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BACKGROUND: Helsmoortel-Van der Aa syndrome was officially documented in 2014. Helsmoortel-Van der Aa syndrome is an extremely rare complex neurodegenerative disorder characterized by reduced intellectual capacity, motor dysfunction, facial dysmorphism, impaired development, and an increased predisposition to autism spectrum disorder. In addition, many patients also present with neuropsychiatric disorders, including attention deficit hyperactivity disorder, anxiety disorders, and various behavioral abnormalities. Helsmoortel-Van der Aa syndrome is challenging to identify solely on the basis of symptoms, and genetic investigations, including exome sequencing, may facilitate diagnosis. CASE PRESENTATION: We report a case of 13-year-old Saudi patient who presented with dysmorphic features as illustrated in Fig. 1, severe mental retardation, autism spectrum disorder, and attention deficit hyperactivity disorder. Initial genetic testing was unremarkable; thus, a clinical exome analysis was performed to identify the genetic basis of the condition. CONCLUSIONS: Clinical exome analysis indicated an autosomal dominant Helsmoortel-Van der Aa syndrome with a likely pathogenic de novo variant within the activity-dependent neuroprotector homeobox (ADNP) gene not previously reported in Helsmoortel-Van der Aa syndrome. The patient had a right-sided solitary kidney and polycystic ovaries, conditions that were not previously associated with HVDAS.
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Trastorno del Espectro Autista , Discapacidad Intelectual , Síndrome del Ovario Poliquístico , Riñón Único , Humanos , Femenino , Adolescente , Trastorno del Espectro Autista/genética , Síndrome del Ovario Poliquístico/complicaciones , Síndrome del Ovario Poliquístico/genética , Síndrome del Ovario Poliquístico/diagnóstico , Discapacidad Intelectual/genética , Riñón Único/complicaciones , Secuenciación del Exoma , Proteínas del Tejido Nervioso/genética , Proteínas de Homeodominio/genética , Cardiopatías , Facies , Trastornos del NeurodesarrolloAsunto(s)
Anticuerpos Monoclonales Humanizados , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Resultado del Tratamiento , Facies , Femenino , Displasia Ectodérmica/tratamiento farmacológico , Cardiopatías/tratamiento farmacológico , Cardiopatías Congénitas/complicaciones , Cardiopatías Congénitas/tratamiento farmacológico , Índice de Severidad de la Enfermedad , Masculino , Insuficiencia de CrecimientoRESUMEN
BACKGROUND: Kagami-Ogata syndrome (KOS) and Temple syndrome (TS) are two imprinting disorders characterized by the absence or reduced expression of maternal or paternal genes in the chromosome 14q32 region, respectively. We present a rare prenatally diagnosed case of recurrent KOS inherited from a mother affected by TS. CASE PRESENTATION: The woman's two affected pregnancies exhibited recurrent manifestations of prenatal overgrowth, polyhydramnios, and omphalocele, as well as a small bell-shaped thorax with coat-hanger ribs postnatally. Prenatal genetic testing using a single-nucleotide polymorphism array detected a 268.2-kb deletion in the chromosome 14q32 imprinted region inherited from the mother, leading to the diagnosis of KOS. Additionally, the woman carried a de novo deletion in the paternal chromosome 14q32 imprinted region and presented with short stature and small hands and feet, indicating a diagnosis of TS. CONCLUSIONS: Given the rarity of KOS as an imprinting disorder, accurate prenatal diagnosis of this rare imprinting disorder depends on two factors: (1) increasing clinician recognition of the clinical phenotype and related genetic mechanism, and (2) emphasizing the importance of imprinted regions in the CMA workflow for laboratory analysis.
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Diagnóstico Prenatal , Humanos , Femenino , Embarazo , Adulto , Impresión Genómica , Cromosomas Humanos Par 14/genética , Anomalías Múltiples/genética , Anomalías Múltiples/diagnóstico , Polimorfismo de Nucleótido Simple , Trastornos de Impronta , Pulgar/anomalías , Hipotonía Muscular , Discapacidad Intelectual , Facies , Uñas Malformadas , Hallux/anomalíasRESUMEN
RASopathies are a group of related genetic disorders caused by mutations in genes within the RAS/MAPK signaling pathway. This pathway is crucial for cell division, growth, and differentiation, and its disruption can lead to a variety of developmental and health issues. RASopathies present diverse clinical features and pose significant diagnostic and therapeutic challenges. Studying the landscape of biomarkers in RASopathies has the potential to improve both clinical practices and the understanding of these disorders. This review provides an overview of recent discoveries in RASopathy molecular profiling, which extend beyond traditional gene mutation analysis. mRNAs, non-coding RNAs, protein expression patterns, and post-translational modifications characteristic of RASopathy patients within pivotal signaling pathways such as the RAS/MAPK, PI3K/AKT/mTOR, and Rho/ROCK/LIMK2/cofilin pathways are summarized. Additionally, the field of metabolomics holds potential for uncovering metabolic signatures associated with specific RASopathies, which are crucial for developing precision medicine. Beyond molecular markers, we also examine the role of histological characteristics and non-invasive physiological assessments in identifying potential biomarkers, as they provide evidence of the disease's effects on various systems. Here, we synthesize key findings and illuminate promising avenues for future research in RASopathy biomarker discovery, underscoring rigorous validation and clinical translation.
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Biomarcadores , Proteínas ras , Humanos , Biomarcadores/metabolismo , Proteínas ras/metabolismo , Proteínas ras/genética , Transducción de Señal , Mutación , Mancha Vino de Oporto/genética , Mancha Vino de Oporto/metabolismo , Mancha Vino de Oporto/patología , Síndrome de Costello/genética , Síndrome de Costello/metabolismo , Síndrome de Costello/patología , Displasia Ectodérmica/genética , Displasia Ectodérmica/metabolismo , Displasia Ectodérmica/diagnóstico , Displasia Ectodérmica/patología , Insuficiencia de Crecimiento/genética , Insuficiencia de Crecimiento/metabolismo , Animales , Cardiopatías Congénitas/genética , Cardiopatías Congénitas/metabolismo , Cardiopatías Congénitas/patología , FaciesRESUMEN
BACKGROUND: Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation is a rare autosomal dominant disease caused by mutations in KIF11 which disrupt EG5 protein function, impacting the development and maintenance of retinal and lymphatic structures due to its expression in the retinal photoreceptor cilia. The primary ocular finding in MCLMR is chorioretinopathy. Additional features can include microphthalmia, angle-closure glaucoma, persistent hyperplastic primary vitreous, cataract, pseudo-coloboma, persistent hyaloid artery, and myopic or hypermetropic astigmatism. The appearance of the chorioretinal lesions as white to pinkish, round, non-elevated atrophic areas devoid of blood vessels resembles the lacunae in Aicardy syndrome. Due to the lack of systematic description of the lesions and significant phenotypical variability, there is an impending need for a detailed report of each case. CASE PRESENTATION: A child with microcephaly detected in the third trimester of gestation began her following in the ophthalmology department due to a non-visually significant cataract. Shortly after, she developed nystagmus and large-angle alternating esotropia with cross-fixation. Her fundus initially showed a pallid optic disc and pigmentary changes, developing thereafter retinal lacunae and a retinal fold. Her differential diagnosis accompanied the dynamic changes in her fundus, which included congenital infections, Leber´s Congenital Amaurosis and Aicardy syndrome. At 19 months old, genetic testing identified a heterozygous mutation (c.1159 C > T, p.Arg387*) in the KIF11 gene. The patient underwent bilateral medial rectus muscle recession surgery at 2 years old for persistent esotropia, with significant improvement. Refraction revealed a hyperopic astigmatism in both eyes (+ 0.25 -2.50 × 180 OD and + 0.75 -2.00 × 170 OS). She continues to require right eye patching for 2 hours daily. CONCLUSIONS: This case report expands the phenotypic spectrum of MCLMR by demonstrating a unique combination of retinal features which sheds new light on differential diagnosis from Aicardy syndrome. Our findings emphasize the significant phenotypic variability associated with MCLMR, particularly regarding ocular involvement. This underscores the importance of detailed clinical evaluation and comprehensive reporting of cases to improve our understanding of the disease spectrum and genotype-phenotype correlations.
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Discapacidad Intelectual , Linfedema , Microcefalia , Humanos , Microcefalia/genética , Microcefalia/diagnóstico , Femenino , Linfedema/genética , Linfedema/diagnóstico , Discapacidad Intelectual/genética , Discapacidad Intelectual/diagnóstico , Enfermedades de la Retina/diagnóstico , Enfermedades de la Retina/genética , Displasia Retiniana , Cinesinas , FaciesRESUMEN
While it is widely thought that de novo mutations (DNMs) occur randomly, we previously showed that some DNMs are enriched because they are positively selected in the testes of aging men. These "selfish" mutations cause disorders with a shared presentation of features, including exclusive paternal origin, significant increase of the father's age, and high apparent germline mutation rate. To date, all known selfish mutations cluster within the components of the RTK-RAS-MAPK signaling pathway, a critical modulator of testicular homeostasis. Here, we demonstrate the selfish nature of the SMAD4 DNMs causing Myhre syndrome (MYHRS). By analyzing 16 informative trios, we show that MYHRS-causing DNMs originated on the paternally derived allele in all cases. We document a statistically significant epidemiological paternal age effect of 6.3 years excess for fathers of MYHRS probands. We developed an ultra-sensitive assay to quantify spontaneous MYHRS-causing SMAD4 variants in sperm and show that pathogenic variants at codon 500 are found at elevated level in sperm of most men and exhibit a strong positive correlation with donor's age, indicative of a high apparent germline mutation rate. Finally, we performed in vitro assays to validate the peculiar functional behavior of the clonally selected DNMs and explored the basis of the pathophysiology of the different SMAD4 sperm-enriched variants. Taken together, these data provide compelling evidence that SMAD4, a gene operating outside the canonical RAS-MAPK signaling pathway, is associated with selfish spermatogonial selection and raises the possibility that other genes/pathways are under positive selection in the aging human testis.
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Mutación de Línea Germinal , Discapacidad Intelectual , Proteína Smad4 , Humanos , Masculino , Proteína Smad4/genética , Discapacidad Intelectual/genética , Contractura/genética , Adulto , Facies , Espermatozoides/metabolismo , Espermatozoides/patología , Criptorquidismo/genética , Trastornos del Crecimiento/genética , Deformidades Congénitas de la Mano/genética , Selección Genética , Alelos , Edad Paterna , Testículo/patología , Testículo/metabolismoRESUMEN
OBJECTIVE: To explore the clinical phenotype and genetic basis of a child with Bainbridge-Ropers syndrome (BRPS). METHODS: A child with BRPS who had visited Nanjing Children's Hospital on June 26, 2019 was selected as the study subject. Clinical data of the child was reviewed. Genomic DNA was extracted from peripheral blood samples of the child and her parents. Whole exome sequencing (WES) was carried out, and candidate variant was verified by Sanger sequencing and bioinformatic analysis. RESULTS: The child was a 6-month-old girl with peculiar facial features, feeding difficulties, malnutrition, global developmental delay, hypotonia, mildly elevated aminotransferase and ulnar deviation. Results of WES showed that she has harbored a c.1533_1534del variant of the ASXL3 gene. Sanger sequencing confirmed that neither of her parents has carried the same variant. No similar case had been retrieved from the HGMD and ClinVar databases. No frequency for this variant among Asian populations was available in the ExAC, 1000 Genomes, and gnomAD databases. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.1533_1534del variant of the ASXL3 gene was determined to be likely pathogenic (PVS1+PS2+PM2_Supporting). CONCLUSION: The ASXL3 gene c.1533_1534del variant probably underlay the BRPS in this child. Above finding has provided a reference for the clinical diagnosis and genetic counseling for children with similar disorders.
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Anomalías Múltiples , Discapacidades del Desarrollo , Trastornos del Neurodesarrollo , Femenino , Humanos , Lactante , Anomalías Múltiples/genética , Discapacidades del Desarrollo/genética , Secuenciación del Exoma , Facies , Mutación , Trastornos del Neurodesarrollo/genética , Fenotipo , Proteínas RepresorasRESUMEN
Ankyrin repeat domain containing-protein 11 (ANKRD11), a transcriptional factor predominantly localized in the cell nucleus, plays a crucial role in the expression regulation of key genes by recruiting chromatin remodelers and interacting with specific transcriptional repressors or activators during numerous biological processes. Its pathogenic variants are strongly linked to the pathogenesis and progression of multisystem disorder known as KBG syndrome. With the widespread application of high-throughput DNA sequencing technologies in clinical medicine, numerous pathogenic variants in the ANKRD11 gene have been reported. Patients with KBG syndrome usually exhibit a broad phenotypic spectrum with a variable degree of severity, even if having identical variants. In addition to distinctive dental, craniofacial and neurodevelopmental abnormalities, patients often present with skeletal anomalies, particularly postnatal short stature. The relationship between ANKRD11 variants and short stature is not well-understood, with limited knowledge regarding its occurrence rate or underlying biological mechanism involved. This review aims to provide an updated analysis of the molecular spectrum associated with ANKRD11 variants, investigate the prevalence of the short stature among patients harboring these variants, evaluate the efficacy of recombinant human growth hormone in treating children with short stature and ANKRD11 variants, and explore the biological mechanisms underlying short stature from both scientific and clinical perspectives. Our investigation indicated that frameshift and nonsense were the most frequent types in 583 pathogenic or likely pathogenic variants identified in the ANKRD11 gene. Among the 245 KBGS patients with height data, approximately 50% displayed short stature. Most patients showed a positive response to rhGH therapy, although the number of patients receiving treatment was limited. ANKRD11 deficiency potentially disrupts longitudinal bone growth by affecting the orderly differentiation of growth plate chondrocytes. Our review offers crucial insights into the association between ANKRD11 variants and short stature and provides valuable guidance for precise clinical diagnosis and treatment of patients with KBG syndrome.
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Fenotipo , Proteínas Represoras , Humanos , Proteínas Represoras/genética , Anomalías Múltiples/genética , Discapacidad Intelectual/genética , Anomalías Dentarias/genética , Anomalías Dentarias/patología , Craneosinostosis/genética , Craneosinostosis/patología , Deleción Cromosómica , Enfermedades del Desarrollo Óseo , FaciesRESUMEN
BACKGROUND: TCF4 acts as a transcription factor that binds to the immunoglobulin enhancer Mu-E5/KE5 motif. Dominant variants in TCF4 are associated with the manifestation of Pitt-Hopkins syndrome, a rare disease characterized by severe mental retardation, certain features of facial dysmorphism and, in many cases, with abnormalities in respiratory rhythm (episodes of paroxysmal tachypnea and hyperventilation, followed by apnea and cyanosis). Frequently, patients also develop epilepsy, microcephaly, and postnatal short stature. Although TCF4 is expressed in skeletal muscle and TCF4 seems to play a role in myogenesis as demonstrated in mice, potential myopathological findings taking place upon the presence of dominant TCF4 variants are thus far not described in human skeletal muscle. METHOD: To address the pathological effect of a novel deletion affecting exons 15 and 16 of TCF4 on skeletal muscle, histological and immunofluorescence studies were carried out on a quadriceps biopsy in addition to targeted transcript studies and global proteomic profiling. RESULTS: We report on muscle biopsy findings from a Pitt-Hopkins patient with a novel heterozygous deletion spanning exon 15 and 16 presenting with neuromuscular symptoms. Microscopic characterization of the muscle biopsy revealed moderate fiber type I predominance, imbalance in the proportion of fibroblasts co-expressing Vimentin and CD90, and indicate activation of the complement cascade in TCF4-mutant muscle. Protein dysregulations were unraveled by proteomic profiling. Transcript studies confirmed a mitochondrial vulnerability in muscle and confirmed reduced TCF4 expression. CONCLUSION: Our combined findings, for the first time, unveil myopathological changes as phenotypical association of Pitt-Hopkins syndrome and thus expand the current clinical knowledge of the disease as well as support data obtained on skeletal muscle of a mouse model.
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Hiperventilación , Discapacidad Intelectual , Factor de Transcripción 4 , Hiperventilación/genética , Hiperventilación/metabolismo , Hiperventilación/fisiopatología , Humanos , Discapacidad Intelectual/genética , Discapacidad Intelectual/metabolismo , Factor de Transcripción 4/genética , Factor de Transcripción 4/metabolismo , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Facies , Niño , Exones , Músculo Cuádriceps/metabolismo , Músculo Cuádriceps/patologíaRESUMEN
BACKGROUND: Mowat-Wilson syndrome (MWS) is a rare genetic condition resulting in multiple congenital anomalies, including facial dysmorphism, structural anomalies of the internal organs, functional disorders, and, although less commonly, ocular abnormalities. To present a child with MWS and eye abnormalities. METHODS: A 3-year-old boy was born at 37 weeks of pregnancy with dysmorphic features, neurodevelopmental disorders, genetically confirmed MWS, nystagmus, strabismus, and suspicion of congenital glaucoma. Ophthalmic examination was carried out under general anesthesia; eyeball ultrasound and electrophysiological examination (flash visual evoked potentials) were also performed. RESULTS: The examinations revealed nystagmus, a normal response of pupils to light in both eyes, and normal intraocular pressure, that is, 17 and 18â mmâ Hg in the right and left eye, respectively. Corneal thickness was 606 µm in the right eye and 588 µm in the left eye. Gonioscopy revealed displacement of Schwalbe line anterior to the limbus of the cornea (posterior embryotoxon). Fundus examination revealed a pink optic disk with a cup-to-disc ratio of 0.5, macular pigment regrouping, and normal blood vessels. Flash visual evoked potentials: P2 latency was normal. P2 amplitude from the left hemisphere was reduced to 50%, and P2 amplitude over the right hemisphere was normal. CONCLUSION: Children with genetically determined congenital anomalies need regular ophthalmic checkups to accurately assess the eye and determine the prospects of vision function development.
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Enfermedad de Hirschsprung , Discapacidad Intelectual , Microcefalia , Humanos , Masculino , Preescolar , Microcefalia/genética , Microcefalia/diagnóstico , Discapacidad Intelectual/genética , Enfermedad de Hirschsprung/genética , Enfermedad de Hirschsprung/diagnóstico , Enfermedad de Hirschsprung/fisiopatología , Facies , Potenciales Evocados Visuales/fisiología , Anomalías del Ojo/diagnóstico , Anomalías del Ojo/genética , Anomalías del Ojo/fisiopatologíaRESUMEN
Myhre syndrome (MS, MIM 139210) is a rare multisystemic disorder caused by recurrent pathogenic missense variants in SMAD4. The clinical features have been mainly documented in childhood and comprise variable neurocognitive development, recognizable craniofacial features, a short stature with a pseudo-muscular build, hearing loss, thickened skin, joint limitations, diverse cardiovascular and airway manifestations, and increased fibrosis often following trauma or surgery. In contrast, adults with MS are underreported obscuring potential clinical variability. Here, we describe 24 adults with MS, including 17 diagnosed after the age of 18 years old, and we review the literature on adults with MS. Overall, our cohort shows a milder phenotype as well as lower mortality rates compared to what has been published in literature. Individuals with a codon 500 variant in SMAD4 present with a more pronounced neurodevelopmental and systemic phenotype. However, in contrast to the literature, we observe cardiovascular abnormalities in individuals with the p.(Arg496Cys) variant. In addition, we describe scoliosis as a new manifestation and we report fertility in two additional males with the p.(Arg496Cys). In conclusion, our study contributes novel insights into the clinical variability of MS and underscores the importance of variant-specific considerations, and we provide recommendations for the management of MS in adulthood.
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Discapacidad Intelectual , Fenotipo , Proteína Smad4 , Humanos , Masculino , Adulto , Femenino , Proteína Smad4/genética , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Discapacidad Intelectual/diagnóstico , Criptorquidismo/genética , Criptorquidismo/patología , Adolescente , Trastornos del Crecimiento/genética , Trastornos del Crecimiento/patología , Persona de Mediana Edad , Mutación Missense , Facies , Estudios de Asociación Genética , Deformidades Congénitas de la ManoRESUMEN
Rare early-onset lower urinary tract disorders include defects of functional maturation of the bladder. Current treatments do not target the primary pathobiology of these diseases. Some have a monogenic basis, such as urofacial, or Ochoa, syndrome (UFS). Here, the bladder does not empty fully because of incomplete relaxation of its outflow tract, and subsequent urosepsis can cause kidney failure. UFS is associated with biallelic variants of HPSE2, encoding heparanase-2. This protein is detected in pelvic ganglia, autonomic relay stations that innervate the bladder and control voiding. Bladder outflow tracts of Hpse2 mutant mice display impaired neurogenic relaxation. We hypothesized that HPSE2 gene transfer soon after birth would ameliorate this defect and explored an adeno-associated viral (AAV) vector-based approach. AAV9/HPSE2, carrying human HPSE2 driven by CAG, was administered intravenously into neonatal mice. In the third postnatal week, transgene transduction and expression were sought, and ex vivo myography was undertaken to measure bladder function. In mice administered AAV9/HPSE2, the viral genome was detected in pelvic ganglia. Human HPSE2 was expressed and heparanase-2 became detectable in pelvic ganglia of treated mutant mice. On autopsy, wild-type mice had empty bladders, whereas bladders were uniformly distended in mutant mice, a defect ameliorated by AAV9/HPSE2 treatment. Therapeutically, AAV9/HPSE2 significantly ameliorated impaired neurogenic relaxation of Hpse2 mutant bladder outflow tracts. Impaired neurogenic contractility of mutant detrusor smooth muscle was also significantly improved. These results constitute first steps towards curing UFS, a clinically devastating genetic disease featuring a bladder autonomic neuropathy.
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Dependovirus , Modelos Animales de Enfermedad , Técnicas de Transferencia de Gen , Glucuronidasa , Vejiga Urinaria , Animales , Ratones , Humanos , Vejiga Urinaria/fisiopatología , Glucuronidasa/genética , Glucuronidasa/metabolismo , Dependovirus/genética , Terapia Genética/métodos , Vectores Genéticos , Seudoobstrucción Intestinal/genética , Seudoobstrucción Intestinal/terapia , Seudoobstrucción Intestinal/fisiopatología , Enfermedades Urológicas , FaciesRESUMEN
Trichohepatoenteric syndrome (THES), also known as phenotypic diarrhea or syndromic diarrhea, is a rare autosomal recessive genetic disorder caused by mutations in SKIC2 (THES-type 2) or SKIC3 (THES-type 1) and is characterized by early onset diarrhea, woolly brittle hair, facial dysmorphic features and liver disease. We report the case of a 24-month-old girl who presented with chronic diarrhea since the neonatal period along with intrauterine growth restriction (IUGR), developmental delay, dysmorphic features, congenital heart defects, liver disease, and recurrent infections. The diagnosis was made through whole-exome sequencing analysis, which detected a homozygous variant (c.4070del, p.Pro1357Leufs*10) in the SKIC3 gene. The patient required parenteral nutrition and was hospitalized for the first 10 months of life and then discharged on PN after showing improvement. She remained stable on PN after discharge despite a few admissions for central line infections. Recent follow-up at the age of 2 years revealed that she was stable on long-term parenteral nutrition and that she had advanced chronic liver disease.
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Diarrea , Enfermedades del Cabello , Homocigoto , Humanos , Femenino , Diarrea/genética , Enfermedades del Cabello/genética , Enfermedades del Cabello/diagnóstico , Preescolar , Diarrea Infantil/genética , Mutación , Nutrición Parenteral , Hepatopatías/genética , Hepatopatías/diagnóstico , Secuenciación del Exoma , Retardo del Crecimiento Fetal/genética , ADN Helicasas , FaciesRESUMEN
O'Donnell-Luria-Rodan (ODLURO) syndrome is an autosomal dominant genetic disorder caused by mutations in the KMT2E (lysine methyltransferase 2E) gene. The Third Xiangya Hospital of Central South University admitted a 12-year and 9-month-old male patient who presented with growth retardation, intellectual disability, and distinctive facial features. Peripheral blood was collected from the patient, and DNA was extracted for genetic testing. Chromosome karyotyping showed 46XY. Whole-exome sequencing and low-coverage massively parallel copy number variation sequencing (CNV-seq) revealed a 506 kb heterozygous deletion in the 7q22.3 region, which includes 6 genes, including KMT2E. The patient was diagnosed with ODLURO syndrome. Both the patient's parents and younger brother had normal clinical phenotypes and genetic test results, indicating that this deletion was a de novo mutation. The clinical and genetic characteristics of this case can help increase clinicians' awareness of ODLURO syndrome.
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Discapacidad Intelectual , Humanos , Masculino , Discapacidad Intelectual/genética , Niño , N-Metiltransferasa de Histona-Lisina/genética , Mutación , Trastornos del Crecimiento/genética , Anomalías Múltiples/genética , Cromosomas Humanos Par 7/genética , Cariotipificación , Fenotipo , Variaciones en el Número de Copia de ADN , Secuenciación del Exoma , Heterocigoto , Contractura , Microcefalia , FaciesRESUMEN
Importance: Somatic variants in the RAS/MAPK pathway genes are commonly associated with melanocytic nevi and melanoma, whereas germline variants in these genes are associated with RASopathies, syndromes involving multiple organs, including the skin. Nevi counts may be higher in some RASopathies, but studies on features observed through dermoscopy are limited. Objective: To determine the distinguishing dermoscopic features of melanocytic nevi and how the RAS pathway influences them by comparing nevi in patients with cardiofaciocutaneous syndrome (CFC) and Costello syndrome (CS). Design, Setting, and Participants: In this prospective cohort study, patients with CFC and CS, 2 RASopathies caused by variants in the downstream and upstream components of the RAS/MAPK pathway, were recruited from the international CFC and CS family conferences. Some patients with CFC also elected to participate in a longitudinal follow-up study. Main Outcomes and Measures: The main outcomes were dermoscopic features and, in the longitudinal follow-up study, nevi counts, which were recorded over time. Results: A total of 39 patients, 16 with CFC and 23 with CS, were enrolled (overall cohort: 26 [66.7%] female; median [IQR] age, 13.0 [7.6-22.0] years). The 112 nevi overall frequently displayed an organized dermoscopic pattern (CFC, 61 [84.7%]; CS, 34 [85.0%]) rather than a disorganized pattern (CFC, 6 [8.3%]; CS, 1 [2.5%]). Of the organized nevi, homogenous brown was the most common pattern (CFC, 41 [67.2%]; CS, 22 [64.7%]), followed by reticular (CFC, 11 [18.0%]; CS, 7 [20.6%]) and globular (CFC, 9 [14.8%]; CS, 5 [14.7%]). Pigmented networks occurred in 12 nevi in CFC (16.7%) and 6 nevi in CS (15%; P > .99). Of these, 6 CFC-associated nevi (50%) and no CS-associated nevi had atypical networks (P = .05). Six patients with CFC in the follow-up study developed significantly more nevi within 5 years (median [IQR] increase, 24.5 [10-120] nevi; P = .04). Conclusions and Relevance: In this cohort study, the findings suggest that nevi in patients with CFC and CS commonly display organized homogenous brown dermoscopic patterns, and the number of nevi may significantly increase over time in those with CFC. A disorganized pattern and atypical networks may be more frequent in patients with CFC. Future studies are needed to determine the risk of melanoma in individuals with CFC or CS.
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Síndrome de Costello , Dermoscopía , Insuficiencia de Crecimiento , Nevo Pigmentado , Neoplasias Cutáneas , Humanos , Nevo Pigmentado/patología , Nevo Pigmentado/genética , Nevo Pigmentado/diagnóstico , Masculino , Femenino , Síndrome de Costello/genética , Síndrome de Costello/patología , Estudios Prospectivos , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/diagnóstico , Niño , Adolescente , Insuficiencia de Crecimiento/etiología , Adulto Joven , Estudios de Seguimiento , Adulto , Cardiopatías Congénitas/complicaciones , Cardiopatías Congénitas/genética , Cardiopatías Congénitas/patología , Preescolar , Facies , Síndromes Neurocutáneos/diagnóstico , Síndromes Neurocutáneos/patología , Síndromes Neurocutáneos/genética , Estudios de Cohortes , Estudios Longitudinales , Displasia EctodérmicaRESUMEN
Nicolaides-Baraitser syndrome (NCBRS) is a rare autosomal dominant genetic condition that is characterized by severe intellectual disability, dysmorphic facial features, short stature, sparse hair, and early onset seizures. This diagnosis is established by suggestive clinical findings and the identification of a heterozygous SMARCA2 pathogenic variant by molecular genetic testing. There are not, however, consensus clinical diagnostic criteria for this condition as there are so few documented cases. Here, we present a case of prenatally diagnosed caudal regression with sacral agenesis and congenital vertical talus (rocker bottom feet) that was ultimately found to have a de novo SMARCA2 pathogenic variant. The patient had an amniocentesis with normal karyotype and microarray followed by failed direct rapid whole exome sequencing (WES) due to maternal cell contamination. She elected for termination of the pregnancy based on the clinical prognosis of the ultrasound findings; WES revealed a pathogenic variant after her termination. We believe this is the first case of these findings associated with NCBRS. If any future cases of either finding are found in association with a SMARCA2 genetic variant, caudal regression and rocker bottom feet should be included in the spectrum of physical traits associated with this pathogenic variant.
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Anomalías Múltiples , Facies , Discapacidad Intelectual , Factores de Transcripción , Adulto , Femenino , Humanos , Embarazo , Anomalías Múltiples/genética , Anomalías Múltiples/diagnóstico por imagen , Anomalías Múltiples/diagnóstico , Secuenciación del Exoma , Deformidades Congénitas del Pie , Hipotricosis , Discapacidad Intelectual/genética , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/diagnóstico por imagen , Sacro/anomalías , Sacro/diagnóstico por imagen , Factores de Transcripción/genética , Ultrasonografía PrenatalRESUMEN
Hearing impairments and dental anomalies are found in many genetic syndromes. Otodental syndrome is a rare combination of hearing loss and the presence of a pathognomonic dental phenotype known as globodontia, in which the tooth exhibits an abnormal globe shape. There is no histologic evidence of structural anomalies in the enamel, dentin, or pulp. This report describes the case of a 12-year-old boy who had hearing loss and 2 supernumerary globe-shaped teeth in the sites of the permanent maxillary central incisors. The diagnosis of otodental syndrome was established based on the clinical, radiographic, and histologic features, but other conditions, including dens evaginatus, talon cusp, dens invaginatus, and compound odontoma, should be included in the differential diagnosis. Dental treatment consisted of the extraction of both anomalous teeth, allowing spontaneous eruption of the impacted permanent central incisors. Early diagnosis of otodental syndrome permits a multidisciplinary approach to prevent other pathologic conditions, reduce functional damage, and avoid social problems.
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Incisivo , Humanos , Masculino , Niño , Incisivo/anomalías , Diente Supernumerario/complicaciones , Diente Supernumerario/diagnóstico por imagen , Diente Supernumerario/cirugía , Anomalías Dentarias/diagnóstico , Diagnóstico Diferencial , Anomalías Múltiples , Enfermedades del Desarrollo Óseo , Discapacidad Intelectual , FaciesRESUMEN
BACKGROUND: Trichohepatoenteric syndrome (THES) is characterized by neonatal-onset intractable diarrhea. It often requires long-term total parenteral nutrition (TPN). In addition, other characteristic findings of the syndrome include growth retardation, facial dysmorphism, hair abnormalities, various immunological problems and other rare system findings. Two genes and their associated pathogenic variants have been associated with this syndrome: SKIC3 and SKIC2. METHODS AND RESULTS: In this case series, the clinical findings and molecular analysis results of a total of 8 patients from 5 different families who presented with persistent diarrhea and were diagnosed with THES were shared. Pathogenic variants were detected in the SKIC3 gene in 6 of our patients and in the SKIC2 gene in 2 patients. It was planned to compare the clinical findings of our patients with other patients, together with literature data, and to present yet-undefined phenotypic features that may be related to THES. In our case series, in addition to our patients with a novel variant, patient number 2 had a dual phenotype (THES and Spondyloepimetaphyseal dysplasia, sponastrime type) that has not been reported yet. Delay in gross motor skills, mild cognitive impairment, radioulnar synostosis, osteoporosis, nephropathy and cystic lesions (renal and liver) were observed as unreported phenotypic findings. CONCLUSIONS: We are expanding the clinical and molecular repertoire of the syndrome regarding patients diagnosed with THES. We recommend that the NGS (next-generation sequencing) multigene panel should be used as a diagnostic tool in cases with persistent diarrhea.
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Enfermedades del Cabello , Fenotipo , Humanos , Femenino , Masculino , Lactante , Enfermedades del Cabello/genética , Enfermedades del Cabello/diagnóstico , Genotipo , Preescolar , ADN Helicasas/genética , Diarrea Infantil/genética , Diarrea Infantil/diagnóstico , Mutación/genética , Diarrea/genética , Diarrea/diagnóstico , Niño , Recién Nacido , Retardo del Crecimiento Fetal , FaciesRESUMEN
Heterozygous de novo mutations in the Activity-Dependent Neuroprotective Homeobox (ADNP) gene underlie Helsmoortel-Van der Aa syndrome (HVDAS). Most of these mutations are situated in the last exon and we previously demonstrated escape from nonsense-mediated decay by detecting mutant ADNP mRNA in patient blood. In this study, wild-type and ADNP mutants are investigated at the protein level and therefore optimal detection of the protein is required. Detection of ADNP by means of western blotting has been ambiguous with reported antibodies resulting in non-specific bands without unique ADNP signal. Validation of an N-terminal ADNP antibody (Aviva Systems) using a blocking peptide competition assay allowed to differentiate between specific and non-specific signals in different sample materials, resulting in a unique band signal around 150 kDa for ADNP, above its theoretical molecular weight of 124 kDa. Detection with different C-terminal antibodies confirmed the signals at an observed molecular weight of 150 kDa. Our antibody panel was subsequently tested by immunoblotting, comparing parental and homozygous CRISPR/Cas9 endonuclease-mediated Adnp knockout cell lines and showed disappearance of the 150 kDa signal, indicative for intact ADNP. By means of both a GFPSpark and Flag-tag N-terminally fused to a human ADNP expression vector, we detected wild-type ADNP together with mutant forms after introduction of patient mutations in E. coli expression systems by site-directed mutagenesis. Furthermore, we were also able to visualize endogenous ADNP with our C-terminal antibody panel in heterozygous cell lines carrying ADNP patient mutations, while the truncated ADNP mutants could only be detected with epitope-tag-specific antibodies, suggesting that addition of an epitope-tag possibly helps stabilizing the protein. However, western blotting of patient-derived hiPSCs, immortalized lymphoblastoid cell lines and post-mortem patient brain material failed to detect a native mutant ADNP protein. In addition, an N-terminal immunoprecipitation-competent ADNP antibody enriched truncating mutants in overexpression lysates, whereas implementation of the same method failed to enrich a possible native mutant protein in immortalized patient-derived lymphoblastoid cell lines. This study aims to shape awareness for critical assessment of mutant ADNP protein analysis in Helsmoortel-Van der Aa syndrome.