Background/Objectives: The Fibroblast Growth Factor Receptor 1 (FGFR1, MIM*136350) is a protein member of the fibroblast growth factor receptor (FGFR) family, with various biological functions, such as the normal development control. It contains an extracellular site for the ligand (three Ig-like domains, IgI, IgII, IgIII), a single transmembrane and a cytoplasmic protein tyrosine kinase (TK) domain. Variants in this gene have been associated with a wide spectrum of genetic disorders, including the clinical entity known as FGFR1-related Hartsfield or Hartsfield syndrome (HRTFDS, MIM#615465), which is an autosomal dominant or recessive disorder characterized by the clinical association of split-hand/foot malformation (SHFM) and holoprosencephaly (HPE). Dysmorphic facies, including cleft/lip palate, genitourinary anomalies, cardiovascular defects and intellectual disability/developmental delay (ID/DD) can also be a part of the clinical picture. Methods: The malformation phenotype of HRTFDS has been reviewed in 26 previously reported patients in terms of single congenital defects, mutational spectrum, impacted protein domains and inheritance. Molecular basis, clinical management, main differential diagnoses and genetic counseling were also illustrated. Results: SHFM was identified in every patient. The other main associated features included craniofacial defects, skeletal malformation identified at radiography, genitourinary anomalies, HPE and cardiovascular disorders. FGFR1 causative variants mainly impact the TK domain and have a smaller impact on other protein sites (IgII, IgIII). Conclusions: This study extensively recapitulates the malformation phenotype associated with HRTFDS and the underlying molecular perturbations. A multidisciplinary clinical approach is fundamental, in which genetic counseling can have an important role. However, our results are partial and refer to a restricted number of patients, pointing out the necessity of other descriptions and similar research. Additional studies will expand clinical and molecular knowledge as well as further clarify the biological mechanisms.

De novo inherited Xq25 deletion: hints from preimplantation genetic testing in alobar holoprosencephaly.

Holoprosencephaly (HPE) is the most common structural anomaly of developing forebrain, characterized by incomplete separation of the cerebral hemispheres. While mutations in the Sonic Hedgehog (SHH) signaling pathway remain the most established genetic cause, recent studies have identified an expanding list of genes and molecular networks involved in the pathogenesis of HPE. These include modulators of the NODAL, NOTCH, WNT/PCP, FGF, and RAS/ERK1/2 pathways as well as components of ciliary structures and cohesin complexes. Incomplete penetrance, broad phenotypic heterogeneity, and gene-environment interactions complicate diagnostic and counselling efforts. This review summarizes recent insights into the molecular mechanisms of HPE, highlighting key signalling networks, gene candidates, and phenotypic correlations. We also discuss under-recognised contributors such as cohesin and ciliary gene defects, which may account for a significant subset of unresolved cases. Finally, we propose a diagnostic framework incorporating clinical stratification, extended gene panels, and consideration of syndromic features.

Objective: To report a case of semi-lobar holoprosencephaly (HPE) diagnosed at term in the context of an unmonitored diabetic pregnancy, emphasizing the importance of early prenatal screening. Case Report: A primigravida with poorly controlled type 1 diabetes and no structured prenatal care was admitted in preterm labor at 36 weeks. An emergency ultrasound revealed intrauterine growth restriction, microcephaly, and semi-lobar HPE with major facial dysmorphism (hypotelorism, single nostril). The infant was delivered vaginally. At birth, the newborn exhibited profound clinical signs of life-threatening instability and died within 12 hours. Karyotype was normal. Conclusion: Semi-lobar HPE is a severe congenital brain malformation often associated with craniofacial anomalies and poor prognosis. This case highlights the critical role of prenatal ultrasound in early detection, especially in high-risk pregnancies, allowing timely counseling, multidisciplinary management, and the consideration of medical termination in severe cases.

ABSTRACT Holoprosencephaly (HPE) is the most frequent developmental disorder of the forebrain. In HPE, the early single anlage of the forebrain, the anterior neural plate (ANP) which encompasses the future telencephalon and eye field, fails to divide. BMP signaling and antagonism are overall important for nervous system development. The focus of this study was on the role of the ligand bmp7b and the receptor bmpr1ba during forebrain development. The zebrafish loci of bmp7b and bmpr1ba were targeted transiently with CRISPR/Ca9. Crispants for both bmp7b and bmpr1ba presented HPE and cyclopia, one central eye. Subsequently, the ANP was addressed in bmp7b Crispants. The morphology of the eye field was affected, with important markers, rx3, six3b and cxcr4a expressed condensed at the midline. Induced expression of bmp4 is also known to result in HPE. Such bmp4 induction altered the expression of bmpr1ba. Zebrafish Crispants for bmp7b and bmpr1ba can be used as a novel HPE model. A challenge in future analyses will be the penetrance of phenotypes in Crispants. The advantages are, however, that analyses can be conducted anywhere, without the need of mutant lines. One important aspect for future analysis will be the role of individual bmp ligands, receptors and antagonists in forebrain development.

Holoprosencephaly (HPE) is a rare, complex brain malformation arising from incomplete prosencephalon cleavage, typically associated with microcephaly and facial dysmorphism. Coexisting severe hydrocephalus leading to macrocephaly in HPE, particularly the semilobar type, presents a distinct clinical picture. Hyponatremia often complicates neurological conditions involving increased intracranial pressure, potentially worsening prognosis. The aim of this case report is to meticulously describe the clinical presentation, diagnostic evaluation, management approach, and early outcomes of this rare and complex neonatal neurological disorder. A male neonate, born at 35+3 weeks gestation to a mother with severe preeclampsia, presented with marked macrocephaly (head circumference 50 cm), a prominent fontanel, and bilateral sunset eyes. Initial CT scan confirmed hydrocephalus. Subsequent evaluation and a repeat CT scan at one month revealed brachycephaly (cephalic index 98) and semilobar holoprosencephaly. Head circumference progressed to 64 cm by the time of ventriculoperitoneal (VP) shunt surgery at approximately 5 weeks of age. Laboratory investigations showed hyponatremia (120 mEq/L), hyperkalemia, and hypochloremia. At three months, the patient exhibited significant growth and developmental delays and malnutrition. In conclusion, this case highlights an unusual presentation of semilobar HPE characterized by severe congenital hydrocephalus causing marked macrocephaly, rather than microcephaly, complicated by brachycephaly and significant hyponatremia. Early, comprehensive diagnostic evaluation and multidisciplinary management are crucial in such complex neurodevelopmental disorders to address multifaceted challenges and attempt to optimize outcomes.

Here we report a patient with holoprosencephaly (HPE) associated with 45, XY,der(18)t(18;21)(p11.2;q21.3),-21 derived from a paternal balanced reciprocal translocation. Array comparative genomic hybridization analysis revealed 18p11.32-p11.21 and 21q11.2-q21.3 deletions. So far, nine cases of monosomy 18p with an unbalanced translocation (18;21) have been reported, four of which presented with HPE. Our case provides a detailed long-term clinical course and helps us to better understand these rare genetic events.

Holoprosencephaly (HPE) is a well-described forebrain patterning disorder in mid-late gestation fetuses and infants. Here, we used a novel, whole-brain multimodal approach (ultrasonography, magnetic resonance imaging, and histology with 3-dimensional [3D] reconstructions with cell mapping) in earlier-gestation specimens than previously reported. In one 13- and two 22-gestational week fetuses and age-matched controls, we elucidated heretofore underappreciated HPE findings of (1) abnormal clustering of immature (doublecortin-immunoreactive) cells in the midline and paramedian forebrain, (2) linear arrays of cells in the intermediate zone of the cerebral mantle (reminiscent of subcortical band heterotopia, but possibly transient), (3) "reactive"-appearing glial fibrillary acidic protein-immunoreactive cortical cells, and (4) apparent "midline fusion" of rostral ganglionic eminences. We observed disorganization of orbitofrontal cortices and midline structures, rostral subarachnoid (marginal zone) heterotopia, and lateral displacement of the hippocampal formations utilizing multiscale multimodal 3D analytics. These findings shed light on the temporal evolution of HPE at earlier gestational ages. Moreover, this approach is scalable to include the wide range of phenotypes of HPE and is applicable to other neurologic disorders, including developmental as well as adult vascular, infectious, neoplastic, and degenerative conditions for which spatial analyses permit a fuller understanding of their pathologic spectrum.

Holoprosencephaly (HPE) is a complex forebrain congenital malformation with widely variable outcomes. It represents a disorder of ventral induction, which begins in the fifth gestational week. Its main feature is forebrain cleavage failure, which prevents the brain complete division into right and left hemispheres, the normal development of midline structures, and the deep brain structure. Based on the severity of prosencephalic cleavage failure, three classic forms (lobar, semilobar, and alobar) were described, and subsequently, interhemispheric variant (syntelencephaly) and septopreoptic variants were proposed. This review proposes a practical imaging approach to diagnosing HPE spectrum disorders, allowing an easier recognition and earlier diagnosis, which is essential for prenatal care and adequate parental counseling. In addition, we intend to simplify the understanding of HPE through a didactic discussion, schematic illustrations, and descriptions of each entity's current classification and critical neuroimaging features, as well as the main differential diagnosis of HPE.

BackgroundCongenital hypopituitarism (CH) and its associated syndromes, septo-optic dysplasia (SOD) and holoprosencephaly (HPE), are midline defects that cause significant morbidity for affected people. Variants in 67 genes are associated with CH, but a vast majority of CH cases lack a genetic diagnosis. Whole exome and whole genome sequencing of CH patients identifies sequence variants in genes known to cause CH, and in new candidate genes, but many of these are variants of uncertain significance (VUS).MethodsThe International Mouse Phenotyping Consortium (IMPC) is an effort to establish gene function by knocking-out all genes in the mouse genome and generating corresponding phenotype data. We used mouse embryonic imaging data generated by the Deciphering Mechanisms of Developmental Disorders (DMDD) project to screen 209 embryonic lethal and sub-viable knockout mouse lines for pituitary malformations.ResultsOf the 209 knockout mouse lines, we identified 51 that have embryonic pituitary malformations. These genes not only represent new candidates for CH, but also reveal new molecular pathways not previously associated with pituitary organogenesis. We used this list of candidate genes to mine whole exome sequencing data of a cohort of patients with CH, and we identified variants in two unrelated cases for two genes, MORC2 and SETD5, with CH and other syndromic features.ConclusionsThe screening and analysis of IMPC phenotyping data provide proof-of-principle that recessive lethal mouse mutants generated by the knockout mouse project are an excellent source of candidate genes for congenital hypopituitarism in children.

DISP1 deficiency: Monoallelic and biallelic variants cause a spectrum of midline craniofacial malformations

Mutations in PRDM15 lead to a syndromic form of holoprosencephaly (HPE) known as the Galloway-Mowat syndrome (GAMOS). While a connection between PRDM15, a zinc finger transcription factor, and WNT/PCP signaling has been established, there is a critical need to delve deeper into their contributions to early development and GAMOS pathogenesis. We used the South African clawed frog Xenopus laevis as the vertebrate model organism and observed that prdm15 was enriched in the tissues and organs affected in GAMOS. Furthermore, we generated a morpholino oligonucleotide-mediated prdm15 knockdown model showing that the depletion of Prdm15 leads to abnormal eye, head, and brain development, effectively recapitulating the anterior neural features in GAMOS. An analysis of the underlying molecular basis revealed a reduced expression of key genes associated with eye, head, and brain development. Notably, this reduction could be rescued by the introduction of wnt4 RNA, particularly during the induction of the respective tissues. Mechanistically, our data demonstrate that Prdm15 acts upstream of both canonical and non-canonical Wnt4 signaling during anterior neural development. Our findings describe severe ocular and anterior neural abnormalities upon Prdm15 depletion and elucidate the role of Prdm15 in canonical and non-canonical Wnt4 signaling.

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.

Introduction: Holoprosencephaly (HPE) is a rare brain malformation, which results from a cleavage defect of the prosencephalon. Three forms have been described as: alobar, semi-lobar, and lobar forms. Case Report: We report a rare case of holoprosencephaly, diagnosed at the maternity of the Ibn Rochd Hospital Center in Casablanca. Conclusion: Holoprosencephaly is secondary to a cleavage anomaly of the prosencephalon, the diagnosis is based on echotomography, computed tomography (CT) scan and nuclear magnetic resonance imaging (MRI). It is important to perform a karyotype to look for a chromosomal anomaly. Holoprosencephaly, although rare, should be recognized and diagnosed; minor forms are likely to benefit from medical replacement therapy or ventricular shunting.

Disorder of the formation of the cavum septum pellucidum (CSP) occurs in a wide range of pathologies of the brain. Its identification from 18 to 37 weeks is a necessary rule of prenatal screening, which must also be performed in postnatal studies of premature infants. Unimaged CSP should be considered as a potential indicator of cerebral dysfunction and such severe malformations as agenesis (dysgenesis) of the corpus callosum, holoprosencephaly (HPE), schizencephaly, Aicardi syndrome, hydrocephalus and septo-optic dysplasia (SOD). A special place in the differential diagnosis of unimaged CSP is represented by SOD, lobar HPE, and its mild subtype - septopreoptic HPE. The literature describes the isolated absence of SP, without finding other signs related to HPE or SOD, as a variant of development. However, the neurological outcome in these children varies from normal to delayed development of the nervous system by different degrees, so this statement remains controversial. The article discusses in detail the anatomy, physiology, pathology of the septal region, the role of echographic studies in the antenatal and postnatal periods, and the correlation of the detected changes with the clinical picture.

Vision is likely our most prominent sense and a correct development of the eye is at its basis. Early eye development is tightly connected to the development of the forebrain. A single eye field and the prospective telencephalon are situated within the anterior neural plate (ANP). During normal development, both domains are split and consecutively, two optic vesicles and two telencephalic lobes emerge. If this process is hampered, the domains remain condensed at the midline. The resulting developmental disorder is termed holoprosencephaly (HPE). The typical ocular finding associated with intense forms of HPE is cyclopia. However, also anophthalmia and coloboma can be associated with HPE. Here, we report that a correct balance of Bone morphogenetic proteins (BMPs) and their antagonists are important for forebrain and eye field cleavage. Experimental induction of a BMP ligand results in a severe form of HPE showing anophthalmia. We identified a dysmorphic forebrain containing retinal progenitors, which we termed crypt-oculoid. Optic vesicle evagination is impaired due to a loss of rx3 and, consecutively, of cxcr4a. Our data further suggest that the subduction of prospective hypothalamic cells during neurulation and neural keel formation is affected by the induction of a BMP ligand.

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.

Abstract Patients carrying pathogenic gene variants encoding factors linked to the sonic hedgehog (SHH) pathway suffer from severe congenital brain malformations including holoprosencephaly (HPE). A poorly understood feature of these common anomalies is the highly variable penetrance, even amongst family members, carrying the same mutation. Modifier genes–genetic variants that can affect the phenotypic outcome of the primary disease-causing gene–contribute to this variability within pedigrees. Modifier genes can confer resilience or susceptibility to a disease, but are difficult to identify in humans. Studying the complex genetic interactions in mouse models of human congenital disorders can be instrumental in the identification of genes, that powerfully modulate SHH signaling pathway capacity and ultimately the penetrance of genetic disturbances. Understanding the underlying complex molecular mechanisms of disease aetiology and can support directing future genetic linkage studies in humans.

Background: We report on a 20-week-old female fetus with a diaphragmatic hernia and other malformations, all of which appeared after the first-trimester ultrasound. Methods and Results: Whole trio exome sequencing (WES) on cell-free fetal DNA (cff-DNA) revealed a de novo frameshift variant of the X-linked STAG2 gene. Loss-of-function (LoF) STAG2 variants cause either holoprosencephaly (HPE) or Mullegama–Klein–Martinez syndrome (MKMS), are de novo, and only affect females, indicating male lethality. In contrast, missense mutations associate with milder forms of MKMS and follow the classic X-linked recessive inheritance transmitted from healthy mothers to male offspring. STAG2 has been reported to escape X-inactivation, suggesting that disease onset in LoF females is dependent on inadequate dosing for at least some of the transcripts, as is the case with a part of the autosomal dominant diseases. Missense STAG2 variants produce a quantity of transcripts, which, while resulting in a different protein, leads to disease only in hemizygous males. Similar inheritance patterns are described for other escapee genes. Conclusions: This study confirms the advantage of WES on cff-DNA and emphasizes the role of the type of the variant in X-linked disorders.

Introduction: Holoprosencephaly (HPE) is a rare congenital malformation of the brain; the incidence rate was 0.49-1.2 cases per 10,000-20,000 term births. HPE occurs due to failure of the prosencephalon division at the stage of brain development during the 4-5 weeks of pregnancy. Alobar HPE is one of the most severe types compared to other types. Most of the fetuses affected by this anomaly will die, and those born alive generally cannot survive for more than a year. This study presented a rare case of a baby with alobar HPE. Case report: A 33-year-old woman referred from Karang asem hospital Bali, G3P0020, 23 weeks gestation, has a poor obstetric history. The ultrasound examination results show no falx cerebri, even cerebellum and hypoechoic picture of the cerebrum. Ultrasound of the face was found a flat nose and hypotelorism. Termination at 28 weeks gestation, a baby boy was born 1000 g with the Apgar score 1-1. Multiple congenital abnormalities were found: flat nose, labiopalatoschizis, polydactyly manus dextra and omphalocele. Conclusion: Alobar HPE is a very rare congenital anomaly. The cause of the disease has not been fully explained. Current therapy is just supportive and has not been able to resolve the source of the problem. Alobar HPE disease has a poor prognosis.