Holoprosencephaly (HPE) is the most common forebrain developmental anomaly in humans with an incidence rate of 1 in 250 spontaneous pregnancy losses and about 1.2 cases per 10,000-20,000 live births.(1,2,4) HPE results from an incomplete midline division of the prosencephalon and includes an extensive spectrum of intracranial and craniofacial anomalies.(1-3,5) A myriad of clinical manifestations may be present, which consist of neurologic impairment with global developmental delay, intellectual disability, seizures, brain anomalies and facial dysmorphic features. Neonates and infants with mild or pronounced facial dysmorphia may prompt early investigations, however, such features are not always present and the diagnosis is often delayed until the second year of life, when neuroimaging for developmental delay can reveal any anomalous brain morphology.
HPE classification is based on the degree of separation of the cerebral hemispheres and the severity of the clinical presentation. HPE Type 1 is characterized by lack of segmentation or complete fusion of the hemispheres (alobar HPE is the most severe form), characterized by the presence of a small single cerebral ventricle lacking interhemispheric division, corpus callosum, and olfactory bulbs. HPE Type 2 is characterized by partial segmentation of the brain (semilobar or lobar HPE; moderately severe). When semilobar, the frontoparietal lobes fail to separate; however, the interhemispheric fissure is present posteriorly, and the corpus callosum is either absent or hypoplastic. When lobar, a distinct interhemispheric fissure is present; however, some midline continuity of the cingulate gyrus persists. HPE Type 3 demonstrates almost complete segmentation (middle interhemispheric variant, also known as syntelencephaly, MIHV, least severe), with separation of the basal forebrain, anterior frontal lobes and occipital regions and failure to divide the posterior frontal and parietal regions of the cerebral hemispheres along the dorsal midline.(3-5,8,14)
The etiology of HPE is complex and includes both chromosomal and monogenic genetic causes as well as environmental factors, such as maternal type 2 diabetes, alcoholism and prenatal exposure to teratogenic drugs.(5-9,17)
Numeric chromosomal anomalies are found in 25-50% of all HPE cases, and these are more likely to have additional syndromic features. The most common chromosome anomaly associated with HPE is trisomy 13 (about 40% of all HPE cases and 75% of all HPE cases due to chromosomal involvement), trisomy 18 and triploidy. Structural chromosome abnormalities found in HPE include 13q, and del(18p), del(7)(q36), dup(3)(p24-pter), del(2)(p21), and del(21)(q22.3). Copy number variants may account for up to 10% of all HPE cases.(3,4) The monogenic forms of HPE are cytogenetically normal, and include both syndromic (20-25% of all HPE cases) and non-syndromic forms of HPE.(3-5) The most commonly involved genes in syndromic autosomal dominantly inherited HPE are
We present the case of a 7-month old Caucasian female infant, from a well monitored twin pregnancy, gemellus II with intra-uterine growth restriction. The morphology scan at 20 weeks’ gestation revealed HPE and the parents were counselled about the clinical implications. The baby was delivered by caesarean section at 37 weeks’ gestation (weight 2700 g, body length 48 cm and APGAR score 7 and 8 at 1 and 5 minutes). The clinical examination by a neonatologist noted microcephaly with a head circumference of 28 cm at birth. The infant had mild facial dysmorphic features including hypertelorism and a narrow nasal bridge (Figure 1A). There were no findings of ambiguous genitalia. Neurological examination revealed central hypotonia and spasticity on all four extremities. The rest of the physical examination findings were unremarkable.
(A) Seven months old infant presenting with microcephaly and mild facial dysmorphic features, and (B) coronal (a) and sagittal (b) section of trans-fontanelle ultrasound examination revealing a single ventricle.
Postnatal head ultrasonographic examination showed an absence of septum pellucidum, semilobar fusion of the hemispheres and mega cisterna magna (Figure 1B) and a brain MRI with FLAIR confirmed the diagnosis of HPE (Figure 2). Electroencephalography showed bihemispheric foci with a tendency for generalization (Figure 3) and transthoracic echocardiography revealed a subtle mid atrial septal defect, resulting in minimal L-D shunt and adequate kinetics of the heart. The abdominal ultrasonography was normal. Laboratory analyses revealed seropositivity for SARS-CoV-2, HSV and CMV, elevated alkaline phosphatase (303 U/L), non-significantly elevated arginine and C10 acylcarnitine and mild electrolyte disbalance (hypernatremia, hyperkalemia, hyperchloremia, hypercalcemia, hyperphosphatemia, hypermagnesemia).
1,5 T MRI showing mega cisterna magna, rudimentary anterior falx cerebri without formed fronto-parietal interhemispheric fissure, absence of septum pellucidum with agenesis of the corpus callosum, thinning of cerebrum, dysplastic unfused thalamus, rudimentary third brain ventricle, rudimentary temporal and occipital horns and cortical polymorphia with macrogyria and microgyria.
EEG demonstrating bihemispheric foci with a tendency for generalization.
Genomic testing using a panel of 456 genes associated with brain malformations identified a novel and
Molecular model of ZIC2 protein indicating the position of Cys-273.
VARIANT | ZYGOSITY | VARIANT CLASSIFICATION | |
---|---|---|---|
c.818G>A (p.Cys273Tyr) | heterozygous | Likely Pathogenic | |
c.1439C>T (p.Ser480Leu) | heterozygous | Uncertain Significance | |
c.1657A>G (p.Met553Val) | heterozygous | Uncertain Significance | |
c.5293C>T (p.Pro1765Ser) | heterozygous | Uncertain Significance | |
c.1814G>A (p.Ser605Asn) | heterozygous | Uncertain Significance | |
c.1603C>G (p.Gin535Glu) | heterozygous | Uncertain Significance |
List of gene variants identified in the proband, including zygosity and variant interpretation.
Holoprosencephaly affects both genders equally and has been reported in different ethnic groups. The genetic etiology of HPE is complex, including both chromosomal and monogenic forms, resulting in either syndromic or isolated forms of HPE. Pathogenic variants in a dozen of genes have been reported to cause HPE, four of which (
Zinc Finger Protein of Cerebellum (
The most common clinical and often presenting problem in patients with HPC is severe neurological impairment (5,10). Seizures are a frequent clinical feature in children with HPE and the therapeutic approach can be challenged by co-existing electrolyte imbalances. Depending on the severity of the condition, seizures can be difficult to control with antiepileptic drugs. In our case, the child was stabilized with 200 mg daily doses of levetiracetam. In other cases, when chorea is present, carbamazepine is the drug of choice.(16) The possibility of posterior pituitary insufficiency is high in patients with HPE and mild or no facial dysmorphia and the child was advised to be regularly followed up by a pediatric endocrinologist.
The dysmorphic facial features present in most patients with HPE include hypotelorism, midface hypoplasia with a flat nasal bridge, cleft lip and or/palate, and a single maxillary central incisor. The severity of facial dysmorphism is generally proportional with the degree of brain malformation and with the survival rate, except in patients with pathogenic
In conclusion, HPE is the most common brain malformation with a complex etiology that involves both genetic and environmental factors. Less severe forms, without complications, may have a long life span. Mildly affected children may live into adulthood, while severely affected children typically do not survive into early infancy. Although survival rates correlate with the severity of the brain malformation, there is significant variability within each type of HPE. The group with the highest survival rate includes children with isolated HPE or with no associated chromosomal disease or syndrome. When HPE is diagnosed antenatally, careful genetic counselling in the context of variable clinical expressivity and reduced penetrance is essential to allow the family to arrive at their decisions. A multidisciplinary team approach to management is essential to maximize the prognosis of this complex condition.
Written informed consent was obtained from the patient for diagnostic genetic testing and publication of this case report with the accompanying images.