eMedicine Specialties > Radiology > Pediatrics

Holoprosencephaly

Author: David H Tegay, DO, FACMG, Interim Chair, Department of Medicine, Associate Professor of Medicine and Medical Genetics, New York College of Osteopathic Medicine at the New York Institute of Technology; Assistant Professor of Pediatrics, Internal Medicine and Pathology, Stony Brook University Medical Center
Coauthor(s): Harris L Cohen, MD, FACR, Vice Chairman/Associate Chairman (Research Activities), Director, Division of Body Imaging, Professor of Radiology, Stony Brook School of Medicine; Visiting Professor of Radiology, Johns Hopkins School of Medicine; Mark Rosovsky, MD, Attending Radiologist, Advanced Radiology Associates, Bridgeport Hospital
Contributor Information and Disclosures

Updated: Oct 15, 2008

Introduction

Background

Holoprosencephaly denotes an incomplete or absent division of the embryonic forebrain (prosencephalon) into distinct lateral cerebral hemispheres.^1,2,3,4,5

DeMyer historically and roughly categorized holoprosencephaly into 3 types (from most severe to least severe)⁶ : (1) alobar holoprosencephaly, or complete absence of midline forebrain division resulting in a monoventricle and fused cerebral hemispheres; (2) semilobar holoprosencephaly, or incomplete forebrain division resulting in partial separation of the cerebral hemispheres, typically posteriorly; and (3) lobar holoprosencephaly, or complete ventricular separation with focal areas of incomplete cortical division or anterior falcine hypoplasia.

Distinctive midline facial malformations occur in most cases. These malformations are correlated with the degree of holoprosencephaly and have prognostic importance. From most severe to least, the facial phenotypes are as follows: (1) cyclopia, or a single, midline, fused eye beneath a proboscis; (2) ethmocephaly, or ocular hypotelorism with a proboscis; (3) cebocephaly, or ocular hypotelorism with a single nostril; (4) ocular hypotelorism and midline clefting; and (5) milder facial dysmorphic features in combination or in isolation.

Additional clinical manifestations include developmental delay, which is roughly correlated with the degree of holoprosencephaly; variable seizures; pituitary dysfunction; hydrocephalus; and feeding difficulties, which typically result in reduced survival.

Active research into the pathophysiology of holoprosencephaly has revealed multiple teratogenic and genetic causes (both chromosomal and single gene), and further genetic characterization is ongoing.

Related eMedicine topic:
Hydranencephaly

Related Medscape topics:
Resource Center Neonatal Medicine
Specialty Site Neurology & Neurosurgery
Specialty Site Pediatrics

Pathophysiology

Embryogenetic processes

Holoprosencephaly arises from disruption of the normal induction and patterning of the rostral neural tube during early embryogenesis. The primary vesicles of the brain—the prosencephalon, mesencephalon, and rhombencephalon—are discernible by the third embryonic week. Separate lateral telencephalic and diencephalic structures develop from a single prosencephalic vesicle, normally beginning by the fifth embryonic week of gestation.

Genetic factors

Active research into the pathophysiology of holoprosencephaly has revealed multiple teratogenic and genetic causes (both chromosomal and single gene), and further genetic characterization is ongoing.

The involvement of multiple genes has been implicated in ventral forebrain induction; their products include the Sonic Hedgehog (Shh) protein and the Hedgehog signal transduction proteins Patched (Ptc) and Smoothened (Smo), as well as proteins in the Gli family and cholesterol biosynthesis pathways.

A variety of teratogens, chromosomal abnormalities (in 25-50% of cases), and single gene mutations can result in holoprosencephaly. Trisomy 13 (in about 40% of cases) and trisomy 18 are the most frequently identified chromosomal anomalies. A host of chromosomal deletions, duplications, and translocations have also been associated with holoprosencephaly.

A mutation in the Shh gene is the most frequent single-gene cause of nonsyndromic and familial holoprosencephaly. The ZIC2, SIX3, and TGIF genes have also been implicated. However, together with Shh mutations, alterations in these genes only account for the minority of cases of holoprosencephaly.

Many single-gene disorders (18-25%) can result in syndromes with a variable incidence of holoprosencephaly. Examples include Pallister-Hall, Rubinstein-Taybi, Kallmann, Smith-Lemli-Opitz, Meckel, hydrolethalus, pseudotrisomy 13, and microtia -anotia syndromes. Maternal diabetes has been implicated in about 1% of cases.

Related eMedicine topic:
Manifestations of Craniofacial Syndromes

Frequency

United States

Holoprosencephaly is present in 1 in 10,000-20,000 neonates at birth and occurs with a rate of 1 in 250 during embryogenesis.^4,7

International

The international frequency of holoprosencephaly is similar to that in the United States. Leoncini et al reviewed birth data of over 7 million births from areas in North and South America, Europe, and Australia from 2000 to 2004.³ The investigators noted a total of 963 registered cases of holoprosencephaly, yielding an overall prevalence of 1.31 per 10,000 births.³

Mortality/Morbidity

In general, holoprosencephaly results in substantial early morbidity and mortality with a significantly reduced survival. However, individual reports describe long-term survival in all forms of holoprosencephaly. The strongest correlation is a direct relationship between the severity of facial anomalies and increased mortality. In individuals with cyclopia or ethmocephaly, survival is rare beyond 1 week.

Patients with alobar holoprosencephaly have a survival rate of about 50% by age 4-5 months and about 20% at age 12 months. Isolated semilobar and lobar holoprosencephaly have empiric survival rates of about 50% to age 12 months. Ascertainment bias may negatively skew reported survival rates for lobar holoprosencephaly, as more severely affected individuals are overrepresented due to an underdiagnosis of less severely affected cases.

Virtually all surviving individuals have some degree of developmental delay, often persisting as mental retardation; this generally occurs in direct correlation to the severity of holoprosencephaly. However, case reports do describe individuals with lobar holoprosencephaly who have normal or near-normal development. In addition, feeding difficulties leading to aspiration pneumonia and/or failure to thrive frequently occur in individuals within all subtypes.

Data from The Carter Center for Brain Research in Holoprosencephaly and Related Malformations indicate that complication rates in surviving individuals are as follows⁷ :

• Alobar holoprosencephaly –
  • Spasticity in 85%
  • Pituitary/hypothalamic dysfunction (diabetes insipidus, hypogonadism, hypothyroidism) in 85%
  • Hypotonia in 80%
  • Seizures in 60%
  • Hydrocephalus in 10%
  • Choreoathetosis in less than 5%
  • Ambulation, use of hands, and use of words in 0% each
• Semilobar holoprosencephaly –
  • Spasticity in 85%
  • Pituitary/hypothalamic dysfunction (diabetes insipidus, hypogonadism, hypothyroidism) in 74%
  • Hypotonia in 70%
  • Seizures in 50%
  • Choreoathetosis in 20%
  • Ambulation, use of hands, and use of words in 10% each
• Lobar holoprosencephaly –
  • Spasticity in 60%
  • Pituitary/hypothalamic dysfunction (diabetes insipidus, hypogonadism, hypothyroidism) in 50%
  • Hypotonia in 40%
  • Seizures in 50%
  • Choreoathetosis in 40%
  • Ambulation, use of hands, and use of words in 40% each
• Middle interhemispheric fusion variant –
  • Spasticity in 86%
  • Pituitary/hypothalamic dysfunction (diabetes insipidus, hypogonadism, hypothyroidism) in 0%
  • Hypotonia in 60%
  • Seizures in 40%
  • Choreoathetosis in 0%
  • Ambulation, use of hands, and use of words in 50% each

Sex

At birth, the ratio of females to males with holoprosencephaly is 2:1.

• The female-to-male ratio increases as the severity of holoprosencephaly increases.
• In alobar holoprosencephaly, the female-to-male ratio is 3:1, whereas with lobar holoprosencephaly, the ratio is 1:1.
• In addition, females often have more severe facial anomalies. The reason for this sex discrepancy remains unknown.

Age

The age of onset is at 3-4 weeks of gestation. During early embryonic development, the frequency peaks at 1:250 but progressively declines because of high fetal mortality rates and elective pregnancy termination, which results in an incidence at birth of 1:10,000-20,000.

Anatomy

Normally, the embryonic prosencephalon forms distinct lateral telencephalic (cerebral cortex, hippocampus, basal ganglia, olfactory bulbs) and diencephalic (dorsal thalamus, hypothalamus) structures, including the associated ventricles, olfactory and optic bulbs and tracts. In holoprosencephaly, a continuum of deficiencies in embryonic forebrain cleavage range from the most severe, or alobar, forms to the least severe, or lobar, forms.

Alobar holoprosencephaly is the most severe form, consisting of a single brain ventricle (monoventricle) without any formation of an interhemispheric fissure (ie, fused cerebral hemispheres). The falx cerebri, corpus callosum, septum pellucidum, and fornix are absent, as are the olfactory bulbs and optic tracts. The thalami are fused.

Semilobar holoprosencephaly is less severe, with partial formation of the interhemispheric fissure, particularly posteriorly. A rudimentary falx may be present, and a primitive occipital horn may develop.

Lobar holoprosencephaly is the least severe form, with almost complete formation of the interhemispheric fissure and only focal areas of cortical continuity across the interhemispheric fissure, usually anteriorly. Sometimes, lobar holoprosencephaly is limited to an absence of the septum pellucidum.

The middle interhemispheric fusion variant is a relatively recently described anatomic entity that some consider part of the spectrum of holoprosencephaly.⁸ This variant denotes incomplete cleavage of the posterior frontal and parietal lobes, with varying degrees of incomplete cleavage of the basal ganglia and thalami and an absent body of the corpus callosum.

Other frequently associated central nervous system (CNS) malformations include arrhinencephaly (absent olfactory bulbs and tracts), hydrocephalus, and neural migration abnormalities.

Related Medscape topics:
Resource Center Neonatal Medicine
Specialty Site Neurology & Neurosurgery
Specialty Site Ophthalmology

Presentation

Typical facial anomalies are correlated with the degree of holoprosencephaly and have prognostic importance.^1,2 From most severe to least severe, these include the following: (1) cyclopia, in which a single, midline, fused eye exists in a single orbit below a proboscis; (2) ethmocephaly, in which ocular hypotelorism is present with an interorbital proboscis; (3) cebocephaly, in which ocular hypotelorism is present with a single-nostril nose; (4) ocular hypotelorism and midline clefting; and (5) ocular hypotelorism and bilateral clefting.

More subtle facial dysmorphic features may also be present. These include a flat nasal bridge and tip; a single, midline, upper incisor; a bifid uvula; absent nasal bones and nasal septum; and congenital nasal pyriform aperture stenosis (decreased width of the nasal pyriform aperture at the level of the interior meatus).

Microcephaly is the rule, and macrocephaly, if present, is suggestive of hydrocephalus.

Virtually all surviving individuals with the more severe forms of holoprosencephaly have some developmental delay, often persisting as mental retardation. In general, this finding is directly correlated with the severity of holoprosencephaly.

Also not uncommon are seizures, hypotonia and/or hypertonia, extrapyramidal features, such as dystonia and/or chorea; hypothalamic and brainstem dysfunction leading to autonomic dysfunction and swallowing difficulties; pituitary dysfunction, which can manifest as partial or complete panhypopituitarism with resultant endocrine deficiencies; and feeding difficulties, which can lead to aspiration pneumonia and failure to thrive.

Preferred Examination

The imaging study of choice for the diagnosis and classification of holoprosencephaly is cranial magnetic resonance imaging (MRI).^9,10,11 The next best imaging modalities are ultrasonography and cranial computed tomography (CT) scanning.^1,2,12,13,14 Ultrasonography can be limited in cases of microcephaly if there is a very small fontanelle. Transcranial ultrasonography, however, can be performed through the calvaria, at times using the thinner temporal bones. Often this technique requires a transducer of lower frequency, resulting in better penetration, albeit at the loss of some near field resolution.

Prenatal evaluation by means of transabdominal or transvaginal ultrasonography can be used to identify most cases of alobar or semilobar holoprosencephaly. Prenatal MRI can be done in cases in which the infant's head is not easily accessible at the time of ultrasonographic evaluation or in cases in which the anatomy is not satisfactorily delineated at prenatal ultrasonography.

Related Medscape topic:
Resource Center Radiology

Limitations of Techniques

Prenatal sonography is not a reliable method for diagnosing mild forms of holoprosencephaly, such as lobar holoprosencephaly, because of its high false-negative rate. In addition, prenatal ultrasonography often cannot distinguish between alobar holoprosencephaly and semilobar holoprosencephaly. A transabdominal sonographic diagnosis of holoprosencephaly before 16 weeks' gestation is difficult.

Differential Diagnoses

Hydranencephaly

Other Problems to Be Considered

Hydrocephalus
Hydrolethalus syndrome
Meckel syndrome
Pallister-Hall syndrome
Porencephalic cyst
Pseudotrisomy 13
Smith-Lemli-Opitz syndrome
Septo-optic dysplasia
Trisomy 13 (Patau syndrome)
Trisomy 18 (Edward syndrome)
Ventriculomegaly

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