Semilobar Holoprosencephaly Research Articles

Physiotherapy Intervention for Binder’s Syndrome with Holoprosencephaly: A Unique Case Report

Maxillonasal dysplasia, known as Binder’s syndrome, is a rare congenital deformity characterised by distinctive facial features, including a malformed midface and nose, as well as abnormal positions of the nasal bones. In addition, maxillary hypoplasia, or a shorter upper jaw, and nasal abnormalities may manifest as a flattened nose. Many cases of this condition are associated with other malocclusions, and those affected can be easily identified. Individuals with Binder’s syndrome typically present with an undeveloped upper jaw, a projecting lower jaw, a smaller nose, a flat nasal bridge, and midfacial hypoplasia. This is the first case report describing a physiotherapy method for maxillonasal dysplasia. Hereby, the authors present a case report of a six-month-old male child with Binder’s syndrome who exhibited delayed developmental milestones and physical anomalies. The child’s mother had a complicated pregnancy, culminating in an emergency caesarean section due to preterm premature rupture of membranes. The infant, born with Binder’s syndrome and a cleft palate, displayed poor head control, an inability to roll, and reluctance to engage in sensory interactions. Examination revealed bilateral cortical thumbs, hip joint abnormalities, and heightened sensitivity to touch. Magnetic Resonance Imaging (MRI) findings indicated semilobar Holoprosencephaly (HPE) and dysgenesis of the corpus callosum. Physiotherapeutic interventions focused on parent education and home exercise programs targeting developmental milestones. Over the course of two months, the infant showed significant progress in head control and rolling. Furthermore, after four months of training, the child gained sitting control. The present case underscores the importance of early intervention and parental involvement in optimising outcomes for children with Binder’s syndrome.

A Rare Case of Early-diagnosed Trisomy 13 Syndrome with Typical Semilobar Holoprosencephaly, Cyclopia, and Proboscis: A Case Report

Trisomy 13 syndrome is a lethal chromosomal disorder characterized by severe congenital anomalies. We report a case of trisomy 13 syndrome with semilobar holoprosencephaly, cyclopia, proboscis, omphalocele, and an absent nasal bone, prenatally diagnosed by first-trimester ultrasonography. The diagnosis was confirmed by chromosomal analysis. The pregnancy was eventually terminated at 14 weeks of gestation. The poor prognosis of trisomy 13 syndrome and holoprosencephaly prompts the demand for early prenatal diagnosis. We present this case to introduce some of the typical features of semilobar holoprosencephaly, including an anteriorly fused ventricle with partially fused thalami and absent falx, and to sensitize physicians to similar sonographic findings in the future.

The role of routine first-trimester ultrasound screening for central nervous system abnormalities: a longitudinal single-center study using an unselected cohort with 3-year experience

BackgroundTo evaluate the role of a standardized first-trimester scan in screening different kinds of central nervous system malformations and to report a 3-year experience from a tertiary center using an unselected cohort.MethodsThis was a retrospective analysis of prospectively collected data from a single center evaluating first-trimester scans with predesigned standardized protocols performed between 1 May 2017 and 1 May 2020, involving 39,526 pregnancies. All pregnant women underwent a series of prenatal ultrasound scans at 11–14, 20–24, 28–34 and 34–38 weeks of gestation. Abnormalities were confirmed by magnetic resonance imaging, postmortem examination or trained ultrasound professionals. Pregnancy outcomes and some postnatal follow-up were obtained from maternity medical records and telephone calls.ResultsA total of 38,586 pregnancies included in the study. The detection rates of CNS anomalies by ultrasound in the first, second, third and late third trimester were 32%, 22%, 25%, and 16%, respectively. And there were 5% of CNS anomalies missed by prenatal ultrasound. In the first-trimester scan, we diagnosed all cases of exencephaly, anencephaly, alobar holoprosencephaly and meningoencephalocele, and some cases of posterior cranial fossa anomalies (20%), open spina bifida (67%), semilobar holoprosencephaly (75%) and severe ventriculomegaly (8%). Vein of Galen aneurysmal malformation, closed spina bifida, lobar holoprosencephaly, intracranial infection, arachnoid cyst, agenesis of the corpus callosum, cysts of the septum pellucidum and isolated absence of the septum pellucidum were never detected during the first trimester. The abortion rates of fetal CNS anomalies detected by first-trimester scan, second-trimester scan, and third- trimester scan were 96%, 84% and 14%, respectively.ConclusionsThe study showed that almost 1/3 of central nervous system anomalies were detected by the standard first-trimester scan and these cases were associated with a high rate of abortion. Early screening for fetal abnormalities gives parents more time for medical advice and safer abortion if needed. It is therefore recommended that some major CNS anomalies should be screened in the first trimester. The standardized anatomical protocol, consisting of four fetal brain planes, were recommended for routine first trimester ultrasound screening.

Semilobar Holoprosencephaly Caused by a Novel and De Novo ZIC2 Pathogenic Variant.

Holoprosencephaly (HPE) is the most common embryonic forebrain developmental anomaly. It involves incomplete or absent division of the prosencephalon into two distinct cerebral hemispheres during the early stages of organogenesis. HPE is etiologically heterogeneous, and its clinical presentation is very variable. We report a case of a 7 month old female infant, diagnosed with non-syndromic semilobar holoprosencephaly, caused by a novel, de novo pathogenic variant in ZIC2 - one of the most commonly mutated genes in non-syndromic HPE coding for the ZIC2 transcription factor. The patient presented with microcephaly, mild facial dysmorphic features, central hypotonia and spasticity on all four extremities. Ultrasound imaging demonstrated the absence of septum pellucidum, semilobar fusion of the hemispheres and mega cisterna magna and brain MRI with confirmed the diagnosis of HPE. Early diagnosis and management are important for the prevention and treatment of complications associated with this condition.

Antenatal and Postnatal Diagnosis of Semilobar Holoprosencephaly: Two Case Reports

Holoprosencephaly (HPE) is a rare birth defect that occurs during the first few weeks of pregnancy. It results from a disturbance in the usual signaling pathways required for separation of the embryonic prosencephalon into 2 separate cerebral hemispheres. Classically four subtypes have been recognized: alobar, semilobar, lobar, and middle interhemispheric holoprosencephaly. The cause of HPE is unknown but may include genetic disorders. In most cases of holoprosencephaly, the malformations are so severe that babies die before birth. In less severe cases, babies are born with normal or near-normal brain development and facial deformities that may affect the eyes, nose, and upper lip. We report 2 cases of semilobar holoprosencephaly, diagnosed in Children's Hospital of Rabat: the first one was a fetus diagnosed by ultrasonogram at 25 weeks of gestation. The second one was a newborn at 15 days of life diagnosed by brain scan.

Effects of phenobarbital, potassium bromide and topiramate on intractable epilepsies in two cases of holoprosencephaly

We describe the courses of treatment for epilepsies in two patients with semilobar type holoprosencephaly (HPE); a 5-year-old girl and a 30-year-old man. Seizure semiology included eye fixation, upward or lateral gaze, horizontal or vertical nystagmus, eyelid flutter, and grinning facial distortion, which frequently evolved to generalized tonic convulsions. In both patients, ictal electroencephalography revealed seizure onset with rhythmic activity in bilateral frontopolar areas. Administration of phenobarbital with subsequent elevation of blood levels to 30–40 μg/ml alleviated the clustered tonic seizures. This allowed dosage reduction of other antiepileptic drugs that had sedative and/or respiratory adverse effects causing significant distress in these patients. Potassium bromide 20–50 mg/kg/day and topiramate 1–3 mg/kg/day were also beneficial in these patients. A combination regimen of these three antiepileptic drugs could be a promising treatment option for intractable epilepsy in HPE.

Intracerebral retina-like pigmented tissue in a stillborn fetus with holoprosencephaly

A stillbirth fetus with semilobar holoprosencephaly was induced at 24 weeks gestational age. While the eyes appeared unremarkable externally, there was an absence of optic nerves. At the ventral hypothalamicdiencephalic region there was an area of bilateral epithelioid cells containing melanin. Immunohistochemical characterization revealed the cells to be of neuroepithelial origin with features of retinal pigment epithelium. These findings reflect abnormalities in eye development in holoprosencephaly, especially when coupled with other structural defects in the visual system.

Fetal Description of the Pancreatic Agenesis and Holoprosencephaly Syndrome Associated to a Specific CNOT1 Variant.

Holoprosencephaly (HPE) is a clinically and genetically heterogeneous disease, which can be associated with various prenatal comorbidities not always detectable on prenatal ultrasound. We report on the case of a foetus carrying a semi-lobar HPE diagnosed at ultrasound, for which a fetal autopsy and a whole exome sequencing were performed following a medical termination of pregnancy. Neuropathological examination confirmed the semi-lobar HPE and general autopsy disclosed a total pancreas agenesis. Whole exome sequencing found the CNOT1 missense c.1603C>T, p.(Arg535Cys), occurring de novo in the foetus. The same variant was previously reported in 5 unrelated children. All individuals had HPE, and 4 out of 5 presented endo- and exocrine pancreatic insufficiency or total pancreas agenesis. CNOT1 encodes a subunit of the CCRN4-NOT complex, expressed at the early stage of embryonic development. This report is the first fetal description of the phenotype associating HPE and pancreatic agenesis linked to the recurrent CNOT1 missense c.1603C>T, p.(Arg535Cys). This finding strengthens the hypothesis of a specific recurrent variant associated with a particular phenotype of HPE and pancreas agenesis. The fetal autopsy that revealed the pancreas agenesis was crucial in guiding the genetic diagnosis and enabling accurate genetic counselling.

Syntelencephaly: medial interhemispheric variant of holoprosencephaly

Holoprosencephaly (HPE) is a congenital malformation occurring very early in pregnancy and due to abnormal diverticulation of the prosencephalon. This defect in primary brain cleavage may be total or partial, which explains the anatomopathological variants of holoprosencephaly. The main forms of holoprosencephaly include alobar, semilobar and lobar HPE. Syntelencephaly also known as middle interhemispheric variant (MIHV) is a very rare type of HPE. While in the three most common variants, cleavage defect has antero-posterior gradient of severity, syntelencephaly does not follow this rule. The latter is characterised by abnormal communication between cerebral hemispheres in the posterior and parietal frontal regions, with normal inter-hemispheric separation of the anterior frontal lobes, of the occipital regions and central grey nuclei. The trunk of the corpus callosum is achieved at the level of the knee of the corpus callosum (allowing differentiation from lobar HPE) and of the splenium. An azygos cerebral artery is common, consisting of a fusion of the A1 segments of the anterior cerebral arteries to form a single arterial trunk. Other cerebral malformations may be associated with syntelencephaly, the most frequent being cortical dysplasia and grey matter heterotopia. Facial abnormalities are less common in syntelencephaly compared to classic forms of HPE. Prognosis depends mainly on these malformative associations in the brain and other organs, and even on chromosomal aberrations.

Communication Strategies for Patients Who Are Nonverbal.

Communication Strategies for Patients Who Are Nonverbal.

CEP135 associated primary microcephaly-A rare presentation in early second trimester

Primary microcephaly (MCPH) is a rare neurogenic disorder with most cases being inherited in an autosomal recessive pattern. The present report is of a case of second gravid patient with recurrent fetal microcephaly with agenesis of corpus callosum, cerebellar hypoplasia and ventriculomegaly. Maternal TORCH profile and amniotic fluid chromosomal microarray were normal. Following the termination of pregnancy, the autopsy evaluation has shown additional findings of evolving craniosynostosis, and semilobar holoprosencephaly. Whole exome sequencing done on fetal DNA from amniotic fluid, revealed a pathogenic compound heterozygous variant (NM_025009.5) c.2863C>T (p.Arg955Ter) in exon 22 and c.1372_1375del (p.Lys459SerfsTer2) in exon 11 of CEP135 gene: known to cause primary microcephaly-8; and both partners in the couple are heterozygous carriers for the same. With the identification of MCPH genes and with the availability of next-generation sequencing (NGS) based exome sequencing, a definitive prenatal diagnosis of primary microcephaly and also appropriate genetic counselling for the couple has become possible.

Rare Association of Semilobar Holoprosencephaly and Frontonasal Encephalocoele in a Neonate of Twin Pregnancy

Holoprosencephaly is a rare intracranial malformation seen in newborns, resulting from a failure of separation of the forebrain into separate cerebral hemispheres. It is divided into three subtypes-alobar, semilobar and lobar. Encephalocele is a rare neural tube defect characterised by a defect in the cranial vault with herniation of brain parenchyma along with the overlying meninges. Author has reported a case of a male neonate born of a twin pregnancy to a 29-year-old primigravida presenting with a midline swelling in the frontal region. On imaging studies, the patient was diagnosed with semilobar holoprosencephaly and frontonasal encephalocele with dural arteriovenous fistula. Holoprosencephaly and encephalocoele are important congenital malformations; however association of the two conditions has been rarely described in the literature.

Neurological and extra-neurological clinical spectrum observed in pediatric patients with EMC1 gene variants identified by whole exome sequencing

Background: The endoplasmic reticulum membrane protein complex 1 (EMC1) gene encodes a subunit of the EMC with multiple alternatively spliced transcripts encoding different isoforms. Monoallelic and biallelic mutations of the EMC1 gene have been reported for cerebellar atrophy, visual impairment, psychomotor retardation, lipoid proteinosis of Urbach and Wiethe, and Alkuraya-Kucinskas syndrome. Objectives: Herein, we present whole exome sequencing results of eight Saudi pediatric patients with distinctive clinical features which revealed both monoallelic and biallelic variants in the EMC1 gene (CHR1 exon4:19568918, NM_001271429.2, c.364G>A; p.A122T), including two previously reported siblings (CHR1 exon21:19547328, NM_015047.3, c.2602G>A; p.G868R). Results: The patients presented with the neurological and extra-neurological clinical spectrum that included seizures, spastic diplegia, cognitive impairment, axial and appendicular hypotonia, dysmorphic features, joint hyper-flexibility, attention deficit hyperactivity disorder, skeletal dysplasia in addition to generalized global developmental delay, failure to thrive, speech delay, intellectual disability, and visual impairments. Furthermore, brain Magnetic resonance imaging findings were consistent with variable clinical features and revealed brain atrophy, thinning of corpus callosum, semi-lobar holoprosencephaly, white matter abnormality, diffuse paucity of the myelin within the brain parenchyma, and reduction of white matter arborization in the temporal lobes. Conclusion: In conclusion, these clinical cases highlight the importance of the EMC1 gene in disease phenotype and add up to the expanded EMC1-related phenotype.

Case Report of a Term Newborn with Prenatally Diagnosed Alobar Holoprosencephaly

Abstract Holoprosencephaly is a congenital structural abnormality of brain resulting from incomplete cleavage of prosencephalon into two cerebral hemispheres. It is classified as a disorder of organogenesis and brain histogenesis and is typically associated with facial anomalies. Holoprosencephaly is relatively rare – the incidence in live births varies between 1:10,000 – 1:15,000 but is described in 1 out of 250 spontaneously aborted embryos. There are four major varieties of holoprosencephaly according to the degree of separation of the brain hemispheres; this division is crucial for the patient’s prognosis. Three classic subtypes are alobar, semilobar, and lobar holoprosencephaly and there is also a fourth subtype called middle interhemispheric variant. We present a case study of a term newborn with prenatally diagnosed holoprosencephaly with severe facial dys-morphism and associated health complications.

Absent Cavum Septi Pellucidi

Absent Cavum Septi Pellucidi

Prenatal ultrasound findings of holoprosencephaly spectrum: Unusual associations.

The objective of this study is to evaluate the prenatal diagnosis, postnatal characteristics, and the spectrum of associated findings in fetuses with holoprosencephaly (HPE). Fetal neurosonograms, postnatal assessment, and chromosomal analysis were performed in a cohort of 25 fetuses with HPE. The prevalence of HPE in high-risk pregnancies was 4.4:10 000. The alobar subtype was the most frequently encountered, with 17 cases (68%). Interestingly, among them, four cases (16%) presented with the rare agnathia-otocephaly complex. Chromosomal abnormalities were detected in 11 cases (44%), the most frequent being trisomy 13 in seven cases (five alobar, one semilobar, and one lobar HPE), followed by trisomy 18 in two cases with semilobar HPE. One case of alobar HPE had 45, XX, t(18;22) (q10;q10), -18p karyotyping, and one case of semilobar HPE was associated with triploidy. Facial malformations in HPE spectrum ranged from cyclopia, proboscis, and arrhinia that were associated with the alobar subtype to hypotelorism and median cleft that were frequent among the semilobar and lobar subtypes. Associated neural tube defects were identified in 12% of cases. Our study illustrates the clinical and genetic heterogeneity of HPE and describes different chromosomal abnormalities associated with HPE.

A CCR4-NOT Transcription Complex, Subunit 1, CNOT1, Variant Associated with Holoprosencephaly

Holoprosencephaly is the incomplete separation of the forebrain during embryogenesis. Both genetic and environmental etiologies have been determined for holoprosencephaly; however, a genetic etiology is not found in most cases. In this report, we present two unrelated individuals with semilobar holoprosencephaly who have the identical de novo missense variant in the gene CCR4-NOT transcription complex, subunit 1 (CNOT1). The variant (c.1603C>T [p.Arg535Cys]) is predicted to be deleterious and is not present in public databases. CNOT1 has not been previously associated with holoprosencephaly or other brain malformations. In situ hybridization analyses of mouse embryos show that Cnot1 is expressed in the prosencephalic neural folds at gestational day 8.25 during the critical period for subsequent forebrain division. Combining human and mouse data, we show that CNOT1 is associated with incomplete forebrain division.

Nasal fistula, epidermal cyst and hypernatremia in a girl presenting holoprosencephaly due to a rare ZIC2 point mutation

Holoprosencephaly is the most common brain malformation in humans and it is a complex genetic disorder. We report on a patient with holoprosencephaly caused by a rare ZIC2 mutation presenting a bifid nose associated with a nasal fistula and an epidermal cyst, besides hypernatremia. The patient was a 1 year and 4 months old girl that developed an important neuropsychomotor delay. Currently, she uses a wheelchair to move around and only emits sounds. Computed tomography (CT) scan revealed a semilobar holoprosencephaly and a Dandy-Walker variant. Head magnetic resonance imaging also disclosed corpus callosum agenesis and prefrontal subarachnoid space enlargement. On physical examination at 1 year and 4 months of age, we verified growth retardation, microcephaly, bilateral epicantic fold, upslanting palpebral fissures, bifid nose, and limbs spasticity secondary to hypertonia. Later, she began to present hypernatremia; however, its precise cause was not identified. At 6 years and 10 months of age, a nasal fistula was suspected. Facial CT scan showed an epidermal cyst at cartilaginous portion of the nasal septum. High resolution GTG-Banding karyotype was normal. However, molecular analysis through direct sequencing technique showed a mutation at regulatory region of the ZIC2 gene: c.1599*954T > A, a genetic variation previously described only in a Brazilian patient. Our patient presented findings still not reported in literature among patients with holoprosencephaly, including those with ZIC2 mutations. Thus, the spectrum of abnormalities associated to ZIC2 mutations may be broader and include other defects as those observed in our patient.

External and computed tomography analysis of a strophocephalic lamb

The Museum of Anatomy and Embryology Louis Deroubaix attached to the Laboratory of Anatomy, Biomecanics and Organogenesis, ULB, Brussels, possesses in its liquid collections a cephalic extremity of a lamb suffering from strophocephaly. The origins have not been determined. The trunk and the limbs are resected. The piece has been studied and photographed. A volumic computed tomography acquisition has been performed with a Siemens Volume Zoom. For pedagogic and museological purposes, surface reconstructions and 3D printing have been obtained. An otocephaly is observed. Both ears are located in place of the oral cavity. The mandible is welded to the braincase. The eyeballs are close together (synophtalmia) which confirms the presence of a cyclotocephaly. They are surmounted by a rudimentary snout rather than a proboscis. The presence of this muzzle allows the anomaly to be classified as a strophocephaly, a malformation already described in sheeps. CT slices of the brain show a semi-lobar holoprosencephaly with incomplete division of the cerebral hemispheres and ventricules. The CT examination allows the facial anomalies to be allocated to a holoprosencephaly. The singularity of this case, compared to the human cyclotocephalies, is the presence of a differentiated muzzle rather than a simple proboscis. The holoprosencephaly is uncomplete. Such anomalies have been associated with an entire absence of cerebral differentiation but with a complete absence of the muzzle. The tridimensional printing represents an interesting educational tool easily transportable in contrast to the original specimen.

SEC31A mutation affects ER homeostasis, causing a neurological syndrome

BackgroundConsanguineous kindred presented with an autosomal recessive syndrome of intrauterine growth retardation, marked developmental delay, spastic quadriplegia with profound contractures, pseudobulbar palsy with recurrent aspirations, epilepsy, dysmorphism, neurosensory deafness and...