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1.
Medicine (Baltimore) ; 98(42): e17413, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31626096

RESUMO

INTRODUCTION: VACTERL association is an acronym that includes vertebral anomalies (V), anal atresia (A), cardiac defects (C), tracheoesophageal fistula (TEF) or esophageal atresia (EA), renal anomalies (R), and limb defects (L). Airway anomalies have rarely been reported with VACTERL association. PATIENT CONCERNS: A 10-month-old boy who had been diagnosed with anal atresia and received surgical corrections soon after birth consulted our institution by complaining repeated cough and fever. DIAGNOSIS: Diagnosis of VACTERL association was finally made. Bronchoscopy and chest CT with computed tomography angiography confirmed multiple airway abnormalities including bridging bronchus, airway malacia, and complete tracheal rings. INTERVENTIONS: Supplemental oxygen was provided and antibiotics was initiated. OUTCOMES: The patient resolved gradually and was discharged 10 days later. The follow-up showed the patient has remained well just with mild psychomotor retardation. CONCLUSION: Multiple airway anomalies may be seen in VACTERL association. It is worthwhile to make special note for evaluating the tracheobronchial pulmonary system by chest CT and bronchoscopy, especially patients presenting with breathing anomalies.


Assuntos
Canal Anal/anormalidades , Esôfago/anormalidades , Cardiopatias Congênitas/diagnóstico , Rim/anormalidades , Deformidades Congênitas dos Membros/diagnóstico , Coluna Vertebral/anormalidades , Traqueia/anormalidades , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/etiologia , Manuseio das Vias Aéreas/métodos , Broncoscopia , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/terapia , Humanos , Lactente , Deformidades Congênitas dos Membros/complicações , Deformidades Congênitas dos Membros/terapia , Masculino , Oxigenoterapia , Tórax/anormalidades , Tórax/diagnóstico por imagem , Tibet , Tomografia Computadorizada por Raios X
3.
BMJ Case Rep ; 12(4)2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015250

RESUMO

Joubert syndrome (JS) and JS-related disorders are a group of developmental delay, multiple congenital anomalies and complex midbrain-hindbrain malformations. A few cases of JS with multiple pituitary hormone deficiency (MPHD) have been reported in literature. Here, we presented an unusual presentation of JS in a newborn with MPHD. This case is intended to draw attention to the rare association of JS and MDPH by increasing the awareness of this syndrome.


Assuntos
Cerebelo/anormalidades , Anormalidades do Olho/complicações , Terapia de Reposição Hormonal/métodos , Doenças Renais Císticas/complicações , Hormônios Hipofisários/deficiência , Retina/anormalidades , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/tratamento farmacológico , Anormalidades Múltiplas/etiologia , Anormalidades Múltiplas/genética , Assistência ao Convalescente , Encéfalo/diagnóstico por imagem , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/etiologia , Deficiências do Desenvolvimento/genética , Diagnóstico Diferencial , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/tratamento farmacológico , Doenças dos Genitais Masculinos/diagnóstico , Doenças dos Genitais Masculinos/etiologia , Humanos , Hipoglicemia/diagnóstico , Hipoglicemia/etiologia , Recém-Nascido , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/tratamento farmacológico , Imagem por Ressonância Magnética , Masculino , Pênis/anormalidades , Hormônios Hipofisários/metabolismo , Esteroides/administração & dosagem , Esteroides/uso terapêutico , Resultado do Tratamento
4.
J Hum Genet ; 64(6): 561-572, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30858506

RESUMO

Variants have been identified in the embryonic ectoderm development (EED) gene in seven patients with syndromic overgrowth similar to that observed in Weaver syndrome. Here, we present three additional patients with missense variants in the EED gene. All the missense variants reported to date (including the three presented here) have localized to one of seven WD40 domains of the EED protein, which are necessary for interaction with enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2). In addition, among the seven patients reported in the literature and the three new patients presented here, all of the reported pathogenic variants except one occurred at one of four amino acid residues in the EED protein. The recurrence of pathogenic variation at these loci suggests that these residues are functionally important (mutation hotspots). In silico modeling and calculations of the free energy changes resulting from these variants suggested that they not only destabilize the EED protein structure but also adversely affect interactions between EED, EZH2, and/or H3K27me3. These cases help demonstrate the mechanism(s) by which apparently deleterious variants in the EED gene might cause overgrowth and lend further support that amino acid residues in the WD40 domain region may be mutation hotspots.


Assuntos
Anormalidades Múltiplas/genética , Hipotireoidismo Congênito/genética , Anormalidades Craniofaciais/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Deformidades Congênitas da Mão/genética , Histona-Lisina N-Metiltransferase/genética , Complexo Repressor Polycomb 2/genética , Anormalidades Múltiplas/etiologia , Anormalidades Múltiplas/fisiopatologia , Adolescente , Criança , Simulação por Computador , Hipotireoidismo Congênito/etiologia , Hipotireoidismo Congênito/fisiopatologia , Anormalidades Craniofaciais/etiologia , Anormalidades Craniofaciais/fisiopatologia , Proteína Potenciadora do Homólogo 2 de Zeste/química , Feminino , Deformidades Congênitas da Mão/etiologia , Deformidades Congênitas da Mão/fisiopatologia , Histona-Lisina N-Metiltransferase/química , Humanos , Masculino , Simulação de Dinâmica Molecular , Taxa de Mutação , Mutação de Sentido Incorreto/genética , Complexo Repressor Polycomb 2/química , Conformação Proteica , Repetições WD40/genética , Sequenciamento Completo do Exoma
6.
BMC Med Genet ; 20(1): 16, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-30642272

RESUMO

BACKGROUND: KBG syndrome is a very rare autosomal dominant disorder, characterized by macrodontia, distinctive craniofacial findings, skeletal findings, post-natal short stature, and developmental delays, sometimes associated with seizures and EEG abnormalities. So far, there have been over 100 cases of KBG syndrome reported. CASE PRESENTATION: Here, we describe two sisters of a non-consanguineous family, both presenting generalized epilepsy with febrile seizures (GEFS+), and one with a more complex phenotype associated with mild intellectual disability, skeletal and dental anomalies. Whole exome sequencing (WES) analysis in all the family members revealed a heterozygous SCN9A mutation, p.(Lys655Arg), shared among the father and the two probands, and a novel de novo loss of function mutation in the ANKRD11 gene, p.(Tyr1715*), in the proband with the more complex phenotype. The reassessment of the phenotypic features confirmed that the patient fulfilled the proposed diagnostic criteria for KBG syndrome, although complicated by early-onset isolated febrile seizures. EEG abnormalities with or without seizures have been reported previously in some KBG cases. The shared variant, occurring in SCN9A, has been previously found in several individuals with GEFS+ and Dravet syndrome. CONCLUSIONS: This report describe a novel de novo variant in ANKRD11 causing a mild phenotype of KGB syndrome and further supports the association of monogenic pattern of SCN9A mutations with GEFS+. Our data expand the allelic spectrum of ANKRD11 mutations, providing the first Brazilian case of KBG syndrome. Furthermore, this study offers an example of how WES has been instrumental allowing us to better dissect the clinical phenotype under study, which is a multilocus variation aggregating in one proband, rather than a phenotypic expansion associated with a single genomic locus, underscoring the role of multiple rare variants at different loci in the etiology of clinical phenotypes making problematic the diagnostic path. The successful identification of the causal variant in a gene may not be sufficient, making it necessary to identify other variants that fully explain the clinical picture. The prevalence of blended phenotypes from multiple monogenic disorders is currently unknown and will require a systematic re-analysis of large WES datasets for proper diagnosis in daily practice.


Assuntos
Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/genética , Epilepsia Generalizada/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Deficiência Intelectual/genética , Mutação , Fenótipo , Proteínas Repressoras/genética , Convulsões Febris/genética , Anormalidades Dentárias/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/etiologia , Anormalidades Múltiplas/fisiopatologia , Adolescente , Alelos , Doenças do Desenvolvimento Ósseo/diagnóstico por imagem , Doenças do Desenvolvimento Ósseo/etiologia , Doenças do Desenvolvimento Ósseo/fisiopatologia , Brasil , Eletroencefalografia , Epilepsia Generalizada/fisiopatologia , Facies , Feminino , Loci Gênicos , Heterozigoto , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/etiologia , Deficiência Intelectual/fisiopatologia , Canal de Sódio Disparado por Voltagem NAV1.7/genética , Linhagem , Convulsões Febris/fisiopatologia , Anormalidades Dentárias/diagnóstico por imagem , Anormalidades Dentárias/etiologia , Anormalidades Dentárias/fisiopatologia , Sequenciamento Completo do Exoma
7.
Pan Afr Med J ; 30: 219, 2018.
Artigo em Francês | MEDLINE | ID: mdl-30574238

RESUMO

Caudal regression syndrome is a rare malformative syndrome associated, to varying degrees, with agenesis of sacral and coccygeal vertebrae, lower limb shortening and gastrointestinal, genitourinary and cardiovascular abnormalities. Its relationship with gestational diabetes is well established, but its exact cause is poorly established. We here report a rare case of caudal regression syndrome in a 8-month old infant of diabetic mother with polymalformative syndrome and chronic constipation.


Assuntos
Anormalidades Múltiplas/diagnóstico , Constipação Intestinal/etiologia , Gravidez em Diabéticas/fisiopatologia , Anormalidades Múltiplas/etiologia , Anormalidades Múltiplas/fisiopatologia , Doença Crônica , Feminino , Humanos , Lactente , Masculino , Gravidez , Região Sacrococcígea/anormalidades , Síndrome
8.
Am J Med Genet A ; 176(12): 2646-2660, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30548801

RESUMO

Anorectal anomalies (ARA) are common congenital anomalies. The etiology of ARA is unclear and its pathogenesis is controversial. Cases with ARA often have other non-ARA-associated congenital anomalies. The purpose of this study was to assess the prevalence and the types of these associated anomalies in a defined population. The associated anomalies in cases with ARA were collected in all live births, stillbirths, and terminations of pregnancy during 29 years in 387,067 consecutive births in the area covered by our population-based registry of congenital malformations. Of the 202 cases with ARA, representing a prevalence of 5.21 per 10,000, 100 (49.5%) had associated anomalies. There were 7 (3.3%) cases with chromosomal abnormalities, and 31 (15.3%) nonchromosomal recognized dysmorphic conditions, including 17 cases with Vertebral defects, Anal atresia, Cardiac septal defects, esophageal atresia or TracheoEsophageal fistula, Renal anomalies and radial Limb defects association. Sixty two (30.7%) of the cases had nonsyndromic multiple congenital anomalies (MCA). Anomalies in the urogenital, the musculoskeletal, the cardiovascular, the digestive, and the central nervous systems were the most common other anomalies in the cases with MCA. The anomalies associated with ARA could be classified into a recognizable malformation syndrome or pattern in 38 out of the 100 cases (38%) with associated anomalies. This study included special strengths: each affected child was examined by a geneticist, all elective terminations were ascertained, and the surveillance for anomalies was continued until 2 years of age. In conclusion, the overall prevalence of associated anomalies, which was close to one in two cases, emphasizes the need for a routine screening for other anomalies in cases with ARA.


Assuntos
Anormalidades Múltiplas/epidemiologia , Anormalidades Múltiplas/etiologia , Malformações Anorretais/epidemiologia , Malformações Anorretais/etiologia , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/cirurgia , Malformações Anorretais/diagnóstico , Malformações Anorretais/cirurgia , Pré-Escolar , Aberrações Cromossômicas , Feminino , Humanos , Lactente , Recém-Nascido , Nascimento Vivo , Masculino , Razão de Chances , Fenótipo , Vigilância da População , Prevalência , Sistema de Registros , Natimorto
9.
Medicine (Baltimore) ; 97(45): e12822, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30407282

RESUMO

RATIONALE: Vertebral defect, anal atresia, cardiac defect, tracheoesophageal fistula/esophageal atresia, renal defect, and limb defect (VACTERL) association and Müllerian duct anomalies are rare conditions. We present a rare condition with the co-occurrence of the VACTERL association and Müllerian duct hypoplasia to characterize patients' clinical presentations, outcomes, and treatment. PATIENT CONCERNS: An 11-year-old girl presented to our hospital with severe lower abdominal pain, lower vaginal atresia with enlargement of the upper vagina and a bicornuate uterus with a Y-shaped uterine cavity filled with hematometra on pelvic magnetic resonance imaging. Her medical history included congenital anal atresia with a rectovestibular fistula, congenital right renal deficiency, congenital right thumb malformation, and scoliosis. DIAGNOSES: 1. Congenital genital tract malformations, a partial bicornuate uterus, and distal vaginal atresia (U3aC0V4); 2. VACTERL association (congenital anal atresia with rectovestibular fistula, scoliosis with hemi vertebra and butterfly vertebra, unilateral renal agenesis, and finger defect). INTERVENTIONS: Colpotomy, laparoscopic exploration, pelvic adhesiolysis, and hysteroscopy were performed. OUTCOMES: Two months after surgery, a pelvic examination showed an unobstructed vagina which was 10 cm long and 2 fingers wide, without adhesion or constriction. LESSONS: Clinicians should have a high index of suspicion when evaluating patients with genital malformations associated with VACTERL. Early diagnosis of distal vaginal atresia with appropriate surgical intervention decreases long-term morbidity.


Assuntos
Anormalidades Múltiplas/diagnóstico , Canal Anal/anormalidades , Anus Imperfurado/diagnóstico , Esôfago/anormalidades , Cardiopatias Congênitas/diagnóstico , Rim/anormalidades , Deformidades Congênitas dos Membros/diagnóstico , Coluna Vertebral/anormalidades , Traqueia/anormalidades , Útero/anormalidades , Vagina/anormalidades , Anormalidades Múltiplas/etiologia , Adolescente , Anus Imperfurado/etiologia , Feminino , Dedos/anormalidades , Cardiopatias Congênitas/etiologia , Humanos , Deformidades Congênitas dos Membros/etiologia , Fístula Retal/congênito , Escoliose/congênito , Rim Único/congênito
10.
Semin Pediatr Surg ; 27(5): 283-288, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30413258

RESUMO

The development of gastroschisis has long remained an area of interest and controversy. Successive theories about its pathogenesis are herein reviewed and discussed. Two historical assumptions, that omphalocele results from a persistent umbilical hernia, and that gastroschisis does not involve the umbilical cord, are dismissed. Therefore, one can envision gastroschisis for what it is, i.e. a ruptured physiological hernia. The causal agents for this intrauterine accident to occur are yet to be determined. Further bowel damage and complications can be explained by the mesenteric insult.


Assuntos
Gastrosquise/etiologia , Parede Abdominal/embriologia , Anormalidades Múltiplas/etiologia , Gastrosquise/embriologia , Humanos , Fatores de Risco
11.
J Clin Neurosci ; 53: 247-249, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29731280

RESUMO

Klippel-Feil syndrome (KFS) is defined as congenital fusion of two or more cervical vertebrae resulting from a segmentation failure in the developing spine. According to Samartzis et al., the most commonly fused segments are found at C2/3 (74.1%) and C6/7 (70.4%). In patients with C2/3 fusion, especially when there is additional C1 occipitalization, several secondary anomalies including atlantoaxial dislocation (AAD), basilar invagination (BI), Chiari malformation, and syringomyelia can be identified. In this report, we present a case of a 12-year-old patient with C2/3 and occipitalization and a "Full-Spectrum" presentation of associated CVJ abnormalities including C0/1 fusion, AAD, BI, Chiari malformation, syringomyelia, myelopathy and cranial neuropathy received neurological decompression of the cervico-medullary junction by posterior reduction of the AAD and reconstruction of her CVJ using an unconventional hybrid construct due to a high-riding right vertebral artery in C2. To our knowledge, her "Full-Spectrum" presentation may include the most categories of concomitant abnormalities in the literature. In addition, She received neurological decompression of the cervico-medullary junction using an unconventional hybrid construct due to a high-riding vertebral artery in C2. Three months after the surgery, all of her symptoms recovered significantly. Neither Chiari malformation nor syringomyelia could be identified by MRI two years after the surgery. At the last follow-up (4 years), the patient became completely asymptomatic.


Assuntos
Anormalidades Múltiplas/etiologia , Anormalidades Múltiplas/cirurgia , Síndrome de Klippel-Feil/complicações , Síndrome de Klippel-Feil/cirurgia , Anormalidades Múltiplas/patologia , Malformação de Arnold-Chiari/etiologia , Malformação de Arnold-Chiari/cirurgia , Articulação Atlantoaxial/patologia , Articulação Atlantoaxial/cirurgia , Vértebras Cervicais/cirurgia , Criança , Descompressão Cirúrgica/métodos , Feminino , Humanos , Luxações Articulares/etiologia , Luxações Articulares/cirurgia , Síndrome de Klippel-Feil/patologia , Procedimentos Neurocirúrgicos/métodos , Doenças da Medula Espinal/etiologia , Doenças da Medula Espinal/cirurgia , Siringomielia/etiologia , Siringomielia/cirurgia
12.
Neuroradiol J ; 31(4): 403-411, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29260614

RESUMO

Pallister-Killian syndrome (PKS) is a rare chromosomal duplication disorder caused by additional copies of the short arm of chromosome 12 (12p). Clinically PKS is characterized by craniofacial dysmorphism with neonatal frontotemporal alopecia, hypertelorism, and low-set ears as well as kyphoscoliosis, severe intellectual disability, epilepsy, and abnormal muscle tone. Comprehensive high-resolution brain MR findings of PKS in childhood have not been previously illustrated in the medical literature. We present detailed neuroimaging findings from a child with PKS and thoroughly review previously reported structural brain abnormalities in this patient population. MRI abnormalities common to PKS include cerebral volume loss, malformations of cortical development, corpus callosum dysgenesis, white matter disease, and craniofacial malformations. In our patient, new findings of perisylvian with occipital polymicrogyria, vermian dysplasia, brachium pontis signal abnormality, dural anomalies, and unilateral atlas assimilation were noted. Micrencephaly and cortical dysplasia provide a likely explanation for severe intellectual disability and epilepsy in this patient population.


Assuntos
Encéfalo/diagnóstico por imagem , Transtornos Cromossômicos/diagnóstico por imagem , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/etiologia , Anormalidades Múltiplas/terapia , Adolescente , Transtornos Cromossômicos/terapia , Cromossomos Humanos Par 12 , Humanos , Masculino , Neuroimagem
13.
Eur J Pediatr Surg ; 28(2): 176-182, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28061520

RESUMO

BACKGROUND: Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) represents the most common developmental malformation of the upper digestive tract. It is classified into six subtypes according to the classification of Vogt, depending on anatomical variation of this malformation. Around 50% of the patients with EA/TEF present additional anomalies, which often influence, next to the EA/TEF subtype, the overall prognosis of EA/TEF newborns. Here, we investigated the association of the different EA/TEF subtypes with co-occurring congenital anomalies in EA/TEF patients and demonstrate their implications for postnatal diagnostic workup. MATERIALS AND METHODS: We investigated 333 patients of a large German multicenter study born between 1980 and 2012. After evaluation of all available clinical records, 235 patients were included in our analysis. We compared our results with existing data. RESULTS: The highest risk for co-occurring anomalies was seen in patients with most common Vogt 3b (p = 0.024), especially for additional gastrointestinal anomalies (p = 0.04). Co-occurring anomalies of the skin were significantly more common in patients with subtype Vogt 2 (p = 0.024). A significant correlation was observed for an impaired neurodevelopmental outcome and EA/TEF Vogt 3a (p = 0.041). Patients with EA/TEF showed a higher risk to present with any additional congenital anomaly compared with the general population (p < 0.001). CONCLUSION: Our results warrant thorough clinical workup for gastrointestinal anomalies especially in patients with Vogt 3b. Moreover, it might be necessary to focus on a thorough aftercare for neurocognitive development in patients with Vogt 3a. The here presented observations need to be confirmed by future studies.


Assuntos
Anormalidades Múltiplas/epidemiologia , Atresia Esofágica , Fístula Traqueoesofágica , Anormalidades Múltiplas/etiologia , Adolescente , Adulto , Anormalidades Cardiovasculares/epidemiologia , Anormalidades Cardiovasculares/etiologia , Distribuição de Qui-Quadrado , Criança , Pré-Escolar , Anormalidades do Sistema Digestório/epidemiologia , Anormalidades do Sistema Digestório/etiologia , Atresia Esofágica/classificação , Atresia Esofágica/complicações , Atresia Esofágica/epidemiologia , Feminino , Humanos , Masculino , Prevalência , Sistema de Registros , Estudos Retrospectivos , Fístula Traqueoesofágica/classificação , Fístula Traqueoesofágica/complicações , Fístula Traqueoesofágica/epidemiologia , Anormalidades Urogenitais/epidemiologia , Anormalidades Urogenitais/etiologia , Adulto Jovem
14.
Zhongguo Dang Dai Er Ke Za Zhi ; 19(12): 1291-1296, 2017 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-29237532

RESUMO

Infant hemangioma, the most common benign tumor in children, is characterized by rapid proliferation, followed by slower spontaneous involution. However, some patients with facial segmental hemangioma are associated with PHACE syndrome. PHACE syndrome is characterized by vascular nerve and vascular cutaneous lesions of multiple systemic systems, often resulting in structural and functional impairments. Recent studies have demonstrated that the possible pathogeneses of PHACE syndrome mainly include hypoxia, abnormality of mesodermal vascular endothelial cells, genetic abnormality, and abnormality of interstitial mesenchymal stem cells. The current medications for hemangioma with PHACE syndrome include beta blockers, glucocorticoids, and mTOR inhibitors. This review article mainly describes the pathogenesis, diagnoses and treatments of PHACE syndrome, in order to provide directions for diagnosis and treatment of this disorder.


Assuntos
Anormalidades Múltiplas/terapia , Anormalidades do Olho/terapia , Cardiopatias Congênitas/terapia , Hemangioma/terapia , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/etiologia , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/etiologia , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/etiologia , Hemangioma/diagnóstico , Hemangioma/etiologia , Humanos , Lactente
15.
BMJ Case Rep ; 20172017 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-29275387

RESUMO

SLC9A6 gene encodes for a sodium/hydrogen exchanger-6 protein mainly involved in endosomal trafficking and maintaining intraluminal pH. Loss of function mutations in SLC9A6 gene in children has been associated with Christianson syndrome and autism spectrum disorder. We describe a 3-year-old boy with intellectual disability, infantile-onset drug-refractory epilepsy, progressive brain atrophy and large head with a novel missense hemizygous mutation in exon 16 of the SLC9A6 gene on chromosome X. Presence of large head, early developmental regression and progressive cerebral atrophy expand the phenotypic spectrum of SLC9A6 mutations. Our case also highlights the importance of genetic testing in children with unexplained intellectual disability, epilepsy and neurodevelopmental impairments.


Assuntos
Anormalidades Múltiplas/genética , Encéfalo/patologia , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Trocadores de Sódio-Hidrogênio/genética , Anormalidades Múltiplas/etiologia , Atrofia/etiologia , Atrofia/genética , Encéfalo/diagnóstico por imagem , Cefalometria , Pré-Escolar , Anormalidades Craniofaciais/etiologia , Diagnóstico Diferencial , Epilepsia Resistente a Medicamentos/etiologia , Epilepsia Resistente a Medicamentos/genética , Cabeça/patologia , Humanos , Deficiência Intelectual/etiologia , Deficiência Intelectual/genética , Imagem por Ressonância Magnética , Masculino , Mutação , Síndrome
16.
Proc Natl Acad Sci U S A ; 114(43): E9046-E9055, 2017 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-29073101

RESUMO

Kabuki syndrome, a congenital craniofacial disorder, manifests from mutations in an X-linked histone H3 lysine 27 demethylase (UTX/KDM6A) or a H3 lysine 4 methylase (KMT2D). However, the cellular and molecular etiology of histone-modifying enzymes in craniofacial disorders is unknown. We now establish Kabuki syndrome as a neurocristopathy, whereby the majority of clinical features are modeled in mice carrying neural crest (NC) deletion of UTX, including craniofacial dysmorphism, cardiac defects, and postnatal growth retardation. Female UTX NC knockout (FKO) demonstrates enhanced phenotypic severity over males (MKOs), due to partial redundancy with UTY, a Y-chromosome demethylase-dead homolog. Thus, NC cells may require demethylase-independent UTX activity. Consistently, Kabuki causative point mutations upstream of the JmjC domain do not disrupt UTX demethylation. We have isolated primary NC cells at a phenocritical postmigratory timepoint in both FKO and MKO mice, and genome-wide expression and histone profiling have revealed UTX molecular function in establishing appropriate chromatin structure to regulate crucial NC stem-cell signaling pathways. However, the majority of UTX regulated genes do not experience aberrations in H3K27me3 or H3K4me3, implicating alternative roles for UTX in transcriptional control. These findings are substantiated through demethylase-dead knockin mutation of UTX, which supports appropriate facial development.


Assuntos
Anormalidades Múltiplas/etiologia , Face/anormalidades , Doenças Hematológicas/etiologia , Histona Desmetilases/metabolismo , Crista Neural/fisiopatologia , Doenças Vestibulares/etiologia , Animais , Sobrevivência Celular/genética , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Células HEK293 , Histona Desmetilases/genética , Humanos , Lisina/metabolismo , Masculino , Camundongos Knockout , Camundongos Transgênicos , Mutação , Crista Neural/metabolismo , Proteínas Nucleares/genética , Crânio/embriologia
17.
Ann Clin Lab Sci ; 47(3): 357-361, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28667041

RESUMO

Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is a rare disease of functional obstruction affecting the bladder and intestines, characterized by a markedly distended bladder, microcolon, and decreased or absent intestinal peristalsis. Afflicted neonates have very poor prognosis, usually with fatal outcomes in first days to months of life. Placental fetal thrombotic vasculopathy (FTV) is a thrombo-occlusive disorder of the chorionic plate and fetal circulation. Herein, we describe an undocumented association of MMIHS and placental FTV. We present the case of 32-year-old female G4P2-0-1-2, who gave birth to a viable female infant at 35 weeks of gestation via spontaneous vaginal delivery. Fetal MRI, completed at 24 weeks of gestation, revealed a massively distended urinary bladder, bilateral hydronephrosis in the presence of normal amniotic fluid, and poorly visualized bowel loops without meconium extending into the rectum. Given the constellation of these findings, a presumptive diagnosis of MMIHS was established. After birth, the neonate presented with clinical and radiological features consistent with MMIHS. An intact placenta was delivered and macroscopic examination showed numerous thrombi in fetal vasculature. Microscopic examination showed thrombosis and recanulization of fetal vessels in stem villi and histologic changes consistent with placental FTV. Neonatal course was complicated by hypoglycemia, malrotation, anemia, thrombocytopenia, and coagulopathy. The infant was subsequently discharged home with hospice and palliative care. To our knowledge, this is the first case of MMIHS associated with placental FTV documented in the English literature. Our report illustrates the value of pathological examination of the placenta in this rare disease.


Assuntos
Anormalidades Múltiplas/etiologia , Colo/anormalidades , Pseudo-Obstrução Intestinal/etiologia , Doenças Placentárias/etiologia , Bexiga Urinária/anormalidades , Doenças Vasculares/etiologia , Anormalidades Múltiplas/diagnóstico por imagem , Adulto , Colo/diagnóstico por imagem , Feminino , Humanos , Recém-Nascido , Pseudo-Obstrução Intestinal/diagnóstico por imagem , Doenças Placentárias/patologia , Gravidez , Trombose/etiologia , Bexiga Urinária/diagnóstico por imagem
18.
Otol Neurotol ; 38(8): 1081-1084, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28742629

RESUMO

OBJECTIVE: To highlight Noonan syndrome as a clinically recognizable cause of severe to profound sensorineural hearing impairment. STUDY DESIGN: New clinical cases and review. SETTING: Patients evaluated for etiological diagnosis by a medical geneticist in a reference center for hearing impairment. PATIENTS: Five patients presenting with confirmed Noonan syndrome and profound sensorineural hearing impairment. INTERVENTIONS: Diagnostic and review of the literature. RESULTS: Five patients presented with profound sensorineural hearing impairment and molecularly confirmed Noonan syndrome. Sensorineural hearing impairment has been progressive for three patients. Cardiac echography identified pulmonary stenosis in two patients and was normal for the three other patients. Short stature was found in two patients. Mild intellectual disability was found in one patient. Inconspicuous clinical features as facial dysmorphism, cryptorchidism, or easy bruising were of peculiar interest to reach the diagnosis of Noonan syndrome. CONCLUSION: Profound sensorineural hearing impairment can be the main feature of Noonan syndrome. Associated features are highly variable; thus, detailed medical history and careful physical examination are mandatory to consider the diagnosis in case of a sensorineural hearing impairment.


Assuntos
Perda Auditiva Neurossensorial/diagnóstico , Síndrome de Noonan/diagnóstico , Anormalidades Múltiplas/etiologia , Adolescente , Adulto , Estatura , Pré-Escolar , Face/anormalidades , Feminino , Perda Auditiva Neurossensorial/etiologia , Humanos , Lactente , Deficiência Intelectual/etiologia , Masculino , Síndrome de Noonan/complicações , Estenose da Valva Pulmonar/etiologia
19.
J Craniomaxillofac Surg ; 45(8): 1302-1310, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28684073

RESUMO

PURPOSE: Craniofacial microsomia (CFM) is a congenital malformation of structures derived from the first and second pharyngeal arches leading to underdevelopment of the face. However, besides the craniofacial underdevelopment, extracraniofacial anomalies including cardiac, renal and skeletal malformation have been described. The aim of this study is to analyse a large population of patients with regard to demographics, typical phenotypes including craniofacial and extracraniofacial anomalies, and the correlations between the different variables of this condition. MATERIAL AND METHODS: A retrospective study was conducted in patients diagnosed with CFM with available clinical and/or radiographic images. All charts were reviewed for information on demographic, radiographic and diagnostic criteria. The presence of cleft lip/palate and extracraniofacial anomalies were noted. Pearson correlation tests and principal component analysis was performed on the phenotypic variables. RESULTS: A total of 755 patients were included. The male-to-female ratio and right-to-left ratio were both 1.2:1. A correlation was found among Pruzansky-Kaban, orbit and soft tissue. Similar correlations were found between ear and nerve. There was no strong correlation between phenotype and extracraniofacial anomalies. Nevertheless, extracraniofacial anomalies were more frequently seen than in the 'normal' population. Patients with bilateral involvement had a more severe phenotype and a higher incidence of extracraniofacial and cleft lip/palate. CONCLUSION: Outcomes were similar to those of other smaller cohorts. Structures derived from the first pharyngeal arch and the second pharyngeal arch were correlated with degree of severity. Extracraniofacial anomalies were positively correlated with CFM. The findings show that bilaterally affected patients are more severely affected and should be approached more comprehensively.


Assuntos
Anormalidades Múltiplas/etiologia , Síndrome de Goldenhar/complicações , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/epidemiologia , Criança , Feminino , Humanos , Masculino , Estudos Retrospectivos
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