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PURPOSE: Genitopatellar syndrome and Say-Barber-Biesecker-Young-Simpson syndrome are caused by variants in the KAT6B gene and are part of a broad clinical spectrum called KAT6B disorders, whose variable expressivity is increasingly being recognized. METHODS: We herein present the phenotypes of 32 previously unreported individuals with a molecularly confirmed diagnosis of a KAT6B disorder, report 24 new pathogenic KAT6B variants, and review phenotypic information available on all published individuals with this condition. We also suggest a classification of clinical subtypes within the KAT6B disorder spectrum. RESULTS: We demonstrate that cerebral anomalies, optic nerve hypoplasia, neurobehavioral difficulties, and distal limb anomalies other than long thumbs and great toes, such as polydactyly, are more frequently observed than initially reported. Intestinal malrotation and its serious consequences can be present in affected individuals. Additionally, we identified four children with Pierre Robin sequence, four individuals who had increased nuchal translucency/cystic hygroma prenatally, and two fetuses with severe renal anomalies leading to renal failure. We also report an individual in which a pathogenic variant was inherited from a mildly affected parent. CONCLUSION: Our work provides a comprehensive review and expansion of the genotypic and phenotypic spectrum of KAT6B disorders that will assist clinicians in the assessment, counseling, and management of affected individuals.
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Blefarofimosis , Discapacidad Intelectual , Blefarofimosis/genética , Exones , Histona Acetiltransferasas/genética , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , MutaciónRESUMEN
The frequency of dermatological manifestations in diseases due to mitochondrial DNA mutations is not well known, although multiple symmetric lipomatosis has been repeatedly associated to mitochondrial DNA mutations. Here, we present a patient suffering from multiple symmetric lipomatosis and other skin signs. We found a new mitochondrial DNA mutation, m.8357T>C, in the tRNALys -coding gene and, using a cybrid approach, confirmed its pathogenicity. A meta-analysis of the dermatological signs of the patient shows that they are not common in patients with confirmed mitochondrial DNA mutations and suggests that, in these cases, lipomatosis is not related to the oxidative phosphorylation dysfunction, but to an alteration of an additional function associated to particular mitochondrial tRNAs.
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ADN Mitocondrial/genética , Lipomatosis Simétrica Múltiple/genética , ARN de Transferencia/genética , Adulto , Humanos , Lipomatosis Simétrica Múltiple/diagnóstico por imagen , Lipomatosis Simétrica Múltiple/fisiopatología , Masculino , Persona de Mediana Edad , Mitocondrias/genética , Mitocondrias/patología , Mutación/genéticaRESUMEN
Keratitis-ichthyosis-deafness (KID syndrome) is a syndromes ichthyoses that is clinically and genetically heterogeneous requiring early and long-term multidisciplinary monitoring of affected individuals. A review of the clinical, etiopathogenic and therapeutic aspects is presented of this rare congenital ectodermal disorder.
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Sordera , Ictiosis , Queratitis , Humanos , Ictiosis/etiología , Ictiosis/genética , Queratitis/diagnóstico , Queratitis/etiología , Queratitis/terapia , SíndromeAsunto(s)
Predisposición Genética a la Enfermedad , Neurilemoma/genética , Neurofibromatosis/genética , Proteína SMARCB1/genética , Neoplasias Cutáneas/genética , Adulto , Femenino , Ligamiento Genético , Humanos , Intrones/genética , Neurilemoma/patología , Neurofibromatosis/patología , Neoplasias Cutáneas/patologíaAsunto(s)
Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/prevención & control , Síndrome de Down/epidemiología , Pandemias/prevención & control , Neumonía Viral/epidemiología , Neumonía Viral/prevención & control , Adolescente , COVID-19 , Niño , Preescolar , Femenino , Hospitales Pediátricos , Humanos , Lactante , Recién Nacido , Italia/epidemiología , Masculino , Adulto JovenRESUMEN
Trisomic X is a sex chromosomal abnormality that may be presented in mosaic. This is not extremely rare, the majority of cases go undiagnosed. The prevalence has been established to 1/1000 females. It is clinically characterized by tall stature, microcephaly, hypertelorism, congenital abnormalities, and motor and language delays. The association between the trisomic X and gastrointestinal malformations is extremely rare. We report a case of mosaic trisomic X with gastric obstruction expanding the clinical spectrum of this entity and emphasizing its unknown pathogenesis.
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Enfermedades Gastrointestinales/genética , Obstrucción Intestinal/genética , Trastornos de los Cromosomas Sexuales del Desarrollo Sexual/complicaciones , Preescolar , Cromosomas Humanos X/genética , Femenino , Humanos , Aberraciones Cromosómicas Sexuales , Trastornos de los Cromosomas Sexuales del Desarrollo Sexual/genética , Trisomía/genéticaRESUMEN
Pachyonychia congenita is a group of autosomal dominant inheritance pattern disorders characterized by hypertrophic nail dystrophy There are two main clinical subtypes: type 1 and 2. Pachyonychia congenita type 2 is readily differentiated from type 1 by multiple steatocysts and/or presence of natal teeth and can be confirmed by mutations of KRT6B and KRT17. We report the case of a 33-year-o/d female patient with the missense mutation in KRT17 gene (c.280C> T, p.Arg94Cys) and discuss the several clinical features found with this mutation in the literature.
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Paquioniquia Congénita/diagnóstico , Adulto , Femenino , Humanos , Paquioniquia Congénita/genéticaRESUMEN
Mucopolysaccharidoses are a group of lysosomal storage disorders caused by deficiency of enzymes catalyzing the degradation of glycosaminoglycans. Mucopoly-saccharidosis I can present a wide range of phenotypic characteristics with three major recognized clinical entities: Hurler and Scheie syndromes represent phenotypes at the severe and mild ends of the clinical spectrum, respectively, and the Hurler-Scheie syndrome is intermediate in phenotypic expression. These are caused by the deficiency or absence of alpha-L-iduronidase, essential to the metabolism of both dermatan and heparan sulfate, and it is encoded by the lDUA gene. We report the case of a 34-year-old male patient with enzymatic deficiency of alpha-L-iduronidase, accumulation of its substrate and a previously unreported mutation in the IDUA gene that developed a phenotype of Scheie syndrome.
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Iduronidasa/genética , Mucopolisacaridosis I/genética , Mutación Missense , Mutación Puntual , Adulto , Sustitución de Aminoácidos , Dermatán Sulfato/orina , Progresión de la Enfermedad , Exones/genética , Glicosaminoglicanos/metabolismo , Deformidades Adquiridas de la Mano/genética , Heterocigoto , Humanos , Intrones/genética , Imagen por Resonancia Magnética , Masculino , Mucopolisacaridosis I/orina , Fenotipo , Eliminación de Secuencia , Compresión de la Médula Espinal/etiología , Compresión de la Médula Espinal/patología , Evaluación de SíntomasRESUMEN
BACKGROUND: To report ocular manifestations, clinical course, and therapeutic management of patients with molecular genetically confirmed keratitis-ichthyosis-deafness syndrome. METHODS: Four patients, aged 19 to 46, with keratitis-ichthyosis-deafness syndrome from across the UK were recruited for a general and ocular examination and GJB2 (Cx26) mutational analysis. The ocular examination included best-corrected visual acuity, slit-lamp bio-microscopy, and ocular surface assessment. Mutational analysis of the coding region of GJB2 (Cx26) was performed by bidirectional Sanger sequencing. RESULTS: All four individuals had the characteristic systemic features of keratitis-ichthyosis-deafness syndrome. Each patient was found to have a missense mutation, resulting in the substitution of aspartic acid with asparagine at codon 50 (p.D50N). Main ophthalmic features were vascularizing keratopathy, ocular surface disease, hyperkeratotic lid lesions, recurrent epithelial defects, and corneal stromal scarring. One patient had multiple surgical procedures, including superficial keratectomies and lamellar keratoplasty, which failed to prevent severe visual loss. In contrast, oral therapy with ketoconazole stabilized the corneal and skin disease in two other patients with keratitis-ichthyosis-deafness syndrome. The patient who underwent intracorneal bevacizumab injection showed a marked reduction in corneal vascularization following a single application. CONCLUSIONS: Keratitis-ichthyosis-deafness syndrome is a rare ectodermal dysplasia caused by heterozygous mutations in GJB2 (Cx26) with a severe, progressive vascularizing keratopathy. Oral ketoconazole therapy may offer benefit in stabilizing the corneal and skin disease.
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Enfermedades de la Córnea , Sordera , Ictiosis , Queratitis , Humanos , Conexinas/genética , Cetoconazol/uso terapéutico , Sordera/genética , Ictiosis/diagnóstico , Ictiosis/genética , Ictiosis/patología , Síndrome , Queratitis/diagnóstico , Queratitis/tratamiento farmacológico , Queratitis/genética , FenotipoRESUMEN
Communicating the diagnosis of a genetic entity/rare disease to a patient or their parents is a complex process; it requires the doctor, pediatrician, or geneticist to display good communication skills and knowledge in a moment of uncertainty and disorientation for the family group, and sometimes in an inappropriate environment or under time constraints [...].
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Rubinstein-Taybi Syndrome is a rare congenital multisystem syndrome inherited in an autosomal dominant pattern caused by mutations in CREBBP and EP300 genes in approximately 60% and 10% respectively. These genes encode two highly evolutionarily conserved, ubiquitously expressed, and homologous lysine-acetyltransferases, that are involved in number of basic cellular activities, such as DNA repair, cell proliferation, growth, differentiation, apoptosis of cells, and tumor suppression. It is mainly characterized by global developmental delay, moderate to severe intellectual disability, postnatal retardation, microcephaly, skeletal anomalies including broad/short, angled thumbs and/or large first toes, short stature, and dysmorphic facial features. There is an increased risk to develop tumors mainly meningiomas and pilomatrixomas, without a clear genotype-phenotype correlation. Although not considered as characteristic manifestations, numerous cutaneous anomalies have also been reported in patients with this entity. Both susceptibility to the formation of keloids and pilomatricomas are the most often associated cutaneous features. In this review, we discuss the genetics, diagnosis, and clinical features in Rubinstein-Taybi Syndrome with a review of the major dermatological manifestations.
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Discapacidad Intelectual , Pilomatrixoma , Síndrome de Rubinstein-Taybi , Neoplasias Cutáneas , Humanos , Síndrome de Rubinstein-Taybi/genética , Síndrome de Rubinstein-Taybi/diagnóstico , Síndrome de Rubinstein-Taybi/patología , Mutación , Estudios de Asociación Genética , Neoplasias Cutáneas/genéticaRESUMEN
[This corrects the article DOI: 10.1055/s-0041-1732474.].
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Spondylometaphyseal dysplasia Algerian type (MIM no.: 184253) is an uncommon autosomal dominant skeletal dysplasia caused by heterozygous mutations in the COL2A1 gene (MIM no.: 120140). In this case based review, we reported a 5-year-old boy with short stature, severe dorsolumbar scoliosis, lumbar hyperlordosis, short trunk, and severe genu valgum . Radiological examination showed platyspondyly, irregular metaphyseal radiolucencies intermingled with radiodensities, and corner fractures. The patient has a c.3275G > A; p.Gly1092Asp mutation in exon 47 of the COL2A1 gene and a variant of unknown significance in c.1366-13C > A in intron 21. This latter sequence variant could partially or completely disrupt the natural splice acceptor site of intron 21/exon 22 in the COL2A1 gene leading to a potential modification of the phenotypic severity.
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BACKGROUND: Ectodermal dysplasias (EDs) are a large and complex group of disorders affecting the ectoderm-derived organs; the clinical and genetic heterogeneity of these conditions renders an accurate diagnosis more challenging. The aim of this study is to demonstrate the clinical utility of a targeted resequencing panel through enhancing the molecular and clinical diagnosis of EDs. Given the recent developments in gene and protein-based therapies for X-linked hypohidrotic ectodermal dysplasia, there is a re-emerging interest in identifying the genetic basis of EDs and the respective phenotypic presentations, in an aim to facilitate potential treatments for affected families. METHODS: We assessed seventeen individuals, from three unrelated families, who presented with diverse phenotypes suggestive of ED. An extensive multidisciplinary clinical evaluation was performed followed by a targeted exome resequencing panel (including genes that are known to cause EDs). MiSeqTM data software was used, variants with Qscore >30 were accepted. RESULTS: Three different previously reported hemizygous EDA mutations were found in the families. However, a complete genotype-phenotype correlation could not be established, neither in our patients nor in the previously reported patients. CONCLUSIONS: Targeted exome resequencing can provide a rapid and accurate diagnosis of EDs, while further contributing to the existing ED genetic data. Moreover, the identification of the disease-causing mutation in an affected family is crucial for proper genetic counseling and the establishment of a genotype-phenotype correlation which will subsequently provide the affected individuals with a more suitable treatment plan.
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Displasia Ectodermal Anhidrótica Tipo 1 , Displasia Ectodérmica Hipohidrótica Autosómica Recesiva , Displasia Ectodérmica , Humanos , Ectodisplasinas/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Displasia Ectodérmica/diagnóstico , Displasia Ectodérmica/genética , Displasia Ectodermal Anhidrótica Tipo 1/diagnóstico , Displasia Ectodermal Anhidrótica Tipo 1/genética , MutaciónRESUMEN
Noonan syndrome is a relatively common autosomal dominant entity, clinically variable and genetically heterogeneous; characterized by postnatally reduced growth, distinctive facial dysmorphism, cardiac defects and variable cognitive deficits. The PTPN11 gene is located on the long arm of chromosome 12 and is primarily responsible for the clinically diagnosed cases of this entity. We report the case of a 18 month-old boy, evaluated in a multidisciplinary way, with clinic and molecular diagnosis of Noonan syndrome, with the missense mutation in PTPN11 gene, G503R (c.1507 G>A). Several clinical features and the genetic alterations associated with this mutation are discussed.
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Síndrome de Noonan/diagnóstico , Síndrome de Noonan/genética , Humanos , Lactante , Masculino , Técnicas de Diagnóstico MolecularRESUMEN
OBJECTIVES: To establish the frequency of imperforate anus (IA) in the population with Down syndrome (DS) and study the associated risk factors. METHODS: An observational clinical study case control type was performed. The patients were evaluated at the Unit of Medical Genetics, University of the Andes, from February 2006 to February 2011. The patients with DS and IA were compared with 20 DS without IA. Antecedents of parents were obtained. RESULTS: The frequency de IA in the population with DS was 4.79%. The presence of fever in the first trimester of gestation and the rural origin were associated as risk factors of AI in patients with DS [OR: 25.33 (IC 95% 2.07- 310.76; P = 0.009) and OR: 7.50 (IC 95% 1.09 - 51.52; P = 0.043), respectively]. The maternal age superior to 35 years presented a marginal significance (P = 0.048). CONCLUSIONS: These papers emphasize the high frequency of IA in patients with DS and recommend to investigate the prenatal and environmental risk factors that can increase the presence of this anorectal anomaly in the population with DS, in order to consider them in the programs of prevention of congenital pathologies.
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Ano Imperforado/epidemiología , Síndrome de Down/complicaciones , Adolescente , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Factores de Riesgo , Venezuela/epidemiologíaRESUMEN
The term ectodermal dysplasias (EDs) describes a heterogeneous group of inherited developmental disorders that affect several tissues of ectodermal origin. The most common form of EDs is hypohidrotic ectodermal dysplasia (HED), which is characterized by hypodontia, hypotrichosis, and partial or total eccrine sweat gland deficiency. HED is estimated to affect at least 1 in 17,000 people worldwide. Patients with HED have characteristic facies with periorbital hyperpigmentation, depressed nasal bridge, malar hypoplasia, and absent or sparse eyebrows and eyelashes. The common ocular features of HED include madarosis, trichiasis, and ocular chronic surface disease due to dry eye syndrome, which manifests clinically with discomfort, photophobia, and redness. Dry eye is common in HED and results from a combination of ocular surface defects: mucus abnormalities (abnormal conjunctival mucinous glands), aqueous tear deficiency (abnormalities in the lacrimal gland) and lipid deficiency (due to the partial or total absence of the meibomian glands; modified sebaceous glands with the tarsal plate). Sight-threatening complications result from ocular surface disease, including corneal ulceration and perforation with subsequent corneal scarring and neovascularization. Rare ocular features have been reported and include bilateral or unilateral congenital cataracts, bilateral glaucoma, chorioretinal atrophy and atresia of the nasolacrimal duct. Recognition of the ocular manifestations of HED is required to perform clinical surveillance, instigate supportive and preventative treatment, and manage ocular complications.