaly without chromosomal aberration. One had cyclopia, whereas the other had cebocephaly with a proboscis.
Zwetsloot et al. (1989) described the wide variation in brain and facial abnormalities in 3 sibs with holoprosencephaly.
Corsello et al. (1990) reported 2 male monozygotic twins who were identically affected with cyclopia, dystopic proboscis, midface hypoplasia, pseudohydrocephalus, and asymmetric atresia of apparently low-set ears. When holoprosencephaly is combined with severe facial anomalies and postaxial polydactyly, the pseudotrisomy 13 syndrome (264480) should be considered.
Collins et al. (1993) described a family in which a presumably dominant holoprosencephaly was present in 5 affected persons in 2 sibships, the offspring of healthy sisters who were thought to be gene carriers. Of the affected children, 3 had cebocephaly and died shortly after birth. One had left choanal atresia, retinal coloboma, a single central maxillary incisor, microcephaly, short stature, and learning problems. Another had only a single central maxillary incisor. Hypotelorism, microcephaly, and unilateral cleft lip and palate were possible minor manifestations in gene carriers.
Holoprosencephaly is associated with a diagnostic face approximately 80% of the time. Barr and Cohen (2002) reported 3 sibs with autosomal recessive alobar holoprosencephaly and essentially normal faces. A similar family was reported by Khan et al. (1970). Alobar holoprosencephaly with essentially normal faces has also been observed in infants of diabetic mothers (Barr et al., 1983).
Blaas et al. (2002) described a series of 30 Norwegian holoprosencephaly cases, of which 18 were alobar, 5 were semilobar, 2 were lobar, 2 were lobar variants, and 3 were anencephalic. The size or shape of the head was abnormal in 25 (83%) of the cases, and facial features varied considerably. Twenty (67%) of the cases had associated structural anomalies that were not related to the cerebral and facial holoprosencephaly condition. Eleven (37%) of the cases had detectable chromosomal aberrations, and 7 (23%) were suspected to be of nonchromosomal syndromal origin.
Chan et al. (2009) described the occurrence of semilobar holoprosencephaly in the child of a mother with mesiodens and suggested that the supernumerary maxillary tooth (see 187100) may be a microform of HPE.
By detailed ophthalmologic examination of 10 patients with genetically confirmed HPE, Pineda-Alvarez et al. (2011) found that all 10 had at least 2 subtle ophthalmologic anomalies, including refractive errors, microcornea, microphthalmia, astigmatism, blepharoptosis, strabismus, and coloboma. The findings contributed to the understanding of the phenotypic variability of the HPE spectrum and showed that subtle intraocular abnormalities can occur in HPE.
Both recessive and dominant inheritance of holoprosencephaly has been reported.
Cohen and Gorlin (1969) described a Chippewa Indian sibship in which 1 sib had cyclopia and 4 others had cleft lip and/or palate. The parents were related, suggesting autosomal recessive inheritance. Consanguinity was also noted in the cyclopic and cebocephalic cases of Klopstock (1921) and in the ethmocephalic infant reported by Grebe (1954).
Odent et al. (1998) reviewed 258 HPE records involving at least 1 affected child and found 97 cases in 79 families with nonsyndromic, nonchromosomal HPE. A high degree of familial aggregation was found in 29% of families. By segregation analysis, Odent et al. (1998) concluded that autosomal dominant inheritance with incomplete penetrance (82% for major and 88% for major and minor) was the most likely mode of inheritance. Sporadic cases accounted for 68%, and the recurrence risk after an isolated case was predicted to be 13 to 14%.
Ming and Muenke (2002) reviewed examples of digenic inheritance in human disease, in which 2 genes operate synergistically or 1 behaves as a modifier affecting severity of the phenotype. They suggested that HPE may be due to mutation in more than 1 gene and that intrafamilial variability is due to multiple genetic 'hits.' They noted 3 patients who had a mutation in SHH and a second HPE gene (Nanni et al., 1999).
Holoprosencephaly with a different array of extracephalic malformations occurs with trisomy 13, del13q, del18p and triploidy (Holmes et al., 1974).
Corsello et al. (1990) reviewed the variety of chromosomal abnormalities which have been related to holoprosencephaly and also reviewed its clinical variability.
Estabrooks et al. (1990) described a child with a normal face, but with alobar holoprosencephaly established by prenatal ultrasound examination and magnetic resonance imaging (MRI). After birth, the patient was demonstrated to have a minute deletion of chromosome 21q22.3.
Muenke et al. (1995) pointed out that 3 cases of HPE associated with unbalanced translocations or deletions resulting in partial monosomy of chromosome 21 had been reported, suggesting that monosomy of a gene designated HPE1 (Frezal and Schinzel, 1991) could be necessary, and perhaps sufficient, to cause HPE. By analysis of somatic cell hybrid clones that contained rearranged chromosomes 21 from HPE patients, Muenke et al. (1995) defined the HPE minimal critical region in 21q22.3 as D21S113 to qter. To determine whether there were human homologs of the Drosophila 'single-minded' (sim) gene that might be involved in HPE, they established cell hybrid mapping panels to map SIM2 to chromosome 21 within subbands 21q22.2-q22.3. Analysis of the HPE patient-derived somatic cell hybrid showed that SIM2 (see 600892) was not deleted in 2 of the 3 patients and thus was not a likely candidate for HPE1. However, SIM2 did map within the Down syndrome critical region and thus was a candidate gene for contributing to the Down syndrome phenotype.
Byrne et al. (1987) described the association of congenital cytomegalovirus (CMV) infection and cyclopia. The findings supported the suggestion that any infant with congenital ocular defects should be investigated for CMV infection and raised the possibility of a teratogenic role for CMV in cyclopia/holoprosencephaly.
Muenke (1994) reviewed holoprosencephaly as a genetic model for normal craniofacial development. He pictured the wide spectrum of facial features from cyclopia with proboscis above the single eye to ocular hypotelorism and single central upper incisor (in the father of a child with holoprosencephaly) at the other extreme.
Holoprosencephaly is an etiologically heterogeneous entity (Muenke, 1996). There are teratogenic causes, maternal diabetes being the most significant, giving a 200-fold increased risk. Genetic factors are indicated by familial occurrence, the occurrence of holoprosencephaly in some mendelian genetic syndromes, and the association with nonrandom chromosomal aberrations.
The most widely accepted model for HPE is the 'multiple hit hypothesis,' in which combinations of mutations in major and/or minor HPE genes lead to the occurrence of HPE and may account for phenotypic variability (Ming and Muenke, 2002).
Associations Pending Confirmation
For discussion of a possible association between variation in the GAS1 gene and susceptibility to HPE, see 139185.0001-139185.0002.
Mercier et al. (2011) reported the clinical and molecular features of a large European series of 645 HPE probands (51% fetuses) and 699 relatives in order to examine genotype/phenotype correlations. Twenty-five percent of probands had a mutation in 1 of the 4 major genes: SHH, ZIC2, SIX3, and TGIF. Mutations in the SHH, SIX3, and TGIF genes were inherited in more than 70% of cases, whereas most (70%) of the ZIC2 mutations occurred de novo. The facial features were assigned to 4 categories: categories 1 and 2 had severe facial defects, whereas microforms were listed as 3 and 4. Statistical analysis showed a positive correlation between the severity of the brain malformation and facial features for SHH, SIX3, and TGIF, but not for ZIC2. The most severe HPE types were associated with SIX3 and ZIC2 mutations, whereas microforms were associated with SHH mutations. In addition, 3 patients had mutations in GLI2, and array CGH detected gene rearrangements in 22% of 260 patients screened. Fifteen probands had 2 mutations, consistent with the multiple-hit hypothesis. Based on these results, Mercier et al. (2011) proposed an algorithm for molecular analysis in HPE.
Of patients with HPE who survived the neonatal period, alobar, semilobar and lobar HPE occurred in 21%, 60% and 19%, respectively (Hahn et al., 2006). A separate study showed that of patients with nonchromosomal, nonsyndromic HPE, alobar, semilobar and lobar HPE occurred in 17.8%, 36.9%, and 27.3%, respectively (Lazaro et al., 2004).
Cyclopia is characterized by the presence of a single eye, with varying degrees of doubling of the intrinsic ocular structures, located in the middle of the face. It is the severest facial expression of the holoprosencephaly spectrum. Orioli et al. (2011) performed a study describing the prevalence, associated malformations, and maternal characteristics among cases with cyclopia. Data originated in 20 collected datasets from the International Clearinghouse for Birth Defects Surveillance and Research, reported according to a single pre-established protocol. A total of 257 infants with cyclopia were identified. Overall prevalence was 1 in 100,000 births (95% confidence interval 0.89-1.14), with only 1 program being out of range. Across sites, there was no correlation between cyclopia prevalence and number of births or proportion of elective termination of pregnancy. The higher prevalence of cyclopia among older mothers was not statistically significant. The majority of cases were liveborn (122/200; 61%) and females predominated (male/total: 42%). A substantial proportion of cyclopias (31%) were caused by chromosomal anomalies, mainly trisomy 13. Another 31% of the cases of cyclopias were associated with defects not typically related to HPE, with more hydrocephalus, heterotaxia defects, neural tube defects, and preaxial reduction defects than the chromosomal group, suggesting the presence of ciliopathies or other unrecognized syndromes. Cyclopia is a very rare defect without much variability in prevalence by geographic location. The heterogeneous etiology with a high prevalence of chromosomal abnormalities, and female predominance in HPE, were confirmed, but no effect of increased maternal age or association with twinning was observed.
Jaramillo et al. (1988) suggested that holoprosencephaly sequence or, even better, DeMyer sequence (DeMyer et al., 1963) should be the preferred designation.
Bazopoulou-Kyrkanidou (2005) provided a historical review of the lifestyle and behavior of the Cyclopes as described in Homer's Odyssey.
Seppala et al. (2007) generated Gas1 (139185) -/- mice and observed microform holoprosencephaly, including midfacial hypoplasia, premaxillary incisor fusion, and cleft palate, in addition to severe ear defects; however, the forebrain remained grossly intact. Loss of a single Shh allele on a Gas1 -/- background significantly exacerbated the midline craniofacial phenotype. Seppala et al. (2007) concluded that GAS1 and SHH interact and that GAS1 is a potential locus on chromosome 9q21.3-q22 for human craniofacial malformations.
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