RESUMEN
CHARGE syndrome is a rare autosomal dominant syndrome characterized by multiple congenital anomalies including coloboma, heart defects, ear anomalies, and developmental delay, caused by pathogenic variants in the CHD7 gene. The discovery of the molecular basis of this syndrome increased the number of cases reported and expanded the phenotype and clinical variability. Limb anomalies are occasional clinical findings in this syndrome, present in about 30% of reported cases. The occurrence of limb anomalies in this syndrome suggests that it should be considered as part of the phenotypic spectrum. Here, we describe an individual with CHARGE syndrome presenting unilateral monodactyly.
Asunto(s)
Síndrome CHARGE , ADN Helicasas , Fenotipo , Humanos , Síndrome CHARGE/genética , Síndrome CHARGE/diagnóstico , Síndrome CHARGE/patología , Síndrome CHARGE/complicaciones , ADN Helicasas/genética , Proteínas de Unión al ADN/genética , Masculino , Femenino , Mutación , Deformidades Congénitas de las Extremidades/genética , Deformidades Congénitas de las Extremidades/patología , Deformidades Congénitas de las Extremidades/diagnósticoRESUMEN
Bosma arhinia microphthalmia syndrome (BAMS, OMIM #603457) is a rare autosomal dominant disorder caused by heterozygous variation in the SMCHD1 gene on chromosome 18p11. Clinically, it is characterized by microphthalmia, absence or hypoplasia of nose, choanal atresia, anosmia, palatal abnormalities, hypogonadotropic hypogonadism, and cryptorchidism. Here we report a Brazilian patient with a likely pathogenic variation in SMCHD1 gene (c.1418A>T; p.Glu473Val) presenting hemiarhinia associated with short stature and hypogonadotropic hypogonadism. Due to the clinical variability of BAMS, we considered that hemiarhinia, without microphthalmia, in the present case, can be considered a mild form of BAMS and could be considered for screening of SMCHD1 gene variation.
Asunto(s)
Atresia de las Coanas , Proteínas Cromosómicas no Histona , Microftalmía , Mutación Missense , Fenotipo , Humanos , Microftalmía/genética , Microftalmía/patología , Masculino , Mutación Missense/genética , Atresia de las Coanas/genética , Atresia de las Coanas/patología , Proteínas Cromosómicas no Histona/genética , Niño , Nariz/anomalíasRESUMEN
Craniofacial microsomia (CFM), also known as the oculo-auriculo-vertebral spectrum, is a congenital disorder characterized by hypoplasia of the mandible and external ear due to tissue malformations originating from the first and second branchial arches. However, distinguishing it from other syndromes of branchial arch abnormalities is difficult, and causal variants remain unidentified in many cases. In this report, we performed an exome sequencing analysis of a Brazilian family with CFM. The proband was a 12-month-old boy with clinical findings consistent with the diagnostic criteria for CFM, including unilateral mandibular hypoplasia, microtia, and external auditory canal abnormalities. A heterozygous de novo nonsense variant (c.713C>G, p.S238*) in PUF60 was identified, which was predicted to be pathogenic in silico. PUF60 has been reported as a causal gene in Verheij syndrome, but not in CFM. Although the boy showed craniofacial abnormalities and developmental delay that overlapped with Verheij syndrome, the facial asymmetry with unilateral hypoplasia of the mandible observed in this case did not match the previously reported phenotypes of PUF60 variants. Our findings expand the phenotypic range of PUF60 variants that cover CFM and Verheij syndrome.
Asunto(s)
Síndrome de Goldenhar , Fenotipo , Humanos , Masculino , Síndrome de Goldenhar/genética , Síndrome de Goldenhar/patología , Síndrome de Goldenhar/diagnóstico , Lactante , Factores de Empalme de ARN/genética , Proteínas Represoras/genética , Secuenciación del Exoma , Mandíbula/anomalías , Mandíbula/patología , Linaje , Codón sin Sentido/genéticaRESUMEN
The oculoauriculofrontonasal syndrome (OAFNS) is a rare condition, with unknown etiology, characterized by the association of frontonasal dysplasia (FND) and oculoauriculovertebral spectrum (OAVS). Main clinical findings include widely spaced eyes, epibulbar dermoid, broad nose, mandibular hypoplasia, and preauricular tags. Here, we describe a case series of 32 Brazilian individuals with OAFNS and review the literature ascertaining individuals presenting phenotypes compatible with the diagnosis of OAFNS, aiming to refine the phenotype. This series emphasizes the phenotypic variability of the OAFNS and highlights the occurrence of rare craniofacial clefts as a part of the phenotype. The ectopic nasal bone, a hallmark of OAFNS, was frequent in our series, reinforcing the clinical diagnosis. The absence of recurrence, consanguinity, chromosomal, and genetic abnormalities reinforces the hypothesis of a nontraditional inheritance model. The phenotypic refinement provided by this series contributes to an investigation regarding the etiology of OAFNS.
Asunto(s)
Anomalías del Ojo , Síndrome de Goldenhar , Humanos , Oído Externo/anomalías , Anomalías del Ojo/diagnóstico , Anomalías del Ojo/genética , Columna Vertebral/anomalías , Síndrome de Goldenhar/diagnóstico , FenotipoRESUMEN
INTRODUCTION: Craniofacial clefts are rare congenital anomalies that might involve both soft tissue and skeletal components. The association of Tessier cleft number 3 and 4 with choanal atresia appears to be unusual and only few clinical cases have been reported in published literature. OBJECTIVES: Report a series of 13 cases of choanal atresia in patients with Tessier numbers 3 or 4 clefts and the literature review on this topic. METHODS: A literature review was undertaken via PUBMED database before April 2020 addressing the association between Tessier numbers 3 or 4 clefts and choanal atresia. Retrospective chart review of patients diagnosed with both comorbidities at a tertiary hospital expertised in craniofacial anomalies. RESULTS: Literature review yielded 10 studies describing the relationship between choanal atresia and Tessier 3 and 4 facial clefts. We identified 98 patients diagnosed with medial oro-ocular facial clefts (Tessier 3 and 4) and 119 with choanal atresia at our institution over a 20 years time period. Altogether, 13 individuals were diagnosed with both malformations, 3 patients with number 3 cleft, and 10 patients with number 4 cleft. It represents 13.26% of the cases. CONCLUSION: This study highlights the features of Tessier 3 and 4 facial clefts associated with choanal atresia. Although the publications regarding this association are very scarce, the authors present the largest series of cases of Tessier number 3 and 4 clefts with choanal atresia showing that association between these conditions could be not so unusual.
Asunto(s)
Atresia de las Coanas , Anomalías Craneofaciales , Cara/anomalías , Humanos , Estudios RetrospectivosRESUMEN
Auriculocondylar syndrome (ACS) is a rare craniofacial disorder with mandibular hypoplasia and question-mark ears (QMEs) as major features. QMEs, consisting of a specific defect at the lobe-helix junction, can also occur as an isolated anomaly. Studies in animal models have indicated the essential role of endothelin 1 (EDN1) signaling through the endothelin receptor type A (EDNRA) in patterning the mandibular portion of the first pharyngeal arch. Mutations in the genes coding for phospholipase C, beta 4 (PLCB4) and guanine nucleotide binding protein (G protein), alpha inhibiting activity polypeptide 3 (GNAI3), predicted to function as signal transducers downstream of EDNRA, have recently been reported in ACS. By whole-exome sequencing (WES), we identified a homozygous substitution in a furin cleavage site of the EDN1 proprotein in ACS-affected siblings born to consanguineous parents. WES of two cases with vertical transmission of isolated QMEs revealed a stop mutation in EDN1 in one family and a missense substitution of a highly conserved residue in the mature EDN1 peptide in the other. Targeted sequencing of EDN1 in an ACS individual with related parents identified a fourth, homozygous mutation falling close to the site of cleavage by endothelin-converting enzyme. The different modes of inheritance suggest that the degree of residual EDN1 activity differs depending on the mutation. These findings provide further support for the hypothesis that ACS and QMEs are uniquely caused by disruption of the EDN1-EDNRA signaling pathway.
Asunto(s)
Enfermedades del Oído/genética , Oído/anomalías , Genes Dominantes , Genes Recesivos , Mutación , Fenotipo , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Análisis Mutacional de ADN , Enfermedades del Oído/diagnóstico , Enfermedades del Oído/metabolismo , Endotelina-1/genética , Endotelina-1/metabolismo , Femenino , Genotipo , Humanos , Masculino , Datos de Secuencia Molecular , Linaje , Alineación de Secuencia , Transducción de SeñalRESUMEN
OBJECTIVE: This study analyzed the systemic and oral abnormalities in individuals with Kabuki syndrome (KS) that might be investigated to enhance the early diagnosis and treatment by a multidisciplinary team, minimizing the consequences to the individual's health. STUDY DESIGN: Clinical examination was conducted on 15 individuals to investigate orodental alterations such as tooth abnormalities and cleft lip and/or palate, and the patient records were also reviewed to investigate systemic diseases such as cardiopathies, infectious and immunologic diseases, nephropathies, and delayed neuropsychomotor development. RESULTS: All individuals with KS presented cleft lip and/or palate, 11 (73.34%) tooth abnormalities, 5 (33.34%) congenital cardiopathies, 12 (80%) infectious or immunologic diseases, 1 (6.67%) nephropathy, and 14 (93.34%) had an intellectual disability. CONCLUSION: Individuals with KS often have dental anomalies such as hypodontia, cleft or palate, and systemic disorders such as congenital heart disease and infectious diseases. Intellectual disability is present in most cases. These alterations should be investigated as early as possible to prevent the increase in morbidity in these individuals.
Asunto(s)
Anomalías Múltiples , Cara/anomalías , Enfermedades Vestibulares , Humanos , Femenino , Masculino , Enfermedades Vestibulares/complicaciones , Niño , Preescolar , Adolescente , Anomalías Dentarias , Adulto , Discapacidad Intelectual/complicaciones , Lactante , Fisura del Paladar/complicaciones , Enfermedades Hematológicas/complicacionesRESUMEN
The authors describe on a Brazilian girl with coronal synostosis, facial asymmetry, ptosis, brachydactyly, significant learning difficulties, recurrent scalp infections with marked hair loss, and elevated serum immunoglobulin E. Standard lymphocyte karyotype showed a small additional segment in 7p21[46,XX,add(7)(p21)]. Deletion of the TWIST1 gene, detected by Multiplex Ligation Probe-dependent Amplification (MPLA) and array-CGH, was consistent with phenotype of Saethre-Chotzen syndrome. Array CGH also showed deletion of four other genes at 7p21.1 (SNX13, PRPS1L1, HD9C9, and FERD3L) and the deletion of six genes (CACNA2D2, C3orf18, HEMK1, CISH, MAPKAPK3, and DOCK3) at 3p21.31. Our case reinforces FERD3L as candidate gene for intellectual disability and suggested that genes located in 3p21.3 can be related to hyper IgE phenotype.
Asunto(s)
Acrocefalosindactilia/genética , Aberraciones Cromosómicas , Cromosomas Humanos Par 3 , Cromosomas Humanos Par 7 , Síndrome de Job/genética , Discapacidades para el Aprendizaje/genética , Acrocefalosindactilia/complicaciones , Acrocefalosindactilia/diagnóstico , Niño , Preescolar , Bandeo Cromosómico , Deleción Cromosómica , Hibridación Genómica Comparativa , Facies , Femenino , Humanos , Lactante , Síndrome de Job/complicaciones , Síndrome de Job/diagnóstico , Discapacidades para el Aprendizaje/complicaciones , Discapacidades para el Aprendizaje/diagnóstico , FenotipoRESUMEN
Auriculo-condylar syndrome (ACS) is characterized by typical ears malformation (so-called "question mark" ears), prominent cheeks, microstomia, and abnormality of the temporomandibular joint and condyle of the mandible. In this report we describe a new simplex case and a previously unreported family with affected individuals in three generations documenting clinical variability. Linkage study for markers located in candidate region for ACS1 (1p21.1-q23.3) was excluded in our familial case, reinforcing the hypothesis of genetic heterogeneity for this condition. A review of the literature focusing diagnostic criteria and features of ACS was performed.
Asunto(s)
Enfermedades del Oído/diagnóstico , Enfermedades del Oído/genética , Brasil , Niño , Cromosomas Humanos Par 1/genética , Oído/anomalías , Femenino , Heterogeneidad Genética , Ligamiento Genético , Humanos , Mandíbula/anomalías , Microstomía/genética , Linaje , Articulación Temporomandibular/anomalíasRESUMEN
Most patients with Kabuki syndrome (KS) are the only person in their family with the condition. However, familial cases of KS have been described showing evidence that this syndrome can be inherited as a dominant trait with variable expressivity. We report on two related individuals with facial findings characteristic of KS. The proposita had arched eyebrows, long and upward slanting palpebral fissures, cleft lip and palate, retromicrognathia, brachydactyly of hands and feet, stubby fingers, nail hypoplasia, and prominent finger pads. Her mother had eyebrows with dispersed lateral half, long and upward slanting palpebral fissures, retrognathia, abnormal and posteriorly rotated ears, prominent finger pads, brachydactyly of feet, learning difficulties, and psychomotor development delay. DNA sequencing revealed a novel missense mutation in the MLL2 gene in both the proposita and her mother. The mutation (p.R5432Q) was found in the exon 51, within the SET domain of the gene, which confers methyltransferase activity on the protein. Therefore, the epigenetic and transcriptional regulatory properties of this protein may be altered and this suggests that the mutation is the cause of phenotype observed in both the patient and her mother. The clinical signs and the molecular evidence in this family further support the notion that KS is an autosomal dominant condition with variable expressivity. To our knowledge this is the first report of a Brazilian family with recurrence of this syndrome.
Asunto(s)
Anomalías Múltiples/genética , Proteínas de Unión al ADN/genética , Enfermedades Hematológicas/genética , Proteínas de Neoplasias/genética , Enfermedades Vestibulares/genética , Brasil , Cara/anomalías , Femenino , Humanos , Lactante , Masculino , LinajeRESUMEN
The authors describe the clinical findings observed in a Brazilian girl that are suggestive of microphthalmia and linear skin defects (MLS) also known as MIDAS syndrome (OMIM #309801). She also presented with short stature, agenesis of corpus callosum, cleft palate, enamel defects, and genitourinary anomalies, which are rarely reported within the clinical spectrum of MLS. The 11,5 Mb deletion in Xp22.3p22.2 observed in the patient includes the entire HCCS gene (responsible for the MLS phenotype) and also encompasses several other genes involved with behavioral phenotypes, craniofacial and central nervous system development such as MID1, NLGN4X, AMELX , ARHGAP6, and TBL1X. The whole clinical features of our proband possibly represents an unusual MLS syndromic phenotype caused by an Xp22.3p22.2 continuous gene deletion.
RESUMEN
In this article, we report on a Brazilian female patient born to consanguineous parents and presenting with alobar holoprosencephaly, severe eye involvement, and unusual skin hyperpigmented lesions. She was found to have a mutation (c.2240T > C; p.Val751Gly) in exon 15 of the PTCH1 gene. Mutations in this gene are associated with the nevoid basal cell carcinoma syndrome (NBCCS, OMIM 109400) and, in other instances, with holoprosencephaly (holoprosencephaly-7, OMIM 610828). Severe eye involvement ranging from orbital coloboma to microphthalmia has been seldom reported in patients with NBCCS with PTCH1 mutations. To our knowledge, this is the first report of an individual with central nervous system, skin, and eye manifestations due to a PTCH1 mutation. Mechanisms involved in these multisystem manifestations are discussed.
RESUMEN
Auriculocondylar syndrome is a rare craniofacial disorder comprising core features of micrognathia, condyle dysplasia and question mark ear. Causative variants have been identified in PLCB4, GNAI3 and EDN1, which are predicted to function within the EDN1-EDNRA pathway during early pharyngeal arch patterning. To date, two GNAI3 variants in three families have been reported. Here we report three novel GNAI3 variants, one segregating with affected members in a family previously linked to 1p21.1-q23.3 and two de novo variants in simplex cases. Two variants occur in known functional motifs, the G1 and G4 boxes, and the third variant is one amino acid outside of the G1 box. Structural modeling shows that all five altered GNAI3 residues identified to date cluster in a region involved in GDP/GTP binding. We hypothesize that all GNAI3 variants lead to dominant negative effects.
Asunto(s)
Enfermedades del Oído/genética , Oído/anomalías , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/genética , Variación Genética , Región Branquial/metabolismo , Brasil , Enfermedades del Oído/diagnóstico , Femenino , Humanos , Masculino , Linaje , Fenotipo , Conformación ProteicaRESUMEN
This report describes several relatives in three generations of one family and another, unrelated boy with auriculo-condylar syndrome, a rare autosomal dominant disorder. Variation in the severity of the abnormalities was observed. We discuss the findings in our patients in relation to those in the literature.
Asunto(s)
Oído/anomalías , Región Branquial/anomalías , Niño , Femenino , Humanos , Lactante , Cariotipificación , Masculino , Mandíbula/anomalías , LinajeAsunto(s)
Anomalías Múltiples/patología , Anoftalmos/patología , Nariz/anomalías , Fenotipo , Cráneo/anomalías , Anoftalmos/diagnóstico por imagen , Encéfalo/anomalías , Craneosinostosis/diagnóstico por imagen , Craneosinostosis/patología , Humanos , Lactante , Discapacidad Intelectual/patología , Masculino , Nariz/patología , Índice de Severidad de la Enfermedad , Cráneo/diagnóstico por imagen , Síndrome , UltrasonografíaRESUMEN
Hearing loss constitutes an important category of congenital defects that can be isolated or part of the phenotypic spectrum of several syndromes. A clinical genetic study was performed on a sample of 144 patients with nonsyndromic hearing loss, establishing the sex distribution, type, degree, symmetry, laterality, progression, etiology, and, when possible, inheritance pattern.
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Pérdida Auditiva Conductiva/genética , Perdida Auditiva Conductiva-Sensorineural Mixta/genética , Pérdida Auditiva Sensorineural/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Brasil , Niño , Preescolar , Aberraciones Cromosómicas , Diagnóstico Diferencial , Progresión de la Enfermedad , Femenino , Genes Dominantes , Genes Recesivos , Encuestas Epidemiológicas , Pérdida Auditiva Conductiva/diagnóstico , Pérdida Auditiva Conductiva/etiología , Perdida Auditiva Conductiva-Sensorineural Mixta/diagnóstico , Perdida Auditiva Conductiva-Sensorineural Mixta/etiología , Pérdida Auditiva Sensorineural/diagnóstico , Pérdida Auditiva Sensorineural/etiología , Humanos , Lactante , Masculino , Persona de Mediana Edad , Factores Sexuales , SíndromeRESUMEN
BACKGROUND: Cardio-facial-cutaneous syndrome. AIM: To describe the clinical findings of a patient with cardio-facial-cutaneous syndrome and to characterize her communication. METHOD: To investigate the following areas: genetic, speech-language and hearing, otolaryngological, and psychological. RESULTS: Cardiac, cutaneous, and craniofacial alterations were observed, as well as cognitive deficits and significant language impairment with the absence of oral speech. CONCLUSION: The importance of assessing these patients is highlighted, for diagnostic and intervention purposes, so that the work developed in the speech and language therapy can be better directed.
Asunto(s)
Anomalías Múltiples/diagnóstico , Trastornos de la Articulación/diagnóstico , Anomalías Craneofaciales/diagnóstico , Cardiopatías Congénitas/diagnóstico , Anomalías Cutáneas/diagnóstico , Adulto , Audiometría de Respuesta Evocada , Femenino , Humanos , Síndrome de Noonan/diagnóstico , Emisiones Otoacústicas Espontáneas , SíndromeAsunto(s)
Anomalías Múltiples , Enfermedades del Desarrollo Óseo , Huesos del Pie/anomalías , Huesos de la Mano/anomalías , Trastornos de la Pigmentación , Anomalías Múltiples/patología , Enfermedades del Desarrollo Óseo/patología , Brasil , Preescolar , Femenino , Fibroma/patología , Humanos , Recién Nacido , Trastornos de la Pigmentación/patologíaRESUMEN
Oculoauriculovertebral spectrum (OAVS; OMIM 164210) is a complex condition characterized by defects of aural, oral, mandibular and vertebral development. The aetiology of this condition is likely to be heterogeneous; most cases are sporadic, however, familial cases suggesting autosomal recessive and autosomal dominant inheritance have been reported. In this study, we describe the clinical aspects of nine familial cases with evidence of autosomal dominant inheritance and compare them with reports in the literature. Interfamilial and intrafamilial clinical variabilities were observed in this study (reinforcing the necessity of careful examination of familial members). We suggest that oculoauriculovertebral spectrum with autosomal dominant inheritance is characterized mainly by bilateral auricular involvement and rarely presents extracranial anomalies.