Holoprosencephaly

Harvey B Sarnat MD FRCPC MS

Developmental Malformations

Updated 11.05.2023
Released 10.21.1994
Expires For CME 11.05.2026

Holoprosencephaly

Author: Harvey B Sarnat MD FRCPC MS

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Holoprosencephaly

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Introduction

Overview

In this updated review of holoprosencephaly, the author discusses basic diagnostic anatomical features, pathogenetic and etiologic factors, as well as genetic, epidemiologic, and other data essential to understanding this complex disorder. Research indicates that the diverse phenotypic variations may stem from a host of genetic mutations and is further suggestive of gene-environment interactions. In severe forms, the disease is lethal. The treatment of patients with less severe forms continues to be refined but can be substantial.

Key points

	• Holoprosencephaly is the most common congenital malformation to affect the forebrain and often the face in liveborn infants.
	• In its most severe forms, holoprosencephaly is lethal; in milder forms, prolonged survival is possible but may require specialized, long-term care.
	• Hydrocephalus may occur because of atresia of the third ventricle or midbrain cerebral aqueduct.
	• Causes are diverse and include teratogens (maternal diabetes mellitus, ethyl alcohol, cholesterol requirements for hedgehog signaling), chromosomal abnormalities (most often trisomy 13), and gene mutations (most commonly SHH, SIX3, ZIC2, and TGIF), with gene-environmental interactions hypothesized. Most mutations occur de novo, and nearly three-quarters of cases do not have a recognized genetic cause.
	• Despite this, a genetic diagnosis is lacking in some 80% to 90% of patients without aneuploidy. Environmental factors and maternal exposure to teratogenic toxins in early pregnancy are epigenetic factors that may interact with genetics.

Historical note and terminology

The earliest references to holoprosencephaly were from ancient mythology and generally involved cyclopic individuals.

These writings presumably had a basis in fact, for cyclopia occurs naturally in humans and a variety of animals. During the 16th and 17th centuries, several of the natural philosophers described cyclopic individuals, but these were still pictured with both real and imaginary features. The late 18th and 19th centuries brought more accurate portrayals. Sommering's atlas contains a precise line drawing of a full-term hydrocephalic cranium with a rudimentary, single nostril nose; olfactory nerves were absent (277). In 1832, Isidore Geoffrey Saint-Hilaire produced a detailed if somewhat arbitrary morphological classification of holoprosencephaly, the "cyclocephalians," whose details remain largely valid today (92; 278). Taruffi reworked Geoffrey Saint-Hilaire's scheme, using a now defunct term, "hypoproso-aplasia" (288).

By the late 19th century, the external facial features of holoprosencephaly were well documented. The first experimental production of holoprosencephaly was by Dareste (70), and in 1882 Kundrat described the cerebral changes of holoprosencephaly, including absent olfactory nerves, coining the term "arrhinencephaly" (152).

The 20th century brought further developments, first in the anatomic and clinical delineation of the disorder and later in cytogenetics. Yakovlev used the term "holotelencephaly" to describe a cerebrum that had failed to develop into separate hemispheres (312). DeMyer and Zeman first used the term "holoprosencephaly," feeling that the word more accurately described the anomaly as being prosencephalic rather than telencephalic in origin and scope (73). DeMyer and Cohen steadfastly contributed to the clinical understanding of the disorder, and Siebert and colleagues added to the fund of morphologic knowledge. Munke (or Muenke) and colleagues have extended the genetic understanding of this disorder considerably, mapping several genes associated with holoprosencephaly (193; 231).

Clinical manifestations

Presentation and course

Holoprosencephaly is a congenital malformation of the brain. In its most severe form, the cerebrum presents as a unified holosphere, termed "alobar" or "complete" holoprosencephaly.

Holoprosencephaly (gross)

Severe holoprosencephaly with the cerebrum as a unified holosphere. (Contributed by Dr. Joseph Siebert.)
Holoprosencephaly, internal view

Severe holoprosencephaly with the cerebrum as a unified holosphere. (Contributed by Dr. Joseph Siebert.)

In lobar or semilobar (incomplete) holoprosencephaly, the hemispheres are variably separated, such that a hypoplastic falx cerebri and incomplete interhemispheric fissure are found in frontal and occipital regions. Structures of the posterior fossa are variably developed as well. The association of facial changes with holoprosencephaly inspired DeMyer's classic assertion that "the face predicts the brain," although exceptions are recognized (74). Because craniofacial anomalies are induced by prosencephalic and mesencephalic neural crest from the neural tube, it has been suggested that the DeMyer quotation be reversed to “the brain predicts the face” (45). Craniofacial anomalies include the following: close-set orbits (ocular hypotelorism) or infrequently, widely spaced ones (ocular hypertelorism); nasal abnormalities, ranging from flattened nose or deficient nasal septum to single nostril, choanal atresia, or arrhinia; thin lip with indistinct philtrum; single central incisor, cleft upper lip; cleft palate; small mouth; small mandible; or in rare cases, agnathia. In rare cases, alobar holoprosencephaly may be associated with arrhinia or absence of a nose or even a proboscis, with atresia of internal nasal structures, including the nasal septum and turbinate bones; respiratory distress and obstructive apnea may result (35).

Holoprosencephaly is a prototype example of a disorder of genetic programming of developmental processes of the brain and involves gradients of genetic expression along all three axes of the neural tube (94; 240; 244; 44). A universal finding of variable degree is failure of prosencephalic cleavage in the sagittal midline to form two telencephalic hemispheres. A monoventricle of the forebrain persists rather than formation of paired lateral ventricles (296; 220). Animal models of holoprosencephaly have been developed to better understand its pathogenesis (98). Accompanying mid-facial hypoplasias result from involvement of neural crest production and migration from prosencephalic and mesencephalic sites (244). Facial dysplasias are frequent, but not universal, in alobar and semilobar, but not the milder lobar holoprosencephaly, and usually are midfacial hypoplasia. However, rare human cases of holoprosencephaly are reported with diprosopus (craniofacial duplication) (197). Spontaneous cases of holoprosencephaly with similar facial anomalies also are reported in dogs (19; 211).

Delayed or otherwise abnormal myelination associated with holoprosencephaly carries widespread ramifications. Mental retardation is variable but is usually moderate to profound. Mild cases of lobar holoprosencephaly may be only mildly developmentally delayed with borderline intellectual deficits. Attention deficit hyperactivity disorder, subtle midline facial anomalies, hypotelorism, and microcephaly have been reported in siblings of a patient with alobar holoprosencephaly and Sonic hedgehog mutation (115). Most holoprosencephalic infants are hypotonic, but spastic diplegia becomes evident between 6 and 24 months of age in the majority; a minority remain hypotonic in later childhood or have muscle tone that approaches normal.

Epilepsy is not invariable and does not necessarily correlate with the severity of the malformation. Some patients develop infantile spasms or severe myoclonic, partial, generalized, or mixed forms of seizure disorders that often are refractory to conventional anticonvulsant medications and corticotropin. Gelastic seizures have been reported in two patients (08). However, up to 40% of infants and children with alobar/semilobar holoprosencephaly never develop any type of epilepsy, in part, because axons are hyperinsulated by an extracellular proteoglycan, keratan sulfate (249).

In most cases of lobar and semilobar holoprosencephaly, hydrocephalus is a complication, particularly if a dorsal cyst is present. This hydrocephalus is due to fusion of the thalami with obliteration of the third ventricle and aqueductal stenosis if the rostrocaudal gradient of genetic expression extends to the diencephalon and midbrain (244). Hydrocephalus also can be a complication of the milder lobar form of holoprosencephaly with absence of a dorsal cyst than of the more severe alobar or semilobar forms.

Prognosis and complications

Little has been written about prognosis, and that has been influenced by ascertainment bias, which is to say, severely affected patients are more easily recognized and followed than those with milder forms. This will change with improved imaging and recognition of the disorder.

Survival is limited in infants with severe changes of the brain and face, associated anomalies, and chromosomal abnormalities, but much better for those with intermediate or mild forms. Those with the mildest forms probably do not have shortened life spans (109). One review of survival and performance indicated that half of children with alobar holoprosencephaly die before 4 or 5 months of age; 20% to 30% live at least 1 year (20). In one study, the mean age of patients was 4 years (279). In a study of 20 patients who were at least 15 years old, one half had the semilobar form (306). Causes of death include brainstem dysfunction with respiratory failure, intractable seizures, diabetes insipidus, and pneumonia, often aspiration or viral. Other problems include choking during feeding, vomiting after feeding, gastroesophageal reflux, and profound developmental delay. Patients with the alobar form have limited language skills but can develop other consistent forms of response to stimuli, and motor skills are negligible. Sleep disorders and difficulties with thermal regulation occur as well (157). Patients with Sonic hedgehog mutations and mild holoprosencephaly-like phenotype may have significant impairment of language (238). Neurogenic hypernatremia has been reported in a case of semilobar holoprosencephaly (250).

Excessive Hedgehog signaling is associated with an increased risk of certain cancers (36; 14). Hedgehog pathway inhibitors, such as cyclopamine or synthetically modified compounds, are being tested in patients with certain neoplasms (161). Care needs to be exercised, of course, to avoid these regimens in pregnant women. One case of holoprosencephaly has been associated with methotrexate administration at 6 weeks’ gestation (252). Sonic hedgehog also is associated with short-rib polydactyly syndromes as additional extraneural anomalies (166). Postaxial polydactyly and visceral anomalies with holoprosencephaly also can occur in trisomy-13 (51). Sonic hedgehog deficiency in the caudal spinal cord region of the early neural tube, associated with sacral agenesis and defective notochord in that region, also is known and rarely holoprosencephaly and sacral agenesis occur simultaneously at both ends of the neural tube with terminal chromosomal deletion 7q36 --> 7qter (187).

Clinical vignette

This case was first published by Siebert and colleagues and is representative of the course of many newborn infants with holoprosencephaly (264). The infant male had karyotypically documented trisomy 13 and alobar holoprosencephaly with cebocephaly (single-nostril nose and choanal atresia) and ocular hypotelorism.

Holoprosencephaly in newborn infant

Cebocephaly, ocular hypotelorism, and polysyndactyly of the III, IV, and V digits of the hand are typical characteristics of infants with holoprosencephaly. (Contributed by Dr. Joseph Siebert.)

Other stigmata of trisomy 13 included occipital scalp defect; postaxial polydactyly of left hand and both feet; polysyndactyly of III, IV, and V digits of right hand; ventricular septal defect and pericardial defect; hypoplastic penis and undescended testes; malrotation of gut; Meckel diverticulum; fusion of spleen and tail of pancreas; and large kidneys with medullary dysplasia identified focally.

The infant was born at 38 weeks to a gravida 2, 26-year-old para 2 woman. Cesarean section was required because of double footling breech presentation. Respiratory distress was immediate and required intubation. The infant survived 4.5 hours.

Biological basis

Etiology and pathogenesis

Studies have been complicated by several factors, including the remarkably heterogeneous phenotype and the fact that holoprosencephaly is manifested as isolated or syndromic, sporadic or heritable, and karyotypically and cytogenetically normal or abnormal (Table 1).

Table 1. Etiologic Factors

Cause		Number of reports
Chromosomal Monogenic		6 common; numerous uncommon 17
	Autosomal dominant Autosomal recessive X-linked recessive	13 3 1
Environmental Associations Unknown		4 4 8
Adapted from (55; 61; 231; 05).

Etiologic heterogeneity has been well demonstrated. Although numerous teratogenic substances and organisms have been associated with holoprosencephaly (Table 2), most derive from anecdotal case reports and are not considered major causes. Maternal diabetes, retinoic acid, and cholesterol requirements for hedgehog signalling are exceptions to this (229). Alcohol (ethanol) deserves ongoing scrutiny as a probable cause of holoprosencephaly. It impairs neural crest migration, especially in association with genetic factors (275), and has been used experimentally to produce the disorder in fish (280), mice (282; 116), and the pigtail macaque (263). Ethyl alcohol abuse has been implicated by numerous case reports in humans (214; 130; 170; 235; 65; 96). Experiments have shown that ethanol itself, rather than a metabolite, is the responsible agent (119). Methanol is another teratogen that deserves increased scrutiny in humans. It is the chemical with the highest environmental release, is found in numerous products, and has been associated with holoprosencephaly in exposed mice (234). A statistical association of maternal thyroid hormone use and holoprosencephaly has been reported (odds ratio 2.48; 95% confidence limit 1.13-5.44). The authors emphasize that thyroid hormone should not be considered a teratogen at this point but rather that holoprosencephaly could be the result of mothers’ underlying hypothyroidism (123).

Table 2. Postulated or Proven Human Teratogens

Maternal diabetes* Ethanol* Retinoic acid* Chlordiazepoxide Diphenylhydantoin Quinine	Cortisone Estroprogestins Toxoplasma Cytomegalovirus Rubella
Salicylate Misoprostol Maternal hypocholesterolemia	X-Irradiation Contraceptives Sulfasalazine Hyperthermia Maternal low-calorie reducing diet
	Pesticides
* Known teratogens (others are postulated). Adapted from (56; 61; 05).

Because holoprosencephaly can be due to both genetic mutations and also early fetal environmental or maternal exposure to teratogenic toxins, risk factors must consider both etiologies in its pathogenesis (06; 165).

As is the case with many congenital defects, the understanding of holoprosencephaly is undergoing rapid flux as molecular controls and the role of neural crest in craniofacial development become understood. Early thoughts regarding the origin of the disorder were based on anatomic features observed in affected infants and their embryologic correlates. The study of human embryos has been hampered by their paucity and the technical constraints of size and morphologic ambiguity in early development. Three valuable studies are available (315; 313; 259). The craniofacial manifestations typical of holoprosencephalic infants (Table 3) suggested morphogenetic errors in interactions of neuroectoderm with prechordal mesoderm (74) or notochordal and oral plates (60). Later studies further delineated the morphology of the disorder, indicating that pathogenesis occurs in the first 4 weeks of gestation (261; 145; 191; 13). Comparisons with both mild and severe defects of the craniofacial complex (notably, CHARGE syndrome, DiGeorge sequence, fetal alcohol syndrome, Patau syndrome, atelencephaly, aprosencephaly, and anencephaly) implicated faulty morphogenesis at several levels, involving developmental field(s) of the anterior cranium and ethmoid complex (including prechordal mesoderm), with involvement of the cephalic neural crest (261; 265; 269; 267; 191; 143; 158; 275; 75). Other researchers have suggested possible roles of the fetal ependyma (240; 241), disruption of blastogenesis (205), and altered heterochrony (308). The pathogenesis and pathophysiology of holoprosencephaly are becoming better understood with the elucidation of molecular controls, which is reflected in publications of classification systems for CNS malformations based on patterns of genetic expression (243; 245).

Table 3. Facial Changes Associated with Holoprosencephaly

Classification	Major features
Normocephaly	Normal face
Mild facial dysmorphism	Ocular hypotelorism (or rarely, hypertelorism), single central maxillary incisor, unilateral or bilateral cleft lip or palate, flattened nose, iridal coloboma
Premaxillary dysgenesis	Median cleft lip, with variable abnormality or absence of premaxillary structures, nasal anomalies
Cebocephaly	Ocular hypotelorism, single nostril nose with atretic nasal cavity
Ethmocephaly	Ocular hypotelorism (sometimes with synophthalmia), arrhinia, interorbital proboscis
Cyclopia	Single median orbit with absence or variable pairing of ocular structures, arrhinia, occasional supraorbital proboscis, occasionally hypoplastic or absent mandible with otocephaly
Arrhinia	Absence of a nose or proboscis, with atresia of intranasal structures, including turbinate bones and nasal septum

Changes in the central nervous system have traditionally been described as "alobar," "lobar," and "semilobar" (73; 74). Shaw has proffered two simpler and pathogenetically more accurate terms, "complete" and "incomplete" holoprosencephaly (264), a stance that has gained support as the spectrum of anomalies comes to be viewed as a continuum (107). The embryonic forebrain fails to cleave in each of the major anatomical planes. Alobar brains show complete noncleavage of cerebral hemispheres and one midline ventricle, sometimes referred to as a holosphere and monoventricle, respectively. Lobar specimens show complete separation of hemispheres, often with absent olfactory bulbs and tracts (arrhinencephaly) or hypoplastic ones located beneath the olfactory trigone.

Lobar holoprosencephaly (gross)

The olfactory bulbs and tracts are absent. (Contributed by Dr. Joseph Siebert.)

Olfactory bulbs are populated by neuroblasts from the rostral telencephalon, so the association with holoprosencephaly is not unexpected (248). In holoprosencephaly, deep gray nuclei (hypothalami, thalami, lentiform and caudate nuclei, mesencephalic structures) are fused to a variable extent (271).

Other variants also exist. Intermediate changes in affected brains were designated semilobar by DeMyer. Perhaps in part because they are less common, this form has received less attention than alobar or lobar forms. In the semilobar form, frontal lobes are small and variably fused; the falx cerebri is present posteriorly, and the occipital lobes are separate. Dorsal cysts are sometimes present and generally associated with noncleavage of the thalamus (270; 272). Facial changes are generally at the milder end of the spectrum. Imaging studies, chiefly MRI, have identified another variant of holoprosencephaly termed “middle interhemispheric fusion” (17). In one review, this form was noted in 20 of 93 patients diagnosed with holoprosencephaly (270). Frontal and occipital lobes and deep gray nuclei are separate, but the posterior frontal and parietal convexities are joined; the callosal genu and splenium are normal, but the body is absent. Additional study of middle interhemispheric fusion has shown that the sylvian fissures connect in abnormal fashion across the midline (86% of patients), cerebral dysplasia or gray matter heterotopia are common (86%), caudate nuclei are separated by the cerebral hemispheres, and hypothalamus and lentiform nuclei are separated by the third ventricle; 25% had a dorsal cyst and none had ocular hypotelorism (273). These authors suggest that the embryonic roof plate may be involved, in contrast to the floor plate in more typical cases of holoprosencephaly, which is a stance that has received support (103). Genes important to roof plate development may be underexpressed, or genes involved in floor plate or notochord development may be overexpressed (39; 272; 16). In support of this is the observation that deletions in the long arm of chromosome 13, where ZIC2 (a dorsal-patterning gene) is located, have been found in several patients with middle interhemispheric fusion (38; 174). Bone morphogenetic proteins are also important in roof plate signaling and dorsal telencephalic patterning; ablation of the roof plate in mice results in holoprosencephaly (52). Disruption of the dorsalizing effect of bone morphogenetic proteins is thought to be important to cases of middle interhemispheric fusion (88). An additional infrequent but probably also underrecognized variant, septopreoptic holoprosencephaly, consists of midline fusion that is limited to septal or preoptic areas (208).

Changes in the brain are thought to involve failure of the lamina terminalis to develop (162) and displacement or dystrophia of the foramen of Monro (264). Earlier inductive mechanisms are certainly involved, ie, notochordal or prechordal mesodermal induction of the lamina terminalis to form the prosencephalic floor plate (240). Hypoxia may play a role early in development, as evidenced by the presence of cyclopia in an acardiac twin (262). Workers have also identified the twinning process in general as a risk factor for holoprosencephaly (283). Abnormalities in cortical and retinal development (eg, precocious synaptogenesis, altered radial glial fibers) may contribute to the later development of seizure activity (246; 247). Leptomeningeal glioneuronal heterotopia are relatively constant in alobar holoprosencephaly (185), though others have suggested that defects in radial cell migration are probably rare (94). Neuronal abnormalities are also evidenced by EEG changes (see below) and the finding of premature and ectopic development of dendrites and synaptic networks in holoprosencephalic brains (12). Altered synaptogenesis may predispose to epileptogenic activity, with aberrations in cortical architecture manifest in occasional cases as lissencephaly (203; 246).

The contribution of germinal matrix to the pathogenesis of holoprosencephaly has also been considered by several authors. Faulty neuronagenesis may result in hypoplasia of the germinal matrix; with deficient growth of germinal cells, the telencephalic vesicles may not evaginate or may do so incompletely, resulting in one or two lateral ventricles (264). The germinal matrix may also extend into the ventricular cavity through defects in the ependyma. If this tissue fills the lateral or third ventricles, hydrocephalus may result on an obstructive basis (240). Absent lateral and third ventricles (aventriculi) have also been associated with holoprosencephaly, although the finding appears to be more reminiscent of atelencephaly or aprosencephaly (253; 151; 156).

Frontal lobes and lateral ventricles may be joined, but structures caudal to the prosencephalon (ie, oculomotor nuclei, thalami, superior colliculi) may be joined as well, or they may be hypoplastic. The cerebellum may also be dysplastic, and Chiari type 1 malformation, vermian anomalies, and partial rhombencephalosynapsis have been associated with holoprosencephaly (264; 240; 90; 221). Agenesis of the corpus callosum, when associated with holoprosencephaly, consists of complete absence of callosal fibers. This is unlike simple agenesis of the corpus callosum, in which axons do not cross the midline but course posteriorly as a bundle of Probst (240). It is often associated with abnormal karyotype and other CNS or extracranial malformations (93). Agenesis of the corpus callosum can also be partial in some variants. The association of holoprosencephaly and diencephalic hamartoblastoma has been reported (46).

Of particular interest is the dorsal cyst, which is variably present but can be strikingly large. Unfortunately, if unrecognized by antemortem imaging or at autopsy, the diagnosis can be missed; consequently, the association of dorsal cysts with holoprosencephaly is probably underestimated. Dorsal cysts are generally large, membrane-bound, and lie in the sagittal fissure between the cerebral hemispheres (or, in alobar holoprosencephaly, posterior to the single joined cerebrum). Dorsal cysts communicate with the ventricular system but lack a distinct third ventricle or foramen of Monro (258). Most are so fragile or disrupted that their origin cannot be ascertained. Because of anatomic variations, it is possible that different modes of pathogenesis are involved. Some dorsal cysts, for example, seem to represent an ependymal-lined expansion of the single ventricle and may derive from dysgenesis of the galenic system (319; 320). Some may represent extreme dilatation of the third ventricle, possibly resulting from blockage of CSF circulation by noncleavage of thalami (272).

Keratan sulfate is an extracellular proteoglycan secreted by astrocytes in the CNS. One of its important functions in the developing nervous system is to envelop axonal fascicles to ensure that axons do not exit the site programmed for them and that extraneous axons en route cannot enter the fascicle (242). In fetal holoprosencephaly, keratan sulfate not only envelops fascicles, but in addition, ensheathes individual axons within fascicles, further insulating them long before myelination begins and prevents the formation of axodendritic excitatory synapses, which may help explain why up to 40% of infants with alobar and semilobar holoprosencephaly do not develop epilepsy despite severe cortical dysgenesis (249).

Genetics. The genetics of holoprosencephaly is remarkably heterogeneous, as indicated by the substantial number of associated karyotypic abnormalities (62; 59). Numerous studies have shown that the karyotype is abnormal in one half of patients with holoprosencephaly (264; 204). Trisomy 13 is the most common chromosomal aberration, but trisomy 18 and even trisomy 21 and triploidy are also recognized (22; 206; 179). Trisomy 4p has been put forth as a locus for holoprosencephaly (135).

Among genetic mutations, approximately one half appear to be de novo, and even familial mutations are associated with marked phenotypic variability (210). Germ line mosaicism is encountered rarely. However, low-level parental mosaicism may be present in some cases and affect recurrence rates (125). Workers have implicated four morphogens or morphogen families (Nodal, Sonic hedgehog, fibroblast growth factors, and bone morphogenetic proteins) and, to date, mapped eight genes associated with holoprosencephaly (Table 4); at least 13 loci have been identified on 11 different chromosomes (300; 186; 27; 25). On chromosome 21, a gene first designated as HPE1 (193). Another gene (SIX3) resides on the short arm of chromosome 2 (2p21), where interstitial deletions and missense mutations have been identified (100; 192; 309). A homeobox-containing gene, SIX3 (designating six deletions and three translocations), is activated by the transcription factor Sox2 and appears to be involved in anterior neural plate and ocular development (97; 301; 209; 159). SIX3 mutations are associated with more severe holoprosencephalic phenotypes than nonchromosomal, nonsyndromic cases (154). In mice, it regulates sonic hedgehog expression in the forebrain (91). Incomplete penetrance has been identified in individuals with inherited holoprosencephaly due to SIX3 deletions (281).

A third gene (Sonic hedgehog) has been localized to the long arm of chromosome 7, at 7q36 (167; 187). Mutations in this gene are the most frequently encountered genetic abnormality in holoprosencephaly (230) and are thought to be responsible for some sporadic and most autosomal dominant forms of holoprosencephaly (111; 194). Over 100 mutations in SHH are recognized and lead to diverse phenotypes (64; 228; 31). Sonic hedgehog is responsible for central nervous system patterning in the ventral midline (85; 233). In the presence of Sonic hedgehog mutations, genes that are normally expressed ventrally are not induced, either in experimental conditions or clinically (251). Deletions or rearrangements involving 7q (and, subsequently, Sonic hedgehog) as well as translocations suppressing Sonic hedgehog appear to be responsible for the development of holoprosencephaly (233; 48). Sonic hedgehog is also thought to enhance the expression of Goosecoid, a gene expressed in axial head mesoderm (prechordal plate), involved in early organization (ie, dorsoventral patterning) of the head, and absent in cyclops (Zebrafish) mutants (77). Loss of one functional allele ("haploinsufficiency") appears to be a critical feature in the development of holoprosencephaly. For mutations resulting in premature termination of the Sonic hedgehog protein, changes in single amino acids or complete deletions have been identified in both clinical and experimental settings (226). Deletions in Sonic hedgehog are more often associated with severe forms of holoprosencephaly (23), although Sonic hedgehog mutation (and mutations in other HPE genes) has also been associated with single maxillary central incisor (200; 83). Sonic hedgehog is also necessary for the proliferation of neural tube and cranial neural crest cells (07). This supports the proposition that dysregulation of the sonic hedgehog pathway is a risk factor in some cases of anencephaly (195) and for the first time implicates cilia function as well. This is supported by work identifying WDR34 mutations (known to affect sonic hedgehog signaling and planar cell polarity) in anencephalic infants (318).

Individuals with deletions of the short arm of chromosome 18 have a gene (TGIF) mapped to 18p11.3 (207; 99). It is possible that TGIF represses gene transcription normally regulated by retinoic acid, and in this way, might help explain the association between exposure to retinoic acid and holoprosencephaly (300). TGIF also influences pathogenesis through the Nodal signaling pathway (99).

Another major gene associated with holoprosencephaly is ZIC2, which maps to 13q32. A nuclear zinc finger transcription factor gene and homolog to the Drosophila odd-paired gene, ZIC2 has been identified in patients with severe brain malformations but mild craniofacial changes (38; 153). It is responsible for closure of the posterior neuropore as well (15), which presumably explains the association of ZIC2 microdeletions in some patients with neural tube defects (47). Loss of function of this gene through haploinsufficiency is the likely mechanism (39a; 39b; 174). Deletions of 13q, which includes ZIC2, have been observed in patients with holoprosencephaly and cerebellar dysgenesis (181). Research using a number of experimental models indicates that loss of Zic2 function and disruption of the NODAL signal transduction pathway interfere with development of the prechordal plate and subsequent induction of forebrain morphogenesis during gastrulation (303; 121).

Several cases of holoprosencephaly have also been reported with deletions of chromosome 14, for example del(14)(q13q21.1) or (q13q21.2) (49; 134). Mutations in STIL, known to cause severe microcephaly on an autosomal recessive basis, have also been associated with holoprosencephaly (132). Candidate genes continue to be advanced, for example DKK1 (227) and PATCHED-1 (182). PATCHED-1 is the receptor for Sonic hedgehog, and mutations may affect the binding of PATCHED-1 and Sonic hedgehog, or the interactions of PATCHED-1 with other genes that affect Sonic hedgehog signaling. Other genes in the Sonic hedgehog signaling pathway are Smoothened (SMO), a proposed receptor, and GLI, a transcriptional effector. Despite these advances, the molecular basis of holoprosencephaly is unknown in about 70% of cases (27). Other minor genes include DLL1, DISP1, and SUFU (79).

A new avenue of research involves X-linked cohesion complex genes (STAG2, SMC1A) and a subset of non-X-linked variants. The genes are expressed in the prosencephalic folds of mice, and knockdowns cause aberrant expression in several genes associated with holoprosencephaly (148).

The manner in which such genetic changes translate into pathogenesis at the tissue level remains unclear. However, work suggests that cholesterol deficiency (ie, impaired biosynthesis, probably arising from both deficient maternal-fetal transport of exogenous cholesterol and endogenous synthesis) plays an important role in central nervous system development in general and holoprosencephaly in particular (86; 104). Cholesterol is known to modify Hedgehog functioning (173). The Sonic hedgehog protein must be linked to cholesterol to be active (129; 236). Abnormalities in cholesterol synthesis (specifically, a deficit in 7-dehydrocholesterol reductase) account for the appearance of holoprosencephaly in patients with Smith-Lemli-Opitz syndrome. Treating cholesterol-deficient mutant mice with an inhibitor to cholesterol synthesis (BM 15.766) causes holoprosencephaly and other changes resembling Smith-Lemli-Opitz syndrome, notably changes of limbs, external genitalia, and face (155; 304). It also appears from mouse studies that sonic hedgehog signaling is elevated and ectopic, resulting in altered telencephalic morphogenesis (127). Treating Syrian golden hamsters with cyclopamine, a derivative of the desert plant Veratrum californicum (which, when ingested by pregnant ewes, results in cyclopic lambs), produces the cerebral and craniofacial changes of holoprosencephaly (67). In the latter study, changes were associated with transient loss of HNF-3beta immunoreactivity in prechordal mesenchyme, suggesting that an early event in pathogenesis may involve altered expression of particular proteins in prechordal mesenchyme and floor plate, with secondary impairment of neural plate and cranial neural crest, and that cyclopamine may impair cholesterol biosynthesis or prevent cholesterol from participating in autocatalysis of the signaling protein, Sonic hedgehog. In chicks, Sonic hedgehog-mediated dorsoventral patterning of neural tube and somites is interrupted by a mechanism that does not appear to involve interference with cholesterol metabolism. Rather, pathogenesis seems to result from direct antagonism of Sonic hedgehog signal transduction (128). Interestingly, Sonic hedgehog mutations result in a diverse, rather than narrow, spectrum of anomalies (201). The development of both frontonasal and maxillary processes requires Sonic hedgehog; loss of Sonic hedgehog signaling reduces growth, resulting in hypotelorism and cleft lip or palate, whereas excessive Sonic hedgehog increases growth, producing hypertelorism (124). Eye development itself is regulated by sonic hedgehog signaling, which has suggested to some that coloboma should be placed at the mild end of the holoprosencephaly spectrum (95). The first pharyngeal arch, embryonic precursor to the mandible, also requires Sonic hedgehog for development. Disruption of Sonic hedgehog in mouse embryos results in hypoplasia of the first arch (316). The hedgehog signaling pathway is also active in adulthood. Cyclopamine, by interfering with this pathway, may have a therapeutic effect on certain tumors (122).

It appears that both dorsal and ventral patterning are altered in holoprosencephaly, as both insufficient ventralization and excessive dorsalization have been implicated (271). Mutations in ZIC2, a primarily dorsal-patterning gene responsible for holoprosencephaly, and partial deletions of the long arm of chromosome 13 (where ZIC2 is located) may also help explain the rare association of holoprosencephaly and Dandy-Walker malformation (177). It also appears that separate genes responsible for holoprosencephaly may interact with each other (ie, SHH and ZIC2). This suggests a certain digenic effect and underscores the multiple-hit hypothesis (184; 313). It is also possible that an interaction of gene products and environmental factors contributes to the diversity in phenotypic changes (199). This multiple-hit hypothesis continues to receive attention (78). Work shows that alcohol disrupts hedgehog signal transduction (04). Such an interaction might explain the appearance of holoprosencephaly among a subset of offspring of alcohol-abusing mothers (164) or other intrafamilial variation (146). Experimental evidence for the ethanol-induced suppression of sonic hedgehog expression and its ventral telencephalic target gene Nkx2.1 has appeared (116). The effects of ethanol are exacerbated by SHH or GLI2 haploinsufficiency (139). Another gene implicated in holoprosencephaly, TGIF, is also known to regulate genes expressed in dorsal-ventral domains, at least in experimental models (144). An intriguing syndrome is pseudotrisomy 13, which closely mimics trisomy 13, but does not exhibit the karyotypic change. As expected, infants with this condition may exhibit a host of anomalies, including those outside the CNS (37). Studies have shown that the genes ordinarily involved in holoprosencephaly are not mutated in this condition, suggesting that still other genes remain to be discovered (63). A development is the recognition of PRDM15 mutations in patients with holoprosencephaly; the mutation affects NOTCH and WNT/PCP pathways and anterior-posterior patterning (190). Three patients with holoprosencephaly variants, one with phenotypic Kabuki syndrome, and KMT2D mutations have been reported (290; 69).

To date, few molecular studies have been conducted in large population-based samples (198; 229). These suggest that mutations in those holoprosencephaly genes recognized at present may account for less than 5% of all sporadic cases. The variable penetrance and expressivity may be affected by other generally unknown genetic or environmental modifiers, ie, the “autosomal dominant with modifier” model (120). The discovery of double mutations in some individuals raises the additional possibility of polygenic inheritance (79; 189). RAD21 loss-of-function variant is reported rarely in holoprosencephaly (147).

In summary, studies of patients, and some with parents, indicate that both common and uncommon mutations often occur de novo; most cases appear to be autosomal dominant, although infrequent instances of autosomal recessive, digenic, and oligogenic inheritance are recognized (80; 229). Because no genetic cause is identified in some three-quarters of cases, it is important to continue the search for environmental factors.

Future research should clarify the early morphogenetic changes and ultimately provide a synthesis of hypotheses. Additional studies will need to explore the multidimensional gradation of genetic expression, maturation of neurons, and orientation of radial glial fibers or ependyma (244). These have begun to produce new definitions and classifications of holoprosencephaly (57; 243; 244).

Table 4. Gene Mutations Associated with Holoprosencephaly in Humans

Gene	Genetic Action(s)	Phenotypic Effect
SHH	• Encodes sonic hedgehog signaling pathway • Enhances expression of Goosecoid in axial head mesoderm (prechordal plate)	• Regulates ventral patterning, but holoprosencephaly variable • Dorsoventral patterning of head
PATCHED1	• Receptor for sonic hedgehog; encodes SHH signaling pathway	• Regulates ventral development
TGIF	• Represses activity of SMAD transcription factors; activated by nodal signaling pathway; regulates genes expressed in certain dorsal-ventral domains	• Simulates retinoic acid overexposure
TDGF1	• Encodes a protein that serves as coreceptor for nodal signaling	• Associated with milder forms to date (semilobar holoprosencephaly, dysplastic forebrain)
ZIC2	• Zinc finger proteins expressed more often in dorsal than ventral neuroepithelium	• Face more likely normal or mildly dysmorphic with this mutation; important for closure of posterior neuropore; deletions identified in patients with cerebellar anomalies or NTDs
SIX3	• Encodes a homeodomain transcription factor expressed in ventral forebrain	• Development of anterior neural plate and eye; mutations associated with more severe phenotypes
FAST1	• Encodes a transcription factor important to several pathways, including TGF beta, activin, and nodal	• Mutations cause holoprosencephaly and congenital heart disease
DHCR7	• Involved in cholesterol biosynthesis	• Holoprosencephaly within the context of Smith-Lemli-Opitz syndrome
(58; 109; 144; 30)

Epidemiology

Due to several factors, including the rarity of cases and the emphasis on subclassification with its consequent fragmentation of data sets, little is known about the prevalence of holoprosencephaly. Only a few data sets are comprehensive, but even these need to be updated, as they were often conducted before the widespread use of ultrasound and magnetic resonance imaging and mutational analysis for diagnosis. Both American and Spanish studies reached similar estimates of 0.63 and 0.56 per 10,000 live births (224; 295). A study in Scotland revealed a prevalence of 0.37 per 10,000 live births (307), whereas a study in Atlanta showed 0.86 per 10,000 live births (222). A California study showed 1.2 per 10,000 live births (68), which was similar to the finding of 1.09 cases per 10,000 live births in Hawaii (89), 1.7 in the United Kingdom (204), and 1.31 in Italy (163). In New York State, the prevalence from 1984 to 1989 was 0.48 per 10,000 live births (202). In Japan, the prevalence is 1.54 per 10,000 live births (01). The overall prevalence of holoprosencephaly was more accurately indicated by a report of 40 holoprosencephalic specimens per 10,000 induced abortions in the Kyoto collection of embryos (176). These data show that most severely affected fetuses do not reach term. In that cohort, 67% of pregnancies ended with threatened or spontaneous abortion (03). With the increase in prenatal diagnosis and pregnancy termination, workers must use care in reporting prevalences. In earlier studies, for example, the rate of chromosomal abnormality in affected patients was 50% (264). In one study the rate was only 9%, with differences attributed to spontaneous or therapeutic abortion (279). This observation suggests that cases followed clinically in the future will more likely be milder forms. Data collection can be hampered by random variation, sampling error, or therapeutic abortions where diagnosis is not recorded (163). In some states, for example, death certificates are issued only for fetuses aged 20 weeks or more.

In their review of 173 subjects, Lazaro and colleagues found familial occurrences in 30%; 9% had Sonic hedgehog mutations, 3% ZIC2, 3% SIX3, and 1% TGIF (157). The familial rate of 30% is high and may be due in part to inclusion of patients with minor signs. Similar findings have been reported by others (112). However, one should not assume that all family members will carry the same mutation. A report of a single family segregating two novel variants of ZIC2 and GLI2 has appeared (302).

Parental age is not generally thought to be a significant factor, although Olsen and coworkers reported a prevalence 4.2 times higher in mothers under the age of 18 (202), and Forrester and Merz found an increase in women greater than 39 years of age (a large percentage of affected infants have trisomy 13, which is associated with advanced maternal age) (89). A large international study of 257 infants with cyclopia did not support an association with advanced maternal age (206). The effect of low socioeconomic status needs more investigation because poverty is a multifactorial variable linked to a number of congenital disorders. Temporal trends have been reported in a number of studies but are not understood (264).

Holoprosencephaly occurs not only in humans, but also occurs naturally in a variety of animals as well due to similar or identical genetic mutations. It can be induced in rodent models but is also found as a spontaneous anomaly in horses (53). Of possible relevance, horses normally possess a very large massa intermedia due to incomplete cleavage of the thalami, though it does not generally cause obstructive hydrocephalus, even when it almost fills the third ventricle (Sarnat HB, unpublished observation).

Differential diagnosis

Because holoprosencephaly is a malformation complex that occurs in a variety of contexts, the reader is referred to more complete discussions of differential diagnosis and associated syndromes (264; 62; 59). As molecular genetic studies continue, these associations will become understood much better. Citing two examples, abnormal ciliary function has been implicated in Meckel-Gruber syndrome, and more recently, perhaps holoprosencephaly. The gene FGF8 can be involved in both the development of holoprosencephaly and gonadotropin-releasing hormone deficiency of the type observed in Kallmann syndrome (11).

The following anomalies of the central nervous system may occur with or without the cerebral changes of holoprosencephaly:

• microphthalmia or iridal coloboma
• microcephaly or micrencephaly
• arrhinencephaly
• agenesis or dysgenesis of the corpus callosum
• absence of the septum pellucidum
• choroid plexus cysts
• dorsal (third ventricular) cysts
• hydrocephalus
• atelencephaly or aprosencephaly
• hydranencephaly
• neuronal migrational disorders (gray or white matter heterotopia)
• septo-optic-pituitary dysplasia
• Dandy-Walker malformation

The following anomalies of the face may occur with or without the cerebral changes of holoprosencephaly:

• lateral (accessory) nasal proboscis
• nasal anomaly, including arrhinia or partial arrhinia
• agnathia
• ocular hypotelorism or hypertelorism
• midfacial deficiencies
• cleft lip or palate
• single central maxillary incisor
• acalvaria

The following syndromes (and other rarer ones) may have holoprosencephaly as a feature:

• Binder syndrome
• Smith-Lemli-Opitz syndrome
• CHARGE syndrome
• DiGeorge syndrome
• hydrolethalus syndrome
• Hartsfield syndrome
• Kallmann syndrome
• Pallister-Hall syndrome
• Velocardiofacial syndrome
• Septo-optic dysplasia
• Aprosencephaly
• Meckel-Grüber syndrome
• pseudotrisomy 13
• Steinfeld syndrome
• Zellweger syndrome

Diagnostic workup

Because the spectrum of anomalies is so broad, a diagnostic workup must be multifaceted. This point has been demonstrated quantitatively by multivariate (factor) analysis, in which 10 important clinical variables were identified (grade of spasticity, dystonia, choreoathetosis, hypotonia, mobility, upper extremity and hand function, expressive language, feeding and swallowing difficulty, presence of endocrinopathy, and ability to regulate temperature). In that study, five variables were shown to be critical for neuroimaging (severity of holoprosencephaly, degree of nonseparation of caudate, lentiform, thalamic, and hypothalamic nuclei) (106).

Prenatal diagnosis at increasingly earlier ages (ie, first trimester) makes use of transabdominal or transvaginal ultrasound. Early diagnosis (11 to 13 weeks) of holoprosencephaly is possible during routine screening for nuchal translucency (305; 113). Even earlier prenatal diagnosis at 9 weeks gestation has been reported (179). However, care in counseling is advised, as data on false positives and other diagnostic uncertainties remain incomplete (84). Biparietal diameter is also reduced in a significant number of first trimester fetuses with holoprosencephaly (138; 255). Views of orbital configuration and the rostral cerebrum are especially helpful (292; 311; 33). Failure to identify choroid plexus in the first trimester (the “butterfly sign” in normal fetuses) appears to suggest a diagnosis of holoprosencephaly (254). Telencephalic growth can also be assessed by ultrasound, and the presence of a midline seam joining cortical and nuclear gray matter bilaterally can suggest semilobar holoprosencephaly (285). In one study, prenatal diagnosis was reached in 86% of cases (42). This rate is variable, however. In another study, prenatal diagnosis was reached in only 22%. The remainder was identified between birth and 1 year of age (279). Imaging studies may be interpreted incorrectly. In one study, 19% of referred cases carried the erroneous diagnosis of holoprosencephaly (279). Criteria are available to assist with the ultrasonographic differentiation of holoprosencephaly from septo-optic dysplasia, isolated agenesis of the cavum septi pellucidi, and ventriculomegaly (171; 310). Three-dimensional ultrasonography may be used to diagnose holoprosencephalic facies prenatally (160; 10), and inversion rendering can highlight ventricular anatomy for further assessment (291).

Aberrant course of the anterior cerebral artery may be identified by Doppler examination and is suggestive of lobar holoprosencephaly (29) and probably any form that involves some degree of fusion of the frontal lobes (34). Sulcal abnormalities are also said to be specific for holoprosencephaly (28). In cases where ultrasound findings are unclear or workers and parents desire confirmation of findings, prenatal MRI has been successful with the use of pancuronium bromide for temporary arrest of fetal movement. Unfortunately, the rate of false-negative results in prenatal MRI remains significant (212; 133). In the future, prenatal MRI may be unnecessary, given the development of ultrafast MR imaging, which has been used successfully to diagnose holoprosencephaly in the midgestational fetus (219).

Postnatally, physical examination, augmented by imaging studies (traditional radiography and ultrasound, CT, MRI) provides the basis for diagnosis. The Sylvian fissure, for example, is displaced more anteromedially and “Sylvian angle” (angle between lines constructed tangential to Sylvian fissures) increased (greater than 15 degrees) as the severity of holoprosencephaly increases (16). Diffusion tensor imaging has been used to highlight white matter abnormalities and further understand structure-function relationships (141; 41). Angiography, with particular attention given to the anterior cerebral arteries and visualization of dural venous sinuses, may be helpful in differentiating complete and incomplete types from hydranencephaly, severe hydrocephalus, or large subdural hygromas (321). Infrequently, patients may exhibit microphthalmia or anophthalmia, sometimes in association with defects of the first branchial arch (102).

Many neurologic features have gone undocumented in infants with severe holoprosencephaly (264). Electroencephalographic changes are a prime example. Oftentimes, they are not pathognomonic (asynchronous sharp waves and spikes in frontal regions, decreasing potential gradients to occipital region), but abnormalities should nevertheless lead to further studies (256). A series of EEGs from one patient with semilobar holoprosencephaly, dorsal cyst, and large encephalocele showed progression between 3 and 16 months of age from diffuse, poorly regulated but nonparoxysmal slow wave activity to nearly continuous, multifocal, epileptiform activity (240). With increased development of the cerebrum, in lobar or semilobar forms for example, hypsarrhythmia and photic driving increase and fronto-occipital gradients decrease (317). Spasticity appears to be more frequently in the middle interhemispheric variant than other forms (32). To date, this diagnosis has been made in one adult, a 30-year-old woman who suffered cognitive and psychiatric deficits, but no gross neurologic involvement (297).

Likewise, sensory evoked potentials, particularly auditory brainstem evoked response, are not diagnostic but do serve as valuable supplements in working up patients (66). One patient with alobar holoprosencephaly has been described with complete flat waves on EEG and failure to respond to visual evoked potential testing or auditory brain stem response (260).

Additional studies may be required for complete syndrome recognition. Of course, genetic workup is indicated, and guidelines are updated continually, in keeping with diagnostic advances (150). Karyotyping, with high resolution chromosomal banding, is an important early step. Quantitative fluorescent polymerase chain reaction analysis can provide rapid prenatal diagnosis of trisomy 13 (51). Techniques such as array-based CGH, multicolor FISH, and quantitative PCR can identify submicroscopic imbalances (gain or loss) in patients with normal karyotypes (26; 126; 169). Multiplex ligation probe-dependent amplification (MLPA) has been used to identify subtelomeric rearrangements in affected patients (24). Molecular studies are necessary to identify or rule out gene mutations (215). Establishing a pedigree is essential for counseling, although clinicians must realize that penetrance and expressivity are widely variable. When seeing older children, clinicians should remember that, although holoprosencephaly is a congenital disease, patients with milder forms may present later, with symptoms such as spastic diplegia, attention deficits, or hyperactivity (257). New and sometimes subtle findings continue to be associated with holoprosencephaly. Ocular anomalies include microcornea, microphthalmia, blepharoptosis, exotropia, uveal coloboma, and refractive errors (216). Multichannel visual evoked potentials can be used to assess visual pathways in patients with severe cortical anomalies (110). Other examples include absence of the superior labial frenulum, partial or complete absence of the pituitary gland or other abnormalities, ectopic pancreas, and choanal stenosis (175; 81; 140; 172). The practitioner should not assume that intellectual functioning will be reduced in patients with such microforms of holoprosencephaly. Indeed, the reverse has been reported (276).

Management

As with prognosis, management is also evolving as diagnosis becomes increasingly accurate. Management is as demanding as the patient is complex. Unfortunately, patients with holoprosencephaly may also have other conditions or syndromes, which, in turn, can have highly varied etiologies. One fetus born to a diabetic woman has been reported, for example, with alobar holoprosencephaly, cebocephaly, and Klinefelter syndrome (50). One sixth of survivors with holoprosencephaly, especially those with the alobar form or a dorsal cyst, require shunting for hydrocephalus (108). The procedure continues to be refined (239) and can also be successful in the absence of increased intracranial pressure (09). For those with milder forms of holoprosencephaly, intellectual development is highly variable (and mental retardation commonplace), but survival need not be shortened. The association with reduction limb anomalies, particularly radial ray defects, has received emphasis and, of course, impacts treatment in affected individuals (178; 268). Ectrodactyly has been reported in a small number of patients (137). This condition, occurring with or without cleft lip and palate (Hartsfield syndrome) has been associated with FGFR1 mutations and microduplication Xq24 (287; 274). One case of osteogenesis imperfecta has been associated with holoprosencephaly (299). Mobility, function of upper limbs, and language development are variable and difficult to predict but depend, in general, on the severity of cerebral changes (217; 225). The early intervention of physical therapists and special education instructors is necessarily important in combating developmental delay. Plastic surgeons treat those with normal or near-normal potential for mental development and life expectancy, using techniques of midfacial advancement, bipartition expansion, and reconstruction of the nose, upper lip, and palate (82; 114; 188). The classification of clefts in affected patients and associated treatment protocols continue to be refined (43; 118). Congenital nasal pyriform aperture stenosis associated with holoprosencephaly constitutes a treatable form of upper airway obstruction (298). Absence of the nose (arhinia) may be complete or partial (286). Associated conditions may require the attention of additional specialists. For example, endocrine disorders occur in three fourths of patients (217). Dysfunction involves the posterior hypophysis more commonly than anterior (108) or may result from aplasia or hypoplasia of the pituitary gland or from abnormalities related to noncleavage of the hypothalamus. In this regard, holoprosencephaly may overlap with septo-optic-pituitary dysplasia, a condition in which abnormalities occur in deep midline structures, although the cerebral cortex is generally formed. Central diabetes insipidus, growth hormone deficiency, hypocortisolism, and hypothyroidism presumably result from either hypophyseal or hypothalamic abnormalities (284; 142; 293). Inappropriate antidiuretic hormone secretion, with hyponatremia, can be refractory to treatment (54). Beyond isolated diabetes insipidus, pituitary insufficiency is encountered most commonly in patients with GLI1 mutations (289). Patients with GLI2 mutations also present with pituitary anomalies, but, in addition, manifest polydactyly and subtle changes of the face rather than holoprosencephaly (21). Congenital heart disease is fairly common in patients with holoprosencephaly and has also been identified in human embryos (314). Nodal mutations have been associated with cardiac anomalies and laterality defects in some patients with holoprosencephaly (232). Anosmia is a consequence of arrhinencephaly. A case of holoprosencephaly (with additional findings diagnostic of pseudotrisomy 13) has been reported with congenital glaucoma (237). Nonalcoholic fatty liver disease may occur in patients with holoprosencephaly, independent of obesity, within the context of sonic hedgehog signaling inhibition (101). One newborn with semilobar holoprosencephaly and agenesis of the pancreas and gallbladder has been reported (117). Three additional patients with agenesis of the pancreas and holoprosencephaly have been reported and associated with a mutation in CNOT1, a gene involved in embryonic stem cell development and expressed in the prosencephalic neural folds of embryonic mice (72; 149).

Patients with microforms may, of course, require treatment as well. For example, individuals with single central maxillary incisor manifest both phenotypic and genetic heterogeneity and, thus, require a variety of treatments, including long-lasting orthodontia (168; 218).

Seizures are also frequent, even in milder forms, and occurred in one half of the children studied in one large cohort (108). They may be accompanied by hypotonia in early life and spasticity later on. An association with epilepsy, including rarer complex partial forms such as gelastic (laughing) epilepsy, has been reported (08). As mentioned, spastic diplegia is sometimes seen. Anticonvulsant drugs may be required, and as with any seizure disorder; infantile spasms may require corticotropin. Motor function is often impaired. Depending on the severity of holoprosencephalic lesion, hypotonia, dystonia, spasticity, or choreoathetosis may develop (108; 217).

Retroflexion of the holosphere several years after ventricular shunting is rare and is presumably due to secondary collection of subdural fluid (196). Pathology involving the hypothalamus and brainstem results in unstable control of heart rate, respiration, and temperature; other complications include feeding difficulty, erratic sleep, irritability, colic, or constipation (183; 20; 217). Dorsal rhizotomy has been performed for children with severe spasticity and holoprosencephaly (294).

Families, of course, need significant assistance as they seek to deal with such a complex disorder. Support systems need to be individualized and broad-based, including not only medical personnel, but family, friends, and religious advisors (223; 105). Early diagnosis has proven of benefit, especially when it is certain (131).

Media

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Patient Profile

Age range of presentation: 0 month to 5 years
Sex preponderance: female>male, >2:1
Heredity: heredity may be a factor

autosomal dominant

autosomal recessive

sex-linked recessive
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-9: Holoprosencephaly: 742.2

Holoprosencephaly due to trisomy 13: 758.1

Holoprosencephaly due to trisomy 18: 758.2
ICD-10: Holoprosencephaly: Q04.2

Holoprosencephaly due to trisomy 13: Q91.7

Holoprosencephaly due to trisomy 18: Q91.3
OMIM: Holoprosencephaly type 1: %236100

Holoprosencephaly type 2: #157170

Holoprosencephaly type 3: #142945

Holoprosencephaly type 4: #142946

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Holoprosencephaly

Associated Disorders

Alobar holoprosencephaly
Arrhinencephaly
Cebocephaly
CHARGE syndrome
Complete holoprosencephaly
- Goosecoid
- Heterotaxy
- Hypotonia
- Incomplete holoprosencephaly
- Lobar holoprosencephaly
- Otocephaly
- Premaxillary agenesis
- Premaxillary dysgenesis
- Prosencephaly
- Pseudotrisomy 13
- Seizures
- Semilobar holoprosencephaly
- Septopreoptic holoprosencephaly
- Sonic hedgehog mutation
- Spasticity

Differential Diagnosis

Binder syndrome
CHARGE syndrome
DiGeorge syndrome
Kallmann syndrome
pseudotrisomy 13
- Steinfeld syndrome
- Zellweger syndrome
- Goosecoid
- lateral (accessory) nasal proboscis
- fetal alcohol syndrome
- nasal anomaly, including arhinia
- agnathia
- cholesterol deficiency
- dorsal cysts
- alobar
- lobar
- semilobar
- septopreoptic
- ocular hypotelorism or hypertelorism
- midfacial deficiencies
- cleft lip or palate
- single central maxillary incisor
- acalvaria
- microphthalmia or iridal coloboma
- microcephaly or micrencephaly
- arhinencephaly
- agenesis or dysgenesis of the corpus callosum
- absence of the septum pellucidum
- choroid plexus cysts
- dorsal (third ventricular) cysts
- hydrocephalus
- atelencephaly or aprosencephaly
- hydranencephaly
- neuronal migrational disorders (gray or white matter heterotopia)
- septo-optic-pituitary dysplasia
- Dandy-Walker malformation
- Pseudotrisomy 13 (holoprosencephaly-polydactyly syndrome)

Also Relevant

Cerebellar hypoplasia, dysplasia, and enlargement
Intellectual disability
Malformations of the brain
Meckel-Gruber syndrome
Olfactory bulb agenesis, hypoplasias, and dysplasias
- Rhombencephalosynapsis
- Sacral agenesis
- Septo-optic-pituitary dysplasia complex
- Smith-Lemli-Opitz syndrome

Clinical Categories

Developmental Malformations

Holoprosencephaly

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Table 1. Etiologic Factors

Table 2. Postulated or Proven Human Teratogens

Table 3. Facial Changes Associated with Holoprosencephaly

Table 4. Gene Mutations Associated with Holoprosencephaly in Humans

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Author

Former Authors

Patient Profile

ICD & OMIM codes

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Also in This Category

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Epileptic lesions due to malformation of cortical development

Agenesis of the corpus callosum

Epidermal nevus syndromes: neurologic phenotypes

Norrie disease

Aqueductal stenosis

Klippel-Feil syndrome

Cerebellar hypoplasia, dysplasia, and enlargement

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