RESUMEN
Proteus syndrome is caused by an activating AKT1 mutation (c.49G>A, p.Glu17Lys). Many variable features are possible in this mosaic disorder, including: (i) disproportionate, asymmetric, and distorting overgrowth; (ii) bone abnormalities different from those observed in other disorders; (iii) a characteristic cerebriform connective tissue nevus made up of highly collagenized connective tissue; (iv) epidermal nevi in early life, consisting of acanthosis and hyperkeratosis; (v) vascular malformations of the capillary, venous, or lymphatic types; (vi) dysregulated adipose tissue including lipomas, lipohypoplasia, fatty overgrowth, and localized fat deposits; (vii) other unusual features, including bullous lung alterations; specific neoplasms; a facial phenotype associated with intellectual disability and/or seizures, and/or brain malformations; and (viii) deep vein thrombosis, resulting in premature death. Concluding remarks address diagnostic criteria, natural history, management, psychosocial issues, and differential diagnosis.
Asunto(s)
Fenotipo , Síndrome de Proteo/diagnóstico , Síndrome de Proteo/genética , Síndrome de Proteo/patología , Proteínas Proto-Oncogénicas c-akt/genética , Diagnóstico Diferencial , Humanos , Lipoma/genética , Mutación Missense/genéticaRESUMEN
Simon van Creveld received both the MD and PhD degrees and had a multifaceted medical and scientific education at many hospitals and research institutes in the Netherlands, Germany, and the UK. He and his wife were the first to develop insulin for the Netherlands. His major interests were in hemophilia and hemorrhagic disorders, which accounted for 87 of his publications. In 1934, van Creveld demonstrated that a dispersed protein fraction obtained from serum could reduce the clotting time of hemophilic blood. His interest in glycogen storage disease resulted in van Creveld-von Gierke disease for which van Creveld contributed four published articles. The Ellis-van Creveld syndrome, also known as chondroectodermal dysplasia, was published in 1940 and became well known to medical geneticists. During the Nazi occupation of the Netherlands, van Creveld's professorship was taken away from him because he was Jewish. His visits to hospitals of concentration camps to treat babies and give pediatric advice while wearing a Jewish Yellow Star and interacting with SS Commandants in charge, and then leaving can only be described as amazing. After the war, his professorship was returned, and in the same year as his retirement, he established a large Hemophila Treatment and Research Center now known as the Van Creveld Clinic, which celebrated its 40th anniversary in 2005.
Asunto(s)
Enfermedades Genéticas Congénitas , Pediatría , Alemania , Historia del Siglo XIX , Historia del Siglo XX , Países BajosRESUMEN
AKT (AK mouse plus Transforming or Thymoma) is a common oncogene expressed in most tissues. Both AKT2 and AKT3, although important, have more limited distributions. The regulation of all three genes depends on two receptors-a receptor tyrosine kinase with a growth factor ligand, and a G protein coupled receptor, also with a ligand together with an explanation of how their downsteam components function. AKT2 is amplified or overexpressed in cancer with a higher frequency than those found with AKT1. AKT1 is cardioprotective to the heart by supporting its physiological growth and function. AKT2 is closely linked to Type II diabetes and the implications of various types of mutations are discussed. Various AKT3 mutations are important in neurological disorders, such as microcephaly, hemimegalencephaly, and megalencephaly syndromes. Finally, a reduced level of AKT1 in the frontal cortex has been found during post-mortem brain studies of schizophrenic patients in the populations of many countries.
Asunto(s)
Diabetes Mellitus Tipo 2/genética , Neoplasias/genética , Enfermedades del Sistema Nervioso/genética , Proteína Oncogénica v-akt/genética , Proteínas Proto-Oncogénicas c-akt/genética , Animales , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/patología , Diabetes Mellitus Tipo 2/etiología , Humanos , Ratones , Neoplasias/patología , Enfermedades del Sistema Nervioso/patología , Proteína Oncogénica v-akt/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Transducción de SeñalRESUMEN
RAGE stands for Receptor of Advanced Glycation Endproducts. The two main topics discussed are (1) the nature of RAGE signaling and (2) its role in cardiovascular disease. RAGE may occur in membrane-bound form or in secretory form. RAGE signaling involves multiple ligands: (1) several AGEs (2) amyloid ß pecursor protein (APP), (3) high mobility group box 1 (HMGB1), (4) S100A4, (5) S100A8/A9, and (6) S100A12, which are calcium-binding proteins, and (7) S100B, a glial-derived protein. RAGE ligands and various diseases involving RAGE signaling are summarized in tabular form.
Asunto(s)
Enfermedades Cardiovasculares/metabolismo , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Transducción de Señal , Animales , Enfermedades Cardiovasculares/genética , Expresión Génica , Humanos , Ligandos , Receptor para Productos Finales de Glicación Avanzada/genéticaRESUMEN
Terminology discussed here is subsumed under "common misused terms in medical genetics articles" (depressed nasal bridge; anophthalmia; rotated ears; low-set ears; heterotopia; ASD as an abbreviation for autism spectrum disorders; mental retardation; "radiographs revealed something"; and new syndrome) and also subsumed under "erroneous terminology that persists at the editorial and publishing level" (failure to understand the possessive case of names ending in "s"; failure to understand that a comma should not be used before Jr; problematic use of numbers in reference sections; failure to italicize Latin phrases; failure to honor book titles that begin words with upper case letters; omitting the corresponding author; and inadequate citation of foreign languages).
Asunto(s)
Genética Médica , Terminología como Asunto , Escritura/normasRESUMEN
Here, we report two extraordinarily severe cases of Teacher Collins syndrome. Initially, amniotic bands and plical fold disruption were considered, but downslanting eyes made us consider severe Treacher Collins syndrome. A TCOF1 mutation in exon 24 was identified in Patient 1 (c.4355_4356ins14, resulting in p.1456Thrfs*18). Patient 2, who expired on day 4, is so similar to Patient 1 that severe Treacher Collins syndrome may be inferred in this instance. Neither the TCOF1 mutation nor the well-known variability in the expression in affected families with Treacher Collins syndrome (â¼40% of reported cases) can explain the severity of these cases; otherwise, we would be aware of such cases within families from time to time. We are unaware of any recent sporadic cases (â¼60% of reported cases) exactly like ours either with a single exception in the case reported by Writzl et al. [2008] with a TCOF1 mutation. The case described by Otto in 1841 is spectacular. We propose several hypotheses to be considered in explaining this developmental amplification, including some promoter effect on the gene, some position effect on the gene, a polymorphism elsewhere in the gene, a point mutation elsewhere in the gene, a polymorphism in another gene, or a point mutation in another gene, such as POLR1C (which maps to 6p21.1) or POLR1D (which maps to13q12.2). We also review the etiology and pathogenesis of Treacher Collins syndrome, and discuss several other severe cases from the past.
Asunto(s)
Anomalías Múltiples/diagnóstico por imagen , Disostosis Mandibulofacial/diagnóstico por imagen , Anomalías Múltiples/genética , Resultado Fatal , Femenino , Humanos , Mutación INDEL , Recién Nacido , Disostosis Mandibulofacial/genética , Proteínas Nucleares/genética , Fosfoproteínas/genética , Ultrasonografía PrenatalRESUMEN
The story of Ellis-van Creveld syndrome is one of serendipity. By chance, Simon van Creveld and Richard Ellis purportedly met on a train and combined their independently encountered patients with short stature, dental anomalies and polydactyly into one landmark publication in 1940. They included a patient used in work published previously by Rustin McIntosh without naming McIntosh as a coauthor. This patient was followed radiologically by Caffey for nearly two decades. In 1964, Victor McKusick felt compelled to investigate a brief report in an obscure pharmaceutical journal on an unusual geographic cluster of short-statured Amish patients in Pennsylvania. This review highlights the lives of the individuals involved in the discovery of Ellis-van Creveld syndrome in their historic context.
Asunto(s)
Síndrome de Ellis-Van Creveld/historia , Pediatría/historia , Radiología/historia , Europa (Continente) , Historia del Siglo XX , Historia del Siglo XXI , Estados UnidosRESUMEN
Three features of cleidocranial dysplasia that are not always appreciated are hypoplastic iliac wings, short stature, and brachydactyly. Because of the pelvic abnormality, pregnant women may require a cesarean delivery. Short stature and brachydactyly indicate more generalized skeletal abnormalities. These are derived from endochondral and intramembranous ossification, but the distinction between these 2 processes is oversimplified because both processes are involved in long bone and clavicular development. Two sections follow: the biology of RUNX2 and the nature of haploinsufficiency in RUNX2 mutations for cleidocranial dysplasia.
Asunto(s)
Displasia Cleidocraneal/genética , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Humanos , Mutación , FenotipoRESUMEN
Absent sella turcica is an extremely rare and dramatic radiographic finding. It may be isolated or occur in the presence of other anomalies, often involving the adenohypophysis. Our evaluation of a female infant with multiple anomalies including absence of the sella turcica, a normal pituitary in the craniopharyngeal canal, normal pituitary function, choanal atresia and anomalies of the appendiceal skeleton prompted a review of the occurrence and biology of an absent sella turcica.
Asunto(s)
Síndrome de Silla Turca Vacía/diagnóstico , Anomalías Múltiples/diagnóstico , Atresia de las Coanas/diagnóstico , Hibridación Genómica Comparativa , Síndrome de Silla Turca Vacía/genética , Femenino , Humanos , Lactante , Recién Nacido , Huesos de la Pierna/anomalías , Imagen por Resonancia Magnética , Tomografía Computarizada por Rayos XRESUMEN
Topics discussed include asymmetry of the brain; prosopagnosia with asymmetric involvement; the blaspheming brain; effects of the numbers of X chromosomes on brain asymmetry; normal facial asymmetry; kissing asymmetry; left- and right-handedness; left-sided baby cradling; Nodal signaling and left/right asymmetry; primary cilium and left/right asymmetry in zebrafish; right/left asymmetry in snails; species differences in Shh and Fgf8; primary cilium in vertebrate asymmetry; Hedgehog signaling on the cilium; Wnt signaling on the cilium; situs solitus, situs inversus, and situs ambiguus (heterotaxy); ciliopathies; right-sided injuries in trilobites; unilateral ocular use in the octopus; fiddler crabs; scale-eating cichlids; narwhals; left-footed parrots; asymmetric whisker use in rats; and right-sided fatigue fractures in greyhounds.
Asunto(s)
Encéfalo/fisiología , Lateralidad Funcional/genética , Lateralidad Funcional/fisiología , Animales , Encéfalo/anatomía & histología , HumanosRESUMEN
No man's craniosynostosis is discussed under the following headings: historical notes, sutural development, suture closure, craniosynostotic patterns, anatomic and genetic perspectives, types of craniosynostosis, and 2 unusual types of craniosynostosis with large head circumferences.
Asunto(s)
Craneosinostosis/fisiopatología , Acrocefalosindactilia/patología , Adulto , Anciano , Envejecimiento/fisiología , Suturas Craneales/anomalías , Suturas Craneales/embriología , Suturas Craneales/crecimiento & desarrollo , Disostosis Craneofacial/patología , Craneosinostosis/clasificación , Craneosinostosis/genética , Huesos Faciales/embriología , Huesos Faciales/crecimiento & desarrollo , Femenino , Humanos , Masculino , Cráneo/crecimiento & desarrollo , Síndrome , Adulto JovenRESUMEN
This review of holoprosencephaly provides a mythologic and teratologic distillate of the subject under the following headings: Babylonian tablets; Greek mythology; pictures from the 16th through the 20th Centuries; 19th Century teratology; history of more modern concepts and their terminologies; and ocean-going ships named "Cyclops."
Asunto(s)
Holoprosencefalia/historia , Mitología , Teratología , Animales , Mundo Griego , Historia del Siglo XVI , Historia del Siglo XVII , Historia del Siglo XVIII , Historia del Siglo XIX , Historia del Siglo XX , Holoprosencefalia/clasificación , Holoprosencefalia/diagnóstico , Humanos , Medicina en las Artes , Teratología/historiaRESUMEN
In vertebrate hedgehog signaling, hedgehog ligands are processed to become bilipidated and then multimerize, which allows them to leave the signaling cell via Dispatched 1 and become transported via glypicans and megalin to the responding cells. Hedgehog then interacts with a complex of Patched 1 and Cdo/Boc, which activates endocytic Smoothened to the cilium. Patched 1 regulates the activity of Smoothened (1) via Vitamin D3, which inhibits Smoothened in the absence of hedgehog ligand or (2) via oxysterols, which activate Smoothened in the presence of hedgehog ligand. Hedgehog ligands also interact with Hip1, Patched 2, and Gas1, which regulate the range as well as the level of hedgehog signaling. In vertebrates, Smoothened is shortened at its C-terminal end and lacks most of the phosphorylation sites of importance in Drosophila. Cos2, also of importance in Drosophila, plays no role in mammalian transduction, nor do its homologs Kif7 and Kif27. The cilium may provide a function analogous to that of Cos2 by linking Smoothened to the modulation of Gli transcription factors. Disorders associated with the hedgehog signaling network follow, including nevoid basal cell carcinoma syndrome, holoprosencephaly, Smith-Lemli-Opitz syndrome, Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, Carpenter syndrome, and Rubinstein-Taybi syndrome.
Asunto(s)
Enfermedades Genéticas Congénitas/genética , Proteínas Hedgehog/genética , Transducción de Señal , Animales , HumanosRESUMEN
Certain terms used in medical genetics and more often in other medical fields are in need of clarification. The terms cited are frequently misunderstood, mispronounced, and/or misspelled. The discussion includes two Latin-derived terms (genua valga and calvaria), one Greek-derived term (apoptosis), one gene-derived term (RUNX), one syndromic eponym (Kartagener syndrome), and three vascular eponyms (Klippel-Trenaunay syndrome, Parkes Weber syndrome, and Kasabach-Merritt phenomenon).
Asunto(s)
Flujo Genético , Genética Médica , Terminología como Asunto , Humanos , SíndromeRESUMEN
An overview of German, Nazi, and Holocaust medicine brings together a group of subjects discussed separately elsewhere. Topics considered include German medicine before and during the Nazi era, such as advanced concepts in epidemiology, preventive medicine, public health policy, screening programs, occupational health laws, compensation for certain medical conditions, and two remarkable guidelines for informed consent for medical procedures; also considered are the Nuremberg Code; American models for early Nazi programs, including compulsory sterilization, abusive medical experiments on prison inmates, and discrimination against black people; two ironies in US and Nazi laws; social Darwinism and racial hygiene; complicity of Nazi physicians, including the acts of sterilization, human experimentation, and genocide; Nazi persecution of Jewish physicians; eponyms of unethical German physicians with particular emphasis on Reiter, Hallervorden, and Pernkopf; eponyms of famous physicians who were Nazi victims, including Pick and van Creveld; and finally, a recommendation for convening an international committee of physicians and ethicists to deal with five issues: (a) to propose alternative names for eponyms of physicians who exhibited complicity during the Nazi era; (b) to honor the eponyms and stories of physicians who were victims of Nazi atrocities and genocide; (c) to apply vigorous pressure to those German and Austrian Institutes that have not yet undertaken investigations to determine if the bodies of Nazi victims remain in their collections; (d) to recommend holding annual commemorations in medical schools and research institutes worldwide to remember and to reflect on the victims of compromised medical practice, particularly, but not exclusively, during the Nazi era because atrocities and acts of genocide have occurred elsewhere; and (e) to examine the influence of any political ideology that compromises the practice of medicine.
Asunto(s)
Medicina Clínica , Holocausto , Nacionalsocialismo , Medicina Clínica/historia , Epónimos , Alemania , Historia del Siglo XX , Holocausto/ética , Holocausto/historia , Homicidio/historia , Experimentación Humana/ética , Experimentación Humana/historia , Humanos , Consentimiento Informado/ética , Consentimiento Informado/historia , Judíos/historia , Nacionalsocialismo/historia , Prejuicio , Prisioneros/historia , Esterilización Involuntaria/ética , Esterilización Involuntaria/historia , Estados UnidosRESUMEN
The role of hedgehog signaling is analyzed in relation to the developing endocrine glands: pituitary, ovary, testis, adrenal cortex, pancreas, prostate, and epiphyseal growth. Experimental and pathological correlates of these organs are also discussed. The second section addresses a number of topics. First, the pituitary gland, no matter how hypoplastic, is present in most cases of human holoprosencephaly, unlike animals in which it is always said to be absent. The difference appears to be that animal mutations and teratogenic models involve both copies of the gene in question, whereas in humans the condition is most commonly heterozygous. Second, tests of endocrine function are not reported with great frequency, and an early demise in severe cases of holoprosencephaly accounts for this trend. Reported tests of endocrine function are reviewed. Third, diabetes insipidus has been recorded in a number of cases of holoprosencephaly. Its frequency is unknown because it could be masked by adrenal insufficiency in some cases and may not be recognized in others. Because of the abnormal hypothalamic-infundibular region in holoprosencephaly, diabetes insipidus could be caused by a defect in the supra-optic or paraventricular hypothalamic nuclei or in release of ADH via the infundibulum and posterior pituitary.
Asunto(s)
Glándulas Endocrinas/crecimiento & desarrollo , Proteínas Hedgehog/metabolismo , Transducción de Señal , Animales , Glándulas Endocrinas/fisiología , HumanosRESUMEN
Given the knowledge of cyclopic humans and animals and their lethal nature, and given the negative way in which the cyclops is portrayed in mythology and in art, it is unusual that six naval ships--four English and two American--were named "Cyclops." However, there are also important positive attributes of the Cyclopes in Greek mythology, which explain the reasons the ships were given this name. One ship, the USS "Cyclops," with 306 men aboard, was lost at sea in the "Bermuda Triangle" in 1918 without a trace and no wreckage has ever been found.
Asunto(s)
Holoprosencefalia/historia , Mitología , Navíos/historia , Mundo Griego/historia , Historia del Siglo XX , Historia Antigua , Humanos , Reino Unido , Estados UnidosRESUMEN
There are significant differences in the ocular manifestations of Apert and Crouzon syndromes. Here, we present qualitative and quantitative data about the oculo-orbital region to demonstrate these differences. Although ocular protosis and hypertelorism characterize both disorders, the nature of the orbital dystopia differs. In Crouzon syndrome, ocular proptosis is primarily caused by retrusion of the lateral and inferior orbital margins with a very short orbital floor. In Apert syndrome, the eyeglobe actually protrudes in relation to the cranial base and to the orbit, probably resulting from marked protrusion of the lateral orbital wall. The implications account for some of the differences encountered. Asymmetry is associated with Apert syndrome frequently. Exotropia is found in Crouzon syndrome, whereas the V pattern is more characteristic in Apert syndrome with divergent upgaze and esotropic downgaze. Subluxation of the eyeglobe is found in some cases of Crouzon syndrome but is not found in Apert syndrome. Optic atrophy found in approximately 20% of Crouzon syndrome patients is not characteristic of Apert syndrome. Structural alterations of the extraocular muscles have been associated with some cases of Apert syndrome, suggesting that ocular motility disturbances in Apert syndrome may not be caused solely by mechanical factors. Absence of the superior rectus and other extraocular muscles has been recorded. Furthermore, albinoid alterations of the fundus have also been associated with Apert syndrome.
Asunto(s)
Acrocefalosindactilia/complicaciones , Exoftalmia/etiología , Anomalías del Ojo/etiología , Hipertelorismo/etiología , Acrocefalosindactilia/diagnóstico por imagen , Cefalometría , Disostosis Craneofacial/complicaciones , Disostosis Craneofacial/diagnóstico por imagen , Exoftalmia/diagnóstico por imagen , Anomalías del Ojo/diagnóstico por imagen , Humanos , Hipertelorismo/diagnóstico por imagen , RadiografíaRESUMEN
This perspective on RUNX genes discusses their basic biological features, including their DNA-binding alpha subunit, their non-DNA binding beta subunit, and their Runt domain. The evolution of Runx genes begins with one most like Runx3 in invertebrates, progresses to four genes in Drosophila, and to three in vertebrates. Runx genes have two promoters and various numbers of exons and isoforms. All three genes with expressions in the same biological tissues act either synergistically or at different time periods. Runx genes have downstream target genes. Furthermore, Runx genes are mediated by TGFbeta or BMP pathways. They also have cohesin-dependent regulation. Runx1 binds the CD4 silencer and represses transcription in immature double negative thymocytes. Runx1 also activates CD8 as the double negative population progresses to double positive thymocytes. Runx3 establishes epigenetic silencing in CD4 - CD8+ cytotoxic T-cells by binding the CD4 silencer core sequence. Runx1 may also be involved in CD4 silencing in CD8+ T-cells. RUNX1 mutations cause familial thrombocytopenia with a propensity for developing acute myelogenous leukemia; two functional consequences of these mutations include haploinsufficiency and a dominant negative effect. The latter tends to be associated with a higher frequency of leukemia. RUNX2 mutations cause cleidocranial dysplasia; most are of the missense type and commonly occur in the Runt domain. RUNX3 is a tumor suppressor gene with hemizygous deletion of one allele and hypermethylation of the other, resulting in gastric adenocarcinoma.
Asunto(s)
Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Animales , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Enfermedad/genética , Evolución Molecular , Hematopoyesis/genética , Humanos , Sistema Inmunológico/metabolismo , Mutación/genéticaRESUMEN
An international group of clinicians and scientists working in the field of dysmorphology has initiated the standardization of terms used to describe human morphology. The goals are to standardize these terms and reach consensus regarding their definitions. In this way, we will increase the utility of descriptions of the human phenotype and facilitate reliable comparisons of findings among patients. Discussions with other workers in dysmorphology and related fields, such as developmental biology and molecular genetics, will become more precise. Here we summarize the anatomy of the oral region and define and illustrate the terms that describe the major characteristics of the lips and mouth.