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
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INTRODUCTION
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 CDON (Steinfeld syndrome) and FGFR1
(Kallman syndrome 2 and Hartsfield syndrome) and in syndromic
autosomal recessively inherited HPE are CENPF
(Stromme syndrome) and DHCR7 (Smith-Lemli-Opitz
syndrome). The non-syndromic forms of monogenic HPE
are most commonly caused by pathogenic variants in SHH
(5-6 of non-syndromic HPE cases), ZIC2 (about 5% of
non-syndromic HPE cases) and SIX3 (about 3% of nonsyndromic
HPE cases).(3-5)
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