Continuing Education Activity

Holoprosencephaly occurs as a result of anomalous signaling interactions between the neural crest and neural ectoderm. This primarily results in the abnormal structure of the frontal lobes (derived from telencephalon), among other intracranial structures, as well as craniofacial defects. This activity reviews the evaluation and treatment of holoprosencephaly and highlights the role of the interprofessional team in evaluating and treating patients with this condition.

Objectives:

• Describe the pathophysiology of holoprosencephaly.
• Outline the typical presentation of holoprosencephaly.
• Review the management of holoprosencephaly.

Introduction

Holoprosencephaly (HPE) results from an incomplete midline cleavage of the forebrain (prosencephalon) and includes a wide spectrum of intracranial and craniofacial midline defects, along with a myriad of clinical manifestations, which consist of neurologic impairment and dysmorphism of the brain and face. Evidence suggests that holoprosencephaly can be present either sporadically or have a syndromic association. The defect associated with holoprosencephaly occurs at around two to three weeks after conception and is a disorder of gastrulation.[1]

Etiology

On the whole, the most studied cases of holoprosencephaly are those occurring due to chromosomal anomalies but with normal karyotype. They are rarely associated with malformation syndromes. The majority of live births with HPE have a ‘nonsyndromic, nonchromosomal HPE, which describes HPE that cannot be attributed to chromosomal or syndromic causes and includes environmental causes, deletions of or mutations in genes known to be involved in HPE, or currently unidentifiable factors. 

From the above discussion, it can be concluded that the etiology of holoprosencephaly can be divided into-

Genetic Causes

Nonsyndromic monogenic causes: SHH anomalies are the most common defects that have been recorded in HPE patients with associated midline defects. Other main genetic causes include ZIC2, SIX3, and TGIF.[2]

Syndromic causes: Around 32-42 % of the cases occur due to anomalies of chromosome number, most commonly trisomy 13, followed by trisomy 18 and triploidy.

Specific syndromes related to HPE include both autosomal dominant and autosomal recessive syndromes including-

• Autosomal dominant: 1) CDON gene-related Steinfield syndrome

                                         2) FGFR1 gene-related Kallman syndrome two and Hartsfield syndrome

• Autosomal recessive: 1) CENPF gene-related Stromme syndrome

                                         2) DHCR7 gene-related Smith-Lemli-Opitz Syndrome[3]

Nongenetic causes:

HPE is associated with pregestational maternal diabetes. Consistent maternal folic acid use appears to be protective. Animal studies suggest HPE can result from exposure to teratogens, such as ethanol, retinoic acid, food-borne mycotoxins like ochratoxins, cyclopamine (Hedgehog signaling inhibitors), and drugs that interfere with cholesterol biosynthesis.[4]

Epidemiology

Holoprosencephaly occurs rather frequently, and is observed in 1:250 conceptuses; due to a high rate of fetal demise, the birth prevalence is between 1:8000 to 1:16000 live births and is similar among different international populations. In the United States, seemingly higher prevalence rates have been reported in African-American, Hispanic, and Pakistani ethnicities, most likely attributable to decreased prenatal diagnosis and termination rates in these groups.[1][5]

Pathophysiology

To understand the pathogenesis of holoprosencephaly, one must understand the relationship between the development of the face and the brain. The successful development of the brain and face occurs due to reciprocal signaling of several 'signaling molecules' between the surface ectoderm and neural crest cells that determine the migration of primitive embryonal cells, leading to the formation of highly developed structures. Incomplete diverticulation and cleavage of the embryonic forebrain is the reason for the intracranial pathology. Blocking this signaling alters the dorso-ventral polarity, anterior-posterior axis, and inhibits bilateral symmetry of the forebrain. Shh is one such signaling molecule. Inhibiting Shh expression in the basal telencephalon subsequently impedes the dorso-ventral polarity and inhibits the induction of Shh expression in the Frontonasal Ectodermal Zone (FEZ), leading to multiple midline facial defects. Various degrees of a block in the Shh signaling determine the severity of the disease manifestation.

Incomplete penetrance and variable expressivity make it difficult to predict disease manifestation in the offspring. The parents carrying defined mutations may not have either physical or neurological symptoms. Current studies suggest a multi-hit origin of HPE, explaining the lack of clinical manifestations in patients presenting with the concerned mutations.[6][7][8][9]

History and Physical

A standardized diagnostic protocol, including dysmorphology examination, complete family history and ascertainment of risk factors, and neuroimaging, would cover the spectrum of presenting features of these disorders.

The pathogenesis of holoprosencephaly is related to abnormal genes that are responsible for the normal development of the head and the face. Hence, clinically, the spectrum of the presentation can range from mild craniofacial defects, like single maxillary central incisor with normal neurological function, to severe cranio-facio-neurological defects like cyclopia or proboscis with an alobar variant. In moderate to severe cases, the craniofacial symptoms have proven to be an indicator of the severity of the intracranial lesion.

Severe facial phenotypes are associated with the alobar variant of holoprosencephaly and include-

• Pronounced microcephaly.
• Cyclopia: Single, centrally placed eye, synophthalmia, or anophthalmia. Proboscis may be single or absent and may or may not be accompanied by hypognathism.
• Cebocephaly: A combination of ocular hypotelorism and a single nostril nose.
• Ethmocephaly: Proboscis (a tube-like nasal appendage with a single nostril located above the ocular region) with ocular hypotelorism.[10]

Less severe facial phenotypes are associated with the following intracranial manifestations including- 

• Hypotelorism is associated with the lobar variant.
• Midface hypoplasia with a flat nasal bridge, cleft lip and/or palate, and agenesis of the columella are associated with the lobar variant.
• Ocular colobomas, along with other severe features, are related to the alobar variant while, when present alone, are a sign of lobar/middle interhemispheric variant.
• Single maxillary central incisor-microform variant.

Individuals with a mild variant of holoprosencephaly, usually have a relative with frank holoprosencephaly. These patients typically present with only the craniofacial anomalies without the accompanying neurological defect.[1]

Evaluation

In a pediatric patient fulfilling the above mentioned clinical triad of typical morphology, family history, and environmental factors, the next step is to confirm the type of intracranial anomaly by neuroimaging. Evaluation of holoprosencephaly can take place as early as the prenatal period. This is done by ultrasonography and MRI. In severe forms of holoprosencephaly, a USG can detect the anomaly as early as the first trimester. An MRI is used for diagnosis in the third trimester. Postnatal neuroimaging includes USG, which is the preferred imaging modality in infants with open anterior fontanelles. In older children, a CT or MRI may be considered. However, they come with their own risks. While the CT could cause excess radiation exposure, the risk of excess sedation exists with MRI. The pattern observed in imaging could include:

Alobar holoprosencephaly: This occurs due to diffuse cortical nonseparation, the corpus callosum and olfactory bulbs are absent entirely. The deep gray nuclei are fused, and a single midline ventricle is seen in these patients.

Semilobar form: There exists nonseparation of the frontal lobes, the anterior corpus callosum is absent, fused deep gray nuclei, and absent anterior horns of lateral ventricles.

Lobar forms: Nonseparation of basal frontal brains, absent corpus callosum adjacent to affected areas with hypoplastic olfactory bulbs, and the azygous anterior cerebral artery (anteriorly displaced) is associated with this defect.

Middle intrahemispheric variant: Nondisjunction between bilateral frontal and parietal lobes, an absent body of the corpus callosum, and azygous anterior cerebral artery are visible in these patients.[1]

Once the diagnosis is confirmed, the patient is evaluated for a syndromic association. This changes the course of management in that it includes the evaluation of the coexisting features that may exist and might require further medical or surgical attention.

Following this, genetic testing is carried out to determine the existence of any chromosomal anomaly by conducting cytogenetic and molecular testing. If this reveals any kind of chromosomal or genetic anomaly that is associated with holoprosencephaly, it would further mandate genetic counseling for the parents, should they decide to conceive another child.[11]

Treatment / Management

The management in patients with holoprosencephaly is symptomatic and requires a multidisciplinary approach. It targets each organ system, and the related complications, individually. 

• Epilepsy is a common complication in patients with HPE. A single seizure occurs in around 50% of all HPE children, some of whom may require multidrug antiepileptic therapy.[12]
• Although, ideally, holoprosencephaly presents with microcephaly, when associated with macrocephaly, it would indicate coexisting hydrocephalus. This would have to be immediately treated with shunt surgery while preventing over drainage of CSF.[13]
• Motor anomalies, when present, warrant treatment. Spasticity and dystonia would require pharmacological interventions, including intrathecal baclofen pumps, and oral trihexyphenidyl, along with physical and occupational therapy. 
• Orofacial motor dysfunction is compounded by structural anomalies like cleft palate/lip causes aspiration, which further progresses to pneumonia, hence posing a serious challenge for feeding. This can require structural surgical correction.
• The hormone dysregulation caused by the absence of a well-formed hypothalamus can manifest as pituitary hormone deficiencies, most commonly diabetes insipidus. The manifestation of other hormonal deficits is rare. However, prednisone, thyroxine, and growth hormone supplements may be required in people with overt symptoms of deficiency. 
• Poor nerve migration to the gastrointestinal tract causes poor gastric and colonic motility and gastroesophageal reflux. This can be managed by placement of a gastrostomy tube in very severe facial defects, sometimes indicating medications and anti-reflux procedures in isolated severe GERD.[1]

Differential Diagnosis

Septo-optic dysplasia: In addition to enlarged ventricles and hypothalamo-pituitary axis failure, it also consists of optic nerve degeneration and absent septum pellucidum, which are both absent in holoprosencephaly.[14]

DiGeorge syndrome: Abnormalities such as cleft palate, hypertelorism, are associated with other anomalies like cardiopulmonary anomalies like aortic arch anomalies and conotruncal defects. Other anomalies like T cell deficiency and signs of hypocalcemia as a result of parathyroid hypoplasia are seen as well.[15]

Hydranencephaly: A CT of the head shows absent bilateral cerebral hemispheres with no cortical mantle, and a fluid-filled cavity. However, since the entire falx is preserved, this rules out holoprosencephaly.[16]

Porencephalic cyst: On MRI, it appears as an abnormal accumulation of CSF within the brain parenchyma, rather than an absence/midline fusion of cerebral lobes, as seen in holoprosencephaly.[17]

Arachnoid cyst: This occurs in conjunction with HPE or could be the only finding. It occurs secondary to trauma or could be inherited in an autosomal manner. It does not present with facial defects unless coexisting holoprosencephaly exists.[18]

Prognosis

Moderate to severe cases of HPE generally have a poor prognosis. the mortality rate increases as follows, with 33% in the first 24 hours after birth, to 58% in the 1 month, to 50% between the 4 and the 5 months, to between 70% to 80% in the 1 year of life. The survival rate after 1 year of life is only around 29%. A very small number survive until adulthood. Mild to moderate cases typically survive till adulthood, but live with the accompanying complications.[12]

Complications

Neurological complications associated with holoprosencephaly include epilepsy with or without clinically evident seizure activity, motor impairment such as hypotonia and dystonia, with or without spasticity.[7] Hydrocephalus is a common complication with the alobar variant of holoprosencephaly, thus presenting with a macrocephaly rather than microcephaly, sometimes clouding the initial clinical suspicion.[13]

Gastrointestinal tract anomalies like poor gastric and colonic motility and gastroesophageal reflux are a result of poor neuronal migration during development.[19]

Additionally, the hypothalamus being a midline structure is unformed in these patients. Non-formation of the hypothalamus is associated with various endocrinal symptoms due to pituitary hormone deficiency, along with impaired homeostatic functions like thirst, hunger, and temperature. Hormone irregularities of the posterior pituitary are far more common than those of the anterior pituitary. Patients must be screened repeatedly for electrolyte levels to diagnose diabetes insipidus. Regarding the anterior pituitary insufficiency, both hypothyroidism and hypocortisolism can prove to be lethal, while growth hormone and gonadotrophic hormone deficiency can lead to stunting and sexual immaturity.[1]

Deterrence and Patient Education

Genetic testing is recommended for the parents with a child showing apparent symptoms or in those showing mild variants.[3] However, the indication for testing depends on the clinical suspicion of the disease, which itself is very difficult given the numerous phenotypic variations. Compounding the diagnosis further is the numerous number of genes involved along with a multi-hit process. The de-novo occurrence of some mutations which show a specific defect in the parents has also been observed. In this case, the chances of HPE in a subsequent pregnancy are greatly reduced.[11]

Pearls and Other Issues

Here are some important points

• Holoprosencephaly occurs due to incomplete midline cleavage of the forebrain(prosencephalon) and includes a wide spectrum of intracranial and craniofacial midline defects.
• The etiology of holoprosencephaly could be genetic or sporadic. Genetic causes can be further classified into syndromic and nonsyndromic causes.
• The severity of the craniofacial defects often correlates with the degree of the intracranial anomaly.
• A diagnosis can also be established prenatally using a USG in the first trimester and MRI in the third trimester.
• An MRI is used for a definitive diagnosis of holoprosencephaly. Depending on the clinical and MRI findings, HPE can be classified into alobar, semi-lobar, lobar, and middle intrahemispheric variant.
• Most patients with holoprosencephaly have either associated seizures, hydrocephalus, motor dysfunction, endocrine dysfunction, or gastric dysmotility.
• Prognosis depends on the degree of an anomaly in the patient. While the alobar, labor, and semi lobar variant have a poorer prognosis, the middle intrahemispheric variant has a fairly better prognosis.
• Genetic testing is recommended for the parents with a child showing apparent symptoms or in those showing mild variants.

Enhancing Healthcare Team Outcomes

An interprofessional team provides a holistic and integrated approach to accurately diagnose and help achieve the best possible outcomes. The complications that commonly accompany holoprosencephaly require a multidisciplinary approach. Endocrine dysfunction that commonly accompanies some variants of HPE should be treated life long by a pediatric endocrinologist. Associated gastrointestinal anomalies are attended to by pediatric gastroenterologists. Neurological anomalies like seizures, movement disorders, facial anomalies, and hydrocephalus, are attended to by the neurologist and the neurosurgeon.

Dysphagia or reflux related to the cleft palate is treated by a plastic surgeon in conjunction with the pediatric surgeon. The importance of psychological aid and genetic counseling must not be undermined and should be offered to all parents. Child psychiatrists and psychologists can be consulted for the emotional and behavioral consequences of holoprosencephaly.

Collaboration with shared decision making and good communication among the interprofessional team is key for a good outcome. The interprofessional care provided to the patient must use an integrated care pathway combined with an evidence-based approach to planning and evaluation of all joint activities. The earlier signs and symptoms of a complication are identified, the better is the prognosis and outcome.[20]