Holoprosencephaly 

Updated: Sep 06, 2019
Author: Nusrat Ahsan, MD; Chief Editor: Luis O Rohena, MD, MS, FAAP, FACMG 

Overview

Practice Essentials

Holoprosencephaly is a congenital Induction disorder of the brain occurring at 3-6 weeks' gestation, with failed segmentation of the neural tube. This leads to incomplete separation of the prosencephalon (forebrain).[1, 2, 3, 4]

Classification of holoprosencephaly

Holoprosencephaly has four subtypes: alobar holoprosencephaly, semilobar holoprosencephaly, lobar holoprosencephaly, and a middle interhemispheric fusion variant (syntelencephaly).[2, 5]

Alobar holoprosencephaly is the most severe form, with no separation of the cerebral hemispheres; it is characterized by a single ventricle, absence of the corpus callosum and interhemispheric fissure, and fused thalami.

In semilobar holoprosencephaly, the cerebral hemispheres are fused anteriorly, while lobar holoprosencephaly is characterized by fusion of the cerebral hemispheres at the frontal lobes.

A middle interhemispheric fusion variant results from nonseparation of posterior frontal and parietal lobes.

Some researchers have attempted to incorporate degree of nonseparation of subcortical structures into the classification system.[6] The term septopreoptic holoprosencephaly has been used to describe a mild subtype of lobar holoprosencephaly with nonseparation restricted to the septal or preoptic region.[7]

Most cases of holoprosencephaly are characterized by various midline craniofacial malformations. The most severe craniofacial deformity is cyclopia, with a single or partially divided eye existing in a single orbit, along with a proboscis (tubular appendage) above the eye and an absent nose (arhinia). Several less severe midline malformations have been described, such as a single central maxillary incisor.[8, 9, 10]

Microform of holoprosencephaly is a term assigned to the relatives of probands who have minor craniofacial anomalies but no cerebral abnormalities suggestive of holoprosencephaly on neuroimaging. They may have neurodevelopmental issues.[11, 12, 13, 14, 15]

Symptoms of holoprosencephaly

Seizures are common in holoprosencephaly.[16, 17] Patients often have feeding difficulties and resultant malnutrition.[18] Pituitary dysfunction is also common.[19] Other problems include temperature dysregulation, disturbed sleep cycle, brainstem dysfunction, and recurrent respiratory tract infections.[20, 21] The severity of developmental delay depends on the severity of the brain malformation. Movement disorders include spasticity, hypotonia, choreoathetosis, and dystonia.[22]

Workup

Prenatal diagnosis options include karyotype analysis, microarray testing, ultrasonography, and magnetic resonance imaging (MRI). It is possible to arrive at an etiologic diagnosis prenatally in many cases.[23, 24, 25] Karyotype is abnormal in about a third of holoprosencephaly cases, with trisomy 13 being the most common such anomaly.[26, 27]

Management

Medical care is necessary for problems commonly associated with holoprosencephaly, such as seizures, movement disorders, pituitary dysfunction, failure to thrive, feeding issues, and gastroesophageal reflux. Neurosurgical intervention is needed if hydrocephalus is present.

Anatomy

During early human brain development, the forebrain divides into telencephalon and diencephalon. Telencephalon develops into cerebral hemispheres and subcortical structures such as basal ganglia, amygdala, and hippocampus. Diencephalon gives rise to the thalamus and hypothalamus.

Pathophysiology

A combination of genetic and environmental factors is thought to be responsible for the pathogenesis of holoprosencephaly. Defective sterol metabolism leading to abnormalities in the sonic hedgehog (SHH) signaling pathway may have a role in its causation.[28, 29, 30, 31, 32]  However, many genes besides SHH have also been associated with holoprosencephaly.[33]

Using a collection of over 44,000 human conceptuses from Kyoto University, in Japan, Abe et al reported that spontaneous abortions occurred in about 30% of women with a conceptus suffering from holoprosencephaly, approximately twice the rate found in pregnancies in general. The study also indicated that an association exists between bleeding in pregnancy and holoprosencephaly, with such bleeding experienced by 70% of women with a holoprosencephalic conceptus.[34]

Etiology

Environmental causes

Maternal diabetes mellitus is a known risk factor.[35] Maternal use of alcohol, retinoic acid, aspirin, misoprostol, and cholesterol-lowering agents has been implicated, as has maternal smoking.[36, 37, 38, 39, 40, 41, 42, 43, 44, 45]

Heritable causes

Holoprosencephaly is associated with chromosomal abnormalities such as trisomy 13, trisomy 18, and triploidy.[46, 47, 48, 49, 50, 51] It has been reported with Down syndrome, but the association is thought to be coincidental.[52, 53]  Many other chromosomal abnormalities have been reported as a cause.[54, 55, 56]

Many syndromes are associated with holoprosencephaly, including Smith-Lemli-Opitz syndrome, Meckel-Gruber syndrome, Pallister-Hall syndrome, caudal dysgenesis, and Aicardi syndrome.[57, 58, 59, 60, 61, 62, 63, 64, 65]

Mutations in various genes have been reported in nonsyndromic holoprosencephaly, including SHH, ZIC2, SIX3, and TGIF, and are inherited in an autosomal-dominant fashion. Autosomal-recessive and X-linked patterns have also been described.[66, 67, 68, 69, 70, 71, 72, 73, 74, 75]

Epidemiology

United States statistics

Holoprosencephaly has an estimated birth prevalence rate of approximately 1 in 10,000 births.[26, 76, 77] This is likely to be an underestimation.

International statistics

Holoprosencephaly occurs worldwide.[78, 79, 80, 81, 82, 83] The frequency among all pregnancies has been reported to be 1 in 250 based on a study on embryos obtained through induced abortion, making this the most common human forebrain malformation.[84]

Racial differences in incidence

Ethnic variations have been reported.[77, 80] However, these may be due to lower prenatal detection rates in certain groups and lower rates of pregnancy terminations.[85]

Sexual differences in incidence

Holoprosencephaly has been reported to be more common in females than in males.[81, 86]  [87]

Prognosis

The prognosis of holoprosencephaly depends on the severity of the malformation.

The recurrence risk is high if parental carrier state is established, although its exact quantification may not be possible.[88] The recurrence risk is usually low if the genetic abnormalities occur de novo in the proband, although there is always the possibility of germline mosaicism.[89]

Complications

Possible complications of holoprosencephaly include those due to secondary manifestations such as seizures and ventriculoperitoneal shunt malfunction.

Mortality/morbidity

Mortality and morbidity associated with holoprosencephaly depend on the severity of the malformations. Most affected pregnancies result in miscarriage. Among live births, those with the severe type often die within days of birth.[79]  Persons with milder malformations usually survive beyond infancy.[90]

 

Presentation

History

A diagnosis of holoprosencephaly may be made prenatally or it may be obvious at birth because of the craniofacial abnormalities.

The severity of craniofacial malformations and holoprosencephaly correspond in most cases, but not all.[91, 92] The categorization of the type of holoprosencephaly requires neuroimaging.

Seizures are common.[16, 17]  Patients often have feeding difficulties and resultant malnutrition.[18] Pituitary dysfunction is also common.[19] Other problems include temperature dysregulation, disturbed sleep cycle, brainstem dysfunction, and recurrent respiratory tract infections.[20, 21]  A detailed prenatal and family history should be documented in all cases.

 

Physical Examination

The severity of developmental delay depends on the severity of the malformation. Movement disorders include spasticity, hypotonia, choreoathetosis, and dystonia.[22]  In the absence of microcephaly, hydrocephalus should be considered a possibility.[93]

 

DDx

Diagnostic Considerations

Absent olfactory bulbs and tracts are commonly associated with holoprosencephaly,[2]  and a dorsal cyst is commonly present.[94]

Several other brain malformations have been reported to occur with, but are not specific to, holoprosencephaly.[63, 74, 95, 96, 97, 98, 99, 100, 101]

Differential Diagnoses

  • Septo-optic dysplasia

 

Workup

Approach Considerations

Prenatal diagnosis options include karyotype analysis, microarray testing, ultrasonography, and MRI. It is possible to arrive at an etiologic diagnosis prenatally in many cases.[23, 24, 25]

Genetic Testing

Karyotype has been reported to be abnormal in about a third of cases of holoprosencephaly, with trisomy 13 being the most common karyotype anomaly.[26, 27] Genetic testing is commercially available for the common genetic mutations. Microarray testing has revealed a high prevalence of copy number variations.[74, 102]

MRI

A brain MRI is preferred over a computed tomography (CT) scan for classifying the type of holoprosencephaly.

Early fetal magnetic resonance image shows alobar Early fetal magnetic resonance image shows alobar holoprosencephaly. Courtesy of Dorothy I. Bulas, MD.

EEG

Electroencephalography (EEG) is indicated for suspected seizures.

 

Treatment

Medical Care

Medical care is necessary for problems commonly associated with holoprosencephaly, such as seizures, movement disorders, pituitary dysfunction, and gastroesophageal reflux.

Surgical Care

Neurosurgical intervention may be required if hydrocephalus is present. A gastrostomy tube is needed for feeding difficulties and poor weight gain.

 

Medication

Medication Summary

Anticonvulsants are used for treatment of seizures, as well as for long-term prophylaxis in patients with epilepsy.

Spasticity, choreoathetosis, and dystonia may require symptomatic treatment.

Hormone replacement therapy is used in cases of pituitary dysfunction.

H2 receptor antagonists, proton pump inhibitors (PPIs), and promotility agents are used for gastroesophageal reflux.

Anticonvulsant Agents

Class Summary

These agents prevent seizure recurrence and terminate clinical and electrical seizure activity.

Valproic acid (Depakote, Depakote ER, Depakene, Depacon, Stavzor)

Considered the drug of first choice for primary generalized epilepsy, valproate has a very wide spectrum and is effective in most seizure types, including myoclonic seizures. It has multiple mechanisms of anticonvulsant effects, including increasing gamma-aminobutyric acid (GABA) levels in brain, as well as T-type calcium channel activity. The extended-release (ER) formulation allows for once-a-day administration.

Phenytoin (Dilantin, Phenytek)

Phenytoin works for tonic-clonic seizures and is often used because it can be administered once a day. Long-term side effects of osteopenia and cerebellar ataxia now temper its use by neurologists. This agent is one of the most difficult antiepileptic drugs (AEDs) to use owing to its zero-order kinetics and narrow therapeutic index. In addition, it can have significant bidirectional drug interactions.

Carbamazepine (Tegretol, Tegretol XR, Carbatrol, Epitol, Equetro)

This older antiepileptic drug is used as a second-choice agent along with phenytoin. It has active metabolite 10-11 epoxide. Like phenytoin, carbamazepine has been associated with osteopenia.

Lamotrigine (Lamictal, Lamictal ODT, Lamictal XR)

Lamotrigine is a newer antiepileptic drug with a very broad spectrum of activity, like valproate. It is FDA approved for both primary generalized and partial-onset epilepsy.

Lamotrigine has several mechanisms of action that may account for its effectiveness. A major disadvantage is that the dose has to be increased very slowly over several weeks to minimize the chance of rash, especially if the patient is receiving valproic acid.

Zonisamide (Zonegran)

One of newer antiepileptics recently introduced in the US market, zonisamide has been studied extensively in Japan and Korea and seems to have broad-spectrum properties. It blocks T-type calcium channels, prolongs sodium channel inactivation, and inhibits carbonic anhydrase.

Felbamate (Felbatol)

Felbamate is approved by the FDA for medically refractory partial seizures and Lennox-Gastaut syndrome. This agent has multiple mechanisms of action, including (1) inhibition of NMDA-associated sodium channels, (2) potentiation of GABA-ergic activity, and (3) inhibition of voltage-sensitive sodium channels. It is used only as drug of last resort in medically refractory cases because of the risk of aplastic anemia and hepatic toxicity, which necessitates regular blood tests.

Topiramate (Topamax)

An AED with a broad spectrum of antiepileptic activity, topiramate is approved for generalized tonic-clonic seizures. It has multiple mechanisms of action, including state-dependent sodium channel–blocking action; it also potentiates inhibitory activity of the neurotransmitter GABA. It may block glutamate activity and is a carbonic anhydrase inhibitor.

Levetiracetam (Keppra, Keppra XR)

Levetiracetam is indicated for primary generalized tonic-clonic seizures in adults and children aged 6 years or older, as well as for use in juvenile myoclonic epilepsy and for partial seizures.

Rufinamide (Banzel)

An AED that is structurally unrelated to current antiepileptics, rufinamide modulates sodium channel activity, particularly prolongation of the channel's inactive state. It significantly slows sodium channel recovery and limits sustained repetitive firing of sodium-dependent action potentials. Rufinamide is indicated for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome.

Primidone (Mysoline)

Primidone decreases neuron excitability and increases seizure threshold.

Ethosuximide (Zarontin)

Ethosuximide is a succinimide AED that is effective only against absence seizures. It has no effect on generalized tonic-clonic, myoclonic, atonic, or partial seizures. Its mechanism of action is based on reducing current in T-type calcium channels on thalamic neurons. Spike-and-wave pattern during petit mal seizures are thought to be initiated in thalamocortical relays by activation of these channels.

Ethosuximide is available in large 250-mg capsules, which may be difficult for some children to swallow, and as a syrup (250 mg/5 mL).

Lamotrigine (Lamictal, Lamictal ODT, Lamictal XR)

Lamotrigine is a triazine derivative used in neuralgia. It inhibits release of glutamate and voltage-sensitive sodium channels, leading to stabilization of neuronal membrane.

Phenobarbital

Phenobarbital works at CNS GABA receptors to potentiate CNS inhibition. It exhibits anticonvulsant activity in anesthetic doses. Phenobarbital is the best-studied barbiturate in the treatment of status epilepticus (SE).

In SE, achieving therapeutic levels as quickly as possible is important. Intravenous doses may require approximately 15 min to attain peak levels in the brain. To terminate generalized convulsive SE, administer up to 15-20 mg/kg. If the patient has received a benzodiazepine, the potential for respiratory suppression significantly increases. Ventilation and intubation may be necessary. Hypotension may require treatment.

Phenobarbital is generally used after phenytoin or fosphenytoin fails. However, it can be used in lieu of phenytoin in certain circumstances.

If the intramuscular route is chosen, administer this agent into a large muscle such as the gluteus maximus or vastus lateralis or other areas where the risk of encountering nerve trunk or major artery is low. Permanent neurologic deficit may result from injection into or near peripheral nerves.

Restrict IV use to conditions in which other routes are not possible, either because patient is unconscious or because prompt action is required.

A trend is to recommend agents other than phenobarbital (propofol, midazolam, other barbiturates) for refractory SE.

Decarboxylase Inhibitors

Class Summary

In order for a dopamine agonist to offer clinical benefit, it must stimulate D2 receptors. The role of other dopamine-receptor subtypes is currently unclear.

Levodopa/Carbidopa (Sinemet, Parcopa)

The active component is an L-isomer of dopamine (ie, L-dopa). Carbidopa is a peripheral DOPA hydroxylase inhibitor; by preventing peripheral metabolism, it increases the concentration of dopamine in the central nervous system (CNS). The total L-dopa dose required varies from person to person.

Anticholinergic Agents

Class Summary

These agents are thought to work centrally by suppressing conduction in the vestibular cerebellar pathways. They may have an inhibitory effect on the parasympathetic nervous system.

Trihexyphenidyl

Trihexyphenidyl is a synthetic anticholinergic noted to have a marked benefit in muscle spasm conditions, such as dystonia.

Benztropine (Cogentin)

By blocking striatal cholinergic receptors, benztropine may help balance cholinergic and dopaminergic activity in striatum. This agent can be used as an alternative to trihexyphenidyl.

Skeletal Muscle Relaxants

Class Summary

These agents may be used in any dystonia but most commonly in the childhood-onset type.

Baclofen (Lioresal, Gablofen)

Baclofen is a centrally acting muscle relaxant; its precise mechanism of action is unknown. It is a GABA analog and may exert its effects by stimulation of GABA-beta receptors. Baclofen inhibits monosynaptic and polysynaptic reflexes at the spinal level by hyperpolarization of afferent terminals.

Histamine H2 Antagonists

Class Summary

H2 blockers are reversible competitive blockers of histamine at H2 receptors, particularly those in the gastric parietal cells (where they inhibit acid secretion). The H2 antagonists are highly selective, they do not affect the H1 receptors, and they are not anticholinergic agents.

Some gastroenterologists recommend PPIs as being more effective than H2 blockers in promoting lesion cicatrization for hemorrhagic esophagitis and gastroesophageal reflux. Studies with omeprazole (Prilosec) and pantoprazole (Protonix) in IV forms have been encouraging, but they are not yet approved by the FDA for use in children.

Ranitidine (Zantac)

This agent inhibits histamine stimulation of H2 receptors in gastric parietal cells, which reduces gastric acid secretion, gastric volume, and hydrogen ion concentrations.

Famotidine (Pepcid)

Famotidine competitively inhibits histamine at the H2 receptors in gastric parietal cells, reducing gastric acid secretion, gastric volume, and hydrogen concentrations.

Nizatidine (Axid, Axid AR)

This agent competitively inhibits histamine at the H2 receptor of the gastric parietal cells, resulting in reduced gastric acid secretion, gastric volume, and hydrogen concentrations.

Cimetidine (Tagamet HB 200)

This agent inhibits histamine at H2 receptors of gastric parietal cells, which results in reduced gastric acid secretion, gastric volume, and hydrogen concentrations.

Proton Pump Inhibitors

Class Summary

PPIs are used to reduce gastric acid hypersecretion. Dosing should be adequate to achieve a basal acid output (BAO) of less than 10 mEq/h. Dosing may vary in each patient. Children may require relatively higher doses per kilogram than adults.

Lansoprazole (Prevacid)

Lansoprazole is a substituted benzimidazole that covalently and irreversibly binds the hydrogen potassium/ATPase, thereby inhibiting acid secretion. This agent is available as an IV formulation, oral (PO) caps, or solutabs. Strawberry-flavored solutabs can be dissolved in water for easy administration to children. Dissolve the 15-mg solutab in 4 mL of water and the 30-mg solutab in 10 mL of water.

Omeprazole (Prilosec)

Omeprazole is a substituted benzimidazole that suppresses acid secretion by specific inhibition of hydrogen potassium/ATPase at the secretory surface of the parietal cell.

Pantoprazole (Protonix)

Pantoprazole is a substituted benzimidazole that suppresses acid secretion by specific inhibition of hydrogen potassium/ATPase at the secretory surface of the parietal cell.

Prokinetic Agents

Class Summary

Prokinetics are promotility agents, proposed for use in severe constipation-predominant symptoms.

Metoclopramide (Reglan, Metozolv)

Metoclopramide is characterized by remarkable coordination of gastric and duodenal motility.

Cisapride (Propulsid)

Cisapride indirectly improves GI motility by promoting acetylcholine release from postganglionic nerve endings in the myenteric plexus. It was withdrawn from the US market on July 14, 2000, but the manufacturer will make it available to certain patients meeting clinical eligibility criteria for a limited-access protocol only.

Estrogens/Progestins

Class Summary

Contraceptives reduce secretion of LH and FSH from the pituitary by decreasing the amount of gonadotropin-releasing hormone (GnRH).

Ethinyl estradiol and drospirenone (YAZ, Zarah, Ocella, Loryna, Gianvi)

This formulation is an oral contraceptive that contains ethinyl estradiol 20 µg and drospirenone 3 mg. It is indicated for PMDD in women who choose to use an oral contraceptive as their method of contraception.

Norethindrone acetate/ethinyl estradiol (Ortho-Novum, Nortrel, Cyclafem)

Norethindrone acetate and ethinyl estradiol are used as an oral contraceptive in women who choose to use an oral contraceptive as their method of contraception.