RESUMEN
Genetics has become a critical component of medicine over the past five to six decades. Alongside genetics, a relatively new discipline, dysmorphology, has also begun to play an important role in providing critically important diagnoses to individuals and families. Both have become indispensable to unraveling rare diseases. Almost every medical specialty relies on individuals experienced in these specialties to provide diagnoses for patients who present themselves to other doctors. Additionally, both specialties have become reliant on molecular geneticists to identify genes associated with human disorders. Many of the medical geneticists, dysmorphologists, and molecular geneticists traveled a circuitous route before arriving at the position they occupied. The purpose of collecting the memoirs contained in this article was to convey to the reader that many of the individuals who contributed to the advancement of genetics and dysmorphology since the late 1960s/early 1970s traveled along a journey based on many chances taken, replying to the necessities they faced along the way before finding full enjoyment in the practice of medical and human genetics or dysmorphology. Additionally, and of equal importance, all exhibited an ability to evolve with their field of expertise as human genetics became human genomics with the development of novel technologies.
Asunto(s)
Genética Médica , Humanos , Historia del Siglo XX , Historia del Siglo XXI , Genética HumanaRESUMEN
Mandibulofacial dysostosis with microcephaly (MFDM) is a multiple malformation syndrome comprising microcephaly, craniofacial anomalies, hearing loss, dysmorphic features, and, in some cases, esophageal atresia. Haploinsufficiency of a spliceosomal GTPase, U5-116 kDa/EFTUD2, is responsible. Here, we review the molecular basis of MFDM in the 69 individuals described to date, and report mutations in 38 new individuals, bringing the total number of reported individuals to 107 individuals from 94 kindreds. Pathogenic EFTUD2 variants comprise 76 distinct mutations and seven microdeletions. Among point mutations, missense substitutions are infrequent (14 out of 76; 18%) relative to stop-gain (29 out of 76; 38%), and splicing (33 out of 76; 43%) mutations. Where known, mutation origin was de novo in 48 out of 64 individuals (75%), dominantly inherited in 12 out of 64 (19%), and due to proven germline mosaicism in four out of 64 (6%). Highly penetrant clinical features include, microcephaly, first and second arch craniofacial malformations, and hearing loss; esophageal atresia is present in an estimated â¼27%. Microcephaly is virtually universal in childhood, with some adults exhibiting late "catch-up" growth and normocephaly at maturity. Occasionally reported anomalies, include vestibular and ossicular malformations, reduced mouth opening, atrophy of cerebral white matter, structural brain malformations, and epibulbar dermoid. All reported EFTUD2 mutations can be found in the EFTUD2 mutation database (http://databases.lovd.nl/shared/genes/EFTUD2).
Asunto(s)
Anomalías Múltiples/genética , Pérdida Auditiva/genética , Discapacidad Intelectual/genética , Disostosis Mandibulofacial/genética , Microcefalia/genética , Mutación , Factores de Elongación de Péptidos/genética , Ribonucleoproteína Nuclear Pequeña U5/genética , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/patología , Secuencias de Aminoácidos , Bases de Datos Genéticas , Expresión Génica , Haploinsuficiencia , Pérdida Auditiva/diagnóstico , Pérdida Auditiva/patología , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/patología , Disostosis Mandibulofacial/diagnóstico , Disostosis Mandibulofacial/patología , Microcefalia/diagnóstico , Microcefalia/patología , Modelos Moleculares , Datos de Secuencia Molecular , Penetrancia , Fenotipo , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Empalme del ARN , Empalmosomas/genéticaAsunto(s)
Cambio Climático , Política de Salud , Salud , Política Ambiental , Salud Global , Humanos , Cooperación Internacional , Salud PúblicaRESUMEN
IDEAS (intellectual disabilities evaluation and advice system) provides the opportunity for physicians who are sending samples for the Greenwood Genetic Center (GGC) 92-gene X-linked intellectual disability (XLID) (formerly X-linked mental retardation) panel to have their male patient's clinical features reviewed by an experienced panel of six Clinical Geneticists. They were asked to obtain parental consent, complete a one-page information form, and provide A-P and lateral photographs. The panel members independently reviewed the material and forwarded comments about clinical features, possible diagnoses, and/or further testing for the patient. We present the results of the first 55 patients evaluated. In only a single case did all panelists agree on a non-XLID diagnosis, later proven by genetic testing. The XLID gene panel diagnosed an additional five (9%) cases, but in only two cases did one panelist suggest the correct gene, which was one of four they suggested. This paper examines the possible reasons for the low rate of clinical diagnosis and suggests that, while the data received were often incomplete, the most important reasons for lack of diagnoses were the source of referral and selection of patients for review. We did note that there were a number of instances where we disagreed with the submitted information as to whether the individual was dysmorphic and with the stated presence of certain physical signs, most often downslanted palpebrae and posterior ear angulation. These differences in assessment of clinical signs and the general lack of completeness and detail provided in the standard data sheet, including that regarding the extended family history, lead us to raise concerns regarding the feasibility of establishing high quality central clinical databases designed to aid in the interpretation of exomic/genomic variants.
Asunto(s)
Discapacidad Intelectual Ligada al Cromosoma X/diagnóstico , Guías de Práctica Clínica como Asunto , Femenino , Asesoramiento Genético , Pruebas Genéticas/métodos , Pruebas Genéticas/normas , Humanos , Masculino , FenotipoRESUMEN
OBJECTIVE: Whole genome sequencing and the screening of 103 families recently led us to identify PRRT2 (proline-rich-transmembrane protein) as the gene causing infantile convulsions (IC) with paroxysmal kinesigenic dyskinesia (PKD) (PKD/IC syndrome, formerly ICCA). There is interfamilial and intrafamilial variability and the patients may have IC or PKD. Association of IC with hemiplegic migraine (HM) has also been reported. In order to explore the mutational and clinical spectra, we analyzed 34 additional families with either typical PKD/IC or PKD/IC with migraine. METHODS: We performed Sanger sequencing of all PRRT2 coding exons and of exon-intron boundaries in the probands and in their relatives whenever appropriate. RESULTS: Two known and 2 novel PRRT2 mutations were detected in 18 families. The p.R217Pfs*8 recurrent mutation was found in ≈50% of typical PKD/IC, and the unreported p.R145Gfs*31 in one more typical family. PRRT2 mutations were also found in PKD/IC with migraine: p.R217Pfs*8 cosegregated with PKD associated with HM in one family, and was also detected in one IC patient having migraine with aura, in related PKD/IC familial patients having migraine without aura, and in one sporadic migraineur with abnormal MRI. Previously reported p.R240X was found in one patient with PKD with migraine without aura. The novel frameshift p.S248Afs*65 was identified in a PKD/IC family member with IC and migraine with aura. CONCLUSIONS: We extend the spectrum of PRRT2 mutations and phenotypes to HM and to other types of migraine in the context of PKD/IC, and emphasize the phenotypic pleiotropy seen in patients with PRRT2 mutations.
Asunto(s)
Discinesias/diagnóstico , Discinesias/genética , Epilepsia Benigna Neonatal/diagnóstico , Epilepsia Benigna Neonatal/genética , Ligamiento Genético/genética , Proteínas de la Membrana/genética , Trastornos Migrañosos/diagnóstico , Trastornos Migrañosos/genética , Proteínas del Tejido Nervioso/genética , Convulsiones/diagnóstico , Convulsiones/genética , Secuencia de Bases , Corea/diagnóstico , Corea/epidemiología , Corea/genética , Discinesias/epidemiología , Epilepsia Benigna Neonatal/epidemiología , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Trastornos Migrañosos/epidemiología , Datos de Secuencia Molecular , Mutación/genética , Linaje , Convulsiones/epidemiologíaRESUMEN
Rhombencephalosynapsis (RES) is an uncommon cerebellar malformation characterized by fusion of the hemispheres without an intervening vermis. Frequently described in association with Gómez-López-Hernández syndrome, RES also occurs in conjunction with VACTERL features and with holoprosencephaly (HPE). We sought to determine the full phenotypic spectrum of RES in a large cohort of patients. Information was obtained through database review, patient questionnaire, radiographic, and morphologic assessment, and statistical analysis. We assessed 53 patients. Thirty-three had alopecia, 3 had trigeminal anesthesia, 14 had VACTERL features, and 2 had HPE with aventriculy. Specific craniofacial features were seen throughout the cohort, but were more common in patients with alopecia. We noted substantial overlap between groups. We conclude that although some distinct subgroups can be delineated, the overlapping features seen in our cohort suggest an underlying spectrum of RES-associated malformations rather than a collection of discrete syndromes.
Asunto(s)
Anomalías Múltiples/patología , Alopecia/patología , Enfermedades Cerebelosas/patología , Anomalías Craneofaciales/patología , Trastornos del Crecimiento/patología , Síndromes Neurocutáneos/patología , Rombencéfalo/anomalías , Rombencéfalo/patología , Adolescente , Adulto , Canal Anal/anomalías , Canal Anal/patología , Cerebelo/anomalías , Cerebelo/patología , Niño , Preescolar , Esófago/anomalías , Esófago/patología , Femenino , Cardiopatías Congénitas/patología , Holoprosencefalia/patología , Humanos , Lactante , Recién Nacido , Riñón/anomalías , Riñón/patología , Deformidades Congénitas de las Extremidades/patología , Masculino , Fenotipo , Columna Vertebral/anomalías , Columna Vertebral/patología , Tráquea/anomalías , Tráquea/patología , Adulto JovenRESUMEN
Renal coloboma syndrome, also known as papillorenal syndrome is an autosomal-dominant disorder characterized by ocular and renal malformations. Mutations in the paired-box gene, PAX2, have been identified in approximately half of individuals with classic findings of renal hypoplasia/dysplasia and abnormalities of the optic nerve. Prior to 2011, there was no actively maintained locus-specific database (LSDB) cataloguing the extent of genetic variation in the PAX2 gene and phenotypic variation in individuals with renal coloboma syndrome. Review of published cases and the collective diagnostic experience of three laboratories in the United States, France, and New Zealand identified 55 unique mutations in 173 individuals from 86 families. The three clinical laboratories participating in this collaboration contributed 28 novel variations in 68 individuals in 33 families, which represent a 50% increase in the number of variations, patients, and families published in the medical literature. An LSDB was created using the Leiden Open Variation Database platform: www.lovd.nl/PAX2. The most common findings reported in this series were abnormal renal structure or function (92% of individuals), ophthalmological abnormalities (77% of individuals), and hearing loss (7% of individuals). Additional clinical findings and genetic counseling implications are discussed.
Asunto(s)
Coloboma/genética , Bases de Datos Genéticas , Factor de Transcripción PAX2/genética , Insuficiencia Renal/genética , Reflujo Vesicoureteral/genética , Animales , HumanosRESUMEN
X-linked VACTERL-hydrocephalus syndrome (X-linked VACTERL-H) is a rare disorder caused by mutations in the gene FANCB which underlies Fanconi Anemia (FA) complementation group B. Cells from affected males have increased chromosome breakage on exposure to DNA cross-linking agents. Only five FANCB mutations found in six affected males, including an affected uncle and nephew, have been reported. We have identified FANCB mutations in a further four affected families. The VACTERL-H phenotype segregates as an X-linked recessive trait in three of these. Each mutation is predicted to truncate the FANCB open reading frame and results in highly skewed X-inactivation in unaffected carrier females. Phenotypic data were available on six affected males. Comparison of the clinical findings in our patients with published clinical data (total 12 patients) shows that ventriculomegaly, bilateral absent thumbs and radii, vertebral defects, renal agenesis, and growth retardation are the major phenotypic signs in affected males. Less frequent are brain, pituitary, ear and eye malformations, gastrointestinal atresias (esophageal, duodenal and anal), tracheoesophageal fistula, lung segmentation defects, and small genitalia. Three of six of our patients survived the perinatal period. One boy lived up to 2 years 10 months but developed aplastic anemia and died of renal failure. These data show that loss-of-function FANCB mutations result in a recognizable, multiple malformation phenotype in hemizygous males for which we propose clinical criteria to aid diagnosis.
Asunto(s)
Proteínas del Grupo de Complementación de la Anemia de Fanconi/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/patología , Cardiopatías Congénitas/genética , Cardiopatías Congénitas/patología , Hidrocefalia/genética , Hidrocefalia/patología , Deformidades Congénitas de las Extremidades/genética , Deformidades Congénitas de las Extremidades/patología , Fenotipo , Canal Anal/anomalías , Canal Anal/patología , Anomalías Cardiovasculares , Análisis Mutacional de ADN , Anomalías del Sistema Digestivo , Esófago/anomalías , Esófago/patología , Femenino , Genes Recesivos/genética , Humanos , Riñón/anomalías , Riñón/patología , Masculino , Anomalías Musculoesqueléticas , Mutación/genética , Linaje , Columna Vertebral/anomalías , Columna Vertebral/patología , Tráquea/anomalías , Tráquea/patología , Inactivación del Cromosoma X/genéticaRESUMEN
Aside from gastroschisis and omphalocele, major defects of the ventral body (thoracoabdominal) wall are relatively uncommon and almost universally lethal. They are most often associated with other anomalies including those of the limbs that may range from amelia to mild positional deformations, unusual craniofacial malformations, and a variety of visceral abnormalities that include the heart, lungs, genitourinary system, and gut. This complex of ventral wall anomalies has been discussed under a broad and changing nomenclature that has included amniotic band disruption complex, amnion rupture sequence, limb-body wall defect (or complex), and simply body wall complex. Three major theories have been suggested to explain this complex: early amnion rupture (operating through uterine pressure and/or disruption by amniotic bands), vascular compromise (primarily hypoperfusion), and an early intrinsic defect of the developing embryo. We present four patients that illustrate the spectrum of ventral body wall defects, and from there critique the current hypotheses of pathogenesis. We conclude that this association of malformations originates as early as the embryonic disc stage, and that some of the observed associated anomalies are secondary complications of the primary disturbance in embryogenesis. We propose a new explanation for the atypical facial clefts and cranial malformations that are often observed.
Asunto(s)
Anomalías Múltiples/etiología , Anomalías Múltiples/patología , Anomalías Craneofaciales , Gastrosquisis , Deformidades Congénitas de las Extremidades , Pared Abdominal/anomalías , Pared Abdominal/embriología , Síndrome de Bandas Amnióticas , Ectromelia , Extremidades/embriología , Femenino , Humanos , Recién Nacido , MasculinoRESUMEN
Temtamy and McKusick suggested mouse disorganization (Ds) as a model for human tibial agenesis, fibular duplication and mirror foot, but the concurrent papers by Winter and Donnai and Donnai and Winter in 1989 kindled interest and led to continued reports of patients hypothesized as human equivalent of Ds (HEDs). Subsequent reports have tended to follow one or other of the two categories outlined; (1) band/constriction with additional anomalies unexplained by bands (ABS); (2) patterns of malformation interpreted as resembling mouse Ds (non-ABS). A review of a series of cases led to a re-read of the original Ds mouse reports by Hummel in 1958 and 1959 and examination of current literature in an attempt to assess the strength of the argument that the patients might represent HEDs. Key to the approach was a paragraph in Hummel's introduction; "some of the developmental anomalies from action of Ds are similar to those caused by other genes teratogens others are unique " The corollary is a patient is likelier to represent human DS if the anomaly(s) match these unique malformations/patterns. Presence of anomalies not specifically noted in Ds would weaken the argument for human equivalence. Reports of possible HEDs were ascertained using PubMed and literature cited by authors subsequent to the 1989 papers, up to and including January, 2010. This paper gives an overview of HEDs patients reported and concludes that the ABS type, even with non-band associated anomalies, is not likely to often represent HEDs. Many non-ABS HEDs patients had equally valid alternative hypothesis or diagnoses, malformations unreported or unusual for the Ds mouse, and/or paucity of the more unusual anomalies of the Ds mouse.
Asunto(s)
Anomalías Múltiples/patología , Síndrome de Bandas Amnióticas/patología , Enfermedades de los Roedores/patología , Animales , Modelos Animales de Enfermedad , Humanos , Recién Nacido , Ratones , FenotipoRESUMEN
Börjeson-Forssman-Lehmann syndrome (BFLS) is a rare X-linked mental retardation syndrome that is caused by germline mutations in PHF6. We describe a 9-year-old male with BFLS, who developed T-cell acute lymphoblastic leukemia (T-ALL). The PHF6 gene is located on the X chromosome and encodes a protein with two PHD-type zinc finger domains and four nuclear localization sequences. Previously, overexpression of Phf6 was observed in murine T-cell lymphomas. Our observation indicates that BFLS may represent a cancer predisposition syndrome and that mutations of PHF6 contribute to T-ALL.
Asunto(s)
Proteínas Portadoras/genética , Discapacidad Intelectual Ligada al Cromosoma X/genética , Mutación , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Niño , Humanos , Masculino , Proteínas RepresorasRESUMEN
Epilepsy and paroxysmal dyskinesia are two episodic cerebral disorders that can share a common genetic basis. Rare families with infantile seizures and paroxysmal dyskinesia [predominantly paroxysmal kinesigenic dyskinesia (PKD)], co-inherited as a single autosomal dominant trait, have been described (infantile convulsions with paroxysmal choreoathetosis; ICCA syndrome) and a disease gene has been mapped at chromosome 16p12-q12 (ICCA region). We report the clinical picture of seven previously unreported families with ICCA syndrome. The identification of novel ICCA families should contribute to better knowledge regarding the clinical manifestations of ICCA syndrome as well as the search for the underlying genetic defect(s).
Asunto(s)
Corea/genética , Convulsiones/genética , Edad de Inicio , Corea/complicaciones , Mapeo Cromosómico , Cromosomas Humanos Par 16/genética , ADN/sangre , ADN/genética , Electroencefalografía , Femenino , Humanos , Lactante , Masculino , Linaje , Convulsiones/complicaciones , SíndromeRESUMEN
Facial angiofibromas are a major diagnostic sign for tuberous sclerosis (TS) and MEN1, and the former is probably the first disease to be considered by a geneticist when such lesions are found. They occur in up to 90% of persons with TS and 40-80% of individuals with MEN1. Early onset facial angiofibromas that are not associated with any other systemic sign appear to be unusual, and their occurrence can leave the clinician with some uncertainty as to their significance, as well as how to proceed. In this article we describe four patients with what appear to be isolated, bilateral facial angiofibromas. We discuss the significance of these lesions with respect to the conditions in which they have been seen, review prior reports of apparently isolated angiofibromas, and provide some rough calculations as to how likely it would be for an underlying systemic condition to be overlooked after different levels of investigation have been performed. We also look at some aspects of the financial cost/benefit ratio of further investigation of TS beyond a clinical examination.
Asunto(s)
Angiofibroma/patología , Neoplasias Faciales/patología , Neoplasias Primarias Múltiples/patología , Adolescente , Adulto , Edad de Inicio , Angiofibroma/genética , Análisis Mutacional de ADN , Neoplasias Faciales/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasia Endocrina Múltiple Tipo 1/diagnóstico , Neoplasia Endocrina Múltiple Tipo 1/genética , Neoplasias Primarias Múltiples/genética , Esclerosis Tuberosa/diagnóstico , Esclerosis Tuberosa/genéticaRESUMEN
The recent series of articles describing human surface anatomy included an article on the ear by Hunter et al. [Hunter et al. (2009); Am J Med Genet Part A 149A: 40-60]. That publication did not include the incisura. This article provides an approach to assessing the incisura in the hope that others may find it useful and/or modify it as appropriate.
Asunto(s)
Anomalías Congénitas/clasificación , Enfermedades del Oído/congénito , Oído/anomalías , Oído/anatomía & histología , Oído/fisiología , Humanos , Modelos Anatómicos , Síndrome , Terminología como AsuntoRESUMEN
The literature abounds with reports of malformation syndromes in which human external ears are variously described as dysplastic, abnormal, large/small, low set, typical, or in some way unusual. Rarely is the ear well illustrated or described in meaningful detail. With few exceptions, such as Down syndrome, there is no real understanding of the degree to which ear morphology is affected in a specific syndrome. This paper describes a retrospective attempt to apply the recently published Morphological Definitions of the ear to compare a control sample of convenience with a group of patients with Cornelia de Lange syndrome (CdLS) (all six papers in this issue are available online, open access at http://www3.interscience.wiley.com/journal/121641055/issue). Although this study has a number of limitations, it demonstrates that the method can be successfully applied and is capable of producing data that can be subjected to statistical analysis. The ears of the patients with CdLS were significantly different from the controls over a number of descriptors, the most significant of which included more frequent apparent posterior rotation, a shorter more serpiginous antihelical stem and sharper antihelical to inferior crus angle, a shorter crus helix, a more V-shaped incisura, and a smaller lobe.
Asunto(s)
Anomalías Congénitas/clasificación , Síndrome de Cornelia de Lange/diagnóstico , Síndrome de Cornelia de Lange/patología , Oído/patología , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Niño , Preescolar , Anomalías Congénitas/diagnóstico , Anomalías Congénitas/patología , Femenino , Guías como Asunto , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Börjeson-Forssman-Lehmann syndrome is an X-linked condition caused by PHF6 mutations. The classical description of males with this disorder includes severe intellectual disability with epilepsy, microcephaly, short stature, obesity, hypogonadism, and gynecomastia. We present three males with PHF6 mutations whose features included deep-set eyes, large ears, coarse face, tapering fingers, and truncal obesity. Unlike the original description of the syndrome; however, the males described herein had varying degrees of intellectual disability and hypogonadism, were of normal to tall stature, had normal to large head sizes, and did not have seizures. This departure from the usual clinical description of Börjeson-Forssman-Lehmann syndrome is consistent with recent reports of males with mutations in PHF6. In addition, we describe the phenotype and X-inactivation pattern in two females heterozygous for PHF6 mutations, both of whom have mild features of the syndrome.
Asunto(s)
Anomalías Múltiples/genética , Proteínas Portadoras/genética , Trastornos del Crecimiento/genética , Adulto , Niño , Cara/anomalías , Femenino , Dedos/anomalías , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Humanos , Hipogonadismo , Lactante , Masculino , Discapacidad Intelectual Ligada al Cromosoma X/genética , Persona de Mediana Edad , Obesidad , Linaje , Proteínas Represoras , Síndrome , Inactivación del Cromosoma XRESUMEN
An international group of clinicians 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 introduce the anatomy of the ear and define and illustrate the terms that describe the major characteristics of the ear.
Asunto(s)
Oído/anomalías , Oído/anatomía & histología , Terminología como Asunto , Antropometría , Oído/patología , Humanos , FenotipoRESUMEN
Gastroschisis is a major malformation which requires immediate surgical care to return the exposed viscera to the abdominal cavity, parenteral nutrition until bowel motility permits oral feedings, and evaluation for coexisting malformations. Almost all cases are diagnosed prenatally using midtrimester ultrasound and maternal serum alphafetoprotein measurement. This allows most infants to be delivered in a tertiary care facility where the best mode of delivery and neonatal management can be determined. About 10% of infants with gastroschisis will have other malformations. Half of these are considered related to the gastroschisis (intestinal atresia or stenosis, malrotation, cryptorchidism, amyoplasia, urinary tract obstruction). Other associated malformations occur which are not recognized to be secondary to the gastroschisis. Prominent among these are cardiac and limb defects. Fetal and neonatal mortality are increased, but neither appear related to lethal malformations.