Balkan Journal of Medical Genetics

SEMILOBAR HOLOPROSENCEPHALY CAUSED BY A NOVEL AND DE NOVO ZIC2 PATHOGENIC VARIANT
Nonkulovski D1, Sofijanova A1, Spasovska T1, Gorjan Milanovski2, Muaremoska-Kanzoska Lj1, Arsov T2,3
*Corresponding Author: Prof Todor Arsov MD MGC PhD, Faculty of Medical Sciences, University Goce Delcev in Shtip, North Macedonia, E-mail: todor.arsov@ugd.edu.mk
page: 71

DISCUSSION

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 (SHH, ZIC2, SIX3, and TGIF) are identified as more common and considered “major” causal genes.(20) Sonic Hedgehog (SHH) pathogenic variants are the most common single gene variants causing HPE and these patients are considered ‘prototypical HPE patients’. Approximately 10-30% of pathogenic SHH variants occur de novo.(5,21) The SHH gene affects mechanisms responsible for normal division of the prosencephalon during the embryogenesis. The associated phenotype is variable, ranging from an extremely severe form with craniofacial dysmorphia, including cyclopia and proboscis, to mild or non-penetrant forms without any notable deviations. The spectrum of the phenotypic presentation range from alobar HPE to microcephaly and hypoplasia of the pituitary gland in one family, and from HPE to an asymptomatic non-penetrant form in another family.(21) Sine Oculis Homeobox, Drosophila, Homolog of 3 (SIX3) codes for a transcription factor which controls the activity of genes involved in the embryonic development of the lens, retina, eye bulbs and forebrain. Variants in this gene are usually found in patients with severe HPE phenotypes including atelencephaly, complete absence of telencephalon or syntelencephaly.(5) Pathogenic variants in Transforming Growth Factor Beta-1 Induced Factor (TGIF1) are found in 1-2% of patients with HPE.(5,15,21) This gene is important for normal development of the forebrain and at least 13 TGIF1 pathogenic variants have been found to cause nonsyndromic holoprosencephaly.(5) Zinc Finger Protein of Cerebellum (ZIC2) is one of the genes most commonly associated with HPE. It plays a crucial role in the period of early embryogenesis, directly affecting the development of the dorsal telencephalon.(5,23) Almost 90% of patients with ZIC2 HPE have structural brain anomalies that do not correlate with the extent of facial dysmorphia (10) therefore suggesting that ZIC2 HPE is predominantly isolated, without syndromic or facial dysmorphic features common in HPE. These features are caused by chromosomal anomalies and pathogenic variants in other genes. The phenotype of ZIC2 HPE patients can vary from mild forms to most severe HPE with microcephaly and cyclopia or synophthalmia below a proboscis. Less severely affected infants have microcephaly, and if the condition is complicated with hydrocephalus, the patient may have macrocephaly. HPE can be recognized in utero when brain morphology changes are seen during a prenatal ultrasound screening, as was the case with our patient. Postnatal diagnosis is usually prompted by neurological symptoms and typical facial dysmorphic features and established upon MRI examination. In our reported case, the child has an obvious structural brain anomaly and mild facial dysmorphia. 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 ZIC2 variants, as seen in our case.(5,20,23) Analysis of a large cohort of patients with pathogenic ZIC2 variants demonstrated a common facial phenotype consisting of bitemporal narrowness and short nose with anteverted nares (not present in our case), flat nasal bridge and upslanting palpebral fissures (mildly present in our particular case), broad and deep philtrum, and disproportionally large ears, shown in Figure 1.(23) ZIC2 variants occur de novo in approximately 72% of ZIC2 HPE patients (5,10) and there are no reported families with ZIC2 HPE where the pathogenic variant has been ascertained in more than 2 generations. The penetrance of ZIC2 pathogenic variants is estimated to be very high, 96% for any manifestation and 90% for brain malformations.( 10) The pathogenic ZIC2 variant identified in our case occurred de novo (neither parent carried the pathogenic variant in blood DNA, paternity confirmed), and the family was counselled about the recurrence risk in the context of the possibility of gonadal mosaicism. 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.

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