Holoprosencephaly

Etiology

Extensively researched cases of HPE primarily focus on individuals with normal karyotypes but with chromosomal anomalies, and these cases seldom coincide with malformation syndromes. In most live births affected by HPE, the condition is classified as nonsyndromic and nonchromosomal, indicating that it cannot be ascribed to syndromic or chromosomal origins. This category encompasses environmental causes, deletions, or gene mutations that play a role in HPE or unidentified factors.

The etiology of HPE can be divided into several categories, as follows:

Genetic Causes

Nonsyndromic monogenic causes: SHH anomalies are the most common defects recorded in HPE patients with associated midline defects. Other leading genetic causes include ZIC2, SIX3, and TGIF.[7]

The main functions of these genes include the following: 

• Zinc finger protein (ZIC2) - Arrangement of the anterior notochord
• SIX homeobox 3 (SIX3 ) - Arrangement of the anterior-posterior polarity of brain vesicles
• Sonic hedgehog (SHH) - Telencephalic vesicle and optic cup patterning from the neural tube's ventral midline section
• Bone morphogenetic protein - Craniofacial patterning
• Fibroblast growth factor - Craniofacial patterning
• TG interacting factors (Tgifs) 1 and 2 - Regulation of SHH signaling [8]

Syndromic causes: Approximately 32% to 42% of the cases occur due to anomalies of chromosome number, most commonly trisomy 13 (Patau syndrome), followed by trisomy 18 and triploidy.[9] Patau syndrome is commonly caused by mosaicism, complete trisomy, or even by translocation of chromosome 13.[10] Almost 24% to 45% of these patients have associated HPE.[11]

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

• Autosomal Dominant: 
  • CDON gene-related Steinfield syndrome
  • FGFR1 gene-related Kallman syndrome and Hartsfield syndrome (holoprosencephaly, cleft lip and palate, and ectrodactyly)
  • Agnathia-Otocephaly Complex (gene PRRX1)
  • Culler-Jones syndrome
  • CHARGE syndrome                                                                                                           
• Autosomal Recessive:                                                                              
  • CENPF gene-related Stromme syndrome
  • DHCR7 gene-related Smith-Lemli-Opitz Syndrome - intellectual disability, dysmorphisms of the face, congenital cardiac anomalies, and male external genitalia defects [12][13] 
  • HHAT (encoding Hedgehog acyltransferase)
  • PLCH1 (encoding phospholipase C eta-1)
  • STIL [encoding a factor required for maintenance of primary cilia) [3]
  • Hydrolethalus syndrome (HYLS1 and KIF7 genes)
  • Genoa syndrome
  • Lambotte syndrome                                                                                                        
• X-linked:
  • X-linked holoprosencephaly-13 (HPE13) (STAG2) [14]                                               
• Variants in genes:
  • Driver genes: Essential to the phenotype of the patient carrying a variant-SHH, ZIC2, SIX3, FGF8, and FGFR1
  • Silent modifier gene: BOC
  • Predisposing genes: All other genes responsible

Nongenetic Causes

HPE exhibits associations with various maternal factors. Pregestational maternal diabetes is 1 such factor. Additionally, maintaining consistent maternal folic acid supplementation appears to offer protective benefits. Studies in animals have provided insights into potential teratogenic influences leading to HPE, including exposure to substances like ethanol, salicylate, retinoic acid, mycotoxins such as ochratoxins, Hedgehog signaling inhibitors like cyclopamine, and drugs that disrupt cholesterol biosynthesis.[15] Furthermore, environmental factors, including polycyclic aromatic hydrocarbons from sources like cigarette smoke and charred meats, Δ9-tetrahydrocannabinol (THC) found in cannabis, and piperonyl butoxide (PBO), a pesticide synergist frequently detected in indoor dust, also warrant consideration in understanding HPE's etiology.[3]

Epidemiology

HPE manifests relatively frequently, with an occurrence rate of approximately 1 in 250 conceptuses. However, the condition's birth prevalence, ranging from 1 in 8000 to 1 in 16,000 live births, remains consistent across diverse international populations. Within the United States, certain ethnic groups, including African-American, Hispanic, and Pakistani communities, appear to exhibit slightly elevated prevalence rates. This phenomenon is likely due to reduced rates of prenatal diagnosis and associated terminations within these particular groups.[2][16]

Pathophysiology

Understanding the relationship between the development of the face and the brain to comprehend the pathogenesis of HPE is essential. The successful development of the brain and face occurs due to the reciprocal signaling of several 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 dorsoventral polarity and anterior-posterior axis and inhibits bilateral symmetry of the forebrain. SHH is 1 such signaling molecule. Inhibiting SHH expression in the basal telencephalon subsequently impedes the dorsoventral 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 predicting disease manifestation in offspring difficult. 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 with the concerned mutations.[17][18][19][20] Basal forebrain patterning occurs during the third and fourth week of embryogenesis. This directs the cleavage of the prosencephalon during the fifth and sixth weeks of gestation.[1]

History and Physical

A standardized diagnostic protocol, including dysmorphology examination, complete family history and ascertainment of risk factors, and neuroimaging, covers these disorders' presenting features. The pathogenesis of HPE is related to abnormal genes responsible for the development of the head and the face. Hence, clinically, the spectrum of the presentation can range from mild craniofacial defects, like a single maxillary central incisor with normal neurological function, to severe cranio-facial-neurological defects, like cyclopia or proboscis with an alobar variant. In moderate to severe cases, craniofacial symptoms have proven to indicate the severity of the intracranial lesion.

Severe facial phenotypes are associated with the alobar variant of HPE and include the following:

• Pronounced microcephaly                                                                                                                                 
• Cyclopia: Single, centrally placed eye, synophthalmia, or anophthalmia. Proboscis (a tube-like nasal appendage with a single nostril above the ocular region) 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 with ocular hypotelorism [21]

Less severe facial phenotypes are associated with intracranial manifestations as follows: 

• Hypotelorism is associated with the lobar variant.                                                                                               
• The lobar variant is associated with midface hypoplasia, a flat nasal bridge, cleft lip and/or palate, and agenesis of the columella.                                                                                                                     
• Ocular colobomas and other severe features are related to the alobar variant (while when present alone, they are a sign of the lobar/middle interhemispheric variant).                                                                              
• The single maxillary central incisor-microform variant is also a less severe phenotype.

Individuals with a mild variant of HPE usually have a relative with frank HPE. These patients typically present with only craniofacial anomalies without the accompanying neurological defect.[2]

Evaluation

In a pediatric patient fulfilling the clinical triad of atypical morphology, family history, and environmental factors, the next step is to confirm the type of intracranial anomaly by neuroimaging. Evaluation of HPE can take place as early as the prenatal period. Noninvasive prenatal testing (NIPT) is a useful method for diagnosing fetal trisomy 13 in the first trimester.[22] The evaluation includes ultrasonography (USG) and magnetic resonance imaging (MRI). In severe forms of HPE, 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, the preferred imaging modality in infants with open anterior fontanelles. A computed tomography (CT) or MRI may be considered in older children. However, testing comes with risks. While the CT can cause excess radiation exposure, the risk of excess sedation exists with MRI.

Patterns observed on imaging include the following:

• Alobar HPE: This occurs due to diffuse cortical non-separation. The corpus callosum and olfactory bulbs are absent entirely. The deep gray nuclei are fused, and a single midline ventricle is visualized in these patients (see Image. Alobar Holoprosencephaly).                                                                                             
• Semilobar form: The frontal lobes are non-separated, and the anterior corpus callosum is absent. Fused deep gray nuclei and absent anterior horns of lateral ventricles are characteristic. The posterior horns of the lateral ventricles are well-developed.                                                                                              
• Lobar form: This defect is associated with the non-separation of basal frontal brains, the absence of the corpus callosum adjacent to affected areas with hypoplastic olfactory bulbs, and the azygous anterior cerebral artery (anteriorly displaced).                                                                                                                            
• Middle interhemispheric variant (syntelencephaly): In these patients, nondisjunction between bilateral frontal and parietal lobes, an absent body of the corpus callosum, and an azygous anterior cerebral artery are evident.[2] The frontal horns are better developed than in alobar HPE, but the occipital horns are poorly developed and are seen as a single ventricular cavity.                                                                              
• Microform HPE: There are no brain malformations in this variant. However, facial anomalies can be seen that include a single maxillary incisor, clefting, hypotelorism, and retinal coloboma.[23]

Signs on imaging include the following:

• A horse-shoe-shaped mono ventricle can be seen on imaging.                                                                                                                   
• Butterfly sign: This is the visualization of the normal appearance of both choroid plexes in the axial plane on an antenatal ultrasound scan. Its absence suggests HPE.                                                                           
• Absence of cavum septi pellucidi: Individuals with all types of HPE lack a normal cavum septi pellucidi.                                         
• “Snake under the skull” sign: The defective cortical tissue bridge between the 2 frontal gyri in lobar HPE pushes the anterior cerebral artery outside alongside the frontal bone.

Electroencephalography findings are as follows:

• Multifocal spikes that often evolve into hypoarrhythmia are found in EEG.                                                                                   
• The waking EEG in the neonatal period classically shows a continuous high-voltage alpha-theta monorhythmic activity that becomes discontinuous while the child sleeps.

Once the diagnosis of HPE is confirmed, the patient is evaluated for a syndromic association. If a syndromic association is discovered, the management course changes to include evaluating any coexisting features that might require further medical or surgical attention.

Genetic testing is carried out to determine the existence of any chromosomal anomaly by conducting cytogenetic and molecular testing. If this reveals any chromosomal or genetic anomaly associated with HPE, it further mandates genetic counseling for the parents should they decide to conceive another child.[24]

Treatment / Management

Managing HPE is symptomatic and requires a multidisciplinary approach. This condition targets each organ system and the related complications as follows:

• Epilepsy is a common complication in patients with HPE. A single seizure occurs in approximately 50% of all children with HPE, some of whom may require multidrug antiepileptic therapy.[13]                                                    
• When HPE is associated with macrocephaly, coexisting hydrocephalus is typically present; this should be immediately treated with shunt surgery while preventing over-drainage of cerebrospinal fluid (CSF).[25]               
• Motor anomalies, when present, warrant treatment. Spasticity and dystonia require pharmacological interventions, including intrathecal baclofen pumps, oral trihexyphenidyl, and physical and occupational therapy.                                                                                                                                                         
• Orofacial motor dysfunction is compounded by structural anomalies like cleft palate/lip causing aspiration, further progressing to pneumonia, posing a serious feeding challenge; 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 patients with overt deficiency symptoms.                                                                                                                                 
• Poor nerve migration to the gastrointestinal tract causes poor gastric and colonic motility and gastroesophageal reflux; this can be managed by placing a gastrostomy tube in severe facial defects. Medications and antireflux procedures in patients with isolated severe gastroesophageal reflux disease are indicated in other cases.[2]
(B3)

Differential Diagnosis

When considering a diagnosis of HPE, it is crucial to explore a range of potential differential diagnoses, including the following:

Septo-Optic dysplasia: In addition to enlarged ventricles and hypothalamic-pituitary axis failure, this diagnosis also consists of optic nerve degeneration and absent septum pellucidum.[26]

DiGeorge syndrome: Abnormalities such as the cleft palate and hypertelorism are associated with other anomalies, including cardiopulmonary anomalies like aortic arch and conotruncal defects. Other anomalies like T-cell deficiency and hypocalcemia resulting from parathyroid hypoplasia are also seen.[27]

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, HPE is excluded.[28]

Porencephalic cyst: On MRI, this finding appears as an abnormal accumulation of CSF within the brain parenchyma rather than an absence/midline fusion of cerebral lobes, as seen in HPE.[29]

Arachnoid cyst: This diagnosis occurs in conjunction with HPE or could be the only finding. Arachnoid cysts occur secondary to trauma or could be inherited in an autosomal manner. This condition does not present with facial defects unless coexisting HPE exists.[29][30]

Prognosis

Moderate to severe cases of HPE generally have a poor prognosis. The mortality rate increases with 33% of neonates dying in the first 24 hours after birth, 58% in the first month, 50% between the fourth and fifth months, and 70% to 80% in the first year of life. A very small number of these neonates survive until adulthood. However, a recent study from a huge population registry showed that the 1-year survival rate was 58.1% and the 10-year survival was 36.9% for HPE.[31] Mild to moderate cases typically survive to adulthood but live with complications.[13] About 50% of lobar HPE patients can ambulate and verbally communicate.[1]

Complications

Neurological complications associated with HPE include epilepsy with or without clinically evident seizure activity and motor impairment such as hypotonia and dystonia with or without spasticity.[18] Hydrocephalus is a common complication with the alobar variant of HPE, thus presenting with a macrocephaly rather than microcephaly, sometimes clouding the initial clinical suspicion.[25] Gastrointestinal tract anomalies like poor gastric and colonic motility and gastroesophageal reflux result from poor neuronal migration during development.[32]

The hypothalamus, a midline structure, is unformed in these patients. Non-formation of the hypothalamus is associated with various endocrinal symptoms due to pituitary hormone deficiency and 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 anterior pituitary insufficiency, both hypothyroidism and hypocortisolism can be lethal, while growth hormone and gonadotrophic hormone deficiencies can lead to stunting and sexual immaturity, respectively.[2]