Combined X-linked familial exudative vitreoretinopathy and retinopathy of prematurity phenotype in an infant with mosaic turner syndrome with ring X chromosome.

BACKGROUND: Retinopathy of prematurity (ROP) and familial exudative vitreoretinopathy (FEVR) are two distinct pathologies of retinal angiogenesis with overlapping clinical features. METHODS: Examination, multimodal imaging, and genetic testing were used to guide diagnosis and treatment. RESULTS: We report a combined phenotype of X-linked FEVR and ROP in a 4-month-old girl with mosaic Turner syndrome with ring X chromosome born at 26 weeks gestational age. She was initially diagnosed with atypical ROP with a vitreous band causing a localized traction retinal detachment, inferotemporal to the macula in the right eye, vessels to posterior zone 2 with no clear ridge temporally in the left eye, and fluorescein leakage in both eyes. Due to the suspicion of concurrent FEVR, genetic testing using a vitreoretinopathy panel was performed which revealed a mosaic Turner syndrome associated with 45,X/46,X,r(X), subsequently confirmed by chromosome analysis. The deleted region in the ring X chromosome included the NDP and RS1 genes. The patient was treated with laser photocoagulation of the peripheral avascular retina and sub-Tenon's triamcinolone injection in both eyes, intravitreal injection of bevacizumab in the left eye, and pars plicata vitrectomy in the right eye. CONCLUSIONS: In premature neonates with atypical ROP, a clinical suspicion of concurrent FEVR or similar vasculopathy is important and genetic testing may elucidate a genetic etiology, which could influence management and prognosis. Turner syndrome can be connected with co-occurring Mendelian gene disorders, particularly in individuals with mosaicism. The concurrence of FEVR and ROP appears to result in atypical and possibly more severe phenotypes.

Enfermedad de Fabry desde la perspectiva del neurólogo: ¿una causa infrecuente de ictus? / Fabry disease from the neurologist’s point of view: is it a rare cause of strokes?

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Utilidad de la logopedia en la mejora del lenguaje en el tratamiento del síndrome del cromosoma X frágil en niños preescolares / Usefulness of speech therapy in improving language in the treatment of fragile X syndrome in preschool children

El síndrome del cromosoma X frágil (SXF) es la primera causa más frecuente de discapacidad intelectual y la segunda asociada a factores genéticos. Dado que existe una gran variabilidad en el fenotipo conductual que este síndrome presenta, se da la necesidad de realizar una adecuada evaluación de cada caso en particular. Se expone un estudio en el que se realiza un seguimiento exhaustivo de los niveles iniciales y de los logros conseguidos por 2 niños con SXF con mutación completa de 16 y 27 meses; uno recibe tratamiento logopédico y el otro no. Cuando se interpretan los resultados se encuentra que existe la necesidad de una evaluación individualizada que determine los déficits concretos que presenta cada niño en cada área de desarrollo, pues si bien se prevé, según la literatura científica, que existirán necesidades a nivel cognitivo y del lenguaje, se descubre que, aunque haya que intervenir en estas áreas, su necesidad se centra fundamentalmente a nivel motor y de autonomía, sobre todo en el segundo caso(AU)

Fragile X syndrome (FXS) is the most common cause-and the second genetic cause-of intellectual disability. There is wide variability in the behavioral phenotype associated with this syndrome and consequently evaluation should be individualized. We report the exhaustive initial evaluation, follow-up and achievements of two children (aged 16 and 27 months) with FXS with a full mutation. One child received speech therapy, while the other did not. Children with FXS should be individually assessed to determine their specific developmental impairments. Although the literature predicts that affected individuals will show cognitive and language deficits, we found that the two children assessed in this study required interventions aimed at improving motor skills and autonomy, especially the second child(AU)

Juvenile Systemic Lupus Erythematosus associated with Klinefelter's syndrome: A case report

We present the first reported case of juvenile Systemic Lupus Erythematosus with Klinefelter's syndrome in a 14-year-old Iranian boy who had leg ulcers and arthritis. He had low level of testosterone accompanied with hypergonadotropic hypogonadism. This case emphasizes the importance of two X chromosomes as a risk factor for Systemic Lupus Erythematosus in women and men with Klinefelter's syndrome (47, XXY) (AU)

Presentamos el primer caso notificado de lupus eritematoso sistémico de inicio juvenil junto con un síndrome de Klinefelter en un niño iraní de 14 años de edad que presentaba úlceras en piernas y artritis. Presentaba valores reducidos de testosterona acompañados con hipogonadismo hipergonadotrópico. Este caso resalta la importancia de dos cromosomas X como factor de riesgo de lupus eritematoso sistémico en mujeres y hombres con el síndrome de Klinelfelter (47, XXY) (AU)

Síndrome de deleción de genes contiguos en Xp21: una forma inusual de presentación / Delection syndrome In Xp21: An unusual form of presentation

Introducción. Describimos el caso de un lactante en el que la asociación de distrofia muscular de Duchenne (DMD) yuna pseudohipertrigliceridemia condujeron al diagnóstico de un síndrome de deleción de genes contiguos en Xp21. Caso clínico.Niño de 7 meses de edad remitido por retraso psicomotor. En la exploración destacaba una hipotonía axial marcada. Laanalítica mostró una elevación de las enzimas musculares con niveles de creatinfosfocinasa de 12.829 UI/L, junto con cifraselevadas de triglicéridos en sangre. Los hallazgos del electromiograma fueron compatibles con afectación miopática. El estudiogenético de distrofinopatías mostró la existencia de una deleción en el gen de la distrofina. La analítica ampliada identificóconcentraciones elevadas de glicerol tanto en sangre como en orina, compatibles con un déficit de glicerolcinasa. El estudiogenético confirmó la existencia de una deleción en Xp21 de los genes responsables de la DMD, del déficit de glicerolcinasa,de la hipoplasia suprarrenal congénita (gen DAX1) y del retraso mental (gen IL1RAPL1). Conclusiones. En lactantes y niñospequeños con afectación miopática, la elevación de las cifras de creatinfosfocinasa y pseudohipertrigliceridemia debeconsiderarse el síndrome de deleción de genes contiguos en Xp21 para prevenir y tratar las complicaciones metabólicas derivadasde la hipoplasia suprarrenal (AU)

Introduction. We report a case of an infant where the association of Duchenne’s muscular dystrophy (DMD) andpseudohypertriglyceridaemia led to the diagnosis of contiguous gene deletion syndrome in Xp21. Case report. A 7-month-oldmale infant who was referred due to psychomotor retardation. The examination revealed pronounced axial hypotonia. Labfindings showed high levels of muscular enzymes with creatine phosphokinase levels of 12,829 IU/L, together with high bloodlevels of triglycerides. Electromyogram findings were consistent with myopathic compromise. The genetic study for dystrophinopathiesrevealed the existence of a deletion in the dystrophin gene. Further lab findings identified high glycerol concentrationsboth in blood and in urine that were compatible with a glycerol kinase deficiency. The genetic study confirmed the existence ofa deletion in Xp21 of the genes responsible for DMD, the glycerol kinase deficiency, the congenital adrenal hypoplasia (geneDAX1) and mental retardation (gene IL1RAPL1). Conclusions. In infants and small children with myopathic compromise,increased levels of creatine phosphokinase and pseudohypertriglyceridaemia it is essential to take into account contiguousgene deletion syndrome in Xp21 to be able to prevent and treat the metabolic complications arising from adrenal hypoplasia (AU)

Situación actual del diagnóstico prenatal no invasivo / Current state of the non-invasive prenatal diagnosis methods

El diagnóstico prenatal se basa en la obtención de tejido fetal, mediante métodos invasivos, para su posterior análisis genético. La amniocentesis y la biopsia corial son las técnicas más utilizadas, cuyo principal inconveniente es que conllevan un riesgo de aborto, entre el 0,5¿1% y el 3,9%, respectivamente. El aislamiento de células fetales en sangre materna permite obtener material genético del feto de forma no invasiva, pero su escasez en sangre materna dificulta su utilización como método diagnóstico. La relativa abundancia del ADN fetal en la circulación materna, junto con la sensibilidad de la técnica utilizada para su cuantificación, convierten la detección de ADN fetal en plasma materno en un método alternativo para el diagnóstico de las enfermedades ligadas al cromosoma X o la determinación del estado RhD. En este artículo se hace una revisión del estado actual de los métodos de diagnóstico prenatal no invasivo(AU)

Prenatal diagnosis is based on genetic analysis of invasively obtained fetal tissue. Amniocentesis and chorial biopsy are the most used techniques, but carry a potential risk of miscarriage, from 0.5¿1% up to 3.9% respectively. Isolation of fetal cells from maternal blood allows a non-invasive obtention of fetal genetic material, but their scarcity difficults an efficient diagnosis method. The relative abundance of fetal DNA in maternal blood, as well as the sensitivity of quantitative PCR based methods, constitute an attractive alternative method for X-linked diseases and RhD status diagnosis. In this paper, a review of the present state of non-invasive prenatal diagnosis methods is described(AU)

Evidencia de transmisión autosómica dominante a través de la línea materna en un caso de discinesia ciliar primaria / Evidence for autosomal dominant inheritance through the maternal line in a case of primary ciliary diskinesia

Se presenta evidencia de un caso atípico de discinesia ciliar primaria en el que la transmisión genética, en lugar de la clásica autosómica recesiva, parece ser de tipo autosómico dominante transmitida a través de la línea materna. Se trata de un caso de dos hermanos de 29 y 30 años de edad casados y sin hijos, con historia de infertilidad, sinusitis frecuentes e infecciones respiratorias recurrentes. Madre y hermana presentan broncopatía crónica no filiada. Padre sano sin afectación pulmonar o sinusal. En el examen físico, en ambos hermanos, la hermana, y la madre, sólo destaca la presencia de roncus en la auscultación pulmonar. Bioquímica ordinaria normal, incluyendo pruebas de función pulmonar, hepática y renal. El estudio ultraestructural del flagelo espermático por microscopía electrónica indica que los dos hermanos tienen la misma anomalía. En la mayoría de las secciones transversales se encuentra ausencia de ambos brazos de dineína. El filamento de nexina está presente, así como las fibras radiales y el par central. En espermatozoides aislados, coincidiendo con la ausencia de los brazos de dineína, hay también pérdida del par central. No se encontraron anomalías en la vaina fibrosa, ni pérdida de las fibras densas. La pieza intermedia en aproximadamente el 50% de los espermatozoides mostraba una disminución en el número de mitocondrias y de mitocondrias extras no alineadas. Otros hallazgos fueron la presencia de microtúbulos extra periféricos al axonema

An atypical case of primary ciliary dyskinesia is presented in which the inheritance, rather than the classical autosomal recessive, appears to be transmitted as an autosomal dominant trait through the maternal line. The case involves two brothers of 29 and 30 years of age, married without children, with a history of infertility, frequent episodes of sinusitis, and recurrent pulmonary infections. Their mother and sister have chronic bronchopathy of unknown etiology. Their father is healthy without pulmonary problems or sinusitis. At physical exam, both brothers, sister and mother presented with bronchial rhonchi at lung auscultation. Blood analysis and pulmonary function, liver and renal tests were all normal. The ultraestructual study of the sperm flagellum by electron microscopy revealed that both brothers have the same anomaly. Namely, in the majority of the cross-sections, both dynein arms are missing. The nexin filament was present, as well as the radial spokes and the central pair of microtubules. In some sperm, besides the absence of dynein arms, there was also absence of the central pair of microtubules. Neither anomalies of the fibrous sheath nor of the dense fibers were found. In approximately 50% of the spermatozoa, the midpiece had a decreased number of mitochondria and extra non- aligned mitochondria. Other findings included extra peripheral microtubules in the axoneme

Síndrome de Lowe: caso clínico / Lowe syndrome: a case report

El síndrome de Lowe, o síndrome oculocerebrorrenal, es una enfermedad hereditaria recesiva asociada al cromosoma X. Se caracteriza por defectos oculares (cataratas congénitas, glaucoma), defectos del sistema nervioso central (hipotonía generalizada con hiporreflexia y retraso mental severo) y alteraciones renales (disfunción tubular progresiva con acidosis e hiperaminoaciduria). En este artículo presentamos el caso de una mujer portadora asintomática del síndrome de Lowe y las repercusiones que esto conlleva en su historia obstétrica (AU)

Lowe Syndrome, or oculo-cerebro-renal syndrome is a rare X-linked disorder. It is characterized by ocular defects (congenital cataracts, glaucoma), central nervous defects (generalized muscular hypotonia, hyporeflexia, and severe mental retardation), and renal disorders (progressive tubular dysfunction with acidosis and hyperaminoaciduria). This article presents the case of an asymptomatic female carrier and her obstetric consequences (AU)

Celulitis atípica asociada a bacteriemia por Campylobacter jejuni en un paciente con hipogammaglobulinemia ligada al cromosoma X / Atypical cellulitis associated with bacteremia from Campylobacter jejuni in a patient with X-linked hypogammaglobulinemia

Un paciente varón de 18 años de edad, con antecedentes de agammaglobulinemia ligada al cromosoma X o de Bruton, presentó simultáneamente lesiones atípicas de celulitis, en ambas piernas y brazo izquierdo, y bacteriemia por Campylobacter jejuni, sin sintomatología intestinal previa.Tanto C. jejuni como los bacilos del género Helicobacter o Flexispira deben ser considerados causa de septicemias/bacteriemias, celulitis, abscesos, uveítis, artritis y osteomielitis en pacientes con cualquier tipo de inmunodeficiencia, incluida la agammaglobulinemia ligada al X (AU)

Déficit ornitintranscarbamilasa / Ornithine transcarbamylase deficency

El déficit de ornitintranscarbamilasa (OTC) es el trastorno enzimático más frecuente del ciclo de la urea. Se caracteriza por un bloqueo en la utilización de carbamilfosfato en el ciclo, con elevación de aminoácidos precursores en sangre y aumento de ácido orótico en la orina. Es de herencia ligada al cromosoma X. Los hombres hemocigotos generalmente manifiestan la enfermedad de forma grave desde el periodo neonatal, mientras que en las mujeres heterocigotas los síntomas son más tardíos y larvados, por la desigual inactivación de uno de los cromosomas X durante el desarrollo embriogénico, aunque siempre existe el riesgo de hiperamoniemia. El objetivo de este trabajo, con el estudio de un caso clínico de una niña de 14 meses, es conocer fundamentalmente las formas de presentación y las dificultades diagnósticas que pueden tener este grupo de portadoras, porque: a) no siempre se demuestra una importante elevación de aminoácidos y amoniaco en sangre; b) las cifras de ácido orótico en orina pueden ser basalmente normales; c) el déficit enzimático en enterocitos o hepatocitos puede no confirmarse por el mosaicismo celular, y d) el estudio genético nunca será una prueba confirmatoria urgente por la complejidad que entraña. En este caso, la elevación de glutamina y alanina en sangre fue discreta y la excreción de ácido orótico en orina fue normal; sin embargo, tras sobrecarga oral de alopurinol (100 mg), hubo una importante elevación de oroticoaciduria con pico máximo a las 12 horas de la prueba de 80 mmol/mol de creatinina, y permaneció la elevación a las 24 horas. Los controles sanos con la sobrecarga no sobrepasaron elevaciones de 10-20 mmol/mol de creatinina y a las 24 horas se volvieron a cifras presobrecarga. La conclusión es realizar el diagnóstico rápido en probables pacientes heterocigotos por déficit de OTC, con la determinación de aminoácidos en sangre junto con la prueba de sobrecarga de alopurinol (AU)

Development of muscle pathology in canine X-linked muscular dystrophy. II. Quantitative characterization of histopathological progression during postnatal skeletal muscle development.

We have characterized the time course of muscle pathology development during the postnatal maturation of quadriceps and tibialis anterior muscle in dystrophic golden retriever dogs. We determined the percentages of degenerating, regenerating, calcium-positive, hypercontracted, albumin-positive, and C3 complement fraction-positive muscle fibers and the extent of connective tissue proliferation in animals from neonate to adult. Necrotic fibers increased from days 2 to 30, decreased at 60 days (to 0.8%) and increased in older animals to a stable level of around 2%. Hypercontracted fibers peaked at 15 days (19.1%) and declined to 3.7% in adults. Regenerating fibers were numerous at 15 and 30 days (10%), declined at 60 days to 4.7% and declined further in adults. Calcium- and albumin-positive fibers peaked at 30 days (6.5% and 13.8%, respectively) and then declined to around 3% and 5%, respectively, in older dogs. In dystrophic dogs, the extent of fibrosis was significantly greater on 15 days than in controls, but did not then increase with age. In carriers, calcium- and albumin-positive fibers always expressed dystrophin abnormally. Muscle damage occurs before completion of muscle maturation in dystrophic dogs. While necrosis and hypercontraction remain stable in adults, fiber regeneration declines to very low levels. In contrast to Duchenne muscular dystrophy, muscle fibrosis in the muscle studied does not increase with age.

Morphological features and measurements in a human fetus with karyotype 69, XXX: comparison with fetuses of the same CRL, without chromosomal anomalies.

A triploid fetus (karyotype 69, XXX) with crown-rump length (CRL) 94 mm, presenting micro- and retrognathia, low-set ears and crooked feet, was cleared and double-stained with alizarin red S and alcian blue for detecting the ossification patterns in the vertebral column, ribs, ischium, limbs, and face. Longitudinal measurements of some long bones in the upper (humerus, ulna, radius) and lower (femur, tibia, fibula) limb were taken. The values of both the total length (TL) and the ossified part (OL) of each long bone, as well as the OL/TL per cent ratio were considered. Reference points were located on the mandible, i.e. condylar process (Pcl), coronoid process (Pco), gnathion (GN), gonion (GO), superior symphyseal point (SSP) for measuring linear dimensions. Since the aim of this work was to assess the influence of triploidy 69, XXX the skeletal development and growth patterns, all values obtained in the examined specimen were related with those relative to a group of fetuses, without any detectable malformation and chromosomal anomalies, with a CRL mean value of 93 mm. Results evidenced that the triploid fetus presented growth restriction and that the vertebral centra ossification and the mandibular development were much delayed with the normal ossification patterns.

A reinvestigation of non-disjunction resulting in 47, XXY males of paternal origin.

We have used polymorphisms within the Xp/Yp pseudoautosomal region (PAR 1) to determine the frequency and location of recombination in 80 paternally derived 47, XXY males. Of 64 informative results, there were 10 single cross-overs, one double cross-over and 53 without a cross-over. Therefore 2/3 of 47, XXY males of paternal origin result from meiosis in which the X and Y chromosomes fail to recombine. This failure was not associated with the presence of an increase in recombination in the smaller Xq/Yq pseudoautosomal region (PAR 2) or with the presence of microdeletions within PAR 1.

Involvement of the X chromosome in non-Hodgkin lymphoma.

Gain of an X chromosome is observed as a secondary, acquired karyotypic alteration in a significant proportion of malignant lymphomas. To determine the potential involvement of X-linked genes in neoplastic development, we have analyzed the inactivation status of the supernumerary X chromosome in lymphomas in both male and female patients. In males, neither methylation of FMR1 nor expression of XIST was detected, demonstrating that the duplicated chromosome was not subject to inactivation. In females, both expressed polymorphisms and polymorphisms associated with methylation differences between the active and inactive X chromosome were analyzed to determine whether the duplicated chromosome was active or inactive. To facilitate this analysis, allele-specific PCR primers were designed for detection of previously described polymorphisms in the IDSX and G6PD genes. The female lymphomas were shown to be clonal in origin, and duplication of either the active (5 cases) or inactive (4 cases) X chromosome was observed. Correlations between clinical status and the inactivation status of the X chromosome involved in the duplication were not observed in our relatively small sample, although 4/4 informative cases with a t(14;18) showed duplication of the active X chromosome. In the course of these studies, we detected hypermethylation of the androgen receptor (AR) locus in an extremely high proportion of both male (7/9) and female (9/10) samples. These results are discussed with respect to whether sex chromosome aneuploidies in tumors are involved in, or simply the result of, the neoplastic process. Genes Chromosomes Cancer 28:246-257, 2000.

Evaluation of clonality in myeloid stem-cell disorders.

Clonality in myeloid stem-cell disorders can be determined using either indirect methods such as analysis of X-chromosome inactivation patterns (XCIPs), or detection of specific abnormalities such as the chromosomal translocations characteristic of myeloid leukemias. XCIPs are particularly useful for disorders lacking evidence of a specific marker. Most females can be studied using polymerase chain reaction (PCR) analysis of differential DNA methylation patterns in the human androgen receptor (HUMARA) or phosphoglycerate kinase (PGK) genes, and approximately 68% can be studied using transcription assays of three polymorphic genes, glucose-6-phosphate dehydrogenase (G6PD), iduronate-2-sulfatase (IDS), and p55. Studies are limited by the incidence of constitutive and acquired (age-related) skewing and results must be carefully interpreted with reference to appropriate control samples. These techniques have been applied to clonality status of hematological disorders, lineage involvement in a clonal process, and detection of clonal evolution.

Hipoplasia dérmica focal: síndrome de Goltz / Focal dermal hypoplasia: Goltz syndrome

Presentamos una paciente de un año y medio de edad con manifestaciones clínicas de hipoplasia dérmica focal (síndrome de Goltz), las cuales se confirmaron con el estudio histológico. Realizamos una revisión de la literatura referente a la enfermedad

Hipoplasia dérmica focal: síndrome de Goltz / Focal dermal hypoplasia: Goltz syndrome

Presentamos una paciente de un año y medio de edad con manifestaciones clínicas de hipoplasia dérmica focal (síndrome de Goltz), las cuales se confirmaron con el estudio histológico. Realizamos una revisión de la literatura referente a la enfermedad (AU)

Pathological consequences of sequence duplications in the human genome.

As large-scale sequencing accumulates momentum, an increasing number of instances are being revealed in which genes or other relatively rare sequences are duplicated, either in tandem or at nearby locations. Such duplications are a source of considerable polymorphism in populations, and also increase the evolutionary possibilities for the coregulation of juxtaposed sequences. As a further consequence, they promote inversions and deletions that are responsible for significant inherited pathology. Here we review known examples of genomic duplications present on the human X chromosome and autosomes.

Primer caso documentado en Venezuela de adrenoleucodistrofia ligada al cromosoma X / Documented case first in Venezuela of adrenoleukodystrophy thick X chromosome

La adrenoleucodistrofia ligada al cromosoma X (xALD) es un trastorno del metabólismo de los ácidos grasos de cadena muy larga (AGCML) que origina su acumulación en múltiples tejidos y plasma, lo que provoca disfunción del sistema nervioso y las glándulas suprarrenales. Se han descrito seis formas clínicas: Cerebral de la niñez, cerebral de la adolescencia, cerebral de la edad adulta, adrenomieloneuropatía, Addison solo y asintomática. Se presenta el caso de un paciente xALD de forma cerebral de la niñez, quien inicia en forma lenta y progresiva a la edad de 9 años deterioro neurológico dado por: diagrafía, dismetría, trastorno de la marcha, bradilalia, y disartria, acompañados por hipertonía generalizada, con daño de las funciones cognitivas y motoras, concomitantemente imágenes características en la RMN, cortisol normal y AGML elevados en plasma, lo cual confirma el diagnóstico. Conclusión: la xALD es una enfermedad recientemente descrita, de fácil diagnostico. En Venezuela sólo se ha diagnósticado clínicamente. En el paciente descrito se confirmo bioquímicamente la enfermedad en el Instituto Kennedy Krieger, EE.UU