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Holoprosencephaly Overview

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Author Information
National Human Genome Research Institute
National Institutes of Health
Bethesda, Maryland
FAAP, FACMG
Pediatric Neurologist and Clinical Geneticist Consultant, Medical Genetics Branch
National Human Genome Research Institute
National Institutes of Health
Bethesda, Maryland
Departments of Pediatrics and Neurology
George Washington University of the Health Sciences
Attending, Children's National Medical Center
Washington, DC
Chief, Medical Genetics Branch
Director, Medical Genetics Residency and Fellowship
National Human Genome Research Institute
National Institutes of Health
Bethesda, Maryland

Initial Posting: ; Last Update: August 29, 2013.

Summary

Disease characteristics. Holoprosencephaly (HPE) is a structural anomaly of the brain in which there is failed or incomplete separation of the forebrain early in gestation. Classic HPE encompasses a continuum of brain malformations including (in order of decreasing severity): alobar, semilobar, lobar, and middle interhemispheric variant (MIHV) type HPE; a septopreoptic type has also been described. Other CNS abnormalities not specific to HPE may also occur. HPE is accompanied by a spectrum of characteristic craniofacial anomalies in approximately 80% of individuals with HPE. Developmental delay is present in virtually all individuals with the HPE spectrum of CNS anomalies. Seizures and pituitary dysfunction are common. Most affected fetuses do not survive; severely affected children typically do not survive beyond early infancy, while a significant proportion of more mildly affected children survive past 12 months. Mildly manifesting individuals without appreciable brain anomalies on conventional neuroimaging may be described as having “microform” HPE.

Diagnosis/testing. Imaging of the brain by CT scan or (preferably) MRI confirms the diagnosis of HPE, may define the anatomic subtype, and identifies associated CNS anomalies. Approximately 25%-50% of individuals with HPE have a numeric or structural chromosomal abnormality detectable by chromosome analysis. Approximately 18%-25% of individuals with monogenic HPE have a recognizable syndrome and the remainder have nonsyndromic HPE. Molecular genetic testing is possible for many of the genes associated with nonsyndromic HPE. Approximately 10% of individuals with HPE have defects in cholesterol biosynthesis.

Genetic counseling. HPE can result from environmental causes; an inherited or de novo chromosome abnormality; an inherited monogenic syndromic disorder; an inherited or de novo mutation for a gene associated with nonsyndromic autosomal dominant HPE; copy number variations (CNVs); or unknown causes. Genetic counseling and risk assessment depend on determination of the specific cause of HPE in an individual.

Management. Treatment of manifestations: Treatment by a multidisciplinary team when possible; hormone replacement therapy for pituitary dysfunction; antiepileptic drugs for seizures; gastrostomy tube/Nissen fundoplication for feeding difficulties/gastroesophageal reflux; special feeding devices and surgical repair of cleft lip and/or palate; ventriculo-peritoneal shunt placement for hydrocephalus; parental support and counseling.

Prevention of secondary complications: Prompt evaluation of children with hormonal disturbances during times of stress (e.g., illness, surgery); attention to fluid and electrolyte management during surgery.

Surveillance: During health maintenance evaluations, measurement of height, weight, and head circumference and evaluation for endocrine deficiencies.

Definition of Holoprosencephaly

Clinical Manifestations

Holoprosencephaly (HPE), the most common malformation of the forebrain in humans, is a structural anomaly of the brain resulting from failed or incomplete forebrain division in the third to fourth weeks of gestation. The forebrain (prosencephalon) incompletely cleaves into right and left hemispheres, deep brain structures, and the olfactory and optic bulbs and tracts [Golden 1998, Muenke & Cohen 2000, Lacbawan & Muenke 2002, Ming & Muenke 2002, Edison & Muenke 2003, Gropman & Muenke 2005, Dubourg et al 2007].

Types of HPE (reviewed in Hahn & Barnes [2010]) identified in a continuum of brain malformations have traditionally been divided into the following types (in decreasing order of severity):

  • Alobar HPE, the most severe, in which there is a single “monoventricle” and no separation of the cerebral hemispheres
  • Semilobar HPE, in which the left and right frontal and parietal lobes are fused and the interhemispheric fissure is only present posteriorly
  • Lobar HPE, in which most of the right and left cerebral hemispheres and lateral ventricles are separated but the frontal lobes, most rostral aspect of the telencephalon, are fused, especially ventrally
  • Middle interhemispheric fusion variant (MIHF/MIHV or syntelencephaly), in which the posterior frontal and parietal lobes fail to separate, with varying lack of cleavage of the basal ganglia and thalami and absence of the body of the corpus callosum but presence of the genu and splenium of the corpus callosum [Barkovich & Quint 1993]
  • A septopreoptic type, in which non-separation is restricted to the septal and/or preoptic regions; described in small case series [Hahn et al 2010]

Other structural CNS findings that may occur with but are not specific to HPE:

  • Anomalies of midline structures: undivided thalami, absent corpus callosum (OMIM 217990), callosal dysgenesis [Barkovich 1990, Rubinstein et al 1996], absent septum pellucidum, and absent or hypoplastic olfactory bulbs and tracts (arrhinencephaly) and optic bulbs and tracts
  • Macrocephaly secondary to hydrocephalus
  • Dandy-Walker malformation
  • Neuronal migration anomalies
  • Abnormal circle of Willis [Arnold et al 1996]
  • Caudal dysgenesis [Martinez-Frias et al 1994]

A spectrum of craniofacial anomalies accompanies HPE in approximately 80% of affected individuals. The spectrum of facial anomalies begins with cyclopia, the most severe presentation, and extends in an unbroken continuum to the normal face as seen in individuals who have, but are not expressing, a mutation for HPE inherited in an autosomal dominant manner. Common clinical features in individuals without obvious findings such as cyclopia, synophthalmia, or a proboscis, include microcephaly (although hydrocephalus can result in macrocephaly), closely spaced eyes (also known as hypotelorism; potentially severe), depressed nasal bridge, single maxillary central incisor, and cleft lip and/or palate.

The extremely variable phenotypic expression occurs both in simplex HPE (i.e., a single occurrence in a family) and among members of the same family with an inherited form of HPE. Of note, subtle facial anomalies in mildly affected family members, including mild microcephaly, closely spaced eyes, and a sharp, narrow appearance to the nose, can be easily overlooked [Lacbawan et al 2009, Solomon et al 2009a].

Malformations of the nose include complete absence, agenesis of the nasal cartridge, and proboscis (flat nose with a single central nostril without nasal bones) [Hennekam et al 1991].

Palatal anomalies include various midline and lateral clefts, midline palatal ridge [Kjaer et al 1997], bifid uvula, high-arched palate, and absence of the superior labial frenulum [Martin & Jones 1998, Solomon et al 2010a].

A single maxillary central incisor may be present [Nanni et al 2001]; although a nonspecific finding, it is a distinctive microform in autosomal dominant HPE [Berry et al 1984].

Clinical Subtypes of HPE and Range of Possible Craniofacial Findings

Alobar HPE (Figure 1)

Figure 1

Figure

Figure 1. Alobar HPE

A. MRI of alobar holoprosencephaly (HPE), the most severe form of HPE, characterized by an enlarged midline monoventricle (holoventricle, red/thin arrow) with fusion of the frontal lobes and the midline gray matter (more...)

Range of findings:

  • Cyclopia: single eye or partially divided eye in single orbit with a proboscis above the eye
  • Cyclopia without proboscis
  • Ethmocephaly: extremely closely spaced eyes but separate orbits with proboscis between the eyes
  • Cebocephaly: closely spaced eyes with single-nostril nose
  • Closely spaced eyes
  • Anophthalmia or microophthalmia
  • Premaxillary agenesis with median cleft lip, closely spaced eyes, depressed nasal ridge
  • Bilateral cleft lip
  • Relatively normal facial appearance (especially in persons with mutations in ZIC2)

Semilobar HPE (Figure 2)

Figure 2

Figure

Figure 2. Semilobar HPE

A. MRI showing semilobar HPE. Note fusion of the frontal lobes, but presence of some septation posteriorly with presence of a falx and interhemispheric fissure (red/thin arrow). The splenium of the corpus callosum (more...)

Range of findings:

  • Closely spaced eyes
  • Anophthalmia/microophthalmia
  • Depressed nasal bridge
  • Absent nasal septum
  • Flat nasal tip
  • Bilateral cleft lip with median process representing the philtrum-premaxilla anlage
  • Midline cleft (lip and/or palate)
  • Relatively normal facial appearance

Lobar HPE (Figure 3)

Figure 3

Figure

Figure 3. Lobar HPE

A. MRI in axial plane depicting lobar HPE, the least severe of the major types of HPE. The cerebral hemispheres are separated (blue/thick arrows); the ventricles are misshapen as a result of absence of the septum pellucidum. (more...)

Range of findings:

  • Bilateral cleft lip with median process
  • Closely spaced eyes
  • Depressed nasal ridge
  • Relatively normal facial appearance

Middle interhemispheric fusion (MIHF) variant (Figure 4)

Figure 4

Figure

Figure 4. Middle interhemispheric fusion (MIHF)

A. MRI in axial plane depicting middle interhemispheric variant of HPE in which the anterior portions of the frontal lobes and the occipital lobes are well separated. The sylvian fissures (more...)

Range of findings:

  • Closely spaced eyes
  • Depressed nasal bridge
  • Narrow nasal bridge
  • Relatively normal facial appearance

Microforms of HPE (also termed “microform HPE”) (Figure 5)

Figure 5

Figure

Figure 5. Microforms of holoprosencephaly (HPE) spectrum with milder craniofacial anomalies in the absence of neurologic findings

A. Premaxillary agenesis with repaired bilateral clefts of the lip

B. Absence of nasal (more...)

Sometimes observed in relatives of probands with HPE, these include the following:

Clinical manifestations (reviewed in Levey et al [2010] and Solomon et al [2010a]) commonly observed in children with HPE include the following:

  • Developmental delay is present in all individuals with the HPE spectrum of CNS anomalies. The degree of delay is variable, correlating with the severity of the brain malformation, but tends to be severe.
  • Seizures are common, and may be difficult to control.
  • Hydrocephalus can occur, and may result in macrocephaly, rather than the more commonly-observed microcephaly.
  • Neural tube defects occur in a small proportion of individuals.
  • Hypothalamic and brain stem dysfunction may lead to swallowing difficulties and instability of temperature, heart rate, and respiration.
  • Pituitary dysfunction is manifest by partial or complete panhypopituitarism with abnormal function of any or all of the anterior and/or posterior pituitary hormones, though central diabetes insipidus is by far the most common finding in persons with non-chromosomal, nonsyndromic HPE [Lacbawan et al 2009, Solomon et al 2010a].
  • Short stature and failure to thrive are common, especially in more severely affected children. Growth hormone deficiency and/or chromosomal anomalies may in part be responsible for poor growth in some individuals.
  • Feeding difficulties may be a major problem in children with HPE. At least part of the difficulty may derive from axial hypotonia, poor suck as a result of neurologic complications, lethargy, seizures and their effects, side effects of medications, and lack of interest. Often gastroesophageal reflux, choking, and gagging occur with feeds. More common problems include slowness in eating, frequent pauses, and frank vomiting with risk of aspiration. Oral-sensory dysfunction may affect feeding especially when associated with textural aversion and labial and lingual weakness. Children with cleft lip and/or palate often have additional difficulties with oral feeding.
  • Excessive intestinal gas/colic, irritability, and constipation frequently occur [Barr & Cohen 1999].
  • Aspiration pneumonia can be a complication of poor coordination of swallowing.
  • Erratic sleep patterns can occur.

A common misperception is that children with HPE do not survive beyond early infancy. While this is the case for the most severely affected children, a significant proportion of more mildly affected children (as well as some severely affected children) survive past age 12 months. Among affected individuals with a normal karyotype, an inverse relationship exists between the severity of the facial phenotype and length of survival.

  • Infants with cyclopia or ethmocephaly generally do not survive beyond age one week [Croen et al 1996].
  • Approximately 50% of children with alobar HPE die before age four to five months and 20% live past the first year of life [Barr & Cohen 1999].
  • More than 50% of children with isolated semilobar or lobar HPE without significant malformations of other organs are alive at age 12 months [Olsen et al 1997, Barr & Cohen 1999].

Almost all survivors have apparently normal vision and hearing; they smile and demonstrate memory [Barr & Cohen 1999].

Establishing the Diagnosis

Imaging of the brain by CT scan or MRI confirms the diagnosis of HPE, defines the clinical subtype, and identifies associated CNS anomalies [Barkovich & Maroldo 1993, Barkovich et al 2002, Hahn & Barnes 2010]. The study of choice is cranial MRI examination, preferably obtained with adequate sedation at a pediatric center experienced in evaluating children for structural brain anomalies. Review of the study by a radiologist or other clinician familiar with the clinical subtypes of HPE is essential, as subtle midline anomalies may be missed, and non-HPE-related malformation findings may be mistaken for findings of HPE [Solomon et al 2009b].

HPE is most frequently diagnosed during the newborn period when abnormal facial findings and/or neurologic presentation prompt further evaluation (see Clinical Subtypes of HPE and Range of Possible Craniofacial Findings). Often HPE is first identified on prenatal ultrasound examination. Infants with normal facies or only mildly abnormal facies and either mild or intermediate brain anomalies may not be diagnosed until the first year of life when neuroimaging studies obtained during evaluation for developmental delay and/or failure to thrive reveal HPE.

Prevalence

HPE is the most common forebrain defect in humans, with a prevalence of 1:250 in embryos [Edison & Muenke 2003] and approximately 1:10,000 among live-born infants [Matsunaga & Shiota 1977, Orioli et al 2001, Leoncini et al 2008].

Causes of Holoprosencephaly

Environmental Causes

The most common teratogen in humans known to cause holoprosencephaly (HPE) is maternal diabetes mellitus. Infants of diabetic mothers have a 1% risk (a 200-fold increase) for HPE [Barr et al 1983]. Other teratogens, including alcohol and retinoic acid, have been associated with HPE in animal models, although their significance in humans is not established [Johnson & Rasmussen 2010].

More recently, cholesterol-lowering agents (i.e., statins) have been associated with HPE, although a causal relationship between prenatal statin use and HPE in the infant has not yet been proven [Edison & Muenke 2004a, Edison & Muenke 2004b].

An animal model of maternal hypocholesterolemia has been shown to cause HPE. Preliminary studies in humans show that maternal hypocholesterolemia can be associated with HPE in her offspring [Edison & Muenke 2003; Kelley & Muenke, unpublished].

Heritable Causes

Cytogenetic Abnormalities

Approximately 25%-50% of individuals with HPE have a chromosomal abnormality. Chromosomal abnormalities are nonspecific and either numeric or structural. Those with HPE and a normal karyotype cannot be distinguished from those with an abnormal karyotype on the basis of craniofacial abnormality or subtype of HPE; however, individuals with HPE as a result of a cytogenetic abnormality are more likely to have other organ system involvement [Olsen et al 1997].

Numeric chromosomal abnormalities include trisomy 13, trisomy 18, and triploidy. Arrhinencephaly is seen in approximately 70% of individuals with trisomy 13, which has a birth prevalence of 1:5000. Defects of the corpus callosum have been reported with trisomy 18 [Muenke & Beachy 2001, Solomon et al 2010c].

Structural chromosomal abnormalities associated with HPE have been reported in virtually all chromosomes, but the most frequent (in descending order) are deletions or duplications involving various regions of 13q, del(18p), del(7)(q36), dup(3)(p24-pter), del(2)(p21), and del(21)(q22.3) [Muenke & Beachy 2001, Dubourg et al 2007]. Many of these regions are known to harbor known genes associated with autosomal dominant nonsyndromic HPE (Table 1). Significant phenotypic variation exists among individuals with a similar cytogenetic deletion [Schell et al 1996].

Molecular Abnormalities

Copy number variants (CNVs). Chromosomal microarray (CMA) has identified copy number variants (CNVs) in 10% to 20% of all individuals with HPE [Bendavid et al 2009; Author, unpublished data]. These CNVs can include loci already known to be associated with HPE, as well other loci whose relationship to HPE is less well understood [Bendavid et al 2009; Author, unpublished data]. (Detection rates of CNVs may vary among testing laboratories and based on methodologies.) Because of changes in the availability, pricing, and power of CMA, this test has replaced karyotyping as one of the first-line tests in many situations; nonetheless, karyotyping is useful (e.g., to detect balanced translocations) and is an efficient and economical way to evaluate for many chromosome disorders that cause HPE [Pineda-Alvarez et al 2010, Solomon et al 2010c].

Mutations in Single Genes

Syndromic HPE. Approximately 18%-25% of individuals with HPE have a mutation in a single gene causing syndromic HPE. At least 25 different conditions in which HPE is an occasional finding have been described; the majority of these disorders are rare. Some of the more common include the following, categorized by mode of inheritance [Dubourg et al 2007]:

Nonsyndromic HPE. The nonsyndromic forms of HPE that are best understood at a molecular genetic level are inherited in an autosomal dominant manner (see Table 1).

Table 1. Genes Associated with Autosomal Dominant Nonsyndromic HPE

Gene SymbolChromosomal Locus% of Individuals with HPE and Mutations in This GeneSummary Tables of Sequence Variants (pdf)OMIM
Positive Family HistorySimplex Cases
SHH7q3630%-40%<5%Table 2600725
142945
ZIC213q325%2%Table 3603073
609637
SIX32p211.3%RareTable 4603714
157170
TGIF118p11.31.3%RareTable 5602630
142946
GLI22q14UnknownUnknown610829
165230
PTCH19q22.3UnknownUnknown601309
610828
DISP11q42RareRare607502
FGF810q24RareRare600483
FOXH18q24.3RareRare603621
NODAL10q22.1RareRare601265
TDGF1 (CRIPTO)3p23-p21RareRare187395
GAS19q21.33RareRare139185
DLL16q27RareRare606582
CDON11q24.2RareRare608707

Clinical Manifestations of Nonsyndromic HPE

The phenotype of individuals with mutations in genes associated with nonsyndromic HPE is extremely variable even within the same family, ranging from alobar HPE with cyclopia to clinically normal [Gillessen-Kaesbach 1996, Nanni et al 1999, Wallis & Muenke 1999, Gripp et al 2000, Lacbawan et al 2009, Solomon et al 2009a, Solomon et al 2010a, Solomon et al 2010b].

In the majority of individuals with HPE, a correlation exists between the facial anomalies and the gene involved and/or type of mutation (see Figure 6 and Clinical Subtypes of HPE and Range of Possible Craniofacial Findings) [Demeyer et al 1964]. However, it is important to note that many examples exist in which this correlation cannot be made.

Figure 6

Figure

Figure 6. Facial findings in holoprosencephaly (HPE)

A. Alobar HPE with cyclopia and proboscis above the single eye

B. Alobar HPE with cebocephaly and closely spaced eyes

C. Semilobar HPE with microcephaly, (more...)

  • ZIC2. Persons with mutations in ZIC2 who have HPE (even at the most severe end of the spectrum) appear to have a ZIC2-specific facial phenotype consisting of narrow forehead, upslanted palpebral fissures, large ears, a short nose with anteverted nares, and a broad and deep philtrum [Brown et al 1998, Brown et al 2001, Solomon et al 2010a].
  • DISP1. Persons with loss-of-function mutations in DISP1 may have facial features consistent with HPE-spectrum anomalies, but may not have corresponding brain anomalies [Roessler et al 2009c].
  • GLI2. Some individuals with facial findings consistent with HPE-spectrum disorders who have mutations in GLI2 have hypopituitarism and may have additional extracranial anomalies but no CNS findings consistent with HPE [Roessler et al 2003; Author, unpublished data].

Recently, some genotype-phenotype correlations have emerged both among persons with mutations in different genes and among persons with mutations in the same gene.

  • SHH and SIX3. Individuals with mutations in SHH and SIX3 may be part of large kindreds segregating the mutation; many of these families are not identified until ascertainment of the severely affected proband [Roessler et al 1996, Lacbawan et al 2009, Solomon et al 2009a, Mercier et al 2011, Solomon et al 2012a]. Probands with mutations in SIX3 may have a statistically significantly higher representation of more severe types of HPE. Further, preliminary data show some correlation between the severity of HPE type and functional studies of SIX3 mutations using a robust zebrafish model [Domené et al 2008, Lacbawan et al 2009, Solomon et al 2010b, Mercier et al 2011]. Renal/urinary anomalies may be more common in individuals with SHH or ZIC2 mutations than in individuals with holoprosencephaly and mutations in other genes [Mercier et al 2011, Solomon et al 2012a].
  • ZIC2. In the past it was suggested that individuals with ZIC2 mutations have normal or only mildly abnormal facial findings despite severe CNS anomalies [Brown et al 2001]. In a recent review of a large number of persons a characteristic craniofacial appearance: bitemporal narrowing, upslanting palpebral fissures, large ears, a short nose with anteverted nares, and a broad and deep philtrum was observed in those with HPE caused by mutations in ZIC2. Mutations in ZIC2 are more frequently de novo than mutations in other HPE-associated genes, and appear to be high penetrance with relatively few mildly-manifesting individuals [Solomon et al 2010a, Solomon et al 2010b, Mercier et al 2011].
  • GLI2. Mutations in GLI2 can cause panhypopituitarism and polydactyly, and, more rarely, may also result in HPE [Roessler et al 2003, Rahimov et al 2006; Author, unpublished data].
  • TGIF1. As with all HPE-associated genes, sequence-detected variations in TGIF1 may be difficult to interpret due to lack of functional data. However, individuals with mutations in TGIF1 may demonstrate the entire spectrum of severity [El-Jaick et al 2007, Solomon et al 2010b].
  • Other. Persons with mutations in genes less commonly associated with HPE have also been identified, and while the sample sizes are small, some observations can be made.

Mutations in other genes, including CDON, DISP1, DLL1, FGF8, GAS1, FOXH1, NODAL, and TDGF1, have been found in persons with HPE-spectrum anomalies [de la Cruz et al 2002, Roessler et al 2008, Roessler et al 2009c, Roessler et al 2009d, Arauz et al 2010, Ribeiro et al 2010, Bae et al 2011, Dupé et al 2011, Pineda-Alvarez et al 2012].

  • DISP1 loss-of-function mutations may be associated with normal brain structure and development but facial features usually seen in conjunction with frank HPE [Roessler et al 2009c].
  • NODAL mutations may result in HPE but are more commonly associated with cardiac and laterality defects [Roessler et al 2009d].
  • FOXH1 (part of the NODAL signaling pathway) mutations may result in HPE or cardiac defects [Roessler et al 2008].
  • TDGF1 (CRIPTO). Two individuals (one with HPE and one with a midline brain anomaly) have been reported [de la Cruz et al 2002].
  • FGF8. A loss-of-function mutation has been described in three members of one family with a range of classic HPE-spectrum features [Arauz et al 2010].
  • GAS1 is a positive regulator of SHH; mutations may result in the full spectrum of HPE. The functional effects of all reported variants have not been confirmed [Ribeiro et al 2010, Pineda-Alvarez et al 2012]. DLL1 deletions (and a single variant) implicate the NOTCH signaling pathway in the pathogenesis of HPE [Dupé et al 2011].
  • CDON is a SHH coreceptor; mutations may result in a small proportion of HPE [Bae et al 2011].

Additional candidate genes and their chromosomal loci are summarized in Table 6 (pdf).

Molecular Genetics of Nonsyndromic HPE

SHH. Heterozygous missense mutations, nonsense mutations, in-frame expansions, in-frame deletions, and insertions and deletions leading to frameshift mutations have been observed, as well as splice-site mutations [Roessler et al 2009a]. The human sonic hedgehog gene (SHH), one of three Drosophilia homologous genes, was the first HPE-associated gene to be identified. Heterozygous deletions and nonsense, frameshift, and missense mutations in SHH predict a loss-of-function mechanism [Roessler et al 1996, Roessler et al 1997, Vargas et al 1998, Nanni et al 1999, Odent et al 1999, Roessler et al 2009a, Solomon et al 2012a]. SHH encodes a secreted protein, sonic hedgehog, involved in establishing cell fates at several points during development. It is expressed in the Hensen node, the floor plate of the neural tube, the early gut endoderm, the posterior of the limb buds, and throughout the notochord. It has been implicated as the key inductive signal in patterning of the ventral neural tube, the anterior-posterior limb axis, and the ventral somites [Muenke & Beachy 2001]. As understanding of the complex molecular pathogenesis of HPE advances, many HPE-associated genes are now understood to be involved in Hedgehog signaling [Roessler & Muenke 2010].

ZIC2. Heterozygous missense mutations, nonsense mutations, in-frame expansions, in-frame deletions, and insertions and deletions leading to frameshift mutations have been observed, as well as splice-site mutations [Brown et al 1998, Brown et al 2001, Roessler et al 2009b, Solomon et al 2010a]. The protein encoded by ZIC2, zinc finger protein ZIC2, is a member of a family of proteins that includes the Drosophila odd-paired gene (opa) [Aruga et al 1996] and the zebrafish odd-paired like gene (opl) [Grinblat et al 1998], which contain zinc finger DNA binding motifs of specificity very closely related to that of the Gli proteins. ZIC2 may have a role in mediating the response to sonic hedgehog protein signaling. Early in development, ZIC2 is predicted to play a role in axial midline establishment; later, ZIC2 appears to affect the development of the dorsal telencephalon [Cheng et al 2006, Warr et al 2008].

SIX3. Heterozygous missense mutations, nonsense mutations, in-frame expansions, in-frame deletions, and insertions and deletions leading to frameshift mutations have been observed (as well as splice-site mutations) in the entire gene, but mutations are concentrated in the SIX domain and the homeodomain of SIX3 [Wallis et al 1999, Ribeiro et al 2006, Lacbawan et al 2009, Solomon et al 2009a]. In vertebrates, Six3 has been shown to be involved in midline forebrain and eye formation [Oliver et al 1996, Kobayashi et al 1998, Loosli et al 1999, Gestri et al 2005]. Properties of Six3 include: activation of lens specification during eye formation; influence over cellular fate in the developing forebrain through geminin interactions; transcriptional repression of Nodal, Wnt, and BMP signaling targets through complex(es) formed with Groucho; and regulation of SHH in the ventral forebrain [Kawakami et al 1996, Kobayashi et al 2001, Lagutin et al 2003, Del Bene et al 2004, Liu et al 2006, Inbal et al 2007, Geng et al 2008].

TGIF1. Heterozygous deletions and missense mutations of the gene encoding the 5'- TG- 3' interacting factor (TGIF1) have been observed [Gripp et al 2000, El-Jaick et al 2007]. Mutations in TGIF1 predict amino acid substitutions in the amino terminal transcription repression domain. TGIF1 modulates the TGF beta pathway, components of which have been shown to be involved in HPE in animal models.

GLI2. Heterozygous missense, nonsense, frameshift, and splice-site mutations have been observed [Roessler et al 2003, Rahimov et al 2006]. Three Gli genes have been implicated in vertebrate Shh signal mediation. In animal models, Gli2 has been shown, of the three Gli genes, to act as the central transcriptional activator; more recently, it has been shown that the amino-terminal transcriptional repressor domain of GLI2 plays a central role in the pathogenic dominant-negative activity resulting from mutations [Roessler et al 2005].

PTCH1. PATCHED-1 (PTCH1), the receptor for SHH, normally represses SHH signaling. The repression is relieved when SHH binds to PTCH1. Five different mutations in PTCH1 have been detected in six unrelated individuals with HPE [Ming & Muenke 2002, Rahimov et al 2006]. Upon binding of SHH, the repressive activity of PTCH1 is relieved, and the SHH signaling pathway is activated. Haploinsufficiency for PTCH1 has been shown to cause nevoid basal cell carcinoma syndrome (Gorlin syndrome). PTCH1 mutations have been found in clinically normal individuals in HPE pedigrees, consistent with the phenotype described in pedigree analysis of autosomal dominant HPE, including kindreds with SHH mutations. As with those individuals who have mutations in SHH, craniofacial anomalies are present in those with PTCH1 mutations. No clinical features distinguish individuals with PTCH1 mutations from those in the HPE population as a whole or those with identified SHH mutations.

Multifactorial Inheritance

The pathogenesis of HPE is felt to involve multiple interacting genetic and environmental factors, though in terms of genetic factors, recent evidence points to the role of a single major mutation modified by variants of individually smaller effect [Ming & Muenke 2002, Roessler et al 2012]. Abnormal sterol metabolism has been demonstrated in a significant number of persons with alterations in HPE-associated genes. The accumulation of sterol intermediates may be caused by either defective regulation of cholesterol biosynthesis or defects in its intracellular transport. These mechanisms may aggravate SHH signaling, leading to the brain malformation syndrome [Haas et al 2007, Haas & Muenke 2010].

Evaluation Strategy

Identification of the cause of holoprosencephaly (HPE) aids in establishing prognosis and mode of inheritance for genetic counseling.

To help establish the cause of HPE, the work-up for an individual with HPE includes the following:

  • Prenatal history to identify possible environmental causes
  • Physical examination to identify findings that could establish the diagnosis of monogenic syndromic HPE
  • A detailed family history with emphasis on pregnancy loss, neonatal deaths, and relatives with abnormal craniofacial findings and/or developmental delay to determine if monogenic nonsyndromic HPE is a consideration
  • Focused examination of the parents to identify microforms of HPE (see Clinical Subtypes of HPE and Range of Possible Craniofacial Findings, microforms of HPE)
  • Genetic testing
    • For affected children in whom environmental or monogenic causes seem unlikely, chromosome analysis of blood that examines at least 20 metaphases at the 550-band level or greater should be performed. Note: Chromosome analysis of the parents is recommended only if the proband has an abnormal karyotype (other than a trisomy or triploidy) or if the child with HPE is deceased, and therefore chromosome analysis on the proband is not possible. For logistical reasons, karyotype may be performed prior to chromosomal microarray, though the latter test is clearly of higher diagnostic yield.
    • Submicroscopic deletions for HPE-related genes (e.g., SHH, ZIC2, TGIF1, SIX3) have been identified by deletion/duplication analysis (e.g., quantitative PCR, FISH, multiple ligation-dependent probe amplification [MLPA], chromosomal microarray [CMA]) in up to 5% of individuals with HPE [Bendavid et al 2006a, Bendavid et al 2006b, Bendavid et al 2007, Lacbawan et al 2009, Solomon et al 2010a]; therefore, these methods should be performed to detect submicroscopic deletions in the currently known HPE-related genes. While CMA has the highest diagnostic yield and may identify both known HPE-associated loci as well as other genomic anomalies, logistical considerations including availability of the various testing modalities may influence testing decisions.
    • If monogenic nonsyndromic HPE is confirmed or likely, molecular genetic testing of the genes in which mutation is known to cause HPE should be considered (Table 1). A panel of known HPE-associated genes (typically SHH, ZIC2, SIX3, and TGIF1) are usually sequenced simultaneously, but clues from clinical presentation (see Clinical Manifestations of Nonsyndromic HPE for discussion on presentations associated with mutations in specific genes) may influence the decision about which genes to test [Pineda-Alvarez et al 2010, Solomon et al 2010b].
    • CMA may be pursued both in persons with classic non-chromosomal, nonsyndromic HPE and in those with HPE and other anomalies. By CMA, pathogenic anomalies may be detected in up to 10% of individuals with HPE who have normal karyotypes and normal sequencing of the commercially available HPE-associated genes [Author, unpublished data].

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

If a proband with HPE is found to have an inherited or de novo chromosome abnormality, a specific syndrome associated with holoprosencephaly (HPE), or a disease-causing mutation in a single gene, counseling for that condition is indicated [Mercier et al 2010].

For probands with HPE without a clear etiology, recurrence risk for family members is likely to be low, but may be as high as 50% because of the possibility of germline mosaicism for a mutation in one of the genes associated with nonsyndromic HPE [Lacbawan et al 2009, Solomon et al 2010a].

Mode of Inheritance

Nonsyndromic HPE may be inherited in an autosomal dominant manner or may be the result of an inherited or de novo chromosome abnormality.

Risk to Family Members—Autosomal Dominant

Parents of a proband

  • Some individuals diagnosed with autosomal dominant nonsyndromic HPE have an affected parent.
  • However, a proband with autosomal dominant nonsyndromic HPE may have the disorder as the result of a de novo gene mutation. The proportion of cases caused by new gene mutations is estimated to be approximately 10%-30% for SHH, 70%-80% for ZIC2, and 10%-20% for SIX3 [Lacbawan et al 2009, Solomon et al 2010a, Solomon et al 2010b].
  • Recommendations for the evaluation of parents of a child with nonsyndromic HPE and no known family history of HPE include evaluation for microforms of HPE. In some cases, a single microform is the only clue that a given individual has autosomal dominant nonsyndromic HPE and thus is at increased risk of having affected offspring. Note, however, that none of the microforms is pathognomonic for HPE and each can occur as an isolated finding apart from the HPE spectrum.

Sibs of a proband. The risk to the sibs of the proband depends on the status of the parents:

Offspring of a proband

  • Every child of an individual with a gene mutation for autosomal dominant nonsyndromic HPE has a 50% chance of inheriting the mutation.
  • Although severely affected individuals do not reproduce, individuals with mild forms and microforms of autosomal dominant HPE may do so. The clinical symptoms and severity are variable; the phenotype may range from mild to severe.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected or has a disease-causing mutation, his or her family members are at risk.

Risk to Family Members—Numeric Chromosome Abnormality

Parents of a proband

  • Parents of a child with a numeric chromosome abnormality (e.g., trisomy or triploidy) are expected to be chromosomally and phenotypically normal.
  • Parents of a child with a structural unbalanced chromosome rearrangement (e.g., deletion, duplication) are at risk of having a balanced chromosome rearrangement and should be offered chromosome analysis.

Sibs of a proband

  • Sibs of a child with a numeric chromosome abnormality have a slightly increased risk of having a similar chromosome abnormality (depending on the specific abnormality and the age of the mother) with a similar or different phenotype.
  • The risk to the sibs of a child with a structural unbalanced chromosome rearrangement depends on the chromosome status of the parents:
    • If neither parent has a structural rearrangement, the risk to sibs is negligible.
    • If a parent has a balanced structural rearrangement, the risk is increased and depends on the specific rearrangement and possibly other variables.

Offspring of a proband. Individuals with HPE and a chromosome rearrangement are unlikely to reproduce.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent has a chromosome rearrangement, his or her family members are at risk and can be offered chromosome analysis.

Carrier Detection

If a parent has a chromosome rearrangement, at-risk family members can be tested by chromosome analysis.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Experiences of families with prenatal diagnosis. Redlinger-Grosse et al [2002] reviewed the experiences of individuals who received a prenatal diagnosis of HPE.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

High-risk pregnancies

Molecular genetic testing. Prenatal diagnosis is possible for families in which a disease-causing mutation has been identified in an affected family member. While interpretation of certain mutations (e.g., a stop codon) is relatively straightforward, the lack of availability of functional analyses may raise challenges for the interpretation of many variations in any gene, even ones clearly associated with HPE.

Testing is performed using DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Fetal ultrasound examination. For families with autosomal dominant nonsyndromic HPE and no identifiable disease-causing mutation, alobar HPE can be diagnosed by prenatal ultrasound examination by 16 weeks' gestation [Blaas et al 2000, Leonard et al 2000]. Milder degrees of HPE including semilobar or lobar HPE cannot reliably be detected by prenatal ultrasound examination.

Lobar HPE can be recognized in utero with sonography. However, a specific diagnosis is often difficult and relies on qualitative evaluation of the morphology of the ventricles. MRI may demonstrate an abnormal appearance of the fornices, which are rudimentary and fused into a single fascicle running within the third ventricle. This finding was demonstrated by sonography in a 30-week-old fetus with lobar HPE; the finding was confirmed after birth by both ultrasound examination and MRI. Therefore, antenatal demonstration of an echogenic linear structure running within the third ventricle is a specific sign of lobar HPE, and can assist this difficult diagnosis.

Fetal MRI has been used in several centers to evaluate CNS structure when ultrasound studies have suggested the presence of an anomaly [Guo et al 2001, Blaicher et al 2003, Sharma et al 2003, Blaicher et al 2004, Wald et al 2004]. MRI is particularly useful for the evaluation of the posterior fossa and the median telencephalon as well as for etiologic clarification of hydrocephalus. Ultrafast MRI minimizes artifacts of fetal motion. Because MRI involves no exposure to radiation, it appears to be safe.

Chromosomal analysis. For families in which a parent has a balanced chromosomal rearrangement, fetal karyotype can be analyzed from fetal cells obtained by CVS at approximately ten to 12 weeks' gestation or amniocentesis usually performed at approximately 15 to 18 weeks' gestation.

Chromosomal microarray (CMA). The presence of certain detected CNVs may be difficult to interpret and may or may not contribute to HPE in a given instance. In instances in which genomic anomalies are detected by CMA, HPE may variably be accompanied by other phenotypic findings not typically associated with HPE. As with detection of any anomaly by genetic testing, identification of a genomic anomaly by CMA should prompt discussion of familial testing (possibly including parents, siblings, and other relatives) in order to provide accurate genetic counseling [Bendavid et al 2009, Pineda-Alvarez et al 2010].

Low-risk pregnancies. When HPE is found on routine prenatal ultrasound examination in a fetus not known to be at increased risk for HPE, a high-resolution ultrasound examination to determine the presence of additional structural anomalies is indicated [Sonigo et al 1998]. Additional testing on amniotic fluid may be done to establish the cause of the HPE for recurrence risk counseling of the parents. Such testing can include the following:

  • Fetal karyotype
  • CMA if the karyotype is normal (or instead of karyotype) to detect microdeletions of the four genes in which mutation is most often causative of HPE (SHH, ZIC2, SIX3, and TGIF1), a possible common cause of HPE detected prenatally [Bendavid et al 2006b, Bendavid et al 2007]
  • Sequence analysis of the following genes (in order from most to least common): SHH, ZIC2, SIX3, TGIF1, GLI2, PTCH1, FOXH1, and NODAL

If the fetus has HPE identified by ultrasound examination, decision making about the pregnancy may occur independent of the specific diagnosis established.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Carter Centers for Brain Research in Holoprosencephaly and Related Malformations
    Email: hpe@stanford.edu
  • National Institute of Neurological Disorders and Stroke (NINDS)
    PO Box 5801
    Bethesda MD 20824
    Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in a child diagnosed with holoprosencephaly (HPE), evaluation for the following is recommended at a minimum (other organ systems may also be investigated depending on specific clinical findings):

  • Cleft lip and/or palate
  • Hydrocephalus and/or features of HPE or other cortical anomalies. All children with midline facial anomalies should undergo brain MRI; attention should also be paid to the pituitary region, which often requires high-resolution thin sections.
  • Growth deficiency. Height, weight, and head circumference should be measured. It is important to compare weight to height in addition to plotting absolute measurements. Evaluation should include thyroid function tests, bone age, complete blood count, blood chemistries, sedimentation rate, insulin-like growth factor 1, and insulin-like growth factor binding protein 3. If growth hormone deficiency is found, panhypopituitarism should be assessed by specific hormone testing and brain MRI.
  • Pituitary dysfunction. Sagittal MRI can be used to determine pituitary absence or ectopia and anatomic information. CNS anomalies and absent corpus callosum and/or septum pellucidum may accompany endocrine dysfunction. Serum analysis for specific hormones can be performed to evaluate pituitary function.
  • Oral feeding and swallowing. Evaluation should include assessment of caloric intake, swallowing abilities, oral motor skills, and presence of gastroesophageal reflux. Occupational and speech evaluations are warranted to evaluate and address feeding concerns. Studies for diagnosis of gastroesophageal reflux including esophageal pH probe, milk scan, barium swallow, and/or endoscopy may be considered.

Treatment of Manifestations

Treatment for HPE varies according to the brain malformations and associated anomalies [Levey et al 2010]. Most affected children benefit from a multidisciplinary team approach with clinicians very familiar with HPE.

  • Hormone replacement therapy has been successful in some children with pituitary dysfunction.
  • Antiepileptic drugs can help decrease the frequency and intensity of seizures.
  • Feeding difficulties and failure to thrive may be managed with gastrostomy tube placement and Nissen fundoplication if gastroesophageal reflux and vomiting are issues. Thickening of feeds and upright positioning after feeding may be helpful to alleviate gastroesophageal reflux. To achieve the best growth in the child with HPE, the quality of the feeds is more important than the quantity.
  • Accommodations for oral feeding with cleft lip and/or palate may require specific nipples, cups, and parental training. Early surgical repair may improve feeding.
  • Placement of a ventriculo-peritoneal shunt may be necessary in children with HPE and hydrocephalus.
  • In older children, surgical repair of cleft lip and/or palate may be indicated.
  • For children with cleft lip and/or palate, referral to a specialized cleft or craniofacial clinic is recommended.
  • Onset of new neurologic findings or deterioration warrant evaluation for seizures and/or hydrocephalus and/or shunt malfunction. Such evaluation would include vital sign monitoring, neurologic examination, EEG, and MRI.
  • A major aspect of treatment is support and counseling of the parents [Mercier et al 2010].

Prevention of Secondary Complications

Children with hormonal disturbances should receive prompt evaluation during times of stress (e.g., illness, surgery).

Consultation with subspecialists regarding fluid and electrolyte management should be sought if elective surgery is planned.

Children with diabetes insipidus need careful monitoring of fluid and electrolyte intake.

Surveillance

Height, weight, and head circumference should be measured during health maintenance evaluations.

Evaluation for endocrine deficiencies should be undertaken at appropriate intervals and during health maintenance visits.

Evaluation of Relatives at Risk

A careful family history by a clinical geneticist familiar with HPE is critical, as genetic changes associated with HPE, even in a mildly affected individual, would be considered a risk factor for manifestations such as developmental delay.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Assessment of the risks and benefits of surgery and of the individual's brain abnormality is essential in determining the extent and benefit of surgical intervention.

Consistent with the ethical principle of beneficence, intervention at the earliest time possible is advised.

References

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Suggested Reading

  1. Muenke M, Beachy PA. Holoprosencephaly. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 250. Available online. Accessed 8-19-13.

Chapter Notes

Revision History

  • 29 August 2013 (me) Comprehensive update posted live
  • 3 November 2011 (cd) Revision: clinical testing available for FOXH1 and NODAL
  • 30 March 2010 (me) Comprehensive update posted live
  • 5 March 2008 (me) Comprehensive update posted to live Web site
  • 11 March 2005 (me) Comprehensive update posted to live Web site
  • 27 January 2003 (me) Comprehensive update posted to live Web site
  • 27 December 2000 (pb) Overview posted to live Web site
  • August 2000 (mm) Original submission

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