RESUMO
INTRODUCTION: Fibroblast growth factor 10 (FGF10) is a signaling molecule with a well-established role for lung branching morphogenesis. Rare heterozygous, deleterious variants in the FGF10 gene are known causes of the lacrimo-auriculo-dento-digital (LADD) syndrome and aplasia of lacrimal and salivary glands. Previous studies indicate that pathogenic variants in FGF10 can cause childhood Interstitial Lung Disease (chILD) due to severe diffuse developmental disorders of the lung, but detailed reports on clinical presentation and follow-up of affected children are lacking. METHODS: We describe four children with postnatal onset of chILD and heterozygous variants in FGF10, each detected by exome or whole genome sequencing. RESULTS: All children presented with postnatal respiratory failure. Two children died within the first 2 days of life, one patient died at age of 12 years due to right heart failure related to severe pulmonary hypertension (PH) and one patient is alive at age of 6 years, but still symptomatic. Histopathological analysis of lung biopsies from the two children with early postpartum demise revealed diffuse developmental disorder representing acinar dysplasia and interstitial fibrosis. Sequential biopsies of the child with survival until the age of 12 years revealed alveolar simplification and progressive interstitial fibrosis. DISCUSSION: Our report extends the phenotype of FGF10-related disorders to early onset chILD with progressive interstitial lung fibrosis and PH. Therefore, FGF10-related disorder should be considered even without previously described syndromic stigmata in children with postnatal respiratory distress, not only when leading to death in the neonatal period but also in case of persistent respiratory complaints and PH.
Assuntos
Doenças do Aparelho Lacrimal , Doenças Pulmonares Intersticiais , Criança , Humanos , Recém-Nascido , Fator 10 de Crescimento de Fibroblastos/genética , Fibrose , Doenças do Aparelho Lacrimal/genética , Pulmão , Doenças Pulmonares Intersticiais/genéticaRESUMO
At this time, the mechanism causing lacrimal gland dysfunction is not understood completely. In diseases associated with lacrimal gland involvement (Sjogren's syndrome, sarcoidosis, IgG4-associated disease, etc.) patients have been observed to experience elevated cellular apoptosis, active production of autoantibodies to glandular tissue, increased level of pro-inflammatory cytokines, functional disruption of signaling molecules leading to changes in tear production. Difficulties in differential diagnosis of lacrimal gland dysfunction in above-listed diseases are associated, on the one hand, with similarity of the clinical picture of ophthalmological manifestations, and on the other hand - with complicated morphological interpretation of changes in the glandular tissues. In this view, miRNA is a promising diagnostic and prognostic marker that would help with differential diagnosis as well as with choosing the treatment tactics. Methods of molecular profiling and identification of "molecular phenotypes" of lacrimal gland and ocular surface damage will allow the use of miRNA as biomarkers and prognostic factors for personalized treatment.
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Doenças do Aparelho Lacrimal , Aparelho Lacrimal , MicroRNAs , Síndrome de Sjogren , Humanos , Aparelho Lacrimal/patologia , MicroRNAs/genética , MicroRNAs/uso terapêutico , Síndrome de Sjogren/complicações , Doenças do Aparelho Lacrimal/etiologia , Doenças do Aparelho Lacrimal/genética , CitocinasRESUMO
Adenoid cystic carcinoma (ACC) is a biphasic malignant lesion that can develop at various anatomical sites. Salivary and lacrimal ACC lesions have a high risk of local invasion, metastasis, and poor prognosis. In more distant organs, such as the breast, ACC is a rarer and less aggressive lesion. One of the major predictors of mortality of ACC is perineural invasion, which can be seen in 30 % of breast lesions, 85% of salivary lesions, and almost 100 % of lacrimal gland tumors. The biological differences between these three ACC tumors are still poorly understood. We focused on the current understanding of the genetic variations observed on ACC tumors and prognostic differences associated with distinct anatomical sites. A special effort was made to present the currently available therapies alongside the emerging strategies under development.
Assuntos
Carcinoma Adenoide Cístico , Neoplasias Oculares , Doenças do Aparelho Lacrimal , Aparelho Lacrimal , Neoplasias das Glândulas Salivares , Carcinoma Adenoide Cístico/diagnóstico , Carcinoma Adenoide Cístico/genética , Carcinoma Adenoide Cístico/terapia , Neoplasias Oculares/diagnóstico , Neoplasias Oculares/patologia , Neoplasias Oculares/terapia , Humanos , Aparelho Lacrimal/patologia , Doenças do Aparelho Lacrimal/diagnóstico , Doenças do Aparelho Lacrimal/genética , Doenças do Aparelho Lacrimal/terapia , Neoplasias das Glândulas Salivares/diagnóstico , Neoplasias das Glândulas Salivares/genética , Neoplasias das Glândulas Salivares/terapiaRESUMO
Congenital absence or hypoplasia of the major salivary glands is rarely observed and easily overlooked in the clinic. Lacrimo-auriculo-dento-digital syndrome (LADD) is a congenital anomaly disorder that is characterized by aplasia, atresia, or hypoplasia of the lacrimal and salivary glands and caused by FGFR2, FGFR3, or FGF10 gene mutation. Autoimmune polyendocrine syndrome type 1 (APS-I) caused by an AIRE gene mutation is a rare inherited autoimmune disease characterized by chronic mucocutaneous candidiasis, Addison disease, and hypoparathyroidism. However, simultaneous mutations in pathogenic genes of the two syndromes (LADD and APS-I) in one patient is rarely observed. Herein, we have presented a patient with main complaints of xerostomia and xerophthalmia that was diagnosed with LADD syndrome with AIRE mutation.
Assuntos
Doenças do Aparelho Lacrimal , Sindactilia , Anormalidades Dentárias , Humanos , Anormalidades Dentárias/diagnóstico , Anormalidades Dentárias/genética , Anormalidades Dentárias/patologia , Sindactilia/genética , Doenças do Aparelho Lacrimal/genética , MutaçãoRESUMO
The lacrimal gland adenoid cystic carcinoma (LACC) is a major orbital malignancy. The recurrence rate and mortality rate are higher in high proliferation LACC(HP-LACC) compared with low proliferation LACC(LP-LACC). In this study, miRNA microarray was used to explore the differentially expressed miRNAs profiling between HP-LACC and LP-LACC and its potential signaling pathway. Tissues from 17 patients with LACC were collected and made into tissue microarrays. Patients were divided into a high proliferation group and a low proliferation group based on Ki-67 value. HE, immunofluorescence (IF), and Immunohistochemistry (IHC) were performed on the tissue microarrays. Eight LACC tissues(4 HP-LACC and 4 LP-LACC) were made into miRNA microarrays and analyzed for miRNA profiles. Differentially expressed miRNAs were analyzed by volcano plot and heat map. Target gene were predicted using the miRWalk and miRDB for these differentially expressed miRNAs, the intersection of the results are used as targets for further gene ontology and KEGG pathway analysis.The four differentially expressed miRNAs were validated by qRT-PCR, the miRNAs with statistically significant differences validated by dual luciferase reporter and qRT-PCR. Finally, IHC was used for their downstream signaling pathway proteins.HE staining showed the presence of tubular, cribriform, and basaloid structures in LACC. IF showed the presence of CK7,P63 fluorescence expression in all three structures.Patients were divided into HP-LACC and LP-LACC based on Ki-67 median value of 11%. IHC and survival analysis showed with the increase of KI-67 ratio, the proportion of P63 decreased, and the expression of P53 increased. The disease-free survival and overall survival of the patients decreased. IHC and survival analysis showed as Ki-67 expression increased, P63 expression decreased, P53 expression elevated, with prognosis worse. Heat map and volcano plot yielded 15 differentially expressed miRNAs between HP-LACC and LP-LACC.The 15 differential miRNAs were used to predict target genes in miRWalk and miRDB databases respectively, and there were 559 target genes after intersection.559 predicted target genes obtained. Go and KEGG analysis showed that these target genes exerted important biological functions through multiple signaling pathways. Among the 15 differentially expressed miRNAs, miR-29a-3p was verified to be significant by qRT-PCR. Dual luciferase reporter and tissue microarray immunohistochemical assays validated that AKT2 was a direct target gene of miR-29a-3p. Current studies have identified differentially expressed miRNAs associated with LACCs of variable proliferation ability, and found that AKT2 is a direct target gene of miR-29a-3p, which will contribute to target gene therapy in patients with high proliferation LACC in the future.
Assuntos
Carcinoma Adenoide Cístico , Neoplasias Oculares , Doenças do Aparelho Lacrimal , Aparelho Lacrimal , MicroRNAs , Carcinoma Adenoide Cístico/genética , Proliferação de Células , Neoplasias Oculares/genética , Perfilação da Expressão Gênica , Humanos , Antígeno Ki-67/metabolismo , Aparelho Lacrimal/metabolismo , Doenças do Aparelho Lacrimal/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína Supressora de Tumor p53/genéticaRESUMO
Pulmonary acinar hypoplasia (PAH) and lacrimo-auriculo-dento-digital (LADD) syndrome have both been associated with loss-of-function variants in, or deletions of FGF10. Here we report a multi-generational family with seven members manifesting varying features of LADD syndrome, with one individual dying in early infancy of PAH. Whole genome sequencing in one family member identified a 12,158 bp deletion on chromosome 5p12 that removes two of the three exons of FGF10. Allele-specific PCR demonstrated that all affected family members, including the individual with PAH, carried the 12 kb deletion. We conclude the deletion is pathogenic and expands the mutational spectrum of FGF10 variants in LADD syndrome. The common mechanism underlying the variable clinical features of LADD syndrome is defective terminal branching of salivary and lacrimal glands and pulmonary acini, regulated by the TBX4-FGF10-FGFR2 pathway. The variable phenotypic expressivity of FGF10 haploinsufficiency from relatively benign to lethal is likely due to variation at other genetic loci.
Assuntos
Fator 10 de Crescimento de Fibroblastos , Doenças do Aparelho Lacrimal , Sindactilia , Anormalidades Dentárias , Anormalidades Múltiplas , Éxons , Fator 10 de Crescimento de Fibroblastos/genética , Perda Auditiva , Humanos , Doenças do Aparelho Lacrimal/genética , Sindactilia/genética , Anormalidades Dentárias/genéticaRESUMO
The congenital absence of tear production or alacrima is a distinctively unusual clinical sign that harbors a wide variety of etiologies. While alacrima can be only isolated to the lacrimal system, it is more often associated with progressive multisystem involvement from underlying genetic disorders. Recognizing the subtle ocular signs in these diseases will promote a timely diagnosis and management before potential life-threatening consequences occur. Hence, the current article will review the ophthalmological findings, systemic manifestations, genetic associations, and differential diagnosis of congenital alacrima.
Assuntos
Síndromes do Olho Seco , Oftalmopatias Hereditárias , Doenças do Aparelho Lacrimal , Aparelho Lacrimal , Síndromes do Olho Seco/etiologia , Oftalmopatias Hereditárias/complicações , Oftalmopatias Hereditárias/diagnóstico , Humanos , Aparelho Lacrimal/anormalidades , Doenças do Aparelho Lacrimal/complicações , Doenças do Aparelho Lacrimal/diagnóstico , Doenças do Aparelho Lacrimal/genética , LágrimasRESUMO
This study aimed to analyze the role of the FcepsilonRI (FcεRI) signaling pathway in the pathogenesis of benign lymphoepithelial lesion of lacrimal gland (LGBLEL). Transcriptomic analysis was performed on LGBLEL and orbital cavernous hemangioma (CH) patients diagnosed via histopathology in Beijing Tongren Hospital, Capital Medical University, between July 2010 and October 2013. Four LGBLEL and three orbital CH patients, diagnosed between October 2018 and August 2019, were randomly selected as experimental and control groups, respectively. RT-PCR, immunohistochemical staining, and western blotting were used to verify genes and proteins related to the FcεRI signaling pathway. Transcriptomic analysis showed that the FcεRI signaling pathway was upregulated in the LGBLEL compared with the CH group. The mRNA expression levels of important genes including SYK, p38, JNK, PI3K, and ERK were significantly increased in the LGBLEL group (P = 0.0066, P = 0.0002, P = 0.0003, P < 0.0001, P < 0.0001, respectively). Immunohistochemical staining results showed that SYK, p38, and ERK were positively expressed in LGBLEL, while JNK and PI3K were not. The protein contents of P-SYK, P-p38, P-JNK, P-PI3K, and P-ERK were significantly higher in the LGBLEL than in the CH group (P = 0.0169, P = 0.0074, P = 0.0046, P = 0.0157, P = 0.0156, respectively). The FcεRI signaling pathway participates in the pathogenesis of LGBLEL.
Assuntos
Doenças do Aparelho Lacrimal/metabolismo , Doenças do Aparelho Lacrimal/patologia , Aparelho Lacrimal/metabolismo , Aparelho Lacrimal/patologia , Receptores de IgE/metabolismo , Estudos de Casos e Controles , Dacriocistite/genética , Dacriocistite/metabolismo , Dacriocistite/patologia , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Hemangioma Cavernoso/genética , Hemangioma Cavernoso/metabolismo , Hemangioma Cavernoso/patologia , Humanos , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Doenças do Aparelho Lacrimal/genética , Neoplasias Orbitárias/genética , Neoplasias Orbitárias/metabolismo , Neoplasias Orbitárias/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/genéticaRESUMO
PURPOSE: To highlight the increasing importance of gene fusions in the diagnosis, prognosis, and therapy of ocular adnexal tumors. DESIGN: Perspective. METHODS: A focused review of gene fusions, their pathogenic mechanism, and gene fusion detection methods in lacrimal gland and primary orbital and ocular adnexal soft tissue tumors; reappraisal of diagnostic, prognostic, and therapeutic approach to ocular adnexal tumors in light of emerging molecular genetic data. RESULTS: The widespread implementation of fluorescence in situ hybridization and next-generation sequencing methods in pathology practice has led to identification of recurrent gene rearrangements and fusions in a variety of tumors. As a result, molecular genetic methods have become the gold standard for diagnosis of tumors with overlapping histology and immunophenotype, such as small round blue cell tumors. Identification of canonic gene fusions has led to development of sensitive and specific immunohistochemical markers, such as STAT6 in solitary fibrous tumor. In addition to diagnostic accuracy, gene fusions have prognostic implications, such as unfavorable prognosis of PAX3-FOXO1 fusion in alveolar rhabdomyosarcoma. Finally, recognition of gene fusions as a driving mechanism in neoplasia has led to development of U.S. Food and Drug Administration-approved targeted therapies, such as TRK inhibitors for NTRK fusion-positive cancers. CONCLUSION: The discovery of recurrent gene fusions in various tumors, including those involving ocular adnexa, has led to a deeper insight into the molecular mechanisms of these neoplasms, revolutionizing our approach to their diagnosis, prognostication, and therapy.
Assuntos
Neoplasias Oculares/genética , Fusão Gênica/genética , Doenças do Aparelho Lacrimal/genética , Neoplasias Orbitárias/genética , Neoplasias de Tecidos Moles/genética , Biomarcadores Tumorais/genética , Variações do Número de Cópias de DNA , Neoplasias Oculares/diagnóstico , Rearranjo Gênico , Testes Genéticos/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hibridização in Situ Fluorescente , Doenças do Aparelho Lacrimal/diagnóstico , Neoplasias Orbitárias/diagnóstico , Prognóstico , Neoplasias de Tecidos Moles/diagnósticoRESUMO
Ocular perivascular epithelioid cell tumor (PEComa) is exceedingly rare. We reported two examples involving the choroid and subconjunctival tissue, respectively, in patients aged 17 and 20 years. Both tumors comprised packets and sheets of large polygonal cells with moderately pleomorphic nuclei and prominent nucleoli, traversed by delicate fibrovascular septa. Melanin pigmentation was present in one case. The tumors showed HMB45 and TFE3 immunoreactivity. TFE3 gene translocation was confirmed by FISH break-apart probes. RNA seq revealed PRCC-TFE3 and NONO-TFE3 fusions, with the former representing the first description of PRCC-TFE3 in PEComa. Critical reappraisal of the reported cases showed that ocular PEComa frequently affected young patents with melanin pigmentation, frequent TFE3 protein expression, and/or TFE3 gene translocation. No recurrence or metastasis was reported after complete excision despite the presence of cytologic atypia.
Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Biomarcadores Tumorais/genética , Proteínas de Ciclo Celular/genética , Neoplasias da Coroide/genética , Neoplasias Oculares/genética , Fusão Gênica , Doenças do Aparelho Lacrimal/genética , Proteínas de Neoplasias/genética , Neoplasias de Células Epitelioides Perivasculares/genética , Adolescente , Biomarcadores Tumorais/análise , Neoplasias da Coroide/química , Neoplasias da Coroide/patologia , Neoplasias da Coroide/cirurgia , Neoplasias Oculares/química , Neoplasias Oculares/patologia , Neoplasias Oculares/cirurgia , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Doenças do Aparelho Lacrimal/metabolismo , Doenças do Aparelho Lacrimal/patologia , Doenças do Aparelho Lacrimal/cirurgia , Masculino , Melaninas/análise , Neoplasias de Células Epitelioides Perivasculares/química , Neoplasias de Células Epitelioides Perivasculares/patologia , Neoplasias de Células Epitelioides Perivasculares/cirurgia , RNA-Seq , Adulto JovemRESUMO
Purpose: Obstruction of the tear drainage causes a range of ocular surface disorders. Hitherto, the genetics of tear duct development and obstruction has been scarcely explored, and related animal models are lacking. This study aims to study the potential role of the Wnt/PCP pathway mediated by Prickle 1 in tear duct development and diseases. Methods: A severe hypomorphic Prickle 1 mutant was generated. Histology and immunohistochemistry were performed to compare wild type, Prickle 1 hypomorphic, and null mutant tear ducts. In situ hybridization was conducted to identify the signaling components in the developing tear ducts. Three-dimensional (3D) reconstruction was used to detect the human embryonic tear duct. Results: Here, we report that a severe Prickle 1 hypomorph mouse line exhibited epiphora. This phenotype was due to the blockage of the tear drainage by incompletely formed nasolacrimal duct (NLD) and lacrimal canaliculi (LC), which also causes precocious eyelid opening. We observed a dose-dependent requirement of Prickle 1 for tear duct outgrowth. An investigation of the expression of Wnt/PCP core genes demonstrated a subset of PCP signaling components expressed in the developing tear duct. Furthermore, Prickle 1 is not required for the expression of Fgfr2/Fgf10 and p63 genes, which are associated with the NLD and LC hypoplasia in humans. Last, we showed that Prickle 1 expression in the developing tear drainage system is conserved between mice and humans. Conclusions: The study suggests that malformed tear ducts caused by disruption of Prickle 1 underlies the epiphora and precocious eyelid opening.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Anormalidades do Olho/genética , Pálpebras/fisiologia , Proteínas com Domínio LIM/genética , Doenças do Aparelho Lacrimal/genética , Aparelho Lacrimal/anormalidades , Animais , Western Blotting , Anormalidades do Olho/metabolismo , Anormalidades do Olho/fisiopatologia , Proteínas do Olho/metabolismo , Feminino , Humanos , Imageamento Tridimensional , Imuno-Histoquímica , Hibridização In Situ , Aparelho Lacrimal/metabolismo , Aparelho Lacrimal/fisiopatologia , Doenças do Aparelho Lacrimal/metabolismo , Doenças do Aparelho Lacrimal/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Microscopia de Fluorescência , Lágrimas/metabolismo , Via de Sinalização WntRESUMO
BACKGROUND: Lacrimo-auriculo-dento-digital (LADD) syndrome is a rare autosomal dominant disorder caused by mutations in one of the three genes: fibroblast growth factor receptor 2 (FGFR2), FGFR3, or FGF10. Affected patients have hypoplasia/aplasia of lacrimal ducts/glands, hypoplasia/aplasia of salivary glands, dental anomalies, ear anomalies, hearing loss, and digital anomalies. CASE PRESENTATION: Proband was an 11-year-old male with xerostomia, xerophthalmia, and a referring diagnosis of Sjogren syndrome. He presented with microdontia, hypodontia, low-set/cupped ear auricles, and hearing loss in the left ear. METHODS: Whole exome sequencing (WES) was performed on proband. Variations and segregation within the family were verified using Sanger sequencing. RESULTS: Molecular studies revealed a novel heterozygous missense mutation in exon 11 of FGFR2: c.1547C>T (p.Ala516Val), compatible with LADD syndrome. CONCLUSION: To the best of our knowledge, this is the first report of a family with LADD syndrome in Korea. The combination of xerostomia and xerophthalmia, seen in patients with LADD syndrome, may be misdiagnosed as Sjogren syndrome. WES may be a useful clinical tool in ascertaining the affected gene in patients with suspected genetic disorders. Here, a literature review and summary of 23 case reports/series of LADD syndrome are presented, which may help to identify patients with this condition.
Assuntos
Anormalidades Múltiplas/genética , Perda Auditiva/genética , Doenças do Aparelho Lacrimal/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Sindactilia/genética , Anormalidades Dentárias/genética , Anormalidades Múltiplas/diagnóstico , Adulto , Criança , Diagnóstico Diferencial , Perda Auditiva/diagnóstico , Humanos , Doenças do Aparelho Lacrimal/diagnóstico , Masculino , Mutação de Sentido Incorreto , Linhagem , Glândulas Salivares/patologia , Síndrome de Sjogren/diagnóstico , Sindactilia/diagnóstico , Anormalidades Dentárias/diagnósticoRESUMO
NGLY1 deficiency is the first and only autosomal recessive congenital disorder of N-linked deglycosylation (NGLY1-CDDG). To date, no patients with NGLY1 deficiency has been reported from mainland China or East Asia in English literature. Here, we present six patients with a diagnosis of NGLY1-CDDG on the basis of clinical phenotype, genetic testing, and functional studies. We retrospectively analyzed clinical phenotypes and NGLY1 genotypes of six cases from four families. Informed consent was obtained for diagnosis and treatment. In-silico tools and in vitro enzyme activity assays were used to determine pathogenicity of NGLY1 varaints. All patients had typical features of NGLY1-CDDG, including global developmental delay, microcephaly, hypotonia, hypertransaminasemia, alacrimia, and feeding difficulty. Dysmorphic features found in our patients include flat nasal bridge, loose and hollow cheeks, short stature, malnutrition, and ptosis. Pachylosis could be a novel cutaneous feature that may be explained by lack of sweat. We found three novel variants, including one missense (c.982C > G/p.Arg328Gly), one splice site (c.1003+3A > G), and one frame-shift (c.1637-1652delCATCTTTTGCTTATAT/p.Ser546PhefsTer) variant. All mutations were predicted to be disease causing with in-silico prediction tools, and affected at least one feature of gene splicing. Protein modeling showed missense variants may affect covalent bonding within the protein structure, or interrupt active/binding amino-acid residues. In vitro studies indicated that proteins carrying missense variants (p.Arg328Gly and p.Tyr342Cys) lost the enzyme activity. We expanded clinical phenotype and genetic mutation spectrum of NGLY1-CDDG by reporting six cases, three novel variants, and novel clinical features from mainland China.
Assuntos
Defeitos Congênitos da Glicosilação/genética , Deficiências do Desenvolvimento/genética , Oftalmopatias Hereditárias/genética , Transtornos da Alimentação e da Ingestão de Alimentos/genética , Doenças do Aparelho Lacrimal/genética , Microcefalia/genética , Hipotonia Muscular/genética , Mutação , Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/deficiência , Defeitos Congênitos da Glicosilação/patologia , Deficiências do Desenvolvimento/patologia , Oftalmopatias Hereditárias/patologia , Transtornos da Alimentação e da Ingestão de Alimentos/patologia , Feminino , Humanos , Lactente , Doenças do Aparelho Lacrimal/patologia , Masculino , Microcefalia/patologia , Hipotonia Muscular/patologia , Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/genéticaRESUMO
BACKGROUND: Allgrove syndrome (OMIM 231550) is a rare autosomal recessive disease characterized by non-CAH primary adrenal insufficiency (non-CAH PAI), alacrima, and achalasia. It is caused by mutations in the AAAS gene. The syndrome is also associated with variable progressive neurological impairment and dermatological abnormalities. METHODS AND RESULTS: We diagnosed 23 patients from 14 families with Allgrove syndrome, based on the presence of at least two characteristic symptoms, usually adrenal insufficiency and alacrima, between 2008 and 2018. A previously described nonsense variant of AAAS was detected in 19 patients from 12 families at homozygous state. Another novel homozygous mutation (c.394-397delCTGT) in AAAS was detected in four patients from two families. Presenting symptoms were alacrima (23/23; 100%), adrenal insufficiency (18/23; 78%), achalasia (13/23; 57%), short stature/growth retardation (16/23; 70%), hyperreflexia (15/23; 65%), palmoplantar hyperkeratosis (13/23; 57%), hyperpigmentation of the skin (10/23; 43%), hypoglycemia-induced convulsion (7/23; 30%), swallowing difficulty and vomiting (6/23; 26%). Serum DHEAS concentrations were low in all patients (23/23; 100%). CONCLUSIONS: Clinical symptoms vary even among patients carrying the same mutation. Triple A syndrome should be considered in the etiology of non-CAH PAI in Arab populations and in Southeast Turkey. Any child with non-CAH PAI should be evaluated for the presence of alacrima and/or achalasia or family history of alacrima and/or achalasia. Children with alacrima and/or achalasia should also be investigated for adrenal insufficiency. Definitive molecular diagnosis is essential for early diagnosis and management of adrenal insufficiency, neurological symptoms, and growth retardation in patients and early diagnosis of as yet asymptomatic cases in the family, together with genetic counseling.
Assuntos
Insuficiência Adrenal/diagnóstico , Insuficiência Adrenal/genética , Acalasia Esofágica/diagnóstico , Acalasia Esofágica/genética , Adolescente , Insuficiência Adrenal/epidemiologia , Criança , Pré-Escolar , Acalasia Esofágica/epidemiologia , Oftalmopatias Hereditárias/diagnóstico , Oftalmopatias Hereditárias/epidemiologia , Oftalmopatias Hereditárias/genética , Feminino , Humanos , Doenças do Aparelho Lacrimal/diagnóstico , Doenças do Aparelho Lacrimal/epidemiologia , Doenças do Aparelho Lacrimal/genética , Masculino , Mutação/genética , Turquia/epidemiologiaRESUMO
Patients with pathogenic mutations in NGLY1 cannot make tears and have global developmental delay and liver dysfunction. Traditionally, NGLY1 cleaves intact N-glycans from misfolded, retrotranslocated glycoproteins before proteasomal degradation. We demonstrate that Ngly1-null mouse embryonic fibroblasts, NGLY1 knockout human cells, and patient fibroblasts are resistant to hypotonic lysis. Ngly1-deficient mouse embryonic fibroblasts swell slower and have reduced aquaporin1 mRNA and protein expression. Ngly1 knockdown and overexpression confirms that Ngly1 regulates aquaporin1 and hypotonic cell lysis. Patient fibroblasts and NGLY1 knockout cells show reduced aquaporin11 mRNA, supporting NGLY1 as regulating expression of multiple aquaporins across species. Complementing Ngly1-deficient cells with catalytically inactive NGLY1 (p.Cys309Ala) restores normal hypotonic lysis and aquaporin1 protein. We show that transcription factors Atf1/Creb1 regulate aquaporin1 and that the Atf1/Creb1 signaling pathway is disrupted in Ngly1-deficient mouse embryonic fibroblasts. These results identify a non-enzymatic, regulatory function of NGLY1 in aquaporin transcription, possibly related to alacrima and neurological symptoms.
Assuntos
Aquaporina 1/genética , Aquaporinas/genética , Defeitos Congênitos da Glicosilação/genética , Oftalmopatias Hereditárias/genética , Doenças do Aparelho Lacrimal/genética , Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/deficiência , Transcrição Gênica , Fator 1 Ativador da Transcrição/genética , Fator 1 Ativador da Transcrição/metabolismo , Animais , Aquaporina 1/metabolismo , Aquaporinas/metabolismo , Linhagem Celular , Defeitos Congênitos da Glicosilação/metabolismo , Defeitos Congênitos da Glicosilação/patologia , Oftalmopatias Hereditárias/metabolismo , Oftalmopatias Hereditárias/patologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Regulação da Expressão Gênica , Teste de Complementação Genética , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/genética , Isoenzimas/metabolismo , Doenças do Aparelho Lacrimal/metabolismo , Doenças do Aparelho Lacrimal/patologia , Camundongos , Camundongos Knockout , Osmose , Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/antagonistas & inibidores , Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/genética , Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/metabolismo , Polissacarídeos/metabolismo , Cultura Primária de Células , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de SinaisRESUMO
Claudins are key components of the tight junction, sealing the paracellular cleft or composing size-, charge- and water-selective paracellular channels. Claudin-10 occurs in two major isoforms, claudin-10a and claudin-10b, which constitute paracellular anion or cation channels, respectively. For several years after the discovery of claudin-10, its functional relevance in men has remained elusive. Within the past two years, several studies appeared, describing patients with different pathogenic variants of the CLDN10 gene. Patients presented with dysfunction of kidney, exocrine glands and skin. This review summarizes and compares the recently published studies reporting on a novel autosomal-recessive disorder based on claudin-10 mutations.
Assuntos
Claudinas/genética , Claudinas/metabolismo , Nefropatias/genética , Mutação , Predisposição Genética para Doença , Humanos , Hipo-Hidrose/genética , Ictiose/genética , Nefropatias/metabolismo , Doenças do Aparelho Lacrimal/genética , Domínios Proteicos , Xerostomia/genéticaRESUMO
The skeletal structure of the mammalian middle ear, which is composed of three endochondral ossicles suspended within a membranous air-filled capsule, plays a critical role in conducting sound. Gene mutations that alter skeletal development in the middle ear result in auditory impairment. Mutations in fibroblast growth factor receptor 2 (FGFR2), an important regulator of endochondral and intramembranous bone formation, cause a spectrum of congenital skeletal disorders featuring conductive hearing loss. Although the middle ear malformations in multiple FGFR2 gain-of-function disorders are clinically characterized, those in the FGFR2 loss-of-function disorder lacrimo-auriculo-dento-digital (LADD) syndrome are relatively undescribed. To better understand conductive hearing loss in LADD, we examined the middle ear skeleton of mice with conditional loss of Fgfr2. We find that decreased auditory function in Fgfr2 mutant mice correlates with hypoplasia of the auditory bulla and ectopic bone growth at sites of tendon/ligament attachment. We show that ectopic bone associated with the intra-articular ligaments of the incudomalleal joint is derived from Scx-expressing cells and preceded by decreased expression of the joint progenitor marker Gdf5. Together, these results identify a role for Fgfr2 in development of the middle ear skeletal tissues and suggest potential causes for conductive hearing loss in LADD syndrome.
Assuntos
Anormalidades Múltiplas/genética , Orelha Média/metabolismo , Perda Auditiva/genética , Doenças do Aparelho Lacrimal/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Sindactilia/genética , Anormalidades Dentárias/genética , Animais , Desenvolvimento Ósseo , Orelha Média/anormalidades , Orelha Média/embriologia , Fator 5 de Diferenciação de Crescimento/metabolismo , Mutação com Perda de Função , Camundongos , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genéticaRESUMO
PURPOSE: Secretory carcinoma has been described in the breast, salivary glands, skin, and other organs, but has not been reported in the lacrimal gland to date. Since lacrimal and salivary glands show similar tumors, we hypothesized that lacrimal secretory carcinoma may exist but has been misclassified in the past. DESIGN: We undertook a retrospective review of all lacrimal gland tumors at 2 tertiary institutions with centralized ocular pathology practices. METHODS: A total of 350 lacrimal tumors were reviewed by the authors. Candidate tumors were tested for ETV-NTRK rearrangement by fluorescence in situ hybridization and the presence of the translocation was confirmed by next-generation sequencing. RESULTS: We identified a single case of secretory carcinoma. The diagnosis was confirmed by demonstrating specific immunohistochemical profile and the presence of ETV6-NTRK3 gene fusion, which is characteristic of secretory carcinoma of other sites. The tumor occurred in a young man who was treated with surgery alone with no recurrence during 12 years of follow-up. CONCLUSION: Secretory carcinoma is a new lacrimal gland carcinoma type that should be added to the spectrum of low-grade lacrimal gland tumors.
Assuntos
Carcinoma/diagnóstico , Neoplasias Oculares/diagnóstico , Doenças do Aparelho Lacrimal/diagnóstico , Adulto , Biomarcadores Tumorais/genética , Carcinoma/genética , Carcinoma/cirurgia , Neoplasias Oculares/genética , Neoplasias Oculares/cirurgia , Rearranjo Gênico/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Técnicas Imunoenzimáticas , Hibridização in Situ Fluorescente , Doenças do Aparelho Lacrimal/genética , Doenças do Aparelho Lacrimal/cirurgia , Masculino , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Estudos Retrospectivos , Tomografia Computadorizada por Raios XAssuntos
Neoplasias Oculares/patologia , Doenças do Aparelho Lacrimal/patologia , Antígenos de Neoplasias/genética , Biomarcadores Tumorais , Neoplasias Oculares/diagnóstico por imagem , Neoplasias Oculares/genética , Neoplasias Oculares/cirurgia , Humanos , Doenças do Aparelho Lacrimal/diagnóstico por imagem , Doenças do Aparelho Lacrimal/genética , Doenças do Aparelho Lacrimal/cirurgia , Proteínas de Neoplasias/genéticaRESUMO
PURPOSE: Lacrimal gland tumours constitute a wide spectrum of neoplastic lesions that are histologically similar to tumours of the salivary gland. In the salivary gland, pleomorphic adenoma (PA) is frequently characterized by recurrent chromosomal rearrangements of the PLAG1 and HMGA2 genes, a genetic feature retained in carcinoma ex pleomorphic adenoma (ca-ex-PA) that makes it possible to distinguish ca-ex-PA from de novo carcinomas. However, whether PLAG1 and HMGA2 gene rearrangements are found in lacrimal gland PA and ca-ex-PA is not known. METHODS: Twenty-one lacrimal gland PAs and four ca-ex-PAs were retrospectively reviewed and subjected to break-apart fluorescence in situ hybridization (FISH) for rearrangements of the PLAG1 gene. Cases without PLAG1 abnormalities were subjected to HMGA2 break-apart FISH. Immunohistochemical staining for PLAG1 and HMGA2 protein was performed and correlated with gene status. RESULTS: Sixteen of 21 PAs showed rearrangement of PLAG1 and were all positive for PLAG1 protein. Two of the remaining five PAs showed rearrangement of HMGA2 and were the only cases positive for HMGA2 with immunohistochemistry. The three FISH-negative PAs expressed PLAG1 protein. All four ca-ex-PAs showed rearrangement of PLAG1 and expressed PLAG1 protein. None of the de novo carcinomas showed rearrangement of either of the two genes or expression of the two proteins. CONCLUSION: Rearrangement of PLAG1 and HMGA2 and expression of the corresponding proteins are frequent and specific findings in lacrimal gland PA and ca-ex-PA. The mechanism for PLAG1 overexpression in FISH-negative PAs is yet to be clarified.