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Children (Basel, Switzerland) Mar 2023Holoprosencephaly (HPE) is the most common malformation of the prosencephalon in humans. It is characterized by a continuum of structural brain anomalies resulting from... (Review)
Review
Holoprosencephaly (HPE) is the most common malformation of the prosencephalon in humans. It is characterized by a continuum of structural brain anomalies resulting from the failure of midline cleavage of the prosencephalon. The three classic subtypes of HPE are alobar, semilobar and lobar, although a few additional categories have been added to this original classification. The severity of the clinical phenotype is broad and usually mirrors the radiologic and associated facial features. The etiology of HPE includes both environmental and genetic factors. Disruption of sonic hedgehog (SHH) signaling is the main pathophysiologic mechanism underlying HPE. Aneuploidies, chromosomal copy number variants and monogenic disorders are identified in a large proportion of HPE patients. Despite the high postnatal mortality and the invariable presence of developmental delay, recent advances in diagnostic methods and improvements in patient management over the years have helped to increase survival rates. In this review, we provide an overview of the current knowledge related to HPE, and discuss the classification, clinical features, genetic and environmental etiologies and management.
PubMed: 37189898
DOI: 10.3390/children10040647 -
Indian Pediatrics Jun 2011Holoprosencephaly affects 1 in 8,000 live births and is the most common structural anomaly of the developing forebrain, resulting in facial dysmorphism, neurologic... (Review)
Review
CONTEXT
Holoprosencephaly affects 1 in 8,000 live births and is the most common structural anomaly of the developing forebrain, resulting in facial dysmorphism, neurologic impairment, and additional clinical sequelae. Given the increasing relative contribution of genetic diseases to perinatal morbidity and mortality in India, proper recognition and management of holoprosencephaly can improve care for a significant number of affected Indian children.
EVIDENCE ACQUISITION
We used the PubMed database (search terms: "holoprosencephaly," "HPE," "holoprosencephaly India") and cross-referenced articles regarding holoprosencephaly, using our research group's extensive experience as a guide for identifying seminal papers in the field.
RESULTS
Holoprosencephaly is classified into four types based on the nature of the brain malformations as seen on neuroimaging and/or pathologic examination, with typically recognizable craniofacial phenotypes. Despite the identification of several genetic loci and other etiologic agents involved in pathogenesis, additional causes are elusive. Moreover, satisfactory explanations for phenomena such as incomplete penetrance and variable expressivity are lacking.
CONCLUSIONS
For each patient, pediatricians should follow a diagnostic protocol including dysmorphology examination, complete family history and ascertainment of risk factors, and neuroimaging. Many medical issues, including hypothalamic dysfunction, endocrinologic dysfunction, motor impairment, respiratory issues, seizures, and hydrocephalus should be prioritized in management. Pediatricians should work with genetic specialists to identify syndromic forms and to perform cytogenetic investigation, molecular screening, and genetic counseling in order to fully characterize prognosis and recurrence risk.
Topics: Holoprosencephaly; Humans
PubMed: 21743112
DOI: 10.1007/s13312-011-0078-x -
Birth Defects Research Jan 2021Holoprosencephaly is the most common malformation of the forebrain (1 in 250 embryos) with severe consequences for fetal and child development. This study evaluates...
BACKGROUND
Holoprosencephaly is the most common malformation of the forebrain (1 in 250 embryos) with severe consequences for fetal and child development. This study evaluates nongenetic factors associated with holoprosencephaly risk, severity, and gene-environment interactions.
METHODS
For this retrospective case control study, we developed an online questionnaire focusing on exposures to common and rare toxins/toxicants before and during pregnancy, nutritional factors, maternal health history, and demographic factors. Patients with holoprosencephaly were primarily ascertained from our ongoing genetic and clinical studies of holoprosencephaly. Controls included children with Williams-Beuren syndrome (WBS) ascertained through online advertisements in a WBD support group and fliers.
RESULTS
Difference in odds of exposures between cases and controls as well as within cases with varying holoprosencephaly severity were studied. Cases included children born with holoprosencephaly (n = 92) and the control group consisted of children with WBS (n = 56). Pregnancy associated risk associated with holoprosencephaly included maternal pregestational diabetes (9.2% of cases and 0 controls, p = .02), higher alcohol consumption (adjusted odds ratio [aOR], 1.73; 95% CI, 0.88-15.71), and exposure to consumer products such as aerosols or sprays including hair sprays (aOR, 2.46; 95% CI, 0.89-7.19). Significant gene-environment interactions were identified including for consumption of cheese (p < .05) and espresso drinks (p = .03).
CONCLUSION
The study identifies modifiable risk factors and gene-environment interactions that should be considered in future prevention of holoprosencephaly. Studies with larger HPE cohorts will be needed to confirm these findings.
Topics: Case-Control Studies; Child; Female; Gene-Environment Interaction; Holoprosencephaly; Humans; Pregnancy; Retrospective Studies; Risk Factors
PubMed: 33111505
DOI: 10.1002/bdr2.1834 -
Molecular Genetics and Metabolism Oct 1999Holoprosencephaly (HPE) is the most common developmental defect of the forebrain in humans. Several distinct human genes for holoprosencephaly have now been identified.... (Review)
Review
Holoprosencephaly (HPE) is the most common developmental defect of the forebrain in humans. Several distinct human genes for holoprosencephaly have now been identified. They include Sonic hedgehog (SHH), ZIC2, and SIX3. Many additional genes involved in forebrain development are rapidly being cloned and characterized in model vertebrate organisms. These include Patched (Ptc), Smoothened (Smo), cubitus interuptus (ci)/Gli, wingless (wg/Wnt, decapentaplegic (dpp)/BMP, Hedgehog interacting protein (Hip), nodal, Smads, One-eyed pinhead (Oep), and TG-Interacting Factor (TGIF). However, further analysis is needed before their roles in HPE can be established. Here we present an overview of the presently known genes causing human holoprosencephaly and describe candidate genes involved in forebrain development identified in other systems. A model is discussed for how these genes may interact within and between several different signaling pathways to direct the formation of the forebrain.
Topics: Gene Expression Regulation, Developmental; Holoprosencephaly; Humans; Prosencephalon
PubMed: 10527664
DOI: 10.1006/mgme.1999.2895 -
The Journal of Clinical Investigation Jun 2009Holoprosencephaly (HPE), the most common human forebrain malformation, occurs in 1 in 250 fetuses and 1 in 16,000 live births. HPE is etiologically heterogeneous, and... (Review)
Review
Holoprosencephaly (HPE), the most common human forebrain malformation, occurs in 1 in 250 fetuses and 1 in 16,000 live births. HPE is etiologically heterogeneous, and its pathology is variable. Several mouse models of HPE have been generated, and some of the molecular causes of different forms of HPE and the mechanisms underlying its variable pathology have been revealed by these models. Herein, we summarize the current knowledge on the genetic alterations that cause HPE and discuss some important questions about this disease that remain to be answered.
Topics: Animals; Disease Models, Animal; Holoprosencephaly; Humans; Mutation; Phenotype; Prosencephalon
PubMed: 19487816
DOI: 10.1172/JCI38937 -
American Journal of Medical Genetics.... Jun 2018Nonchromosomal, nonsyndromic holoprosencephaly (NCNS-HPE) has traditionally been considered as a condition of brain and craniofacial maldevelopment. In this review, we... (Review)
Review
Nonchromosomal, nonsyndromic holoprosencephaly (NCNS-HPE) has traditionally been considered as a condition of brain and craniofacial maldevelopment. In this review, we present the results of a comprehensive literature search supporting a wide spectrum of extracephalic manifestations identified in patients with NCNS-HPE. These manifestations have been described in case reports and in large cohorts of patients with "single-gene" mutations, suggesting that the NCNS-HPE phenotype can be more complex than traditionally thought. Likely, a complex network of interacting genetic variants and environmental factors is responsible for these systemic abnormalities that deviate from the usual brain and craniofacial findings in NCNS-HPE. In addition to the systemic consequences of pituitary dysfunction (as a direct result of brain midline defects), here we describe a number of extracephalic findings of NCNS-HPE affecting various organ systems. It is our goal to provide a guide of extracephalic features for clinicians given the important clinical implications of these manifestations for the management and care of patients with HPE and their mutation-positive relatives. The health risks associated with some manifestations (e.g., fatty liver disease) may have historically been neglected in affected families.
Topics: Abnormalities, Multiple; Biomarkers; Disease Susceptibility; Endocrine System Diseases; Genetic Predisposition to Disease; Hedgehog Proteins; Holoprosencephaly; Humans; Mutation; Phenotype; Signal Transduction
PubMed: 29761634
DOI: 10.1002/ajmg.c.31616 -
Discovery Medicine Mar 2015In recent decades, dozens of genes that cause isolated and combined pituitary hormone deficiencies have been discovered. We will review the clinically relevant genes... (Review)
Review
In recent decades, dozens of genes that cause isolated and combined pituitary hormone deficiencies have been discovered. We will review the clinically relevant genes known to cause isolated and combined pituitary hormone deficiencies in humans. This review will address genetic causes of adrenocorticotropic hormone deficiency, thyroid stimulating hormone deficiency, growth hormone deficiency, hypogonadotropic hypogonadism, and diabetes insipidus. Additionally, we will discuss genetic causes of combined pituitary hormone deficiency, septo-optic dysplasia, holoprosencephaly, and multisystemic syndromes in which hypopituitarism is a significant component. With the widespread clinical availability of next generation sequencing and ongoing identification of new disease causing genes, genetic diagnoses are determined for increasing numbers of patients. With new insights into mechanisms of disease resulting from multiple gene interactions, an increasingly nuanced understanding of the underlying genetic etiology of pituitary hormone deficiencies is possible.
Topics: Adrenal Insufficiency; Diabetes Insipidus; Female; Genetic Predisposition to Disease; Genetic Testing; High-Throughput Nucleotide Sequencing; Holoprosencephaly; Human Growth Hormone; Humans; Hypogonadism; Hypopituitarism; Male; Mutation; Phenotype; Thyrotropin
PubMed: 25828521
DOI: No ID Found -
Frontiers in Neuroanatomy 2020The hypothalamus is a heterogeneous rostral forebrain region that regulates physiological processes essential for survival, energy metabolism, and reproduction, mainly... (Review)
Review
The hypothalamus is a heterogeneous rostral forebrain region that regulates physiological processes essential for survival, energy metabolism, and reproduction, mainly mediated by the pituitary gland. In the updated prosomeric model, the hypothalamus represents the rostralmost forebrain, composed of two segmental regions (terminal and peduncular hypothalamus), which extend respectively into the non-evaginated preoptic telencephalon and the evaginated pallio-subpallial telencephalon. Complex genetic cascades of transcription factors and signaling molecules rule their development. Alterations of some of these molecular mechanisms acting during forebrain development are associated with more or less severe hypothalamic and pituitary dysfunctions, which may be associated with brain malformations such as holoprosencephaly or septo-optic dysplasia. Studies on transgenic mice with mutated genes encoding critical transcription factors implicated in hypothalamic-pituitary development are contributing to understanding the high clinical complexity of these pathologies. In this review article, we will analyze first the complex molecular genoarchitecture of the hypothalamus resulting from the activity of previous morphogenetic signaling centers and secondly some malformations related to alterations in genes implicated in the development of the hypothalamus.
PubMed: 33324176
DOI: 10.3389/fnana.2020.607111 -
American Journal of Medical Genetics.... Nov 2013Dental anomalies are common congenital malformations that can occur either as isolated findings or as part of a syndrome. This review focuses on genetic causes of... (Review)
Review
Dental anomalies are common congenital malformations that can occur either as isolated findings or as part of a syndrome. This review focuses on genetic causes of abnormal tooth development and the implications of these abnormalities for clinical care. As an introduction, we describe general insights into the genetics of tooth development obtained from mouse and zebrafish models. This is followed by a discussion of isolated as well as syndromic tooth agenesis, including Van der Woude syndrome (VWS), ectodermal dysplasias (EDs), oral-facial-digital (OFD) syndrome type I, Rieger syndrome, holoprosencephaly, and tooth anomalies associated with cleft lip and palate. Next, we review delayed formation and eruption of teeth, as well as abnormalities in tooth size, shape, and form. Finally, isolated and syndromic causes of supernumerary teeth are considered, including cleidocranial dysplasia and Gardner syndrome.
Topics: Abnormalities, Multiple; Animals; Anterior Eye Segment; Cleft Lip; Cleft Palate; Cysts; Dentition; Developmental Disabilities; Ectodermal Dysplasia; Eye Abnormalities; Eye Diseases, Hereditary; Holoprosencephaly; Humans; Lip; Mice; Orofaciodigital Syndromes; Tooth
PubMed: 24124058
DOI: 10.1002/ajmg.c.31382 -
International Journal of Molecular... Sep 2021The Hedgehog (HH) signalling pathway is one of the major pathways controlling cell differentiation and proliferation during human development. This pathway is complex,... (Review)
Review
The Hedgehog (HH) signalling pathway is one of the major pathways controlling cell differentiation and proliferation during human development. This pathway is complex, with HH function influenced by inhibitors, promotors, interactions with other signalling pathways, and non-genetic and cellular factors. Many aspects of this pathway are not yet clarified. The main features of Sonic Hedgehog (SHH) signalling are discussed in relation to its function in human development. The possible role of SHH will be considered using examples of holoprosencephaly and short-rib polydactyly (SRP) syndromes. In these syndromes, there is wide variability in phenotype even with the same genetic mutation, so that other factors must influence the outcome. mutations were the first identified genetic causes of holoprosencephaly, but many other genes and environmental factors can cause malformations in the holoprosencephaly spectrum. Many patients with SRP have genetic defects affecting primary cilia, structures found on most mammalian cells which are thought to be necessary for canonical HH signal transduction. Although SHH signalling is affected in both these genetic conditions, there is little overlap in phenotype. Possible explanations will be canvassed, using data from published human and animal studies. Implications for the understanding of SHH signalling in humans will be discussed.
Topics: Animals; Cilia; Ciliopathies; Hedgehog Proteins; Holoprosencephaly; Humans; Short Rib-Polydactyly Syndrome; Signal Transduction
PubMed: 34576017
DOI: 10.3390/ijms22189854