RESUMEN
Oral-facial-digital syndrome type 1 (OFD1; OMIM# 311200) is an X-linked dominant ciliopathy caused by mutations in the OFD1 gene. This condition is characterized by facial anomalies and abnormalities of oral tissues, digits, brain, and kidneys. Almost all affected patients are female, as OFD1 is presumed to be lethal in males, mostly in the first or second trimester of pregnancy. Live born males with OFD1 are a rare occurrence, with only five reported patients to date. In four patients the presence of a congenital heart defect (CHD) was observed. Here, we report an affected male fetus with a hemizygous de novo mutation in OFD1 (c.2101C>T; p.(Gln701*)). Ultrasound examination demonstrated severe hydrocephalus, a hypoplastic cerebellum and a hypoplastic left ventricle of the heart. The pregnancy was terminated at 16 weeks of gestation because of poor prognosis. Post-mortem examination of the fetus confirmed severe hypoplasia of the left ventricle of the heart. We emphasize that CHDs should be included in the phenotypic spectrum of OFD1 in males. This justifies molecular analysis of OFD1 when CHD is encountered prenatally in combination with one or more phenotypic features previously described in the OFD1 gene alteration spectrum. The underlying pathogenesis of CHD in OFD1 (and other ciliopathies) probably involves dysfunction of the primary cilia regarding coordination of left-right signalling during early heart development. Whether these CHDs wholly or partly result from defective left right signalling, in which different types of cilia are known to play a critical role, remains a topic of research.
Asunto(s)
Cardiopatías Congénitas/genética , Síndromes Orofaciodigitales/genética , Proteínas/genética , Feto Abortado , Autopsia , Femenino , Genes Ligados a X , Cardiopatías Congénitas/complicaciones , Cardiopatías Congénitas/fisiopatología , Humanos , Masculino , Mutación , Síndromes Orofaciodigitales/complicaciones , Síndromes Orofaciodigitales/fisiopatología , Linaje , Fenotipo , Embarazo , Transducción de SeñalRESUMEN
Varadi syndrome is a subtype of orofaciodigital syndrome (OFDS) that combines the typical features of OFDS and the posterior fossa features of Joubert syndrome. The only gene known to be mutated in Varadi syndrome is C5ORF42. In this report, we describe the phenotype of a patient with Varadi syndrome who is homozygous for a previously reported mutation in TCTN1 (NM_001082538.2:c.342-2A>G, p.Gly115Lysfs*8) and suggest that allelic disorders linked to TCTN1 include Varadi syndrome, in addition to Joubert syndrome and Meckel-Gruber syndrome.
Asunto(s)
Anomalías Múltiples/genética , Cerebelo/anomalías , Anomalías del Ojo/genética , Enfermedades Renales Quísticas/genética , Proteínas de la Membrana/genética , Síndromes Orofaciodigitales/genética , Retina/anomalías , Anomalías Múltiples/fisiopatología , Alelos , Secuencia de Bases/genética , Cerebelo/fisiopatología , Preescolar , Trastornos de la Motilidad Ciliar/genética , Trastornos de la Motilidad Ciliar/fisiopatología , Encefalocele/genética , Encefalocele/fisiopatología , Anomalías del Ojo/fisiopatología , Humanos , Enfermedades Renales Quísticas/fisiopatología , Masculino , Síndromes Orofaciodigitales/fisiopatología , Fenotipo , Enfermedades Renales Poliquísticas/genética , Enfermedades Renales Poliquísticas/fisiopatología , Retina/fisiopatología , Retinitis PigmentosaRESUMEN
The 13 subtypes of oral-facial-digital syndrome (OFDS) belong to the heterogeneous group of ciliopathies. Disease-causing genes encode for centrosomal proteins, components of the transition zone or proteins implicated in ciliary signaling. A unique consanguineous family presenting with an unclassified OFDS with skeletal dysplasia and brachymesophalangia was explored. Homozygosity mapping and exome sequencing led to the identification of a homozygous mutation in IFT57, which encodes a protein implicated in ciliary transport. The mutation caused splicing anomalies with reduced expression of the wild-type transcript and protein. Both anterograde ciliary transport and sonic hedgehog signaling were significantly decreased in subjects' fibroblasts compared with controls. Sanger sequencing of IFT57 in 13 OFDS subjects and 12 subjects with Ellis-Van Creveld syndrome was negative. This report identifies the implication of IFT57 in human pathology and highlights the first description of a ciliary transport defect in OFDS, extending the genetic heterogeneity of this subgroup of ciliopathies.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Ciliopatías/genética , Anomalías Craneofaciales/genética , Enanismo/genética , Oído/anomalías , Cuello/anomalías , Síndromes Orofaciodigitales/genética , Tórax/anomalías , Adolescente , Adulto , Ciliopatías/fisiopatología , Consanguinidad , Anomalías Craneofaciales/fisiopatología , Enanismo/fisiopatología , Oído/fisiopatología , Síndrome de Ellis-Van Creveld/genética , Síndrome de Ellis-Van Creveld/fisiopatología , Exoma/genética , Femenino , Heterogeneidad Genética , Secuenciación de Nucleótidos de Alto Rendimiento , Homocigoto , Humanos , Masculino , Mutación , Cuello/fisiopatología , Síndromes Orofaciodigitales/fisiopatología , Fenotipo , Tórax/fisiopatología , Adulto JovenRESUMEN
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
Febrile seizures are the most common seizures in childhood. They have been observed in 2-5% of children before the age of 5, but in some populations this figure may increase to 15%. It is a common cause of pediatric hospital admissions and cause of anxiety for parents. Febrile seizures could be the first manifestation of epilepsy. About 13% of epileptic patients have a history of febrile seizure, and 30% have had recurrent febrile seizures. Their phenotypic characteristics allow, in the majority of cases, a classification of the seizure, an elaboration of a prognosis and to assume a specific therapeutic attitude. It is possible to describe a spectrum according to their severity, from the benign simple seizure to the more complex, febrile seizure plus, Dravet'syndrome, and FIRES. During the past decade, molecular genetic studies have contributed to the identification of genetic factors involved in febrile seizure and related disorders, making the necessity of a careful follow up of these patients in order to detect risk factors earlier. We have reviewed the medical literature to update current knowledge of febrile seizures, their prognosis and their relation to new epileptic syndromes.
Asunto(s)
Epilepsia Generalizada/genética , Convulsiones Febriles/genética , Factores de Edad , Niño , Preescolar , Epilepsias Mioclónicas/genética , Epilepsias Mioclónicas/fisiopatología , Epilepsia Generalizada/fisiopatología , Femenino , Humanos , Masculino , Síndromes Orofaciodigitales/genética , Síndromes Orofaciodigitales/fisiopatología , Fenotipo , Convulsiones Febriles/fisiopatologíaRESUMEN
In humans, OFD1 is mutated in oral-facial-digital type I syndrome leading to prenatal death in hemizygous males and dysmorphic faces and brain malformations, with polycystic kidneys presenting later in life in heterozygous females. To elucidate the function of Ofd1, we have studied its function during zebrafish embryonic development. In wild-type embryos, ofd1 mRNA is widely expressed and Ofd1-green fluorescent protein (GFP) fusion localizes to the centrosome/basal body. Disrupting Ofd1 using antisense morpholinos (MOs) led to bent body axes, hydrocephalus and oedema. Laterality was randomized in the brain, heart and viscera, likely a consequence of shorter cilia with disrupted axonemes and perturbed intravesicular fluid flow in Kupffer's vesicle. Embryos injected with ofd1 MOs also displayed convergent extension (CE) defects, which were enhanced by loss of Slb/Wnt11 or Tri/Vangl2, two proteins functioning in a non-canonical Wnt/Planar Cell Polarity (PCP) pathway. Pronephric glomerular midline fusion was compromised in vangl2 and ofd1 loss of function embryos and we suggest this anomaly may be a novel CE defect. Thus, Ofd1 is required for ciliary motility and function in zebrafish, supporting data showing that Ofd1 is essential for primary cilia function in mice. In addition, our data show that Ofd1 is important for CE during gastrulation, consistent with data linking primary cilia and non-canonical Wnt/PCP signalling.
Asunto(s)
Cilios/fisiología , Síndromes Orofaciodigitales/genética , Proteínas de Pez Cebra/metabolismo , Animales , Tipificación del Cuerpo , Polaridad Celular , Centrosoma/metabolismo , Cilios/genética , Femenino , Humanos , Masculino , Síndromes Orofaciodigitales/embriología , Síndromes Orofaciodigitales/metabolismo , Síndromes Orofaciodigitales/fisiopatología , Transducción de Señal , Pez Cebra , Proteínas de Pez Cebra/genéticaAsunto(s)
Lipoma/fisiopatología , Síndromes Orofaciodigitales/fisiopatología , Polidactilia/fisiopatología , Lengua/patología , Humanos , Lactante , Lipoma/complicaciones , Lipoma/diagnóstico , Masculino , Síndromes Orofaciodigitales/complicaciones , Síndromes Orofaciodigitales/diagnóstico , Polidactilia/complicaciones , Polidactilia/diagnósticoRESUMEN
The oral-facial-digital syndrome type I (OFD I) is characterized by multiple congenital malformations of the face, oral cavity and digits. A polycystic kidney disease (PKD) is found in about one-third of patients but long-term outcome and complications are not well described in the international literature. Renal findings have been retrospectively collected in a cohort of 34 females all carrying a pathogenic mutation in the OFD1 gene with ages ranging from 1 to 65 years. Twelve patients presented with PKD - 11/16 (69%) if only adults were considered -with a median age at diagnosis of 29 years [IQR (interquartile range) = (23.5-38)]. Among them, 10 also presented with renal impairment and 6 were grafted (median age = 38 years [IQR = (25-48)]. One grafted patient under immunosuppressive treatment died from a tumor originated from a native kidney. The probability to develop renal failure was estimated to be more than 50% after the age of 36 years. Besides, neither genotype-phenotype correlation nor clinical predictive association with renal failure could be evidenced. These data reveal an unsuspected high incidence rate of the renal impairment outcome in OFD I syndrome. A systematic ultrasound (US) and renal function follow-up is therefore highly recommended for all OFD I patients.
Asunto(s)
Envejecimiento , Síndromes Orofaciodigitales/complicaciones , Insuficiencia Renal/etiología , Adolescente , Adulto , Niño , Preescolar , Estudios de Cohortes , Femenino , Estudios de Asociación Genética , Humanos , Lactante , Riñón/patología , Persona de Mediana Edad , Síndromes Orofaciodigitales/genética , Síndromes Orofaciodigitales/patología , Síndromes Orofaciodigitales/fisiopatología , Proteínas/genética , Adulto JovenRESUMEN
The skeletal ciliopathies are a heterogeneous group of disorders with a significant clinical and genetic variability and the main clinical features are thoracic hypoplasia and short tubular bones. To date, 25 genes have been identified in association with skeletal ciliopathies. Mutations in the KIAA0753 gene have recently been associated with Joubert syndrome (JBTS) and orofaciodigital (OFD) syndrome. We report biallelic pathogenic variants in KIAA0753 in four patients with short-rib type skeletal dysplasia. The manifestations in our patients are variable and ranging from fetal lethal to viable and moderate skeletal dysplasia with narrow thorax and abnormal metaphyses. We demonstrate that KIAA0753 is expressed in normal fetal human growth plate and show that the affected fetus, with a compound heterozygous frameshift and a nonsense mutation in KIAA0753, has an abnormal proliferative zone and a broad hypertrophic zone. The importance of KIAA0753 for normal skeletal development is further confirmed by our findings that zebrafish embryos homozygous for a nonsense mutation in kiaa0753 display altered cartilage patterning.
Asunto(s)
Ciliopatías/genética , Predisposición Genética a la Enfermedad , Proteínas Asociadas a Microtúbulos/genética , Músculo Esquelético , Anomalías Múltiples/genética , Anomalías Múltiples/fisiopatología , Cerebelo/anomalías , Cerebelo/fisiopatología , Niño , Preescolar , Ciliopatías/fisiopatología , Anomalías del Ojo/genética , Anomalías del Ojo/fisiopatología , Femenino , Homocigoto , Humanos , Lactante , Enfermedades Renales Quísticas/genética , Enfermedades Renales Quísticas/fisiopatología , Masculino , Músculo Esquelético/anomalías , Mutación , Síndromes Orofaciodigitales/genética , Síndromes Orofaciodigitales/fisiopatología , Linaje , Fenotipo , Retina/anomalías , Retina/fisiopatologíaRESUMEN
The paper presents the electromyographic (EMG) findings of the soft palate in three patients: a patient with Mohr syndrome and cleft palate, a patient with palatal asymmetry and rhinolalia and a patient with vertical oro-ocular facial cleft with marked asymmetry of the cleft palate. In the first patient, electrical silence was registered in one half of the palate. In the second patient, moderate loss of active motor units was registered in the hypoplastic part of the palate. In the third patient, in spite of asymmetry, the EMG finding was normal on both sides of the palate.
Asunto(s)
Labio Leporino/fisiopatología , Fisura del Paladar/fisiopatología , Síndromes Orofaciodigitales/fisiopatología , Paladar Blando/anomalías , Paladar Blando/fisiopatología , Trastornos del Habla/fisiopatología , Preescolar , Labio Leporino/diagnóstico , Fisura del Paladar/diagnóstico , Electromiografía , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Síndromes Orofaciodigitales/diagnóstico , Trastornos del Habla/diagnósticoRESUMEN
Abnormal respiration with episodic tachypnea-apnea can occur in several syndromes (particularly, the Rett, Joubert, Mohr and Dandy-Walker syndromes). These syndromes are briefly reviewed. In the Rett syndrome, in contrast to in most other genetically determined syndromes, the onset of breathing abnormalities does not occur in the neonatal period.
Asunto(s)
Anomalías Múltiples/diagnóstico , Encefalopatías/diagnóstico , Síndrome de Dandy-Walker/diagnóstico , Hidrocefalia/diagnóstico , Síndromes Orofaciodigitales/diagnóstico , Trastornos Respiratorios/diagnóstico , Apnea/complicaciones , Apnea/diagnóstico , Apnea/fisiopatología , Encefalopatías/genética , Encefalopatías/fisiopatología , Síndrome de Dandy-Walker/complicaciones , Síndrome de Dandy-Walker/fisiopatología , Diagnóstico Diferencial , Femenino , Humanos , Lactante , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Discapacidad Intelectual/fisiopatología , Masculino , Síndromes Orofaciodigitales/complicaciones , Síndromes Orofaciodigitales/fisiopatología , Trastornos Respiratorios/complicaciones , Trastornos Respiratorios/fisiopatología , SíndromeRESUMEN
Oro-Facial Digital Syndrome (OFDS) is a generic term for group of apparently distinctive genetic diseases that affect the development of the oral cavity, facial features, and digits. One of these is OFDS type I (OFDS-I) which has rarely been reported in Asian countries. This is the case report of a 13 year old patient with OFDS type I who reported to the Department of Pedodontics and Preventive Dentistry, with the complaint of discolored upper front teeth.
Asunto(s)
Síndromes Orofaciodigitales/diagnóstico , Adolescente , Femenino , Humanos , Síndromes Orofaciodigitales/fisiopatologíaRESUMEN
BACKGROUND: Oral-facial-digital type 1 syndrome (OFD1; OMIM 311200) belongs to the expanding group of disorders ascribed to ciliary dysfunction. With the aim of contributing to the understanding of the role of primary cilia in the central nervous system (CNS), we performed a thorough characterization of CNS involvement observed in this disorder. METHODS: A cohort of 117 molecularly diagnosed OFD type I patients was screened for the presence of neurological symptoms and/or cognitive/behavioral abnormalities on the basis of the available information supplied by the collaborating clinicians. Seventy-one cases showing CNS involvement were further investigated through neuroimaging studies and neuropsychological testing. RESULTS: Seventeen patients were molecularly diagnosed in the course of this study and five of these represent new mutations never reported before. Among patients displaying neurological symptoms and/or cognitive/behavioral abnormalities, we identified brain structural anomalies in 88.7%, cognitive impairment in 68%, and associated neurological disorders and signs in 53% of cases. The most frequently observed brain structural anomalies included agenesis of the corpus callosum and neuronal migration/organisation disorders as well as intracerebral cysts, porencephaly and cerebellar malformations. CONCLUSIONS: Our results support recent published findings indicating that CNS involvement in this condition is found in more than 60% of cases. Our findings correlate well with the kind of brain developmental anomalies described in other ciliopathies. Interestingly, we also described specific neuropsychological aspects such as reduced ability in processing verbal information, slow thought process, difficulties in attention and concentration, and notably, long-term memory deficits which may indicate a specific role of OFD1 and/or primary cilia in higher brain functions.
Asunto(s)
Enfermedades del Sistema Nervioso Central/fisiopatología , Síndromes Orofaciodigitales/fisiopatología , Enfermedades del Sistema Nervioso Central/genética , Enfermedades del Sistema Nervioso Central/psicología , Estudios de Cohortes , Femenino , Humanos , Imagen por Resonancia Magnética , Mutación , Pruebas Neuropsicológicas , Síndromes Orofaciodigitales/genética , Síndromes Orofaciodigitales/psicologíaAsunto(s)
Proteínas de Unión al ADN/genética , Sordera/genética , Distonía/genética , Proteínas de Transporte de Membrana , Mutación , Análisis Mutacional de ADN , Sordera/complicaciones , Distonía/complicaciones , Salud de la Familia , Femenino , Enfermedades Genéticas Ligadas al Cromosoma X , Humanos , Membranas Intracelulares/metabolismo , Masculino , Mitocondrias/metabolismo , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales , Proteínas Mitocondriales/metabolismo , Síndromes Orofaciodigitales/complicaciones , Síndromes Orofaciodigitales/genética , Síndromes Orofaciodigitales/fisiopatología , LinajeAsunto(s)
Anomalías Múltiples/genética , Fisura del Paladar/fisiopatología , Hipogonadismo/fisiopatología , Discapacidad Intelectual/genética , Seudohipoparatiroidismo/fisiopatología , Estereognosis , Síndrome de Turner/fisiopatología , Adolescente , Adulto , Niño , Defectos de la Visión Cromática , Eunuquismo/fisiopatología , Femenino , Humanos , Masculino , Trastornos del Olfato , Síndromes Orofaciodigitales/fisiopatología , Aberraciones Cromosómicas Sexuales/fisiopatología , TactoRESUMEN
Data reported at an international meeting on the sensory and motile functions of cilia, including the primary cilium found on most cells in the human body, have thrust this organelle to the forefront of studies on the cell biology of human disease.
Asunto(s)
Síndrome de Bardet-Biedl/fisiopatología , Cilios/fisiología , Síndromes Orofaciodigitales/fisiopatología , Enfermedades Renales Poliquísticas/fisiopatología , Transducción de Señal/fisiología , Animales , Síndrome de Bardet-Biedl/genética , Cilios/ultraestructura , Humanos , Modelos Biológicos , Síndromes Orofaciodigitales/genética , Enfermedades Renales Poliquísticas/genéticaRESUMEN
Episodic tachypnea is a typical neonatal presentation of Joubert syndrome, but may also occur in infants with other anomalies of the cerebellar vermis. Even though fetuses at risk for Joubert syndrome are usually closely followed by ultrasound, this respiratory pattern has only once been described prenatally. We describe a patient who presented prenatally with posterior meningocele, Dandy-Walker cyst, and four limb polydactyly on ultrasound. Amniocentesis showed a normal male karyotype and normal 7DHC. At 31 weeks, episodic fetal tachypnea was noted on ultrasound. The working diagnosis was Joubert syndrome or oro-facio-digital syndrome type VI (OFD VI). At birth, in addition to the findings noted prenatally, he had multiple nodules of his tongue, a Y-shaped metacarpal and micropenis. His respiratory pattern was notable for alternating tachypnea and apnea with respiratory rates up to 200 followed by apnea and bradycardia. Magnetic resonance image showed Dandy-Walker with massive 4th ventricle, complete absence of the cerebellar vermis, hypoplastic brainstem, and small meningocele. Development is profoundly delayed and he remains ventilator dependent. Both the previously described Joubert patient with prenatally recognized tachypnea, and our patient are atypical for Joubert syndrome since they have polydactyly (which occurs in only 8% of Joubert patients) and hamartomas of the tongue (which occur in 2%). Despite the tongue hamartomas, these patients are not entirely typical for OFD VI, since their polydactyly is postaxial. The observation of prenatal tachypnea in these two patients, but not in typical Joubert patients, suggests they have either a variant of OFD VI or a new Joubert or OFD-like syndrome.
Asunto(s)
Síndromes Orofaciodigitales/diagnóstico , Trastornos Respiratorios/diagnóstico , Adulto , Femenino , Humanos , Recién Nacido , Masculino , Síndromes Orofaciodigitales/complicaciones , Síndromes Orofaciodigitales/fisiopatología , Fenotipo , Embarazo , Trastornos Respiratorios/congénito , Trastornos Respiratorios/etiología , Trastornos Respiratorios/fisiopatología , Mecánica Respiratoria , Ultrasonografía PrenatalRESUMEN
We describe a three generation family with three females showing minor features of orofaciodigital syndrome type I and a severely affected male in the third generation. In addition to the classical features of OFD I, the male had bilateral duplication of the halluces, a feature diagnostic of OFD II, and an atrioventricular septal defect. Heart defects have not previously been reported in OFD I but have been reported in OFD II. It is important to examine the mothers of all male neonates with orofaciodigital syndrome with care before making a diagnosis of OFD II.
Asunto(s)
Síndromes Orofaciodigitales/diagnóstico , Adulto , Femenino , Humanos , Lactante , Masculino , Síndromes Orofaciodigitales/fisiopatología , Linaje , Diagnóstico PrenatalRESUMEN
A patient with oculodentodigital dysplasia (ODDD) syndrome was evaluated because of complaints of intermittent diarrhea of many years duration. Gastrointestinal manifestations have not been routinely described in patients with ODDD, which is a hereditary disorder characterized by abnormal eye findings, defective tooth enamel, various phalangeal aberrations, a distinctive facial appearance, and skeletal dysplasias. Steatorrhea was documented, but the usual methods for investigating this were thwarted by the patient's abnormal gastric anatomy and poor gastric motility. A combined endoscopic-fluoroscopic, guidewire-directed intubation procedure was performed to permit study of the small bowel. Pancreatic function was normal, and culture of an aspirate from the jejunum revealed a mixed bacterial flora. Treatment for presumed small bowel bacterial overgrowth with antibiotics and a reduced fat diet brought relief of diarrheal symptoms and produced weight gain. The clinical approach to this particular patient and the relationship between the ODDD syndrome and the described gastrointestinal anomalies are discussed.