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Holoprosencephaly Overview

, MD, , MD, FACMG, and , MD, MPH.

Author Information and Affiliations

Initial Posting: ; Last Update: March 5, 2020.

Estimated reading time: 35 minutes


The purpose of this overview is to increase the awareness of clinicians regarding the genetic causes of holoprosencephaly and to inform genetic counseling of family members. The following are the goals of this overview.

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.

1. Clinical Characteristics of Holoprosencephaly

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 [Gropman & Muenke 2005, Dubourg et al 2007, Grinblat & Lipinski 2019].

While HPE is often first identified on prenatal ultrasound examination [Kousa et al 2018], it is most frequently diagnosed during the newborn period when abnormal facial findings and/or neurologic presentation prompt further evaluation. 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 [Weiss et al 2018b].

Imaging of the brain by CT scan or MRI defines the type of HPE and identifies associated CNS anomalies [Hahn & Barnes 2010, Griffiths & Jarvis 2016, Kousa et al 2018]. 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 and/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].

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.

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.

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.

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.

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.

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

Other Structural CNS Findings

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

  • Anomalies of midline structures: undivided thalami, agenesis of the corpus callosum (OMIM 217990), callosal dysgenesis [Kidron et al 2016], 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
  • Caudal dysgenesis

Craniofacial Anomalies

The continuum of craniofacial anomalies, present in approximately 80% of individuals with HPE, includes cyclopia, synophthalmia, or a proboscis at the severe end and normal facies in individuals who have, but are not expressing, an HPE pathogenic variant inherited in an autosomal dominant manner. Common subtle facial features in individuals without obvious craniofacial findings include microcephaly (although hydrocephalus can result in macrocephaly), closely spaced eyes (also known as hypotelorism; potentially severe), depressed nasal ridge, and cleft lip and/or palate. A single maxillary central incisor may be present; although a nonspecific finding, it is a distinctive microform in autosomal dominant HPE [Lacbawan et al 2009, Richieri-Costa & Ribeiro 2010].

Of note, subtle facial anomalies in mildly affected family members 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).

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

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.

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].

2. Genetic Causes of Holoprosencephaly

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].

Table 1.

Syndromes with Holoprosencephaly as an Occasional Finding: Monogenic Causes

MOIGeneDisorderClinical Subtype(s) of HPECraniofacial FindingsOther Key Features / CommentCitation
AD CDON Steinfeld syndrome (OMIM 184705)Microform HPECHD, absent gallbladder, renal dysplasia, & radial defects Jones et al [2016]
FGFR1 Kallman syndrome 2 (See Isolated GnRH Deficiency.)Cleft lip & palateAssoc of isolated hypogonadotropic hypogonadism & HPE Dubourg et al [2016]
Hartsfield syndrome HPE-related craniofacial featuresUnique assoc of HPE & ectrodactylySimonis et al [2013], Hong et al [2016], Palumbo et al [2019]
AR CENPF Strømme syndrome Alobar HPEMicrocephalyIntestinal atresia & variable ocular abnormalities Alghamdi et al [2020]
DHCR7 Smith-Lemli-Opitz syndrome Alobar HPEMicrocephaly, short nose & anteverted nares~5% of affected persons have HPE. Weaver et al [2010]

AD = autosomal dominant; AR = autosomal recessive; CHD = congenital heart disease; HPE = holoprosencephaly; MOI = mode of inheritance

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.

Figure 6.

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

Table 2a.

Nonsyndromic Holoprosencephaly: Most Common Monogenic Causes

Gene 1% of All
Other Key Features / CommentSelected
OMIM Entries
SHH 5.4%-5.9% 2Spectrum of HPE-related craniofacial features
  • Affected persons may be part of large kindreds segregating the variant; many of these families are not identified until ascertainment of the severely affected proband3
  • Renal/urinary anomalies may be more common than in those w/pathogenic variants in other HPE genes. 4


4.8%-5.2% 2Bitemporal narrowing, upslanted palpebral fissures, large ears, short nose w/anteverted nares, & broad & deep philtrum 3
  • Renal/urinary anomalies may be more common than in those w/pathogenic variants in other HPE genes. 4
  • Pathogenic variants are more frequently de novo than are variants in other HPE genes & appear to have high penetrance w/relatively few mildly manifesting persons. 5


~3% 6Spectrum of HPE-related craniofacial features
  • Affected persons may be part of large kindreds segregating the variant; many of these families are not identified until ascertainment of the severely affected proband3
  • May be assoc w/more severe types of HPE
TGIF1 <1% 2Spectrum of HPE-related craniofacial featuresMay demonstrate the entire spectrum of severity 7 142946

Table 2b.

Nonsyndromic Holoprosencephaly: Less Common Monogenic Causes

Gene 1% of All
Other Key Features / CommentSelected
CDON RareRareRange of classic HPE-spectrum features described in several unrelated persons 2 614226
CNOT1 <1.5%Microtia, microcephaly, epicanthal folds, long philtrum
  • Semilobar HPE described in 2 unrelated persons
  • Neonatal diabetes mellitus requiring insulin may be a feature.
  • Pancreatic exocrine insufficiency may be present.
  • May be assoc w/sensorineural & conductive hearing loss w/ossicle anomalies 3
DISP1 <1.2%Bilateral cleft lip/palate, hypotelorism, single central maxillary incisorFacial features may be consistent w/HPE-spectrum anomalies w/o corresponding brain anomalies. 4 607502
DLL1 <1%RareFacial features may be consistent w/HPE-spectrum anomalies. 5 606582
FGF8 <2.2%Spectrum of HPE-related craniofacial featuresRange of classic HPE-spectrum features described in several unrelated persons 6 600483
FGFR1 ~ 1.2%Spectrum of HPE-related craniofacial featuresIsolated HPE 7
KMT2D RareSpectrum of HPE-related craniofacial featuresRange of classic HPE-spectrum features described in 2 unrelated persons 8
PPP1R12A RareWide spectrum of craniofacial featuresHPE, urogenital malformations, & DD 9
RAD21 RareSpectrum of HPE-related craniofacial features
  • Range of HPE-spectrum features described in 5 unrelated persons.
  • May be assoc w/mild forms of HPE 10
SMC1A RareSpectrum of HPE-related craniofacial featuresRange of classic HPE-spectrum features described in 5 unrelated females 10
SMC3 RareHPE-related craniofacial featuresHPE-spectrum features described in 1 person w/semilobar HPE 10
STAG2 RareSpectrum of HPE-related craniofacial featuresRange of classic HPE-spectrum features described in 6 unrelated females 10
STIL RareRare
  • May present w/a range of classic HPE-spectrum features
  • AR inheritance in all reported persons 11

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)

3. Evaluation Strategies to Identify the Genetic Cause of Holoprosencephaly in a Proband

Establishing a specific genetic cause of holoprosencephaly (HPE) can aid in discussions of prognosis (which are beyond the scope of this GeneReview) and genetic counseling.

Evaluations to determine a specific genetic cause of holoprosencephaly usually involve the following.

Prenatal history to identify possible environmental causes. The most common teratogen in humans known to cause HPE is diabetes mellitus. While both gestational and pre-gestational diabetes are risk factors for HPE, pre-gestational diabetes requiring insulin confers the highest (>10-fold increased) HPE risk [Johnson & Rasmussen 2010, Tinker et al 2019].

Physical examination. A detailed physical examination should be conducted with special emphasis on extracranial features, especially those associated with syndromic forms of HPE (see Table 1) [Kruszka & Muenke 2018]. Of note, it is not uncommon to find extracranial anomalies in individuals with nonsyndromic HPE (see Tables 2a, 2b) [Martinez et al 2018].

Family history. A three-generation family history should be taken with attention to pregnancy loss, neonatal deaths, and relatives with manifestations of holoprosencephaly and/or developmental delay with documentation of relevant findings through direct examination or review of medical records, including results of molecular genetic testing.

Focused examination of the parents and apparently normal sibs (whenever possible) to identify milder manifestations of HPE.

Molecular genetic testing. Approaches can include a combination of gene-targeted testing (multigene panel or single-gene testing) and comprehensive genomic testing (chromosomal microarray analysis, genome sequencing, exome sequencing, or exome array). Gene-targeted testing requires the clinician to hypothesize which gene(s) are likely involved, whereas genomic testing does not.

  • Chromosomal microarray analysis (CMA) using oligonucleotide or SNP arrays detects genome-wide large deletions/duplications in all forms of HPE, including apparently nonsyndromic HPE and HPE with associated anomalies. CMA has been successful in identifying pathogenic variants in up to 14% of individuals with HPE who have a normal karyotype and no causative gene identified on multigene panel testing.
  • Chromosome analysis. Diagnostic methods for detecting chromosome abnormalities in individuals with HPE are not different from those routinely used in the investigation of numeric and structural cytogenetic abnormalities in those with other genetic conditions or birth defects. Recommended methods include: G-banding karyotype and CMA [Kruszka et al 2018]. If there is clinical suspicion for trisomy 13, a karyotype should be done first; otherwise, a CMA should be done first [Pineda-Alvarez et al 2010, Solomon et al 2010c], including trisomy 13.
  • Single-gene testing. When a specific syndromic cause of HPE is considered (Table 1), sequence analysis of the gene of interest is performed first to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used and the gene involved, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to consider gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
  • A multigene panel that includes some or all of the genes listed in Tables 1, 2a, and 2b is most likely to identify the genetic cause of HPE while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Of note, given the rarity of some of the genes associated with HPE, some panels may not include all the genes mentioned in this overview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used; genome sequencing is also possible. If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant or mendelian inheritance – exome array (when clinically available) may be considered to detect multiexon deletions or duplications that cannot be detected by sequence analysis.
    For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

4. Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of 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; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

If a genetic etiology (chromosome abnormality, monogenic condition, or pathogenic variant in a HPE-associated gene) is established in a proband with HPE, specific counseling for recurrence risk is indicated [Hadley et al 2018].

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

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

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

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

High-Risk Pregnancies

Molecular genetic testing. Once the HPE-causing pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk for HPE and preimplantation genetic testing are possible.

Fetal ultrasound examination. For families with nonsyndromic HPE and no identifiable etiology, alobar HPE can be diagnosed by prenatal ultrasound examination between ten to 14 weeks of gestation based on abnormal facial morphology (as seen in many cases) and absence of the normal configuration of the choroid plexuses within the lateral ventricles, called "butterfly sign" [Kousa et al 2018, Calloni et al 2019]. 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 ultrasound. However, a specific diagnosis is often difficult and relies on qualitative evaluation of the morphology of the ventricles. Though not specific, antenatal demonstration of an echogenic linear structure running anterior-posterior within the third ventricle is highly suggestive of lobar HPE, and can assist this difficult diagnosis.

Fetal MRI is routinely used as a second-line investigation in several centers to evaluate CNS structure when ultrasound studies have suggested the presence of an anomaly [Edwards & Hui 2018]. MRI is useful for the evaluation of the posterior fossa and the median telencephalon as well as for etiologic clarification of hydrocephalus. Fetal MRI is particularly valuable for clarifying the anatomic subtypes of HPE, and thus informing on its severity [Edwards & Hui 2018, Kousa et al 2018, Calloni et al 2019]. Ultrafast MRI minimizes artifacts caused by fetal motion. Because MRI involves no exposure to radiation, it appears to be safe.

Low-Risk Pregnancies

When HPE is found on routine prenatal ultrasound examination in a fetus not known to be at increased risk for HPE, an extensive fetal examination, preferably using high-resolution ultrasound examination (e.g., examination with 3D ultrasound) to determine the presence of additional structural anomalies is indicated [Edwards & Hui 2018]. Additional testing on amniotic fluid may be done to both establish the cause of HPE and assist in the management of the pregnancy and the recurrence risk counseling of the parents. Such testing can include the following [Kruszka et al 2018]:

  • Fetal karyotype to detect numeric and structural chromosome abnormalities. Fetal karyotype is usually the first test ordered in the context of low-risk pregnancies.
  • CMA if the karyotype is normal (or instead of karyotype) to detect pathogenic deletions or duplications (and aneuploidies if no previous karyotype) in the genes known to cause HPE (see Tables 2a, 2b). Of note, alternative assays such as MLPA may be used for this purpose.
  • Multigene panel sequencing including at least the three following genes: SHH, ZIC2, and SIX3

It is essential to bear in mind that if the fetus has HPE identified by ultrasound examination, medical and parental decision making about the pregnancy may occur independent of a specific genetic diagnosis.


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Chapter Notes

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


Literature Cited

  • Alghamdi M, Alkhamis WH, Jamjoom D, Al-Nafisah G, Tahir A, Abdouelhoda M. Expanding the phenotype and the genotype of Stromme syndrome: A novel variant of the CENPF gene and literature review. Eur J Med Genet. 2020;63:103844. [PubMed: 31953238]
  • Aoi H, Lei M, Mizuguchi T, Nishioka N, Goto T, Miyama S, Suzuki T, Iwama K, Uchiyama Y, Mitsuhashi S, Itakura A, Takeda S, Matsumoto N. Nonsense variants in STAG2 result in distinct sex-dependent phenotypes. J Hum Genet. 2019;64:487-92. [PubMed: 30765867]
  • Arauz RF, Solomon BD, Pineda-Alvarez DE, Gropman AL, Parsons JA, Roessler E, Muenke M. A Hypomorphic allele in the FGF8 gene contributes to holoprosencephaly and is allelic to gonadotropin-releasing hormone deficiency in humans. Mol Syndromol. 2010;1:59-66. [PMC free article: PMC2941840] [PubMed: 21045958]
  • Bae GU, Domené S, Roessler E, Schachter K, Kang JS, Muenke M, Krauss RS. Mutations in CDON, encoding a hedgehog receptor, result in holoprosencephaly and defective interactions with other hedgehog receptors. Am J Hum Genet. 2011;89:231-40. [PMC free article: PMC3155179] [PubMed: 21802063]
  • Bear KA, Solomon BD, Antonini S, Arnhold IJ, França MM, Gerkes EH, Grange DK, Hadley DW, Jääskeläinen J, Paulo SS, Rump P, Stratakis CA, Thompson EM, Willis M, Winder TL, Jorge AA, Roessler E, Muenke M. Pathogenic mutations in GLI2 cause a specific phenotype that is distinct from holoprosencephaly. J Med Genet. 2014;51:413-8. [PMC free article: PMC6417429] [PubMed: 24744436]
  • Bear KA, Solomon BD. GLI2 mutations typically result in pituitary anomalies with or without postaxial polydactyly. Am J Med Genet A. 2015;167A:2491-2. [PubMed: 25974718]
  • Brown LY, Odent S, David V, Blayau M, Dubourg C, Apacik C, Delgado MA, Hall BD, Reynolds JF, Sommer A, Wieczorek D, Brown SA, Muenke M. Holoprosencephaly due to mutations in ZIC2: alanine tract expansion mutations may be caused by parental somatic recombination. Hum Mol Genet. 2001;10:791–6. [PubMed: 11285244]
  • Calloni, SF, Caschera L, Triulzi FM. Disorders of ventral induction/spectrum of holoprosencephaly. Neuroimaging Clin N Am. 2019;29:411-21. [PubMed: 31256862]
  • Dubourg C, Bendavid C, Pasquier L, Henry C, Odent S, David V. Holoprosencephaly. Orphanet J Rare Dis. 2007;2:8. [PMC free article: PMC1802747] [PubMed: 17274816]
  • Dubourg C, Carre W, Hamdi-Roze H, Mouden C, Roume J, Abdelmajid B, Amram D, Baumann C, Chassaing N, Coubes C, Faivre-Olivier L, Ginglinger E, Gonzales M, Levy-Mozziconacci A, Lynch S-A, Naudion S, Pasquier L, Poidvin A, Prieur F, Sarda P, Toutain A, Dupé V, Akloul L, Odent S, de Tayrac M, David, V. Mutational spectrum in holoprosencephaly shows that FGF is a new major signaling pathway. Hum Mut. 2016;37:1329-39. [PubMed: 27363716]
  • Dubourg C, Kim A, Watrin E, de Tayrac M, Odent S, David V, Dupé V. Recent advances in understanding inheritance of holoprosencephaly. Am J Med Genet. 2018;178:258-69. [PubMed: 29785796]
  • Dupé V, Rochard L, Mercier S, Le Pétillon Y, Gicquel I, Bendavid C, Bourrouillou G, Kini U, Thauvin-Robinet C, Bohan TP, Odent S, Dubourg C, David V. NOTCH, a new signaling pathway implicated in holoprosencephaly. Hum Mol Genet. 2011;20:1122-31. [PMC free article: PMC3390777] [PubMed: 21196490]
  • Edwards L, Hui L. First and second trimester screening for fetal structural anomalies. Semin Fetal Neonatal Med. 2018;23:102-11. [PubMed: 29233624]
  • Griffiths PD, Jarvis D. In utero MR imaging of fetal holoprosencephaly: a structured approach to diagnosis and classification. AJNR Am J Neuroradiol. 2016;37:536-43. [PMC free article: PMC7960122] [PubMed: 26564444]
  • Grinblat Y, Lipinski RJ. A forebrain undivided: Unleashing model organisms to solve the mysteries of holoprosencephaly. Developmental Dynamics. 2019;248:626-33. [PubMed: 30993762]
  • Gropman AL, Muenke M. Holoprosencephaly. In: Cassidy SB, Allanson JE, eds. Management of Genetic Syndromes. New York, NY: Wiley-Liss, Inc; 2005:279-96.
  • Hadley DW, Kruszka P, Muenke M. Challenging issues arising in counseling families experiencing holoprosencephaly. Am J Med Genet. 2018;178:238-45. [PubMed: 30182441]
  • Hahn JS, Barnes PD, Clegg NJ, Stashinko EE. Septopreoptic holoprosencephaly: a mild subtype associated with midline craniofacial anomalies. AJNR Am J Neuroradiol. 2010;31:1596-601. [PMC free article: PMC7965016] [PubMed: 20488907]
  • Hahn JS, Barnes PD. Neuroimaging advances in holoprosencephaly: refining the spectrum of the midline malformation. Am J Med Genet Part C Semin Med Genet. 2010;154C:120-32. [PubMed: 20104607]
  • Hong S, Hu P, Marino J, Hufnagel SB, Hopkin RJ, Toromanović A, Richieri-Costa A, Ribeiro-Bicudo LA, Kruszka P, Roessler E, Muenke M. Dominant-negative kinase domain mutations in FGFR1 can explain the clinical severity of Hartsfield syndrome. Hum Mol Genet. 2016;25:1912-22. [PMC free article: PMC5062582] [PubMed: 26931467]
  • Hong S, Hu P, Roessler E, Hu T, Muenke M. Loss-of-function mutations in FGF8 can be independent risk factors for holoprosencephaly. Hum Mol Genet. 2018;27:1989-98. [PMC free article: PMC6251617] [PubMed: 29584859]
  • Hu T, Kruszka P, Martinez AF, Ming JE, Shabason EK, Raam MS, Shaikh TH, Pineda-Alvarez DE, Muenke M. Cytogenetics and holoprosencephaly: A chromosomal microarray study of 222 individuals with holoprosencephaly. Am J Med Genet C Semin Med Genet. 2018;178:175-86. [PMC free article: PMC6127867] [PubMed: 30182442]
  • Hughes JJ, Alkhunaizi E, Kruszka P, Pyle LC, Grange DK, Berger SI, Payne KK, Masser-Frye D, Hu T, Christie MC, Clegg NJ, Everson JL, Martinez AF, Walsh LE, Bedoukian E, Jones MC, Harris CJ, Riedhammer KM, Choukair D, Fechner PY, Rutter MM, Hufnagel SB, Roifman M, Kletter GB, Delot E, Vilain E, Lipinski RJ, Vezina CM, Muenke M, Chitaya D. Loss-of-function variants in PPP1R12A: from isolated sex reversal to holoprosencephaly spectrum and urogenital malformations. Am J Hum Genet. 2020;106:121-8. [PMC free article: PMC7042489] [PubMed: 31883643]
  • Johnson CY, Rasmussen SA. Non-genetic risk factors for holoprosencephaly. Am J Med Genet C Semin Med Genet. 2010;154C:73-85. [PubMed: 20104598]
  • Jones GE, Robertson L, Maniyar A, Shammas C, Phelan MM, Vasudevan PC, Tanteles GA. Microform holoprosencephaly with bilateral congenital elbow dislocation; increasing the phenotypic spectrum of Steinfeld syndrome. Am J Med Genet A. 2016;170:754-9. [PubMed: 26728615]
  • Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519-22. [PubMed: 28959963]
  • Kagan KO, Staboulidou I, Syngelaki A, Cruz J, Nicolaides KH. The 11–13-week scan: Diagnosis and outcome of holoprosencephaly, exomphalos and megacystis. Ultrasound in Obstetrics and Gynecology. 2010;36:10-4. [PubMed: 20564304]
  • Kakar N, Ahmad J, Morris-Rosendahl DJ, Altmüller A, Friedrich K, Barbi G, Nürnberg P, Kubisch C, Dobyns WB, Borck G. STIL mutation causes autosomal recessive microcephalic lobar holoprosencephaly. Hum Genet. 2015;134:45-51. [PubMed: 25218063]
  • Keaton AA, Solomon BD, Kauvar EF, El-Jaick KB, Gropman AL, Zafer Y, Meck JM, Bale SJ, Grange DK, Haddad BR, Gowans GC, Clegg NJ, Delgado MR, Hahn JS, Pineda-Alvarez DE, Lacbawan F, Vélez JI, Roessler E, Muenke M. TGIF Mutations in Human Holoprosencephaly: Correlation between Genotype and Phenotype. Mol Syndromol. 2010;1:211-22. [PMC free article: PMC3214944] [PubMed: 22125506]
  • Kidron D, Shapira D, Ben Sira L, Malinger G, Lev D, Cioca A, Sharony R, Lerman ST. Agenesis of the corpus callosum. An autopsy study in fetuses. Virchows Arch. 2016;468:219-30. [PubMed: 26573426]
  • Kousa YA, du Plessis AJ, Vezina G. Prenatal diagnosis of holoprosencephaly. Am J Med Genet C Semin Med Genet. 2018;178:206-13. [PubMed: 29770996]
  • Kruszka P, Martinez AF, Muenke M. Molecular testing in holoprosencephaly. Am J Med Genet Part C Semin Med Genet. 2018;178:187-93. [PMC free article: PMC6125165] [PubMed: 29771000]
  • Kruszka P, Muenke M. Syndromes associated with holoprosencephaly. Am J Med Genet. 2018;178:229-37 [PMC free article: PMC6125175] [PubMed: 29770994]
  • Kruszka P, Berger SI, Weiss K, Everson JL, Martinez AF, Hong S, Anyane-Yeboa K, Lipinski RJ, Muenke M. A CCR4-NOT transcription complex, subunit 1, CNOT1, variant associated with holoprosencephaly. Am J Hum Genet. 2019a;104:990-3. [PMC free article: PMC6506867] [PubMed: 31006510]
  • Kruszka P, Berger SI, Casa V, Dekker MR, Gaesser J, Weiss K, Martinez AF, Murdock DR, Louie RJ, Prijoles EJ, Lichty AW, Brouwer OF, Zonneveld-Huijssoon E, Stephan MJ, Hogue J, Hu P, Tanima-Nagai M, Everson JL, Prasad C, Cereda A, Iascone M, Schreiber A, Zurcher V, Corsten-Janssen N, Escobar L, Clegg NJ, Delgado MR, Hajirnis O, Balasubramanian M, Kayserili H, Deardorff M, Poot RA, Wendt KS, Lipinski RJ, Muenke M. Cohesin complex-associated holoprosencephaly. Brain. 2019b;142:2631-43. [PMC free article: PMC7245359] [PubMed: 31334757]
  • Lacbawan F, Solomon BD, Roessler E, El-Jaick K, Domené S, Vélez JI, Zhou N, Hadley D, Balog JZ, Long R, Fryer A, Smith W, Omar S, McLean SD, Clarkson K, Lichty A, Clegg NJ, Delgado MR, Levey E, Stashinko E, Potocki L, Vanallen MI, Clayton-Smith J, Donnai D, Bianchi DW, Juliusson PB, Njølstad PR, Brunner HG, Carey JC, Hehr U, Müsebeck J, Wieacker PF, Postra A, Hennekam RC, van den Boogaard MJ, van Haeringen A, Paulussen A, Herbergs J, Schrander-Stumpel CT, Janecke AR, Chitayat D, Hahn J, McDonald-McGinn DM, Zackai EH, Dobyns WB, Muenke M. Clinical spectrum of SIX3-associated mutations in holoprosencephaly: correlation between genotype, phenotype and function. J Med Genet. 2009;46:389-98. [PMC free article: PMC3510661] [PubMed: 19346217]
  • Levey EB, Stashinko E, Clegg NJ, Delgado MR. Management of children with holoprosencephaly. Am J Med Genet C Semin Med Genet. 2010;154C:183-90. [PubMed: 20104615]
  • Martinez AF, Kruszka PS, Muenke M. Extracephalic manifestations of nonchromosomal, nonsyndromic holoprosencephaly. Am J Med Genet C Semin Med Genet. 2018;178:246-57. [PMC free article: PMC6125181] [PubMed: 29761634]
  • Mercier S, Dubourg C, Garcelon N, Campillo-Gimenez B, Gicquel I, Belleguic M, Ratié L, Pasquier L, Loget P, Bendavid C, Jaillard S, Rochard L, Quélin C, Dupé V, David V, Odent S. New findings for phenotype-genotype correlations in a large European series of holoprosencephaly cases. J Med Genet. 2011;48:752-60. [PMC free article: PMC3386902] [PubMed: 21940735]
  • Mouden C, de Tayrac M, Dubourg C, Rose S, Carré W, Hamdi-Rozé H, Babron MC, Akloul L, Héron-Longe B, Odent S, Dupé V, Giet R, David V. Homozygous STIL mutation causes holoprosencephaly and microcephaly in two siblings. PLoS One. 2015;10:e0117418. [PMC free article: PMC4319975] [PubMed: 25658757]
  • Nanni L, Ming JE, Bocian M, Steinhaus K, Bianchi DW, Die-Smulders C, Giannotti A, Imaizumi K, Jones KL, Campo MD, Martin RA, Meinecke P, Pierpont ME, Robin NH, Young ID, Roessler E, Muenke M. The mutational spectrum of the sonic hedgehog gene in holoprosencephaly: SHH mutations cause a significant proportion of autosomal dominant holoprosencephaly. Hum Mol Genet. 1999;8:2479–88 [PubMed: 10556296]
  • Palumbo P, Petracca A, Maggi R, Biagini T, Nardella G, Sacco MC, Di Schiavi E, Carella M, Micale L, Castori M. A novel dominant-negative FGFR1 variant causes Hartsfield syndrome by deregulating RAS/ERK1/2 pathway. Eur J Hum Genet. 2019;27:1113-20. [PMC free article: PMC6777633] [PubMed: 30787447]
  • Petracchi F, Crespo L, Michia C, Igarzabal L, Gadow E. Holoprosencephaly at prenatal diagnosis: Analysis of 28 cases regarding etiopathogenic diagnoses. Prenatal Diagnosis. 2011;31:887–891. [PubMed: 21706511]
  • Pineda-Alvarez DE, Dubourg C, David V, Roessler E, Muenke M. Current recommendations for the molecular evaluation of newly diagnosed holoprosencephaly patients. Am J Med Genet C Semin Med Genet. 2010;154C:93-101. [PMC free article: PMC2815008] [PubMed: 20104604]
  • Pineda-Alvarez DE, Solomon BD, Roessler E, Balog JZ, Hadley DW, Zein WM, Hadsall CK, Brooks BP, Muenke M. A broad range of ophthalmologic anomalies is part of the holoprosencephaly spectrum. Am J Med Genet A. 2011;155A:2713-20. [PMC free article: PMC3200498] [PubMed: 21976454]
  • Richieri-Costa A, Ribeiro LA. Holoprosencephaly and holoprosencephaly-like phenotypes: Review of facial and molecular findings in patients from a craniofacial hospital in Brazil. Am J Med Genet C Semin Med Genet. 2010;154C:149-57. [PubMed: 20104612]
  • Roessler E, Ma Y, Ouspenskaia MV, Lacbawan F, Bendavid C, Dubourg C, Beachy PA, Muenke M. Truncating loss-of-function mutations of DISP1 contribute to holoprosencephaly-like microform features in humans. Hum Genet. 2009;125:393-400. [PMC free article: PMC2774849] [PubMed: 19184110]
  • Roessler E, Vélez JI, Zhou N, Muenke M. Utilizing prospective sequence analysis of SHH, ZIC2, SIX3 and TGIF in holoprosencephaly probands to describe the parameters limiting the observed frequency of mutant gene×gene interactions. Mol Genet Metab. 2012;105:658-64. [PMC free article: PMC3309119] [PubMed: 22310223]
  • Rosa RFM, Correia EPE, Bastos CS, da Silva GS, Correia JD, da Rosa EB, Silveira DB, Targa LV, da Cunha AC, Zen PRG. Trisomy 18 and holoprosencephaly. Am J Med Genet A. 2017;173:1985-7. [PubMed: 28449414]
  • Ruda J, Grischkan J, Allarakhia Z. Radiologic, genetic, and endocrine findings in isolated congenital nasal pyriform aperture stenosis patients. Int J Pediatr Otorhinolaryngol. 2020;128:109705. [PubMed: 31606685]
  • Simonis N, Migeotte I, Lambert N, Perazzolo C, de Silva DC, Dimitrov B, Heinrichs C, Janssens S, Kerr B, Mortier G, Van Vliet G, Lepage P, Casimir G, Abramowicz M, Smits G, Vilain C. FGFR1 mutations cause Hartsfield syndrome, the unique association of holoprosencephaly and ectrodactyly. J Med Genet. 2013;50:585-92. [PMC free article: PMC3756455] [PubMed: 23812909]
  • Solomon BD, Bear KA, Wyllie A, Keaton AA, Dubourg C, David V, Mercier S, Odent S, Hehr U, Paulussen A, Clegg NJ, Delgado MR, Bale SJ, Lacbawan F, Ardinger HH, Aylsworth AS, Bhengu NL, Braddock S, Brookhyser K, Burton B, Gaspar H, Grix A, Horovitz D, Kanetzke E, Kayserili H, Lev D, Nikkel SM, Norton M, Roberts R, Saal H, Schaefer GB, Schneider A, Smith EK, Sowry E, Spence MA, Shalev SA, Steiner CE, Thompson EM, Winder TL, Balog JZ, Hadley DW, Zhou N, Pineda-Alvarez DE, Roessler E, Muenke M. Genotypic and phenotypic analysis of 396 individuals with mutations in Sonic Hedgehog. J Med Genet. 2012a;49:473-9. [PubMed: 22791840]
  • Solomon BD, Lacbawan F, Jain M, Domené S, Roessler E, Moore C, Dobyns WB, Muenke M. A novel SIX3 mutation segregates with holoprosencephaly in a large family. Am J Med Genet A. 2009a;149A:919-25. [PMC free article: PMC2737713] [PubMed: 19353631]
  • Solomon BD, Lacbawan F, Mercier S, Clegg NJ, Delgado MR, Rosenbaum K, Dubourg C, David V, Olney AH, Wehner LE, Hehr U, Bale S, Paulussen A, Smeets HJ, Hardisty E, Tylki-Szymanska A, Pronicka E, Clemens M, McPherson E, Hennekam RC, Hahn J, Stashinko E, Levey E, Wieczorek D, Roeder E, Schell-Apacik CC, Booth CW, Thomas RL, Kenwrick S, Keaton A, Balog JZ, Hadley D, Zhou N, Long R, Velez JI, Pineda-Alvarez DE, Odent S, Roessler E, Muenke M. Mutations in ZIC2 in human holoprosencephaly: description of a novel ZIC2-specific phenotype and comprehensive analysis of 157 individuals. J Med Genet. 2010a;47:513-24. [PMC free article: PMC3208626] [PubMed: 19955556]
  • Solomon BD, Mercier S, Vélez JI, Pineda-Alvarez DE, Wyllie A, Zhou N, Dubourg C, David V, Odent S, Roessler E, Muenke M. Analysis of genotype-phenotype correlations in human holoprosencephaly. Am J Med Genet C Semin Med Genet. 2010b;154C:133-41. [PMC free article: PMC2815217] [PubMed: 20104608]
  • Solomon BD, Pineda-Alvarez DE, Balog JZ, Hadley D, Gropman AL, Nandagopal R, Han JC, Hahn JS, Blain D, Brooks B, Muenke M. Compound heterozygosity for mutations in PAX6 in a patient with complex brain anomaly, neonatal diabetes mellitus, and microophthalmia. Am J Med Genet A. 2009b;149A:2543-6. [PMC free article: PMC2783496] [PubMed: 19876904]
  • Solomon BD, Pineda-Alvarez DE, Gropman AL, Willis MJ, Hadley DW, Muenke M. High intellectual function in individuals with mutation-positive microform holoprosencephaly. Mol Syndromol. 2012b;3:140-2. [PMC free article: PMC3473351] [PubMed: 23112757]
  • Solomon BD, Rosenbaum KN, Meck JM, Muenke M. Holoprosencephaly due to numeric chromosome abnormalities. Am J Med Genet C Semin Med Genet. 2010c;154C:146-8. [PMC free article: PMC2815046] [PubMed: 20104610]
  • Stokes, B, Berger SI, Hall, BA, Weiss K, Martinez AF, Hadley DW, Murdock DR, Ramanathan S, Clark RD, Roessler E, Kruszka P, Muenke M. SIX3 deletions and incomplete penetrance in families affected by holoprosencephaly. Congenit Anom (Kyoto). 2018;58:29-32. [PMC free article: PMC5750110] [PubMed: 28670735]
  • Tekendo-Ngongang C, Kruszka P, Martinez AF, Muenke M. Novel heterozygous variants in KMT2D associated with holoprosencephaly.Clin Genet. 2019;96:266-70. [PMC free article: PMC6690755] [PubMed: 31282990]
  • Tinker SC, Gilboa SM, Moore CA, Waller DK, Simeone RM, Kim SY, Jamieson DJ, Botto LD, Reefhuis J, et al. Specific birth defects in pregnancies of women with diabetes: National Birth Defects Prevention Study, 1997-2011. Am J Obstet Gynecol. 2019;S0002-9378:31030-0. [PMC free article: PMC7186569] [PubMed: 31454511]
  • Toufaily MH, Roberts DJ, Westgate MN, Holmes LB. Triploidy: Variation of Phenotype. Am J Clin Pathol. 2016;145:86-95. [PubMed: 26712875]
  • Weaver DD, Solomon BD, Akin-Samson K, Kelley RI, Muenke M. Cyclopia (synophthalmia) in Smith-Lemli-Opitz Syndrome - first reported case and consideration of mechanism. Am J Med Genet C Semin Med Genet. 2010;154C:142-5. [PMC free article: PMC2815131] [PubMed: 20104611]
  • Weiss K, Kruszka P, Sacoto MJG, Addissie YA, Hadley DW, Hadsall CK, Stokes B, Hu Ping, Roessler E, Solomon B, Wiggs E, Thurm A, Hufnagel RB, Zein WM, Hahn JS, Stashinko E, Levey E, Baldwin D, Clegg NJ, Delgado MR, Muenke M. In-depth investigations of adolescents and adults with holoprosencephaly identify unique characteristics. Genet Med. 2018a;20:14-23. [PMC free article: PMC5763157] [PubMed: 28640243]
  • Weiss K, Kruszka PS, Levey E, Muenke M. Holoprosencephaly from conception to adulthood. Am J Med Genet. 2018b;178:122-7. [PubMed: 30182446]
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