Asunto(s)
Holoprosencefalia/diagnóstico , Homocigoto , Adulto , Cara/anomalías , Cara/fisiopatología , Femenino , Holoprosencefalia/fisiopatología , Humanos , EmbarazoRESUMEN
CONTEXT: In human, Sonic hedgehog (SHH) haploinsufficiency is the predominant cause of holoprosencephaly, a structural malformation of the forebrain midline characterized by phenotypic heterogeneity and incomplete penetrance. The NOTCH signaling pathway has recently been associated with holoprosencephaly in humans, but the precise mechanism involving NOTCH signaling during early brain development remains unknown. OBJECTIVE: The aim of this study was to evaluate the relationship between SHH and NOTCH signaling to determine the mechanism by which NOTCH dysfunction could cause midline malformations of the forebrain. DESIGN: In this study, we have used a chemical inhibition approach in the chick model and a genetic approach in the mouse model. We also reported results obtained from the clinical diagnosis of a cohort composed of 141 holoprosencephaly patients. RESULTS: We demonstrated that inhibition of NOTCH signaling in chick embryos as well as in mouse embryos induced a specific downregulation of SHH in the anterior hypothalamus. Our data in the mouse also revealed that the pituitary gland was the most sensitive tissue to Shh insufficiency and that haploinsufficiency of the SHH and NOTCH signaling pathways synergized to produce a malformed pituitary gland. Analysis of a large holoprosencephaly cohort revealed that some patients possessed multiple heterozygous mutations in several regulators of both pathways. CONCLUSIONS: These results provided new insights into molecular mechanisms underlying the extreme phenotypic variability observed in human holoprosencephaly. They showed how haploinsufficiency of the SHH and NOTCH activity could contribute to specific congenital hypopituitarism that was associated with a sella turcica defect.
Asunto(s)
Proteínas Hedgehog/genética , Holoprosencefalia/genética , Sistema Hipotálamo-Hipofisario/metabolismo , Receptores Notch/genética , Animales , Células Cultivadas , Embrión de Pollo , Estudios de Cohortes , Modelos Animales de Enfermedad , Embrión de Mamíferos , Femenino , Haploinsuficiencia/genética , Proteínas Hedgehog/metabolismo , Holoprosencefalia/metabolismo , Holoprosencefalia/patología , Holoprosencefalia/fisiopatología , Humanos , Sistema Hipotálamo-Hipofisario/patología , Masculino , Ratones , Ratones Transgénicos , Embarazo , Receptores Notch/deficiencia , Estudios Retrospectivos , Transducción de Señal/genéticaRESUMEN
RAC3 is a member of the Rho GTPases family, which has important regulatory functions in aspects of neuronal morphogenesis. Rho GTPases show a conformational change in two regions (switch I and II) through GTP binding, which provides a platform for selective interactions with functionally diverse proteins. Missense variants in the switch I and II regions of RAC3 were recently suggested to cause severe intellectual disability and brain malformations. Here, we report an individual with a novel de novo RAC3 variant (c.101 C>G, p.(Pro34Arg)), which substitutes for an evolutionarily conserved amino acid within the switch I region. The patient showed severe global developmental delay, intellectual disability, epilepsy, and laryngeal dystonia. An imaging study revealed characteristic brain dysplasia, including coexistence of the middle interhemispheric variant of holoprosencephaly and brainstem dysmorphism. Our study supports that RAC3 variants cause syndromic neurodevelopmental disorders and brain structural abnormality, and expands the phenotypic spectrum of RAC3-related disorders.
Asunto(s)
Discapacidades del Desarrollo/genética , Holoprosencefalia/genética , Discapacidad Intelectual/genética , Proteínas de Unión al GTP rac/genética , Sustitución de Aminoácidos/genética , Niño , Preescolar , Secuencia Conservada/genética , Discapacidades del Desarrollo/fisiopatología , Predisposición Genética a la Enfermedad , Holoprosencefalia/fisiopatología , Humanos , Recién Nacido , Discapacidad Intelectual/fisiopatología , Masculino , Mutación Missense/genética , FenotipoRESUMEN
The ill-named "logic of monsters" hypothesis of Pere Alberch - one of the founders of modern evo-devo - emphasized the importance of "internal rules" due to strong developmental constraints, linked teratologies to developmental processes and patterns, and contradicted hypotheses arguing that birth defects are related to a chaotic and random disarray of developmental mechanisms. We test these hypotheses using, for the first time, anatomical network analysis (AnNA) to study and compare the musculoskeletal modularity and integration of both the heads and the fore- and hindlimbs of abnormal cyclopic trisomy 18 and anencephalic human fetuses, and of normal fetal, newborn, and adult humans. Our previous works have shown that superficial gross anatomical analyses of these specimens strongly support the "logic of monsters" hypothesis, in the sense that there is an 'order' or 'logic' within the gross anatomical patterns observed in both the normal and abnormal individuals. Interestingly, the results of the AnNA done in the present work reveal a somewhat different pattern: at least concerning the musculoskeletal modules obtained in our AnNA, we observe a hybrid between the "logic of monsters" and the "lack of homeostasis" hypotheses. For instance, as predicted by the latter hypothesis, we found a high level of left-right asymmetry in the forelimbs and/or hindlimbs of the abnormal cyclopic trisomy 18 and anencephalic human fetuses. That is, a network analysis of the organization of/connection between the musculoskeletal structures of these fetuses reveals a more "chaotic" pattern than that detected by superficial gross anatomical comparisons. We discuss the broader developmental, evolutionary, and medical implications of these results.
Asunto(s)
Anencefalia/fisiopatología , Holoprosencefalia/fisiopatología , Desarrollo Musculoesquelético/fisiología , Teratogénesis/fisiología , Teratología/métodos , Adulto , Brazo/anomalías , Brazo/crecimiento & desarrollo , Femenino , Desarrollo Fetal/fisiología , Feto/anomalías , Cabeza/anomalías , Cabeza/crecimiento & desarrollo , Homeostasis/fisiología , Humanos , Recién Nacido , Pierna/anomalías , Pierna/crecimiento & desarrollo , MasculinoRESUMEN
The utilization of next generation sequencing has been shown to accelerate gene discovery in human disease. However, our confidence in the correct disease-associations of rare variants continues to depend on functional analysis. Here, we employ a sensitive assay of human FGF8 variants in zebrafish to demonstrate that the spectrum of isoforms of FGF8 produced by alternative splicing can provide key insights into the genetic susceptibility to human malformations. In addition, we describe novel mutations in the FGF core structure that have both subtle and profound effects on ligand posttranslational processing and biological activity. Finally, we solve a case of apparent digenic inheritance of novel variants in SHH and FGF8, two genes known to functionally coregulate each other in the developing forebrain, as a simpler case of FGF8 diminished function.
Asunto(s)
Empalme Alternativo/genética , Factor 8 de Crecimiento de Fibroblastos/genética , Factores de Crecimiento de Fibroblastos/genética , Holoprosencefalia/genética , Proteínas de Pez Cebra/genética , Animales , Regulación del Desarrollo de la Expresión Génica , Predisposición Genética a la Enfermedad , Proteínas Hedgehog/genética , Holoprosencefalia/fisiopatología , Humanos , Hibridación in Situ , Mutación/genética , Factores de Riesgo , Transducción de Señal/genética , Pez Cebra/genéticaAsunto(s)
Deleción Cromosómica , Trastornos de los Cromosomas/genética , Holoprosencefalia/genética , Anomalías del Sistema Estomatognático/genética , Adolescente , Preescolar , Trastornos de los Cromosomas/fisiopatología , Cromosomas Humanos Par 18/genética , Femenino , Holoprosencefalia/fisiopatología , Humanos , Recién Nacido , Cariotipificación , Anomalías del Sistema Estomatognático/fisiopatologíaRESUMEN
PURPOSE: To demonstrate how multichannel visual evoked potentials (VEPs) can provide quantitative measures of visual function in children with marked cortical anatomy abnormalities. METHODS: Four children with marked brain pathology (2 holoprosencephaly, 2 giant interhemispheric cysts with hydrocephalus) underwent pattern reversal and flash VEP recordings from 16 equally distributed electrodes. Voltage maps of the major VEP components were constructed, and their distributions were compared to the magnetic resonance imaging (MRI) findings. RESULTS: No reproducible responses were evident in 1 case, and responses were present, but, as expected based on the MRI finding, not over the occipital electrodes in 3 cases. Thus, the standard clinical VEP electrode placement would not have detected responses. The distribution of responses during monocular testing obtained in 2 cases suggested normal decussation of the visual pathways at the chiasm, and voltage mapping indicated which part of the abnormally positioned brain tissue is functional visual cortex. CONCLUSIONS: In children with markedly abnormal brain anatomy, multichannel VEP recordings can provide quantifiable measures of visual pathway function detected in atypical locations. VEPs provide a quantifiable measure of visual function that could be used to assist in determining visual acuity levels, and offered a baseline for monitoring in the context of raised intracranial pressure. These recordings were also able to identify functional anatomical structures that were not apparent on MRI. In a clinical setting, the use of additional recordings from nonstandard electrode placement based on the MRI findings is suggested.
Asunto(s)
Quistes del Sistema Nervioso Central/fisiopatología , Potenciales Evocados Visuales/fisiología , Holoprosencefalia/fisiopatología , Hidrocefalia/fisiopatología , Vías Visuales/fisiopatología , Quistes del Sistema Nervioso Central/diagnóstico por imagen , Preescolar , Femenino , Holoprosencefalia/diagnóstico por imagen , Humanos , Hidrocefalia/diagnóstico por imagen , Hipertensión Intracraneal/fisiopatología , Imagen por Resonancia Magnética , Agudeza Visual/fisiología , Corteza Visual/fisiopatologíaRESUMEN
BACKGROUND: Holoprosencephaly is a rare spectrum of cephalic disorders resulting from a failure or incomplete division of the embryonic forebrain into distinct cerebral hemispheres. It is the most common brain malformation with an incidence of 1:250 during embryogenesis; however, owing to the associated high rates of spontaneous abortion the incidence is 1:16,000 among live deliveries. Pathogenesis of holoprosencephaly is complex and heterogeneous involving genetic abnormalities, teratogenic exposures, and syndromic associations. Among the teratogenic exposures, maternal diabetes is a well-established risk factor associated with a 200-fold increased incidence of holoprosencephaly. CASE PRESENTATION: We report a case of a delayed diagnosis of semilobar holoprosencephaly in a 12-month-old baby boy of African descent who presented to us with a history of global developmental delay, erratic sleep patterns, and poor weight gain. He was born to a type 1 diabetes mellitus mother at 39+ weeks by emergency cesarean section due to fetal distress and breech presentation. The baby weighed 2315 g and had Apgar scores of 6/10 and 8/10 at 1 and 5 minutes respectively. A physical examination done at 12 months of age revealed a small-for-age child with a developmental age of 2 months. He had normal facies but a neurological examination revealed hypotonia in all four limbs. The rest of systemic examination was unremarkable. Hematological and biochemical investigations revealed normal findings except for iron deficiency anemia. The child also underwent magnetic resonance imaging of his brain which revealed distinctive features of semilobar holoprosencephaly. He was treated for iron deficiency anemia with Hemovit syrup (ferric ammonium citrate, folic acid, pyridoxine hydrochloride, cyanocobalamin, and zinc sulfate) 10 ml thrice daily, ferrous sulfate 10 mg once daily, folic acid 1 mg once daily, and multivitamin syrup 5 ml once daily. Furthermore, nutritional and genetic counseling was offered to his parents. CONCLUSIONS: In conclusion, although rare, holoprosencephaly is the commonest structural anomaly of the brain with a complex and multifactorial etiopathogenesis. It is prudent to diagnose it prenatally, classify its severity, and forge its prognosis so that parents are counseled early enough to make informed decisions especially where termination of pregnancy may be implicated.
Asunto(s)
Anemia Ferropénica/dietoterapia , Encéfalo/anomalías , Cesárea , Diabetes Mellitus Tipo 1/fisiopatología , Holoprosencefalia/diagnóstico por imagen , Imagen por Resonancia Magnética , Embarazo en Diabéticas/fisiopatología , Encéfalo/patología , Desarrollo Infantil , Femenino , Asesoramiento Genético , Holoprosencefalia/fisiopatología , Humanos , Lactante , Masculino , Política Nutricional , EmbarazoRESUMEN
The ZIC2 transcription factor is one of the genes most commonly mutated in Holoprosencephaly (HPE) probands. Studies in cultured cell lines and mice have shown a loss of ZIC2 function is the pathogenic mechanism but the molecular details of this ZIC2 requirement remain elusive. HPE arises when signals that direct morphological and fate changes in the developing brain and facial primordia are not sent or received. One critical signal is sent from the prechordal plate (PrCP) which develops beneath the ventral forebrain. An intact NODAL signal transduction pathway and functional ZIC2 are both required for PrCP establishment. We now show that ZIC2 acts downstream of the NODAL signal during PrCP development. ZIC2 physically interacts with SMAD2 and SMAD3, the receptor activated proteins that control transcription in a NODAL dependent manner. Together SMAD3 and ZIC2 regulate FOXA2 transcription in cultured cells and Zic2 also controls the foxA2 expression during Xenopus development. Variant forms of the ZIC2 protein, associated with HPE in man or mouse, are deficient in their ability to influence SMAD-dependent transcription. These findings reveal a new mechanism of NODAL signal transduction in the mammalian node and provide the first molecular explanation of how ZIC2 loss-of-function precipitates HPE.
Asunto(s)
Factor Nuclear 3-beta del Hepatocito/genética , Holoprosencefalia/genética , Proteína Nodal/genética , Proteínas Nucleares/genética , Factores de Transcripción/genética , Xenopus laevis/genética , Animales , Factores de Transcripción Forkhead/biosíntesis , Factores de Transcripción Forkhead/genética , Regulación del Desarrollo de la Expresión Génica , Factor Nuclear 3-beta del Hepatocito/biosíntesis , Holoprosencefalia/fisiopatología , Humanos , Masculino , Ratones , Mutación , Proteína Nodal/metabolismo , Transducción de Señal/genética , Proteína Smad2/genética , Proteína smad3/genética , Xenopus laevis/crecimiento & desarrolloRESUMEN
Mutations in FGFR1 have recently been associated with Hartsfield syndrome, a clinically distinct syndromic form of holoprosencephaly (HPE) with ectrodactly, which frequently includes combinations of craniofacial, limb and brain abnormalities not typical for classical HPE. Unrelated clinical conditions generally without craniofacial or multi-system malformations include Kallmann syndrome and idiopathic hypogonadotropic hypogonadism. FGFR1 is a principal cause for these less severe diseases as well. Here we demonstrate that of the nine FGFR1 mutations recently detected in our screen of over 200 HPE probands by next generation sequencing, only five distinct mutations in the kinase domain behave as dominant-negative mutations in zebrafish over-expression assays. Three FGFR1 mutations seen in HPE probands behave identical to wild-type FGFR1 in rescue assays, including one apparent de novo variation. Interestingly, in one HPE family, a deleterious FGFR1 allele was transmitted from one parent and a loss-of-function allele in FGF8 from the other parent to both affected daughters. This family is one of the clearest examples to date of gene:gene synergistic interactions causing HPE in humans.
Asunto(s)
Labio Leporino/genética , Fisura del Paladar/genética , Dedos/anomalías , Predisposición Genética a la Enfermedad , Deformidades Congénitas de la Mano/genética , Holoprosencefalia/genética , Hipogonadismo/genética , Discapacidad Intelectual/genética , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Alelos , Animales , Niño , Preescolar , Labio Leporino/fisiopatología , Fisura del Paladar/fisiopatología , Modelos Animales de Enfermedad , Femenino , Dedos/fisiopatología , Regulación de la Expresión Génica , Genotipo , Deformidades Congénitas de la Mano/fisiopatología , Secuenciación de Nucleótidos de Alto Rendimiento , Holoprosencefalia/fisiopatología , Humanos , Hipogonadismo/patología , Lactante , Discapacidad Intelectual/fisiopatología , Síndrome de Kallmann/genética , Síndrome de Kallmann/patología , Masculino , Mutación , Linaje , Índice de Severidad de la Enfermedad , Pez Cebra/genéticaRESUMEN
The Hedgehog signalling pathway plays a fundamental role in orchestrating normal craniofacial development in vertebrates. In particular, Sonic hedgehog (Shh) is produced in three key domains during the early formation of the head; neuroectoderm of the ventral forebrain, facial ectoderm and the pharyngeal endoderm; with signal transduction evident in both ectodermal and mesenchymal tissue compartments. Shh signalling from the prechordal plate and ventral midline of the diencephalon is required for appropriate division of the eyefield and forebrain, with mutation in a number of pathway components associated with Holoprosencephaly, a clinically heterogeneous developmental defect characterized by a failure of the early forebrain vesicle to divide into distinct halves. In addition, signalling from the pharyngeal endoderm and facial ectoderm plays an essential role during development of the face, influencing cranial neural crest cells that migrate into the early facial processes. In recent years, the complexity of Shh signalling has been highlighted by the identification of multiple novel proteins that are involved in regulating both the release and reception of this protein. Here, we review the contributions of Shh signalling during early craniofacial development, focusing on Hedgehog receptor function and describing the consequences of disruption for inherited anomalies of this region in both mouse models and human populations.
Asunto(s)
Anomalías Craneofaciales/embriología , Proteínas Hedgehog/fisiología , Desarrollo Maxilofacial/fisiología , Receptores Patched/fisiología , Transducción de Señal , Animales , Movimiento Celular , Cilios/fisiología , Ciliopatías/embriología , Ciliopatías/genética , Ciliopatías/fisiopatología , Anomalías Craneofaciales/genética , Anomalías Craneofaciales/fisiopatología , Diencéfalo/embriología , Modelos Animales de Enfermedad , Ectodermo/embriología , Endodermo/embriología , Cara/anomalías , Cara/embriología , Regulación del Desarrollo de la Expresión Génica , Holoprosencefalia/embriología , Holoprosencefalia/genética , Holoprosencefalia/fisiopatología , Humanos , Desarrollo Maxilofacial/genética , Proteínas de la Membrana/fisiología , Cresta Neural/citología , Cresta Neural/embriología , Receptores Patched/genética , Transducción de Señal/genética , Cráneo/anomalías , Cráneo/embriologíaRESUMEN
INTRODUCTION: We report the case of a 2-year-old boy who showed a huge midline mass in the brain at prenatal assessment. CASE REPORT: After birth, magnetic resonance imaging (MRI) revealed a conglomerate mass with an infolded microgyrus at the midline, which was suspected as a midline brain-in-brain malformation. MRI also showed incomplete cleavage of his frontal cortex and thalamus, consistent with lobar holoprosencephaly. The patient underwent an incisional biopsy of the mass on the second day of life. The mass consisted of normal central nervous tissue with gray and white matter, representing a heterotopic brain. The malformation was considered to be a subcortical heterotopia. With maturity, focal signal changes and decreased cerebral perfusion became clear on brain imaging, suggesting secondary glial degeneration. Coincident with these MRI abnormalities, the child developed psychomotor retardation and severe epilepsy focused on the side of the intracranial mass.
Asunto(s)
Encéfalo/fisiopatología , Coristoma/fisiopatología , Lisencefalias Clásicas y Heterotopias Subcorticales en Banda/fisiopatología , Epilepsia/fisiopatología , Holoprosencefalia/fisiopatología , Encéfalo/patología , Preescolar , Coristoma/complicaciones , Coristoma/patología , Lisencefalias Clásicas y Heterotopias Subcorticales en Banda/complicaciones , Lisencefalias Clásicas y Heterotopias Subcorticales en Banda/patología , Electroencefalografía , Epilepsia/etiología , Femenino , Holoprosencefalia/complicaciones , Holoprosencefalia/patología , Humanos , Recién Nacido , Imagen por Resonancia Magnética , Masculino , Embarazo , Trastornos Psicomotores/etiología , Ultrasonografía PrenatalRESUMEN
OBJECTIVE: The bispectral index (BIS) is a parameter derived by electroencephalography (EEG) which provides a direct measurement of the effects of sedatives and anesthetics on the brain and offers guidance on the adequacy of anesthesia. The literature lacks studies on BIS monitoring in pediatric patients with congenital brain disease undergoing general anesthesia. CLINICAL FEATURES: A 13-year-old child weighing 32kg, suffering from lobar holoprosencephaly, underwent surgery in which the bispectral index (BIS) monitoring the depth of anesthesia showed an abnormal response. Detailed analysis of the trends of BIS values in the different observation times demonstrated sudden falls and repetitive values of BIS likely related to repetitive epileptiform electrical activity caused by sevoflurane. CONCLUSION: The BIS is a very useful monitoring tool for assessing the degree of depth of anesthesia and to analyze the electroencephalographic variations of anesthetics. Particular attention should be given to patients with congenital disorders of the central nervous system in which the BIS may give abnormal responses that do not reflect an accurate assessment of the depth of anesthesia.
Asunto(s)
Anestésicos por Inhalación/farmacocinética , Electroencefalografía , Holoprosencefalia/fisiopatología , Éteres Metílicos/farmacocinética , Monitoreo Fisiológico , Adolescente , Humanos , SevofluranoRESUMEN
Molecular alterations of the GLI2 gene in 2q14.2 are associated with features from the holoprosencephaly spectrum. However, the phenotype is extremely variable, ranging from unaffected mutation heterozygotes to isolated or combined pituitary hormone deficiency, and to patients with a phenotype that overlaps with holoprosencephaly, including abnormal pituitary gland formation/function, craniofacial dysmorphisms, branchial arch anomalies, and polydactyly. Although many point mutations within the GLI2 gene have been identified, large (sub) microscopic deletions affecting 2q14.2 are rare. We report on a family with a 4.3 Mb deletion in 2q14 affecting GLI2 without any dysmorphologic features belonging to the holoprosencephaly spectrum. This family confirms the incomplete penetrance of genomic disturbances affecting the GLI2 gene. However, the family presented here is unique as none of the three identified individuals with a GLI2 deletion showed any typical signs of holoprosencephaly, whereas all patients reported so far were referred for genetic testing because at least one member exhibited holoprosencephaly and related features.
Asunto(s)
Estudios de Asociación Genética , Holoprosencefalia/genética , Factores de Transcripción de Tipo Kruppel/genética , Proteínas Nucleares/genética , Adulto , Cromosomas Humanos Par 2/genética , Femenino , Eliminación de Gen , Heterocigoto , Holoprosencefalia/etiología , Holoprosencefalia/fisiopatología , Humanos , Masculino , Mutación , Linaje , Fenotipo , Polimorfismo de Nucleótido Simple , Proteína Gli2 con Dedos de ZincRESUMEN
The use of amplitude-integrated electroencephalography (aEEG) to assess brain function and detect seizures has been increasing worldwide. Results from previous studies have demonstrated that seizure patterns can be recognized as transient rises on aEEG traces. We report here a case of an infant with neonatal seizures that showed paradoxical transient drops on aEEG traces. The ictal EEG showed initial low-amplitude fast rhythmic activity followed by epileptic recruiting rhythms and high-voltage slow waves. Therefore, downward patterns on aEEG traces should be recognized as suspected seizure patterns.
Asunto(s)
Holoprosencefalia/complicaciones , Holoprosencefalia/fisiopatología , Convulsiones/fisiopatología , Electroencefalografía , Femenino , Holoprosencefalia/diagnóstico , Humanos , Recién Nacido , Convulsiones/diagnóstico , Convulsiones/etiologíaRESUMEN
OBJECTIVES: To determine whether the biparietal diameter measurement is altered in first-trimester fetuses with holoprosencephaly. METHODS: Cases of holoprosencephaly were collected retrospectively from 4 fetal medicine centers, and first-trimester biparietal diameter measurements were reviewed. The diagnosis of holoprosencephaly was established sonographically by the detection of abnormal choroid plexus morphologic characteristics (absent "butterfly" sign) and the identification of a monoventricular cerebral cavity on axial views of the fetal brain. The proportion of fetuses with biparietal diameter measurements below the 5th percentile for crown-rump length was determined. RESULTS: Among 45 cases of holoprosencephaly reviewed, 43 had information on both biparietal diameter and crown-rump length measurements. The biparietal diameter was below the 5th percentile for crown-rump length in 14 (32.6%) fetuses. Chromosomal analysis was available in 41; no statistically significant difference in biparietal diameter measurement between those with associated chromosomal anomalies and those without anomalies was noted. A supplementary analysis using head circumference measurement showed an even greater proportion of fetuses with holoprosencephaly with measurements below the 5th percentile for crown-rump length (18 of 42 [42.9%]). CONCLUSIONS: One-third of first-trimester fetuses with a sonographic diagnosis of holoprosencephaly had a biparietal diameter that was smaller than expected for crown-rump length. In this subset of fetuses, the evaluation of intracranial anatomy for signs of holoprosencephaly may be more difficult to perform due to the smaller size of the brain. Therefore, the detection of a biparietal diameter below the 5th percentile as expected from crown-rump length on the first-trimester scan may be a warning sign of holoprosencephaly and should prompt a detailed examination of the intracranial anatomy.
Asunto(s)
Largo Cráneo-Cadera , Enfermedades Fetales/diagnóstico por imagen , Holoprosencefalia/diagnóstico por imagen , Lóbulo Parietal/diagnóstico por imagen , Ultrasonografía Prenatal , Femenino , Enfermedades Fetales/fisiopatología , Holoprosencefalia/embriología , Holoprosencefalia/fisiopatología , Humanos , Lóbulo Parietal/embriología , Embarazo , Primer Trimestre del Embarazo , Estudios RetrospectivosRESUMEN
We report 24 patients with holoprosencephaly (HPE) spectrum screened for Del 7q36 and subtelomere 13q. They were divided according to the type of HPE into: 6 alobar, 15 semilobar, 1 lobar and 2 middle interhemispheric variant (MIH). All patients presented with global developmental delay. Microcephaly was in 83.3% and midfacial developmental defects were in the form of; cyclopia, arrhinia and agnathia in 2 patients (8.3%), premaxillary agenesis in 2 patients (8.3%), cleft lip and palate in 7 patients (29.2%), hypotelorism in 8 patients (33.3%) and hypertelorism in 9 patients (37.5%). The neurological deficits were as follows: abnormal tone and spasticity were present in all of them with exceptional of a single patient with MIH who presented with hypotonia and was able to walk independently at the age of 3 years, athetoid and/or dystonic movements of limbs in 22 patients, seizures in twelve patients (50%) and abnormal EEG in 15 patients (62.5%). Poor temperature regulation was found in 50% of patients and diabetes insipidus was documented in 3 patients (12.5%). The MRI showed complete or partial fusion of basal ganglia and thalami in 21 patients (87.5%) and 19 patients (79.2%) respectively, fused mesencephalon in 8 patients (33.3%), incomplete separation of mesencephalon from diencephalon in 4 patients (16.7%), dorsal cyst in 10 patients (41.7%), abnormal gyral pattern anteriorly in 15 patients (62.5%), anterior located sylvian fissures in 22 patients (99.7%), complete or partial agenesis of the corpus callosum (ACC) in all patients and Dandy-Walker malformation (DWM) in three patients (12.5%). A small occipital cephalocele was detected clinically and radiological as atretic type in MIH patient. Karyotype analysis demonstrated 47, XY+13 in a patient with alobar holoprosencephaly, 46, XY,t(12;13) (q13q24.1;q14q33) in a semilobar case associated with DWM, 46, XY, del(13)(q34) in one semilobar case and three cases had del 7q36 using FISH technique in two semilobar cases and one lobar case. Conclusion: This study highlights the clinical spectrum in patients with HPE and report a case of HPE and DWM associated with t(12;13). Neuroimaging delineated the pathogenesis underlying developmental defects in HPE. Accurate molecular diagnosis is crucial for further understanding of the pathogenesis of HPE.
Asunto(s)
Holoprosencefalia , Preescolar , Deleción Cromosómica , Cromosomas Humanos Par 13/genética , Cromosomas Humanos Par 7/genética , Análisis Citogenético , Egipto , Femenino , Holoprosencefalia/genética , Holoprosencefalia/patología , Holoprosencefalia/fisiopatología , Humanos , Lactante , MasculinoRESUMEN
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.
Asunto(s)
Dentición , Discapacidades del Desarrollo/fisiopatología , Diente/crecimiento & desarrollo , Diente/patología , Anomalías Múltiples/fisiopatología , Animales , Segmento Anterior del Ojo/anomalías , Segmento Anterior del Ojo/fisiopatología , Labio Leporino/complicaciones , Labio Leporino/fisiopatología , Fisura del Paladar/complicaciones , Fisura del Paladar/fisiopatología , Quistes/complicaciones , Quistes/fisiopatología , Discapacidades del Desarrollo/complicaciones , Discapacidades del Desarrollo/genética , Displasia Ectodérmica/complicaciones , Displasia Ectodérmica/fisiopatología , Anomalías del Ojo/complicaciones , Anomalías del Ojo/fisiopatología , Enfermedades Hereditarias del Ojo , Holoprosencefalia/complicaciones , Holoprosencefalia/fisiopatología , Humanos , Labio/anomalías , Labio/fisiopatología , Ratones , Síndromes Orofaciodigitales/complicaciones , Síndromes Orofaciodigitales/fisiopatologíaRESUMEN
AIM: The aim of this study is to evaluate the clinical, anthropometric, hormonal, and radiological characteristics of children with central diabetes insipidus (DI). METHODS: Case records of 34 children (22 boys and 12 girls) with documented central DI referred to the Pediatric Endocrinology and Adolescent Clinic of Dokuz Eylul University Faculty of Medicine were reviewed. The mean age at diagnosis was 6.4 +/- 5.6 years (range, 0.08-16 years). All patients underwent anterior pituitary function assessment and magnetic resonance imaging of pituitary at diagnosis. The median duration of follow-up was 7.9 +/- 4.5 years. RESULTS: The etiology of central DI was organic in 22 (64.7%) patients, trauma in 2 (5.9%) patients, and idiopathic in 10 (29.4%) patients. Organic causes consisted of craniopharyngioma in 7 patients, Langerhans cell histiocytosis in 4 patients, germinoma in 4 patients, holoprosencephaly in 3 patients, astrocytoma in 1 patient, cavernous hemangioma in 1 patient, Rathke's cleft cyst in 1 patient, and autoimmune polyendocrinopathy in 1 patient. Anterior pituitary hormone deficiencies were documented in 18 (53%) patients. Organic central DI group had a greater prevalence of anterior pituitary hormone deficiency when compared with the idiopathic group (66% and 10%, respectively; p = 0.007). The final height of patients with organic etiology were significantly lower than the idiopathic group (155 and 178, cm respectively; p = 0.021). CONCLUSIONS: Etiological diagnosis is possible in a significant proportion (70.6%) of children with central DI. Findings of this study suggest that accompanying anterior pituitary hormone deficiencies and short stature may be considered as indicators of organic etiology.