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Renal cystic diseases are common conditions whose etiology can be highly heterogeneous. They require a correct approach for adequate diagnosis and management. We aimed to illustrate part of the spectrum of renal cystic diseases through some clinical cases managed in our service. We describe 11 clinical cases including clinical entities such as renal multicystic dysplasia, and autosomal dominant and autosomal recessive polycystic renal disease, among other pathologies. Renal cystic diseases are heterogeneous in their clinical presentation, natural history, radiological findings, and genetic and pathophysiological basis. An integral clinical approach is needed to get a clear etiological diagnosis and offer adequate individualized care and follow-up for patients.
Las enfermedades quísticas renales son condiciones frecuentes cuya etiología puede ser muy heterogénea, por lo que se requiere un adecuado abordaje para su diagnóstico y manejo. El objetivo de este trabajo fue ilustrar parte del espectro de la enfermedad renal quística por medio de casos clínicos manejados en la Fundación Valle del Lili. Se describen 11 casos clínicos que incluyen enfermedades como displasia multiquística renal, enfermedad poliquística renal autosómica dominante y autosómica recesiva, entre otras. Las enfermedades quísticas renales varían en su presentación clínica, historia natural, hallazgos imagenológicos, bases genéticas y fisiopatológicas, por consiguiente, el enfoque diagnóstico y el manejo integral se debe realizar de forma individualizada y con un abordaje multidisciplinario.
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Enfermedades Renales Quísticas , Humanos , Niño , Masculino , Enfermedades Renales Quísticas/genética , Enfermedades Renales Quísticas/diagnóstico por imagen , Femenino , Preescolar , Lactante , Adolescente , Riñón Poliquístico Autosómico Dominante/genética , Riñón Poliquístico Autosómico Dominante/diagnóstico por imagen , Riñón Poliquístico Autosómico Recesivo/genética , Riñón Poliquístico Autosómico Recesivo/diagnóstico por imagen , Riñón Displástico Multiquístico/genética , Riñón Displástico Multiquístico/diagnóstico por imagenRESUMEN
A six-year-old girl with restrictive cardiomyopathy and hypertrabeculation, due to the early onset of her disease, whole exome sequencing was conducted, revealing the presence of a novel heterozygous missense variant in the FLNC gene. The same gene variant was also identified in her father, who, at an adult age, displayed normal imaging results and was symptom-free. This variant has not been reported in population databases or current medical literature and is classified as likely pathogenic.
Menina de seis anos com cardiomiopatia restritiva e hipertrabeculação na qual, devido ao início precoce da doença, foi realizado sequenciamento completo do exoma, revelando a presença de uma nova variante heterozigótica missense no gene FLNC. A mesma variante genética também foi identificada em seu pai, que, já adulto, apresentava resultados de imagem normais e não apresentava sintomas. Esta variante não foi relatada em bancos de dados populacionais ou na literatura médica atual e é classificada como provavelmente patogênica.
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Cardiomiopatía Restrictiva , Mutación Missense , Humanos , Femenino , Cardiomiopatía Restrictiva/genética , Niño , Secuenciación del Exoma , LinajeRESUMEN
Introduction: To date, approximately 600 unique pathogenic variants have been reported in COL3A1 associated with vascular Ehlers-Danlos syndrome (vEDS). The objective of this study was to describe a patient with a novel variant in COL3A1 associated with vEDS. Case report: We describe the clinical history and thorough phenotyping of a patient with brain aneurysms and identified a novel pathogenic variant in COL3A1. This male patient reported transient focal neurologic symptoms. Physical examination showed abnormal atrophic scarring, horizontal stretch marks under the arms, and an acrogeric appearance of the skin of the hands and feet. Brain imaging revealed extensive dilation of both internal carotids and the vertebrobasilar system. Molecular analysis identified a variant in COL3A1 (NM_000090.4):c.3058G>T p.(Gly1020Cys), which was classified as likely pathogenic. Currently, the patient has never had an event concerning dissection/rupture of tissues that could be affected in this condition. Conclusion: This report demonstrates that exhaustive evaluation with clinical and genetic approaches should be considered in patients with vascular abnormalities. vEDS has a variable clinical presentation and often goes unrecognized, even though it is related to life-threatening complications and a shortened life expectancy. Diagnosis confirmed by genetic testing is crucial to determining appropriate surveillance, prevention, treatment, and genetic counseling.
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Mutations in the lecithin-cholesterol acyltransferase (LCAT) gene, which catalyzes the esterification of cholesterol, result in two types of autosomal recessive disorders: Familial LCAT deficiency (FLD) and Fish Eye Disease (FED). While both phenotypes are characterized by corneal opacities and different forms of dyslipidemia, such as low levels of high-density lipoprotein-cholesterol (HDL-C), FLD exhibits more severe clinical manifestations like splenomegaly, anemia, and renal failure. We describe the first clinically and genetically confirmed case of FLD in Colombia which corresponds to a 46-year-old woman with corneal opacity, hypothyroidism, and dyslipidemia, who does not have any manifestations of renal failure, with two pathogenic heterozygous missense variants in the LCAT gene: LCAT (NM_000229.2):c.803G>A (p.Arg268His) and LCAT (NM_000229.2):c.368G>C (p.Arg123Pro). In silico analysis of the mutations predicted the physicochemical properties of the mutated protein, causing instability and potentially decreased LCAT function. These compound mutations highlight the clinical heterogeneity of the phenotypes associated with LCAT gene mutations.
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Abstract Familial chylomicronemia syndrome (FCS) is an autosomal recessive disorder, characterized by alterations in the catabolism of chylomicrons and by increased levels of plasma triglycerides. It has been shown that about 60-90% of FCS patients have biallelic mutations in the LPL gene and the remaining patients have mutations in genes encoding proteins closely related to LPL function. The objective of this manuscript is to illustrate the different clinical scenarios of FCS presentation, and to guide practitioners on the usefulness of genetic tests in each of them. To this end, several published papers about recommendations for the diagnosis of FCS are discussed briefly, in addition to the presentation of several hypothetical cases, highlighting different clinical presentations and possible associated genetic findings. These cases illustrate the multiplicity of potential aspects of family history, clinical manifestations, biochemical parameters, and patterns of genetic variants found in genomic analyses of FCS.
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Resumo Menina de seis anos com cardiomiopatia restritiva e hipertrabeculação na qual, devido ao início precoce da doença, foi realizado sequenciamento completo do exoma, revelando a presença de uma nova variante heterozigótica missense no gene FLNC. A mesma variante genética também foi identificada em seu pai, que, já adulto, apresentava resultados de imagem normais e não apresentava sintomas. Esta variante não foi relatada em bancos de dados populacionais ou na literatura médica atual e é classificada como provavelmente patogênica.
Abstract A six-year-old girl with restrictive cardiomyopathy and hypertrabeculation, due to the early onset of her disease, whole exome sequencing was conducted, revealing the presence of a novel heterozygous missense variant in the FLNC gene. The same gene variant was also identified in her father, who, at an adult age, displayed normal imaging results and was symptom-free. This variant has not been reported in population databases or current medical literature and is classified as likely pathogenic.
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INTRODUCTION: Joubert syndrome is a rare disease of genetic origin with autosomal recessive inheritance and extreme genetic heterogeneity with more than 40 causative genes. Joubert syndrome 7 is caused by mutations in the RPGRIP1L gene. PATIENT CONCERNS: Our report describes a pediatric patient with clinical features compatible with JS type 7 such as hypotonia, developmental delay and aplasia of the cerebellar vermis. DIAGNOSIS: The clinical features and the MRI of the head and neck which showed alterations at the level of the posterior fossa, with absence of the vermis and horizontal disposition of the cerebellar peduncles, were compatible with Joubert syndrome. Whole exome sequencing detected the variants RPGRIP1L (NM_015272.2) c.697Aâ >â T (p. Lys233Ter) and RPGRIP1L (NM_015272.2) c.3545 del (p.Pro1182LeufsTer25). INTERVENTIONS: Resection was performed to correct the polydactyly. At age 2 years umbilical hernia, adenoid surgery and ventilatory tubes surgery were performed. Renal biopsy confirmed interstitial fibrosis and focally accentuated mild tubular atrophy with focal tubular hypertrophy, compatible with the clinical suspicion of Joubert syndrome. Congenital hip dislocation surgery was performed. The patient underwent surgery for correction of concomitant divergent strabismus and continued with glasses for astigmatism and hyperopia. OUTCOMES: Sanger sequencing confirmed the patient´s results and the father was found to be a carrier of RPGRIP1L (NM_015272.2) c.697Aâ >â T (p. Lys233Ter) and the mother and maternal grandmother as carriers of RPGRIP1L (NM_015272.2) c.3545del (p.Pro1182LeufsTer25). RPGRIP1L:c.3545del novel variant is a deletion which changes the reading frame, altering the RPGR1_C terminal domain and giving rise to an incomplete protein whose functions will be altered. CONCLUSION: This is the first genetically confirmed case of JS in Colombia, the first carrier of biallelic RPGRIP1L gene mutations with hip dislocation and incomplete glottic closure and the first report of the novel c.3545del likely pathogenic variant causing JS.
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Anomalías Múltiples , Anomalías del Ojo , Enfermedades Renales Quísticas , Enfermedades Renales , Preescolar , Humanos , Anomalías Múltiples/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Cerebelo/patología , Anomalías del Ojo/genética , Anomalías del Ojo/patología , Enfermedades Renales/patología , Enfermedades Renales Quísticas/genética , Enfermedades Renales Quísticas/patología , Mutación , Retina/anomalíasRESUMEN
Background: Schimke immune-osseous dysplasia (SIOD) is an ultra-rare multisystemic, monogenic, and autosomal recessive inherited disease caused by biallelic mutations in the SMARCAL1 gene. Approximately 100 cases have been reported worldwide. The disease is characterized by skeletal, renal, and immunological abnormalities. Case description: This is a 6-year-old female patient who debuted with nephrotic syndrome at five years of age, with a switch to corticosteroid resistance and poor response to immunosuppressive treatment received. The patient was admitted and referred to our institution due to convulsive status. During her hospitalization, thrombosis was found in the left renal vein, and a renal biopsy report of Collapsing Focal and Segmental Glomerulosclerosis (FSGS) was obtained. The patient had multiple infections during hospitalization, with T lymphocyte lymphopenia and severe IgG hypogammaglobulinemia. Additionally, given dysmorphic facies, delayed weight-height development, and spondyloepiphyseal dysplasia, exome sequencing was performed, finding an homozygous pathogenic variant c.1933Câ¯>â¯T p.Arg645Cys in SMARCAL1, compatible with the diagnosis of SIOD. Discussion: We present the case of a patient that exhibited a severe phenotype of the disease, with skeletal, renal, severe combined immunological compromise and cerebrovascular involvement during follow-up, and the available proposed mechanisms of the disease focused on the clinical manifestations of this patient. It is the first case of SIOD reported in Colombia and the first comprehensive characterization reported in the literature of a patient with homozygosity of the known variant c.1933Câ¯>â¯T p.Arg645Cys. Conclusion: A severe phenotype of the disease with cerebrovascular involvement by homozygosity of the known variant c.1933Câ¯>â¯T p.Arg645Cys in the SMARCAL1 gene can be expected.
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Zhu-Tokita-Takenouchi-Kim syndrome is a multisystem disorder resulting from haploinsufficiency in the SON gene, which is characterized by developmental delay/intellectual disability, seizures, facial dysmorphism, short stature, and congenital malformations, primarily in the central nervous system, along with ophthalmic, dental, pulmonary, cardiologic, renal, gastrointestinal, and musculoskeletal anomalies. In this study, we describe the first Colombian patient with ZTT harboring a novel mutation that has not been previously reported and review the clinical and molecular features of previously reported patients in the literature.
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Congenital muscular dystrophy type 1A (CMD1A) is a rare autosomal recessive disorder caused by mutations in the LAMA2 gene. CMD1A is characterized by peripheral hypotonia and muscle weakness from the first months of life, cerebral white matter abnormalities, and elevated creatine phosphokinase (CPK) levels. We describe an 8-year-old girl from Colombia with clinical features compatible with CMD1A, severe scoliosis corrected with surgery, and feeding difficulty corrected with a gastrostomy. Whole-exome sequencing identified two heterozygous variants: a reported nonsense variant (LAMA2 NM_000426.3:c.4198C>T) and a novel likely pathogenic variant (LAMA2 NM_000426.3:c.9227_9243dup). This is the first genetically confirmed case of CMD1A in Colombia and the first report of the c.9227_9243dup variant causing CMD1A.
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Alleles in the VKORC1, CYP2C9, and CYP4F2 genes can influence Warfarin dose requirement. We aimed to determine the frequency of the polymorphisms in these genes in healthy individuals from Cali, Colombia. Observational study where total blood was collected from 107 healthy donors who attended a higher educational institution in Cali, Colombia. Sanger sequencing of exons 2, 3, 5, and 7 of the CYP2C9 gene; the common promoter region of CYP (rs12777823); exon 11 of CPY4F2 and the polymorphism c.-1639G > A in the VKORC1 gene promoter was performed. CYP2C9*2, CYP2C9*3, CYP2C9*8, CYP2C9*9, CYP2C9*11, CYP4F2*3, rs12777823, and VKORC1*2 were detected. The latter had the highest frequency with 80 (74.8%) participants in a heterozygous or homozygous state. The least frequent allele was CYP2C9*11 with only 1 carrier. Combined haplotypes (VKORC1 *1/*2 or *2/*2 and CYP2C9 *1/*2 or *2/*2) were identified in 14 (13.7%) subjects. Both frequencies found in the VKORC1 and CYP2C9 alleles were similar to the ones reported for Latin Americans of European and Native American Ancestry. VKORC1*2 allele, the main genetic contributor to Warfarin dosing requirement, was the variant with the highest frequency (74.8% subjects, with a frequency of the alternative allele (A) of 50%). Our findings provide researchers with a greater insight regarding the frequency of common polymorphisms that affect anticoagulation treatment in the Cali (Colombia) population.
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Anticoagulantes , Warfarina , Humanos , Warfarina/uso terapéutico , Citocromo P-450 CYP2C9/genética , Anticoagulantes/uso terapéutico , Colombia , Frecuencia de los Genes , Familia 4 del Citocromo P450/genética , Vitamina K Epóxido Reductasas/genética , GenotipoRESUMEN
SETD2 belongs to the family of histone methyltransferase proteins and has been associated with three nosologically distinct entities with different clinical and molecular features: Luscan-Lumish syndrome (LLS), intellectual developmental disorder, autosomal dominant 70 (MRD70), and Rabin-Pappas syndrome (RAPAS). LLS [MIM #616831] is an overgrowth disorder with multisystem involvement including intellectual disability, speech delay, autism spectrum disorder (ASD), macrocephaly, tall stature, and motor delay. RAPAS [MIM #6201551] is a recently reported multisystemic disorder characterized by severely impaired global and intellectual development, hypotonia, feeding difficulties with failure to thrive, microcephaly, and dysmorphic facial features. Other neurologic findings may include seizures, hearing loss, ophthalmologic defects, and brain imaging abnormalities. There is variable involvement of other organ systems, including skeletal, genitourinary, cardiac, and potentially endocrine. Three patients who carried the missense variant p.Arg1740Gln in SETD2 were reported with a moderately impaired intellectual disability, speech difficulties, and behavioral abnormalities. More variable findings included hypotonia and dysmorphic features. Due to the differences with the two previous phenotypes, this association was then named intellectual developmental disorder, autosomal dominant 70 [MIM 620157]. These three disorders seem to be allelic and are caused either by loss-of-function, gain-of-function, or missense variants in the SETD2 gene. Here we describe 18 new patients with variants in SETD2, most of them with the LLS phenotype, and reviewed 33 additional patients with variants in SETD2 that have been previously reported in the scientific literature. This article offers an expansion of the number of reported individuals with LLS and highlights the clinical features and the similarities and differences among the three phenotypes associated with SETD2.
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Trastorno del Espectro Autista , Discapacidad Intelectual , Humanos , Trastorno del Espectro Autista/genética , Discapacidad Intelectual/genética , Hipotonía Muscular/genética , Fenotipo , SíndromeRESUMEN
INTRODUCTION: Wilson disease is characterized by an alteration in copper metabolism that causes its accumulation in different tissues. Its diagnosis is established by the combination of clinical manifestations and paraclinical and genetic studies. Bruton agammaglobulinemia is an X-linked recessive hereditary disease belonging to the group of primary immunodeficiencies and is produced by mutation in the Bruton tyrosine kinase (BTK) gene. CASE REPORT: A 14-year-old Colombian patient with clinical characteristics of Bruton agammaglobulinemia presented with liver disease and clinically and molecularly diagnosed with Wilson disease. DISCUSSION: Bruton agammaglobulinemia and Wilson disease are considered rare diseases because of their low prevalence. We report for the first time a pediatric patient from southwestern Colombia presenting with both entities, and diagnosed clinically and molecularly, an association so far not reported in the literature.
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Agammaglobulinemia , Enfermedades Genéticas Ligadas al Cromosoma X , Degeneración Hepatolenticular , Adolescente , Humanos , Agammaglobulinemia Tirosina Quinasa/genética , Agammaglobulinemia/diagnóstico , Agammaglobulinemia/genética , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Degeneración Hepatolenticular/diagnóstico , Degeneración Hepatolenticular/genética , Mutación/genética , Proteínas Tirosina Quinasas/genéticaRESUMEN
Introduction: Wilson disease is characterized by an alteration in copper metabolism that causes its accumulation in different tissues. Its diagnosis is established by the combination of clinical manifestations and paraclinical and genetic studies. Bruton agammaglobulinemia is an X-linked recessive hereditary disease belonging to the group of primary immunodeficiencies and is produced by mutation in the Bruton tyrosine kinase (BTK) gene. Case report: A 14-year-old Colombian patient with clinical characteristics of Bruton agammaglobulinemia presented with liver disease and clinically and molecularly diagnosed with Wilson disease. Discussion: Bruton agammaglobulinemia and Wilson disease are considered rare diseases because of their low prevalence. We report for the first time a pediatric patient from southwestern Colombia presenting with both entities, and diagnosed clinically and molecularly, an association so far not reported in the literature (AU)
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Humanos , Masculino , Adolescente , Degeneración Hepatolenticular/diagnóstico , Degeneración Hepatolenticular/genética , Agammaglobulinemia/diagnóstico , Agammaglobulinemia/genética , MutaciónRESUMEN
Background: Protein MUTYH, encoded by the gene MUTYH, is an important mismatch repair enzyme in the base-excision repair pathway of DNA repair. When genetically altered, different neoplastic conditions can arise. One of the widely known syndromes associated with MUTYH mutations is MUTYH-associated polyposis, a form of familial colorectal cancer syndrome. MUTYH may also be a driver in other familial cancer syndromes, as well as breast cancer and spontaneous cancer cases. However, some controversies about the role of these alterations in oncogenesis remain, especially when affected in a heterozygous way. Most available data on MUTYH mutations are on Caucasian patients. Material and Methods: We analyzed a small cohort of non-Caucasian, Colombian cancer patients with MUTYH germline heterozygous mutations, clinical features suggestive of familial cancer, and extensive genetic studies with no other mutations and without MUTYH-associated polyposis. Conclusion: With this case series, we intended to provide important data for the understanding of MUTYH as a possible driver of familial cancer, even when only heterozygous mutations are found.
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Up to 40% of rare disorders (RD) present facial dysmorphologies, and visual assessment is commonly used for clinical diagnosis. Quantitative approaches are more objective, but mostly rely on European descent populations, disregarding diverse population ancestry. Here, we assessed the facial phenotypes of Down (DS), Morquio (MS), Noonan (NS) and Neurofibromatosis type 1 (NF1) syndromes in a Latino-American population, recording the coordinates of 18 landmarks in 2D images from 79 controls and 51 patients. We quantified facial differences using Euclidean Distance Matrix Analysis, and assessed the diagnostic accuracy of Face2Gene, an automatic deep-learning algorithm. Individuals diagnosed with DS and MS presented severe phenotypes, with 58.2% and 65.4% of significantly different facial traits. The phenotype was milder in NS (47.7%) and non-significant in NF1 (11.4%). Each syndrome presented a characteristic dysmorphology pattern, supporting the diagnostic potential of facial biomarkers. However, population-specific traits were detected in the Colombian population. Diagnostic accuracy was 100% in DS, moderate in NS (66.7%) but lower in comparison to a European population (100%), and below 10% in MS and NF1. Moreover, admixed individuals showed lower facial gestalt similarities. Our results underscore that incorporating populations with Amerindian, African and European ancestry is crucial to improve diagnostic methods of rare disorders.
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Neurofibromatosis , Enfermedades Raras , Humanos , Colombia , Cara , FenotipoRESUMEN
RESUMEN Los artistas moches (50 y 850 años d. C.) son unos de los mayores representantes plásticos en los andes centrales durante la época prehispánica, dentro de este escenario fue posible el análisis de una pieza de cerámica registrada en el sitio arqueológico Huaca de la Luna, ubicada en Trujillo. La vasija corresponde a dos individuos con características morfológicas que permite asociarlos con el padecimiento de lipodistrofia congénita generalizada tipo 2. Considerando la zona geográfica, los rasgos físicos y los casos actuales de esta enfermedad nos permite indicar que en la sociedad Mochica probablemente existieron personas con lipodistrofia congénita generalizada.
ABSTRACT The Moche artist are among the most outstanding plastic representatives in the central Andes during the pre-Hispanic era, within this scenario, we could analyze a sculptural ceramic piece (code C-1335) recorded in the Huaca de la Luna archaeological site in Trujillo, Perú. The vessel corresponds to two individuals with morphological characteristics that allow them to be associated with type 2 congenital generalized lipodystrophy. Considering the geographical, the physical features, and the current cases of this disease, allow us to indicate that people with generalized congenital lipodystrophy probably existed in Mochica society during pre-Hispanic times.
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PURPOSE: Craniofacial microsomia (CFM) represents a spectrum of craniofacial malformations, ranging from isolated microtia with or without aural atresia to underdevelopment of the mandible, maxilla, orbit, facial soft tissue, and/or facial nerve. The genetic causes of CFM remain largely unknown. METHODS: We performed genome sequencing and linkage analysis in patients and families with microtia and CFM of unknown genetic etiology. The functional consequences of damaging missense variants were evaluated through expression of wild-type and mutant proteins in vitro. RESULTS: We studied a 5-generation kindred with microtia, identifying a missense variant in FOXI3 (p.Arg236Trp) as the cause of disease (logarithm of the odds = 3.33). We subsequently identified 6 individuals from 3 additional kindreds with microtia-CFM spectrum phenotypes harboring damaging variants in FOXI3, a regulator of ectodermal and neural crest development. Missense variants in the nuclear localization sequence were identified in cases with isolated microtia with aural atresia and found to affect subcellular localization of FOXI3. Loss of function variants were found in patients with microtia and mandibular hypoplasia (CFM), suggesting dosage sensitivity of FOXI3. CONCLUSION: Damaging variants in FOXI3 are the second most frequent genetic cause of CFM, causing 1% of all cases, including 13% of familial cases in our cohort.
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Microtia Congénita , Síndrome de Goldenhar , Micrognatismo , Humanos , Síndrome de Goldenhar/genética , Microtia Congénita/genética , Oído/anomalías , CaraRESUMEN
Osteogenesis imperfecta (OI) is a group of genetic skeletal disorders, with a prevalence of 1 in 15,000-20,000 births. OI type V has been described in approximately 150 cases and all patients carry the variant (c.-14C> T) in the IFITM5 gene. However, two other variants, p.S40L and p.N48S have been reported in this gene, leading to clinical phenotypes different from OI type V. Here we described a patient with multiple bone fractures, scoliosis, skull alteration (plagiocephaly), bone deformation, bone rickets, and intramedullary epithelioid osteosarcoma that bears the recently reported heterozygous variant c.143A>G (p.N48S) in the IFITM5 gene. This case supports the pathogenicity of this new variant in the IFITM5 gene and adds information regarding its clinical phenotype.
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Neurofibromatosis type 1 is one of the most common genetic autosomal dominant disorders described, with a prevalence of 1 in 2000 to 1 in 3000 individuals. It is characterized by skin, nerves, and bone abnormalities. Non-related to NF1, hypospadias is a displacement in the urethral opening which in the majority of patients has an idiopathic cause. Here, we describe a patient with neurofibromatosis type 1, hypospadias, and unilateral cryptorchidism. The heterozygous variants c.6789_6792delTTAC, p.(Tyr2264Thrfs*5) and c.140A>G, p.(Tyr47Cys) were found in the NF1 and NR5A1 genes, respectively. This case contributes to the phenotypical characterization of patients with NF1 but also with hypospadias caused by a mutation in the NR5A1 gene, which usually leads to severe sex disorders.