Gene Map Locus: 21q22.3
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Holoprosencephaly, which occurs with a frequency of about 1 in
16,000 live births and about 1 in 200 spontaneous abortions, 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 non-random chromosome aberrations. Autosomal
dominant inheritance has been observed in some instances; almost all
such families show mapping of the phenotype (which varies widely from
cyclopia to almost no manifestation except perhaps a single middle
incisor) to a locus on distal 7q. One of the genetic syndromes that
includes holoprosencephaly as feature is Smith-Lemli-Opitz syndrome
(270400).
Four of the putative holoprosencephaly genes indicated by
nonrandom and recurrent chromosomal aberrations were given specific
symbols at the Human Gene Mapping 11 Conference (Frezal
and Schinzel, 1991): HPE1 on 21q22.3, HPE2 (157170)
on 2p21, HPE3 (142945)
on 7q36, and HPE4 (142946)
on 18p (Overhauser et al., 1995).
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 hypertelorism
and single central upper incisor (in the father of a child with
holoprosencephaly) at the other extreme. Muenke
(1994) pointed out that in addition to the nonrandom chromosome
aberrations found with holoprosencephaly and involving chromosomes 2
(157170),
7 (142945),
18 (142946),
and 21 (HPE1), abnormalities have been related also to chromosomes 3
and 13.
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.
DeMyer et al. (1963) pointed out that
there is a spectrum of holoprosencephalic disorders representing
impaired midline cleavage of the embryonic forebrain. In cyclopia,
the most extreme form, a single eye globe with varying degrees of
doubling of intrinsic ocular structures, arrhinia and a blind-ending
proboscis located above the median eye are found. In ethmocephaly,
the features are extreme orbital hypotelorism, arrhinia, 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.
Ellis (1865) reported twins with cyclopia.
Three children were affected in the family reported by Dominok
and Kirchmair (1961), 1 with cyclopia and 2 with premaxillary
agenesis. 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. Consanguinity
was also noted in the cyclopic and cebocephalic cases of Klopstock
(1921) and in the ethmocephalic infant reported by Grebe
(1954).
Holoprosencephaly with a different array of extracephalic
malformations occurs with trisomy 13, del13q, del18p and triploidy
(Holmes et al., 1974). Pfitzer
and Muntefering (1968) observed 4 affected children whose mothers
were relatives and had the same anomalous karyotype, thought to
represent balanced translocation between chromosome 3 and a
chromosome of the C group. With the introduction of G-banding
techniques, Pfitzer et al. (1982)
demonstrated that this reciprocal 7/C-translocation was a balanced
rearrangement between the short arm of chromosome 3 and the distal
part of the long arm of chromosome 7--t(3;7)(p23;q36). Burrig
et al. (1989) demonstrated a fifth case of cyclopia in this
family, detected prenatally, and showed an unbalanced karyotype
attributable to the above-mentioned balanced translocation. They
could find no reports of cyclopia associated with similar chromosome
abnormalities. Lurie et al. (1990) pointed
out that at least 9 cases of HPE have occurred in patients with
confirmed loss of 7q34-q36; see 142945.
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, endocrine dysgenesis (absence of pituitary gland,
hypoplastic adrenals, etc.), and micropenis. The first-born infant
lived 4 months with 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. Hintz et al.
(1968) reported 2 sisters with premaxillary agenesis. The sisters
had 12 sibs of whom 5 died between 1 and 3 days of unknown causes but
without observable malformations; 6 were normal and 1 male had growth
hormone deficiency, probably on a hypothalamic basis without overt
evidence of the holoprosencephaly complex (Romshe
and Sotos, 1973). Anosmia and hypogonadism (Kallmann syndrome),
when it occurs in both males and females (244200),
may be related. Seidlitz et al. (1983)
described brother and sister with full-blown holoprosencephaly
without chromosomal aberration. One had cyclopia, whereas the other
had cebocephaly with a proboscis. Byrne et al.
(1987) described the association of congenital cytomegalovirus
(CMV) infection and cyclopia. The findings support the suggestion
that any infant with congenital ocular defects should be investigated
for CMV infection and raises the possibility of a teratogenic role
for CMV in cyclopia/holoprosencephaly. Berry et
al. (1984) described an affected brother and sister.
Interestingly, the father and a paternal aunt had a single central
maxillary incisor and hypotelorism. The paternal grandfather was said
to have had a 'skin harelip.' Zwetsloot et al.
(1989) described the wide variation in brain and facial
abnormalities in 3 sibs with holoprosencephaly. Munke
(1989) provided an extensive review of the etiology and
pathogenesis of holoprosencephaly, emphasizing heterogeneity.
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.
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 21q22.3. Estabrooks et al.
(1990) suggested a causal relationship. Thus, several areas of
the genome are under suspicion as the site of mutations causing
holoprosencephaly. Corsello et al. (1990)
reviewed the variety of chromosomal abnormalities which have been
related to holoprosencephaly and also reviewed its clinical
variability. They defined 3 anatomic types of holoprosencephaly:
alobar (with absence of interhemispheric cleavage and single
ventricle); semilobar (posterior interhemispheric fissure with
rudimentary cerebral hemispheres and single ventricle); and lobar
(with clear interhemispheric fissure and 2 lateral ventricles). They
reported the cases of 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.
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 921S113 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)
is not deleted in 2 of the 3 patients and thus is 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.
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%.
Ada Hamosh - updated : 10/29/1998
Victor A. McKusick - updated : 9/24/1998
Victor A. McKusick : 6/3/1986
alopez : 10/29/1998
alopez : 9/29/1998
carol : 9/24/1998
mark : 3/11/1996
mark : 3/11/1996
terry : 2/28/1996
jason : 7/14/1994
davew : 7/11/1994
carol : 5/23/1994
terry : 5/11/1994
mimadm : 2/19/1994
carol : 12/22/1993