Goal 1.

Describe the clinical characteristics of holoprosencephaly.

Goal 2.

Review the genetic causes of holoprosencephaly.

Goal 3.

Provide an evaluation strategy to identify (when possible) the genetic cause of holoprosencephaly in a proband.

Goal 4.

Inform genetic counseling of family members of an individual with holoprosencephaly.

Types of HPE

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

Alobar HPE, in which there is a single "monoventricle" and no separation of the cerebral hemispheres (Figure 1), is the most severe form. The range of findings includes:

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 structures (thalami and basal (more...)

• 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 pathogenic variants in ZIC2)

Semilobar HPE. The left and right frontal and parietal lobes are fused and the interhemispheric fissure is only present posteriorly (Figure 2). The range of findings includes:

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 is present but more anterior (more...)

• Closely spaced eyes
• Anophthalmia/microophthalmia
• Depressed nasal ridge
• 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. 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 (Figure 3). The range of findings includes:

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. The posterior portion (more...)

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

Middle interhemispheric fusion variant (MIHF/MIHV or syntelencephaly). 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 (Figure 4).

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 are oriented nearly vertically (more...)

The range of findings includes:

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

Septopreoptic type. Nonseparation is restricted to the septal and/or preoptic regions; described in small case series [Hahn et al 2010].

Microforms of HPE (also termed "microform HPE") are clinical subtypes of HPE defined by the presence of HPE-related craniofacial anomalies without structural brain defects on imaging. They may occur in simplex HPE (i.e., a single occurrence of HPE in a family) or in relatives of probands with classic forms of HPE (Figure 5). Their clinical spectrum includes the following:

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

• Microcephaly [Solomon et al 2009a]
• Single central maxillary incisor [Lacbawan et al 2009, Richieri-Costa & Ribeiro 2010]
• Closely spaced eyes
• Anosmia/hyposmia (resulting from absence of olfactory tracts and bulbs)
• A broad range of ophthalmologic anomalies, including refractive errors, ptosis, microcornea, and coloboma [Pineda-Alvarez et al 2011]
• Sharp, narrow nasal bridge [Solomon et al 2009a]
• Absent superior labial frenulum
• Midface retrusion
• Congenital nasal pyriform aperture stenosis [Ruda et al 2020]
• Developmental delay (variably present). Of note, individuals with classic HPE-spectrum facial features and pathogenic variants seen in severely affected relatives may be intellectually gifted [Lacbawan et al 2009, Solomon et al 2010b, Solomon et al 2012b].

Clinical Manifestations of HPE

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 nonchromosomal, 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 chromosome 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. Additional 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 [Levey et al 2010].
• Aspiration pneumonia can be a complication of poor coordination of swallowing.
• Erratic sleep patterns can occur.

Life expectancy. 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. In fact, a proportion of individuals with HPE of various subtypes, including severe subtypes, survive until adulthood.

The longer survival may be on account of recent advances in diagnostic methods, including brain imaging methods that allow for early detection of both severe and mild malformations. Improvement in the management of HPE over time may have also contributed to longer survival [Levey et al 2010, Pineda-Alvarez et al 2010, Weiss et al 2018b].

The distribution of HPE subtypes appears to be similar among children, adolescents, and adults, with semilobar HPE representing approximately 50% of HPE in both children and adults. The exception is alobar HPE, which appears to be less frequent in adults than children [Weiss et al 2018a].

Among affected individuals with abnormal chromosome complement, 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.
• Approximately 85% of adults with HPE have a mild or nonclassic facial phenotype [Weiss et al 2018a].

Among affected adolescents and adults, sensorineural hearing loss is found in approximately 30% and cortical vision impairment in approximately 20% [Weiss et al 2018a].

Of note, 60% of adolescent and adult survivors have severe involvement: they are nonambulatory and nonverbal with minimal hand function, and full dependence on caregivers [Weiss et al 2018a]. There is a correlation between the degree of developmental delay and the severity of the brain malformation or HPE subtype [Levey et al 2010, Weiss et al 2018a].

Chromosome Abnormalities with Holoprosencephaly

Approximately 25%-50% of individuals with HPE have a chromosome abnormality. Chromosome abnormalities are nonspecific and either numeric or structural, and can involve any chromosome [Dubourg et al 2018].

Individuals with HPE and a normal chromosome complement cannot be distinguished from those with an abnormal chromosome complement based on craniofacial abnormality or HPE subtype; however, individuals with HPE caused by a chromosome abnormality are more likely to have other organ system involvement, resulting in a more severe clinical course in most.

Numeric chromosome abnormalities. Trisomy 13, the most common cause of HPE, is observed in 40%-60% of HPE of all causes and about 75% of HPE caused by chromosome abnormalities. Birth prevalence of trisomy 13 is 1:5000. Arrhinencephaly is seen in about 70% of individuals with trisomy 13.

The other common aneuploidies associated with HPE include trisomy 18 and triploidy. Various other aneuploidies have been reported [Kagan et al 2010, Solomon et al 2010c, Petracchi et al 2011, Toufaily et al 2016, Rosa et al 2017].

Structural chromosome abnormalities associated with HPE have been reported in virtually all chromosomes. The most frequent are deletions or duplications involving various regions of 13q, and del(18p), del(7)(q36), dup(3)(p24-pter), del(2)(p21), and del(21)(q22.3) [Hu et al 2018]. Many of these regions contain genes known to be associated with autosomal dominant nonsyndromic HPE (Tables 2a, 2b).

Pathogenic copy number variations (CNVs). Chromosomal microarray (CMA) includes array-based comparative genomic hybridization (array CGH) and SNP array. CMA has identified pathogenic CNVs (including loci already known to be associated with HPE) in 10% of all individuals with HPE. Note that CNV detection rates may vary by testing laboratory and methodology [Dubourg et al 2018, Hu et al 2018].

Monogenic Syndromes with Holoprosencephaly as an Occasional Finding

Approximately 18%-25% of individuals with HPE have a pathogenic variant 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 are summarized in Table 1 [Kruszka & Muenke 2018].

Single-Gene Disorders with Isolated (Nonsyndromic) Holoprosencephaly

The nonsyndromic forms of HPE best understood at a molecular genetic level are inherited in an autosomal dominant manner (see Tables 2a, 2b).

The phenotype of individuals with pathogenic variants in genes associated with nonsyndromic HPE is extremely variable even within the same family, ranging from alobar HPE with cyclopia to clinically normal [Solomon et al 2010a, Solomon et al 2010b, Dubourg et al 2018].

In the majority of individuals with HPE, a correlation exists between the facial anomalies and the gene involved and/or type of pathogenic variant (see Figure 6 and Types of HPE). However, it is important to note that in many cases this correlation cannot be made.

Figure 6.

Facial findings in holoprosencephaly (HPE) A. Alobar HPE with cyclopia and proboscis above the single eye

Variants in other candidate genes including FOXH1, GAS1, NODAL, PTCH1, SUFU, and CRIPTO (formerly TDGF1) have seldom been reported in individuals with nonsyndromic HPE. However, because investigations of several large HPE cohorts have failed to reproduce these findings, more data may be needed to confirm the possible role of these genes in HPE pathogenesis.

Although GLI2 pathogenic variants were described as a cause of HPE, it has become clear that GLI2 variants do not cause HPE, but rather a distinct phenotype characterized by pituitary anomalies, polydactyly, and subtle facial features (sometimes similar to HPE facial features) consistent with Culler-Jones syndrome (OMIM 615849) [Bear et al 2014, Bear & Solomon 2015].

Holoprosencephaly of Unknown Cause

Autosomal dominant vs multifactorial. Microtia-anotia (OMIM 600674) and other anomalies

Unknown mode of inheritance [Kruszka & Muenke 2018]

• Caudal dysgenesis (OMIM 600145)
• Pseudotrisomy 13 (OMIM 264480)
• Genoa syndrome (OMIM 601370)
• Brachial amelia, cleft lip, and holoprosencephaly (OMIM 601357)

Chromosome Abnormality – Risk to Family Members

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

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• Many individuals diagnosed with autosomal dominant nonsyndromic HPE (Tables 2a, 2b) inherited a pathogenic variant from a heterozygous parent who may or may not have HPE-spectrum anomalies [Mouden et al 2015].
• Some individuals with autosomal dominant nonsyndromic HPE may have the disorder as the result of a de novo pathogenic variant. The proportion of cases caused by a de novo variant is estimated at 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, Weiss et al 2018a].
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant. Recommendations may also include evaluation of the parents for mild manifestations of HPE.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent.* Germline mosaicism has been suggested based on the finding of several families [Nanni et al 1999, Brown et al 2001, Lacbawan et al 2009, Solomon et al 2010a; Solomon et al 2010b].
  * Misattributed parentage can also be explored as an alternative explanation for an apparent de novo pathogenic variant.
• The family history of some individuals diagnosed with HPE may appear to be negative because of reduced penetrance and failure to recognize the disorder in family members; this is particularly true for families with HPE caused by pathogenic variants in SIX3 [Stokes et al 2018]. In some cases, a single mild manifestation 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 mild manifestations is pathognomonic for HPE and each can occur as an isolated finding apart from the HPE spectrum. Therefore, an apparently negative family history cannot be confirmed unless appropriate molecular genetic testing has been performed on the parents of the proband.

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

• If a parent is affected or has an HPE pathogenic variant (with or without clinical manifestations), the risk to sibs of inheriting the variant is 50%. Empiric studies indicate that sibs who inherit a pathogenic variant have a 20% risk for HPE, 15% risk for an HPE microform, and a 15% likelihood of a normal phenotype.
• If the proband has a known HPE pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is low, but slightly greater than that of the general population because of the possibility of parental germline mosaicism [Nanni et al 1999, Brown et al 2001, Lacbawan et al 2009, Solomon et al 2010a, Solomon et al 2010b].
• If the parents have not been tested for the HPE pathogenic variant in the proband but are clinically unaffected and the family history is negative, the risk to the sibs of the proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for HPE because of the possibility of reduced penetrance in a parent or parental germline mosaicism.

Offspring of a proband

• Every child of an individual with a pathogenic variant for autosomal dominant nonsyndromic HPE has a 50% chance of inheriting the pathogenic variant.
• Although severely affected individuals do not reproduce, individuals with mild forms and microforms of autosomal dominant HPE may do so. The clinical manifestations and severity in offspring may range from mild to severe.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected or has a pathogenic variant, the parent's family members may be at risk.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one STIL pathogenic variant; see Tables 2a, 2b).
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a STIL pathogenic variant and to allow reliable recurrence risk assessment. (Although a de novo pathogenic variant has not been reported in STIL-HPE to date, de novo variants are known to occur at a low but appreciable rate in autosomal recessive disorders [Jónsson et al 2017].)
• Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

• If both parents are known to be heterozygous for a STIL pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. To date, individuals with STIL-HPE are not known to reproduce.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a STIL pathogenic variant.

Carrier detection. Carrier testing for at-risk relatives requires prior identification of the STIL pathogenic variants in the family.

X-Linked Inheritance – Risk to Family Members

Parents of a female proband

• A female proband with X-linked HPE caused by a pathogenic variant in STAG2 or SMC1A may have inherited a pathogenic variant from either her mother or her father, or the pathogenic variant may be de novo.
• To date, the majority of individuals with X-linked HPE are female, represent simplex cases (i.e., a single occurrence in the family), and have the disorder as the result of a de novo pathogenic variant.
• Molecular genetic testing is recommended for both parents of a female proband.
• If the STAG2 or SMC1A pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the proband most likely has a de novo pathogenic variant. Another possible explanation is that the proband inherited a pathogenic variant from a parent with germline mosaicism.
• Note: The mother of a proband who is found to be heterozygous for a STAG2 or SMC1A pathogenic variant may have favorable skewed X inactivation that results in her being mildly affected or unaffected.

Parents of a male proband

• If a male is the only affected family member (i.e., a simplex case), the mother may be heterozygous or the affected male may have a de novo pathogenic variant, in which case the mother is not heterozygous. To date, X-linked HPE has been reported in only one male; the affected male had the disorder as the result of a de novo STAG2 truncating variant [Aoi et al 2019]; SMC1A-HPE has not been reported in a male proband.
• Molecular genetic testing is recommended for the mother of a male proband.
• The father of an affected male will not have the disorder nor will he be hemizygous for an X-linked HPE-causing pathogenic variant; therefore, he does not require further evaluation/testing.

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

• If the mother of the proband has a STAG2 or SMC1A pathogenic variant, the chance of transmitting it in each pregnancy is 50%.
  • Females who inherit the pathogenic variant are at high risk of developing HPE, although skewed X inactivation may result in variable phenotypic expression.
  • Because the large majority of individuals affected with X-linked HPE identified to date are females, it is very likely that males who inherit STAG2 or SMC1A variants either do not survive or present a severe HPE phenotype [Aoi et al 2019, Kruszka et al 2019b].
• If the father of the proband has a STAG2 or SMC1A pathogenic variant, he will transmit it to all his daughters and none of his sons.
• If the proband represents a simplex case and if the STAG2 or SMC1A pathogenic variant cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of parental germline mosaicism.

Sibs of a male proband. The risk to sibs depends on the genetic status of the mother:

• If the mother of the proband has a STAG2 or SMC1A pathogenic variant, the chance of transmitting it in each pregnancy is 50% (see Sibs of a female proband).
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the STAG2 or SMC1A pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is greater than that of the general population because of the possibility of maternal germline mosaicism.

Offspring of a proband

• Each child of a female proband with X-linked HPE has a 50% chance of inheriting the STAG2 or SMC1A pathogenic variant. Female probands with frank HPE are very unlikely to reproduce.
• Each daughter of a male proband with X-linked HPE has a 50% chance of inheriting the STAG2 or SMC1A pathogenic variant. Surviving male probands with frank HPE are very unlikely to reproduce.

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent is affected or has a STAG2 or SMC1A pathogenic variant, the parent's family members may be at risk.

Prenatal Testing and Preimplantation Genetic Testing

Author History

Andrea L Gropman, MD, FAAP, FACMG; Children's National Health System (2000-2020)

Paul Kruszka, MD, MPH (2020-present)

Maximilian Muenke, MD, FACMG (2000-present)

Benjamin D Solomon, MD; National Human Genome Research Institute (2010-2020)

Cedrik Tekendo-Ngongang, MD (2020-present)

Revision History

• 5 March 2020 (bp) Comprehensive update posted live
• 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 live
• 11 March 2005 (me) Comprehensive update posted live
• 27 January 2003 (me) Comprehensive update posted live
• 27 December 2000 (pb) Overview posted live
• August 2000 (mm) Original submission

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