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Von Hippel-Lindau disease (VHL) is a rare autosomal dominant disease characterized by progressive development of cysts and tumors. Juvenile idiopathic arthritis (JIA) is a chronic inflammatory disorder and the most common arthritis in children. Although the mechanism of pathogenesis is not fully understood, JIA is thought to be a polygenic, autoimmune-mediated disease. Inherited or acquired disorders resulting in immune dysregulation can lead to neoplastic and autoimmune disease, but very few cases of patients with VHL and concomitant autoimmune disease are reported in the literature. Herein, we describe, to the best of our knowledge, the first reported case of a child with VHL and inflammatory arthritis, and we discuss three possible pathophysiologic mechanisms that could link VHL and JIA. Understanding the shared pathophysiology and genetics of both diseases may help guide future direction of targeted therapies and lead to improved clinical outcomes.
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Artritis , Enfermedad de von Hippel-Lindau , Niño , Humanos , Lactante , Enfermedad de von Hippel-Lindau/complicaciones , Enfermedad de von Hippel-Lindau/genética , Enfermedad de von Hippel-Lindau/patología , Artritis/complicacionesRESUMEN
BACKGROUND: The inherited macrothrombocytopenias are rare disorders and the underlying cause can be identified in many cases but in some, this can remain enigmatic. Platelet transfusions are often administered during hemorrhagic events. METHODS: A patient with previously unexplained inherited macrothrombocytopenia with a platelet count between 3-20 × 109 /L is described in which studies were performed using exome sequencing (ES) and platelet flow cytometry. RESULTS: Both the hemoglobin and white cell counts were normal. ES revealed two suspicious variants, one likely pathogenic and one a variant of uncertain significance, in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene, and flow cytometry showed diminished expression of surface platelet sialic acid (about 5%) but normal red cell sialic acid. The Thrombopoietin (TPO) level was low, and the patient responded to TPO-mimetic treatment with an increase in the platelet count. CONCLUSION: Two variants in the GNE gene were able to be upgraded to pathogenic with apparently restricted expression to the megakaryocyte lineage. Platelet transfusion may be avoided in these patients with TPO-mimetic treatment.
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Ácido N-Acetilneuramínico , Trombocitopenia , Humanos , Plaquetas , Trombocitopenia/genética , Trombocitopenia/terapia , Mutación , Recuento de Plaquetas , TrombopoyetinaRESUMEN
PURPOSE: The field of genetics and genomics continues to expand at an unprecedented pace. As scientific knowledge is translated to clinical practice, genomic information is routinely being used in preventive, diagnostic, and therapeutic decision-making across a variety of clinical practice areas. As adoption of genomic medicine further evolves, health professionals will be required to stay abreast of new genetic discoveries and technologies and implementation of these advances within their scope of practice will be indicated. METHODS: The Association of Professors of Human and Medical Genetics previously developed medical school genetics core competencies, last updated in 2013. The competencies were reviewed and updated through a structured approach incorporating a modified Delphi method. RESULTS: The updated Association of Professors of Human and Medical Genetics core competencies are presented. Current revisions include competencies that are concise, specific, and assessable. In addition, they incorporate recent advances in clinical practice and promote equity and inclusion in clinical care. CONCLUSION: The 2022 competencies will serve as a guide for medical school leadership and educators involved in curriculum development, implementation, and assessment. Use of these competencies across the undergraduate medical curricula will foster knowledge, skills, and behaviors required in medical practice across a wide range of specialties.
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Educación de Pregrado en Medicina , Genética Médica , Competencia Clínica , Consenso , Curriculum , Genética Médica/educación , Genómica/educación , HumanosRESUMEN
Alterations in the TAOK1 gene have recently emerged as the cause of developmental delay with or without intellectual impairment or behavioral abnormalities (MIM # 619575). The 32 cases currently described in the literature have predominantly de novo alterations in TAOK1 and a wide spectrum of neurodevelopmental abnormalities. Here, we report four patients with novel pathogenic TAOK1 variants identified by research genome sequencing, clinical exome sequencing, and international matchmaking. The overlapping clinical features of our patients are consistent with the emerging core phenotype of TAOK1-associated syndrome: facial dysmorphism, feeding difficulties, global developmental delay, joint laxity, and hypotonia. However, behavioral abnormalities and gastrointestinal issues are more common in our cohort than previously reported. Two patients have de novo TAOK1 variants (one missense, one splice site) consistent with most known alterations in this gene. However, we also report the first sibling pair who both inherited a TAOK1 frameshift variant from a mildly affected mother. Our findings suggest that incomplete penetrance and variable expressivity are relatively common in TAOK1-associated syndrome, which holds important implications for clinical genetic testing.
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Discapacidad Intelectual , Trastornos del Neurodesarrollo , Proteínas Serina-Treonina Quinasas/genética , Niño , Discapacidades del Desarrollo/genética , Humanos , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Hipotonía Muscular , Trastornos del Neurodesarrollo/genética , Fenotipo , Síndrome , Secuenciación del ExomaRESUMEN
PURPOSE: To develop an evidence-based clinical practice guideline for the use of exome and genome sequencing (ES/GS) in the care of pediatric patients with one or more congenital anomalies (CA) with onset prior to age 1 year or developmental delay (DD) or intellectual disability (ID) with onset prior to age 18 years. METHODS: The Pediatric Exome/Genome Sequencing Evidence-Based Guideline Work Group (n = 10) used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) evidence to decision (EtD) framework based on the recent American College of Medical Genetics and Genomics (ACMG) systematic review, and an Ontario Health Technology Assessment to develop and present evidence summaries and health-care recommendations. The document underwent extensive internal and external peer review, and public comment, before approval by the ACMG Board of Directors. RESULTS: The literature supports the clinical utility and desirable effects of ES/GS on active and long-term clinical management of patients with CA/DD/ID, and on family-focused and reproductive outcomes with relatively few harms. Compared with standard genetic testing, ES/GS has a higher diagnostic yield and may be more cost-effective when ordered early in the diagnostic evaluation. CONCLUSION: We strongly recommend that ES/GS be considered as a first- or second-tier test for patients with CA/DD/ID.
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Genética Médica , Discapacidad Intelectual , Niño , Exoma/genética , Genómica , Humanos , Lactante , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Guías de Práctica Clínica como Asunto , Estados Unidos , Secuenciación del ExomaRESUMEN
BACKGROUND: Growth hormone (GH) treatment increases the adult height of short children born small for gestational age (SGA). Catch-up growth is associated with a younger age, shorter height, and prepubertal status at the onset of GH treatment. We report a 12 11/12-year-old girl born SGA who received GH for 5 years without catch-up growth and was diagnosed with Noonan Syndrome (NS). RESULTS: A 5-year-and-9-month-old 46, XX girl born SGA was started on GH treatment at a dose of 0.32 mg/kg/week. Her midparental target height is 158.6 cm. Endocrine work up showed an IGF-1 level 69 ng/ml (Normal (N): 55-238 ng/ml), IGFBP3 2.6 mg/L (N: 1.9-5.2 mg/L), TSH 3.2 mIU/L (N: 0.35-5.5 mIU/L), and a normal skeletal survey. Height was 96 cm (0.1%; Ht SDS -2.9), weight 14 kgs (1%; Wt SDS -2.3), and Tanner 1 breast and pubic hair were observed. Due to the poor catch-up growth on GH treatment, she was referred to Genetics to elucidate genetic or syndromic causes of short stature. She was noted to have posteriorly rotated ears and slight down slanting of the palpebral fissures. Genetic findings showed a heterozygous pathogenic variant in PTPN11 (c.922A > G (p.Asn308Asp)) diagnostic for NS. This finding is de novo given negative parental testing. She was noted to have a heterozygous missense variant of unknown significance (VUS) in FGFR3: c.746C > A (p.Ser249Tyr). FGFR3 is associated with multiple skeletal dysplasias including thanatophoric dysplasia, achondroplasia, and Crouzon syndrome and hypochondroplasia. Clinical correlation is poor for these syndromes. CONCLUSION: Diminished catch-up growth and response to GH treatment in a child born SGA led to the diagnosis of NS. The concomitant diagnosis of SGA and NS may have affected the responsiveness of this child to the growth promoting effect of GH treatment.
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OBJECTIVE: To describe a founder mutation effect and the clinical phenotype of homozygous FRRS1L c.737_739delGAG (p.Gly246del) variant in 15 children of Puerto Rican (Boricua) ancestry presenting with early infantile epileptic encephalopathy (EIEE-37) with prominent movement disorder. BACKGROUND: EIEE-37 is caused by biallelic loss of function variants in the FRRS1L gene, which is critical for AMPA-receptor function, resulting in intractable epilepsy and dyskinesia. METHODS: A retrospective, multicenter chart review of patients sharing the same homozygous FRRS1L (p.Gly246del) pathogenic variant identified by clinical genetic testing. Clinical information was collected regarding neurodevelopmental outcomes, neuroimaging, electrographic features and clinical response to antiseizure medications. RESULTS: Fifteen patients from 12 different families of Puerto Rican ancestry were homozygous for the FRRS1L (p.Gly246del) pathogenic variant, with ages ranging from 1 to 25 years. The onset of seizures was from 6 to 24 months. All had hypotonia, severe global developmental delay, and most had hyperkinetic involuntary movements. Developmental regression during the first year of life was common (86%). Electroencephalogram showed hypsarrhythmia in 66% (10/15), with many older children evolving into Lennox-Gastaut syndrome. Six patients demonstrated progressive volume loss and/or cerebellar atrophy on brain magnetic resonance imaging (MRI). CONCLUSIONS: We describe the largest cohort to date of patients with epileptic encephalopathy. We estimate that 0.76% of unaffected individuals of Puerto Rican ancestry carry this pathogenic variant due to a founder effect. Children homozygous for the FRRS1L (p.Gly246del) Boricua variant exhibit a very homogenous phenotype of early developmental regression and epilepsy, starting with infantile spasms and evolving into Lennox-Gastaut syndrome with hyperkinetic movement disorder.
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Hispánicos o Latinos/genética , Síndrome de Lennox-Gastaut/genética , Proteínas de la Membrana/genética , Mutación/genética , Proteínas del Tejido Nervioso/genética , Espasmos Infantiles/genética , Adolescente , Adulto , Niño , Preescolar , Estudios de Cohortes , Electroencefalografía , Femenino , Hispánicos o Latinos/estadística & datos numéricos , Humanos , Lactante , Masculino , Puerto Rico , Estudios Retrospectivos , Espasmos Infantiles/fisiopatología , Adulto JovenRESUMEN
Transient neonatal diabetes mellitus (TNDM) is a rare form of diabetes that presents in infancy and is characterized by intrauterine growth restriction and hyperglycemia without ketones on urinalysis. Patients are treated with insulin until remission, usually within the first year. Relapse to a permanent state may occur later in life, with a mean age of 14 years. The most common cause of TNDM is a chromosome 6q24 mutation that affects pancreatic ß-cell function. Reports of relapse have been limited. We describe a case of an adolescent female with TNDM due to 6q24 hypomethylation who relapsed at 15 years of age with severe dental disease as the presenting sign.
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Human fetuses with trisomy 21 (T21) have atypical brain development that is apparent sonographically in the second trimester. We hypothesize that by analyzing and integrating dysregulated gene expression and pathways common to humans with Down syndrome (DS) and mouse models we can discover novel targets for prenatal therapy. Here, we tested the safety and efficacy of apigenin, identified with this approach, in both human amniocytes from fetuses with T21 and in the Ts1Cje mouse model. In vitro, T21 cells cultured with apigenin had significantly reduced oxidative stress and improved antioxidant defense response. In vivo, apigenin treatment mixed with chow was administered prenatally to the dams and fed to the pups over their lifetimes. There was no significant increase in birth defects or pup deaths resulting from prenatal apigenin treatment. Apigenin significantly improved several developmental milestones and spatial olfactory memory in Ts1Cje neonates. In addition, we noted sex-specific effects on exploratory behavior and long-term hippocampal memory in adult mice, and males showed significantly more improvement than females. We demonstrated that the therapeutic effects of apigenin are pleiotropic, resulting in decreased oxidative stress, activation of pro-proliferative and pro-neurogenic genes (KI67, Nestin, Sox2, and PAX6), reduction of the pro-inflammatory cytokines INFG, IL1A, and IL12P70 through the inhibition of NFκB signaling, increase of the anti-inflammatory cytokines IL10 and IL12P40, and increased expression of the angiogenic and neurotrophic factors VEGFA and IL7. These studies provide proof of principle that apigenin has multiple therapeutic targets in preclinical models of DS.
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Apigenina/farmacología , Síndrome de Down/tratamiento farmacológico , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Neurogénesis/efectos de los fármacos , Memoria Espacial/efectos de los fármacos , Células Madre/efectos de los fármacos , Líquido Amniótico/citología , Líquido Amniótico/metabolismo , Animales , Citocinas/genética , Citocinas/inmunología , Modelos Animales de Enfermedad , Síndrome de Down/genética , Síndrome de Down/inmunología , Síndrome de Down/patología , Conducta Exploratoria/efectos de los fármacos , Femenino , Feto , Hipocampo/efectos de los fármacos , Hipocampo/inmunología , Hipocampo/metabolismo , Hipocampo/patología , Humanos , Interleucina-7/genética , Interleucina-7/inmunología , Antígeno Ki-67/genética , Antígeno Ki-67/inmunología , Masculino , Ratones , Nestina/genética , Nestina/inmunología , Neurogénesis/genética , Estrés Oxidativo/efectos de los fármacos , Factor de Transcripción PAX6/genética , Factor de Transcripción PAX6/inmunología , Embarazo , Cultivo Primario de Células , Factores de Transcripción SOXB1/genética , Factores de Transcripción SOXB1/inmunología , Factores Sexuales , Células Madre/metabolismo , Células Madre/patología , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/inmunologíaRESUMEN
Our current understanding of the genetic mechanisms that underly cancer pathogenesis is rapidly expanding. Hereditary cancer predisposition syndromes are important to recognize for diagnostic and treatment decision-making but also for family members so they will benefit from surveillance and treatment options. This brief review gives primary care and oncology caregivers a summary of the evolution of hereditary cancer predisposition syndromes, indications for consideration of testing and therapy of patients and families.
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Manejo de la Enfermedad , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Neoplasias/genética , Asesoramiento Genético , Humanos , Oncología Médica , Neoplasias/terapia , Selección de Paciente , Rol del Médico , Medición de Riesgo , Estados UnidosRESUMEN
Anatomical and functional brain abnormalities begin during fetal life in Down syndrome (DS). We hypothesize that novel prenatal treatments can be identified by targeting signaling pathways that are consistently perturbed in cell types/tissues obtained from human fetuses with DS and mouse embryos. We analyzed transcriptome data from fetuses with trisomy 21, age and sex-matched euploid controls, and embryonic day 15.5 forebrains from Ts1Cje, Ts65Dn, and Dp16 mice. The new datasets were compared to other publicly available datasets from humans with DS. We used the human Connectivity Map (CMap) database and created a murine adaptation to identify FDA-approved drugs that can rescue affected pathways. USP16 and TTC3 were dysregulated in all affected human cells and two mouse models. DS-associated pathway abnormalities were either the result of gene dosage specific effects or the consequence of a global cell stress response with activation of compensatory mechanisms. CMap analyses identified 56 molecules with high predictive scores to rescue abnormal gene expression in both species. Our novel integrated human/murine systems biology approach identified commonly dysregulated genes and pathways. This can help to prioritize therapeutic molecules on which to further test safety and efficacy. Additional studies in human cells are ongoing prior to pre-clinical prenatal treatment in mice.
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Síndrome de Down/genética , Regulación del Desarrollo de la Expresión Génica , Redes Reguladoras de Genes , Redes y Vías Metabólicas/genética , Ubiquitina Tiolesterasa/genética , Ubiquitina-Proteína Ligasas/genética , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Síndrome de Down/tratamiento farmacológico , Síndrome de Down/metabolismo , Síndrome de Down/patología , Embrión de Mamíferos , Femenino , Feto , Dosificación de Gen , Redes Reguladoras de Genes/efectos de los fármacos , Humanos , Redes y Vías Metabólicas/efectos de los fármacos , Ratones , Ratones Transgénicos , Transducción de Señal , Bibliotecas de Moléculas Pequeñas/farmacología , Biología de Sistemas/métodos , Ubiquitina Tiolesterasa/metabolismo , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Turner syndrome is a sex chromosome aneuploidy with characteristic malformations. Amniotic fluid, a complex biological material, could contribute to the understanding of Turner syndrome pathogenesis. In this pilot study, global gene expression analysis of cell-free RNA in amniotic fluid supernatant was utilized to identify specific genes/organ systems that may play a role in Turner syndrome pathophysiology. Cell-free RNA from amniotic fluid of five mid-trimester Turner syndrome fetuses and five euploid female fetuses matched for gestational age was extracted, amplified, and hybridized onto Affymetrix(®) U133 Plus 2.0 arrays. Significantly differentially regulated genes were identified using paired t tests. Biological interpretation was performed using Ingenuity Pathway Analysis and BioGPS gene expression atlas. There were 470 statistically significantly differentially expressed genes identified. They were widely distributed across the genome. XIST was significantly down-regulated (p < 0.0001); SHOX was not differentially expressed. One of the most highly represented organ systems was the hematologic/immune system, distinguishing the Turner syndrome transcriptome from other aneuploidies we previously studied. Manual curation of the differentially expressed gene list identified genes of possible pathologic significance, including NFATC3, IGFBP5, and LDLR. Transcriptomic differences in the amniotic fluid of Turner syndrome fetuses are due to genome-wide dysregulation. The hematologic/immune system differences may play a role in early-onset autoimmune dysfunction. Other genes identified with possible pathologic significance are associated with cardiac and skeletal systems, which are known to be affected in females with Turner syndrome. The discovery-driven approach described here may be useful in elucidating novel mechanisms of disease in Turner syndrome.
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Líquido Amniótico , Aneuploidia , Cromosomas Humanos X/genética , Regulación del Desarrollo de la Expresión Génica/genética , ARN Mensajero/genética , Síndrome de Turner/genética , Líquido Amniótico/química , Estudios de Casos y Controles , ADN Complementario/genética , Regulación hacia Abajo , Femenino , Perfilación de la Expresión Génica , Humanos , Cariotipo , Análisis de Secuencia por Matrices de Oligonucleótidos , Especificidad de Órganos , Fenotipo , Proyectos Piloto , Embarazo , Transcriptoma , Regulación hacia ArribaRESUMEN
Microarray analysis of cell-free RNA in amniotic fluid (AF) supernatant has revealed differential fetal gene expression as a function of gestational age and karyotype. Once informative genes are identified, research moves to a more focused platform such as quantitative reverse transcriptase-PCR. Standardized NanoArray PCR (SNAP) is a recently developed gene profiling technology that enables the measurement of transcripts from samples containing reduced quantities or degraded nucleic acids. We used a previously developed SNAP gene panel as proof of concept to determine whether fetal functional gene expression could be ascertained from AF supernatant. RNA was extracted and converted to cDNA from 19 AF supernatant samples of euploid fetuses between 15 to 20 weeks of gestation, and transcript abundance of 21 genes was measured. Statistically significant differences in expression, as a function of advancing gestational age, were observed for 5 of 21 genes. ANXA5, GUSB, and PPIA showed decreasing gene expression over time, whereas CASC3 and ZNF264 showed increasing gene expression over time. Statistically significantly increased expression of MTOR and STAT2 was seen in female compared with male fetuses. This study demonstrates the feasibility of focused fetal gene expression analysis using SNAP technology. In the future, this technique could be optimized to examine specific genes instrumental in fetal organ system function, which could be a useful addition to prenatal care.
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Líquido Amniótico/metabolismo , Feto/metabolismo , Regulación del Desarrollo de la Expresión Génica , Análisis por Micromatrices/métodos , Reacción en Cadena de la Polimerasa/métodos , Femenino , Humanos , Pulmón/metabolismo , Masculino , Análisis de RegresiónAsunto(s)
Amniocentesis/métodos , Líquido Amniótico/química , Feto/química , ARN/aislamiento & purificación , Líquido Amniótico/citología , Sistema Libre de Células/química , Eficiencia , Femenino , Feto/metabolismo , Humanos , Embarazo , Diagnóstico Prenatal , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
We sought to establish a blood-neural barrier (BNB) model of astrocyte contact with endothelial cells (EC) to test the hypothesis that transforming growth factor beta (TGF beta) promotes an EC barrier-phenotype. Astrocyte-EC contact induced BNB properties in EC. Transendothelial resistance was augmented by direct contact between astrocytes-EC, but not by astrocyte-conditioned medium or astrocyte-EC coculture conditioned medium. Coculture of EC and astrocytes led to significant increase in endothelial occludin levels and junctional localization. EC gamma-glutamyl-transferase (GGT) activity was increased by direct contact with astrocytes, by conditioned medium from cocultures or by TGF beta1. Coculture inhibited EC proliferation with no effect on astrocyte proliferation. A neutralizing antibody to TGF beta decreased GGT activity in cocultures and increased cell number. Whereas total TGF beta was not significantly altered by coculture, activated TGF beta increased in astrocyte-EC cocultures. In summary, astrocyte-EC contact induces BNB characteristics in EC and locally activated TGF beta is responsible for part of the induction.