Caracterización fenotípica y genotipica de la deficiencia de glucosa-6-fosfato deshidrogenasa en Argentina: Estudio retrospectivo y descriptivo / Phenotypic and genotypic characterization of glucose-6-phosphate dehydrogenase deficiency in Argentina: Retrospective and descriptive study

La deficiencia de glucosa-6-fosfato deshidrogenasa es la enzimopatía eritrocitaria causada por mutaciones en el gen G6PD, cuya herencia está ligada al cromosoma X. Se analizan las características clínicas y de laboratorio de 24 individuos con deficiencia de G6PD durante 25 años. La edad mediana al momento del diagnóstico fue 10,2 años (rango: 0,6-56,4). El 54,2 % de los pacientes fueron asintomáticos, mientras que el 25 % presentó anemia hemolítica crónica no esferocítica; el 12,5 %, ictericia neonatal y anemia hemolítica posinfecciones, y el 8,3 %, anemia hemolítica aguda pos ingesta de habas. Los 24 pacientes estudiados presentaron variantes descritas previamente en la literatura. Las características clínicas observadas estuvieron acordes con las variantes encontradas. Veintiuna mujeres, pertenecientes a la rama materna de los individuos afectados, pudieron ser identificadas por biología molecular como portadoras de la deficiencia, por lo que recibieron el consejo genético correspondiente.

Glucose-6-phosphate dehydrogenase deficiency is an erythrocyte enzyme disorder caused by mutations in the G6PD gene, which has an X-linked inheritance. Here we analyze the clinical and laboratory characteristics of 24 subjects with G6PD deficiency over 25 years. Their median age at diagnosis was 10.2 years (range: 0.6-56.4). No symptoms were observed in 54.2 % of patients, whereas 25 % had chronic non-spherocytic hemolytic anemia; 12.5 %, neonatal jaundice and postinfectious hemolytic anemia; and 8.3 %, acute hemolytic anemia after ingestion of fava beans. The 24 studied patients had variants that had been previously described in the bibliography. The clinical characteristics observed here were consistent with the variants found. A total of 21 women from the maternal line of affected subjects were identified as deficiency carriers using molecular biology techniques, so they received the corresponding genetic counseling.

Beta talasemia intermedia: características clínicas y estudio molecular. Serie de casos clínicos / Beta thalassemia intermedia: clinical characteristics and molecular analysis. Case series

La beta talasemia intermedia es una hemoglobinopatía de amplio espectro clínico, que surge de la presencia de una o dos mutaciones en el gen HBB, asociada a modificadores genéticos secundarios y/o terciarios. Analizamos las características clínicas y de laboratorio de 29 pacientes con beta talasemia intermedia, evaluados en un período de 23 años. La edad mediana fue de 10,8 años (rango: 0,34-60,4). El 100% de los pacientes mostró anemia microcítica hipocrómica, y solo el 17,2% presentó esplenomegalia y requerimiento transfusional esporádico. El análisis molecular de los pacientes detectó 3 con los dos genes HBB afectados; 2 con un gen HBB afectado y genes alfa cuadriplicados/triplicados; 23 con un gen HBB afectado y genes alfα triplicados; y 1 con dos genes HBB afectados y polimorfismos de genes gama. La correcta identificación de estos pacientes aseguró un adecuado consejo genético y la implementación de controles clínicos regulares.

Beta thalassemiaintermediaisaquantitative haemoglobinopathy covering a broad clinical spectrum, that results from the presence of one or two HBB gene mutations associated with secondary and/or tertiary genetic modifiers. We analyze the clinical and laboratory features of 29 patients with beta thalassemia intermedia, assessed over a period of 23 years. Median age was 10.8 years (range: 0.34-60.4). Hypochromic microcytic anemia was seen in 100% of the patients, while only 17.2% had splenomegaly and occasional transfusion requirement. The molecular analysis of patients detected: 3 with two HBB affected genes; 2 with one HBB affected gene and alpha quadruplicate/triplicate genes; 23 with one HBBaffected gene and alpha triplicate genes and 1 with two HBB affected genes and polymorphisms of gamma genes. The adequate identification of these patients enables us to give appropriate genetic counseling and implementation of regular clinical follow up

Anemia hemolítica grave causada por hemoglobina Southampton: Presentación de caso clínico / Severe hemolytic anemia due to hemoglobin Southampton: Case report

Las hemoglobinopatías estructurales son variantes de la hemoglobina caracterizadas por la síntesis de una molécula cualitativamente diferente de la normal. La mayoría son inocuas, mientras que otras ocasionan cambios fisicoquímicos que determinan manifestaciones clínicas de gravedad variable. En el caso de las hemoglobinas inestables, las alteraciones reducen la solubilidad y facilitan la formación de complejos de hemoglobina desnaturalizada (cuerpos de Heinz) que precipitan, lo cual daña la membrana y destruye prematuramente al eritrocito. Hasta la actualidad se han descrito 142 hemoglobinas inestables, muchas de ellas ocasionan hemólisis crónica, que puede exacerbarse por infecciones o por la ingesta de medicamentos o drogas oxidantes. La hemoglobina Southampton (también conocida como hemoglobina Casper) es una variante inestable que resulta de la sustitución de un residuo de leucina por uno de prolina, en el codón ß106 (CTG ?CCG, como consecuencia de la mutación c.320 T>C. Presentamos una niña con anemia hemolítica grave, esplenomegalia y requerimiento transfusional debidos a hemoglobina Southampton.

Variant hemoglobins are the result of different types of mutations that occur in the globin genes. In many cases, these hemoglobinopathies are harmless, while in others they determine alterations in the physical and chemical properties raising clinical manifestations of variable severity. In the unstable hemoglobinopathies, the changes reduce solubility, inducing the formation of precipitates of denaturated hemoglobin (Heinz bodies), which damage the membrane and finally destroy the red blood cells prematurely. Up to now, more than 142 different unstable hemoglobins have been described, most of them cause chronic hemolysis, increased by infections or drugs. We report the clinical presentation of an unstable hemoglobin (hemoglobin Southampton) in a girl with severe hemolytic anemia, splenomegaly and red blood cell requirement.

Índices eritrocitarios en la esferocitosis hereditaria / Erythrocyte indexes in hereditary spherocytosis

La esferocitosis hereditaria es un grupo heterogéneo de desórdenes caracterizados por la variabilidad en la clínica, en los defectos proteicos del citoesqueleto eritrocitario y en el tipo de herencia. Se estudió la sensibilidad y especificidad de la concentración de hemoglobina corpuscular media (CHCM) y el índice de amplitud de distribución eritrocitaria (ADE) en el screening diagnóstico de la esferocitosis hereditaria. Noventa y cuatro pacientes fueron comparados con niños sanos de igual sexo y edad. Todos los índices se obtuvieron por impedancia eléctrica (autoanalizador hematológico Coulter JT). En los pacientes con esferocitosis hereditaria, la CHCM (35.67±1.33 g/dl) y el ADE (20.60±4.5%), fueron significativamente más elevados que en el grupo control (CHCM 33.48±0.68 g/dl, p 0.000; ADE 13.22±0.9%, p 0.000). Con los valores de corte utilizados en nuestro laboratorio (CHCM ≥ 34.5 g/dl; ADE ≥ 14.5%) ambos índices elevados mostraron una sensibilidad de 81% y una especificidad de 98.9% en el screening de esferocitosis hereditaria. La combinación de ambos índices es un excelente predictor para el diagnóstico de esferocitosis hereditaria.

Hereditary spherocytosis is a group of heterogenous disorders characterized by variability in its clinical manifestations, membrane protein defects and inheritance. We analysed the sensitivity and specificity of mean corpuscular hemoglobin concentration (MCHC) and red cell distribution width (RDW) in the diagnostic screening of hereditary spherocytosis. Ninetyfour patients were compared to equal number of healthy, age-matched children. All indexes were derived from measurements obtained by aperture impedance (Coulter Counter Model JT). In patients with hereditary spherocytosis, MCHC (35.67±1.33 g/dl) and RDW (20.60±4.5%) were significantly higher than in normal control subjects (MCHC 33.48±0.68 g/dl, p: 0.000; RDW 13.22±0.9%, p: 0.000). By using a cutoff for the MCHC of 34.5 g/dl and for the RDW of 14.5%, both indexes showed a sensitivity of 81% and a specificity of 98.9%. The combination of the two test is an excellent predictor for the diagnosis of hereditary spherocytosis.

Tratamiento con vincristina de tres tumores vasculares con fenómeno de Kasabach-Merritt / Vincristine treatment of three vascular tumors with Kasabach-Merritt phenomenon

El fenómeno de Kasabach-Merrit (FKM) es una coagulopatía por consumo que se presenta en las primeras semanas de la vida. Se caracteriza por presentar coagulopatía por consumo, con trombocitopenia y anemia hemolítica microangiopática, asociado a un tumor vascular. El objetivo de este trabajo es presentar tres pacientes con tumores vasculares que manifestaron FKM y fueron tratados con vincristina como droga de segunda línea, atendidos en el Servicio de Dermatología del Hospital de Pediatría J. P. Garrahan. Dos pacientes presentaron el tumor al nacimiento y otro a partir de los dos meses de vida. Dos fueron niñas y uno varón.Todos los pacientes tenían una trombocitopenia severa (3 000/mm_), bajos niveles de fibrinógeno y dimero D elevado. Los tumores estaban localizados en región proximal de miembro inferior, tronco y miembro superior, y región cervical. Ninguno de nuestros pacientes tuvo compromiso de órganos internos. El diagnóstico histológico en dos de ellos fue de hemangioendotelioma kaposiforme (HEK). Los corticoides fueron el tratamiento de primera linea: metilprednisona 3mg/kg/día por vía oral. En un paciente el tumor continuó creciendo a pesar de haber asociado interferón alfa 2 a la corticoterapia y realizarle secundariamente una embolización. Dada la falta de respuesta clínica y hematológica, se decidió iniciar tratamiento con vincristina 1mg/m2/dosis/IV semanal. Todos los pacientes normalizaron los parámetros hematológicos, con franca mejoría clínica, dos pacientes a la quinta y otro a la sexta dosis de vincristina, con involución gradual del tamaño del tumor. Ninguno de los pacientes presentó complicaciones secundarias al tratamiento ni recidivas de su enfermedad a la fecha. La duración promedio de tratamiento fue de 35±6 días. Podemos concluir que el uso de vincristina es considerado en la actualidad una droga de segunda línea en el tratamiento de tumores vasculares con FKM (AU)

Kasabach-Merritt phenomenon (KMP) is a consumptive coagulopathy that typicallly presents in the first few weeks of life. It is characterized by a triad of vascular tumor, thrombocytopenia and coagulopathy. We reviewed the clinical and hematologic data and response to therapeutic with vincristine in three patients who had a vascular tumor and KMP at the Dermatology Department of Hospital de Pediatría J. P. Garrahan.Tumors were present at birth in two patients and in one at two months old. Two were girls and one was a boy. All patients had severe thrombocytopenia (Lowest platelets count 3 000/mm_), consumption of fibrinogen and lower D-dimer levels.Tumors were localized on proximal lower limb, trunk and upper limb and cervical area. None of our patients had internal involvement. Histopathology finding in two of them was kaposiform hemangioendothelioma. First line of treatment was prednisolone 3-5mg/kg/day. In one patient the tumor size continued to increase in spite of simultaneous treatment with corticosteroid and interferon alfa-2a plus embolization. After corticosteroids treatment failure, correction of coagulopathy and tumor regression occurred in our three patients after 5 to 6 doses of vincristine 0.5-1mg/m_ IV weekly with almost complete tumor regression and correction of coagulopathy.The average duration of treatment was 35±6days. None of the patients developed complications due to this intervention nor experienced recurrence of the tumor.The use of vincristine is currently a second line treatment of vascular tumors with KMP (AU)

Efecto de la hidroxiurea en hemoglobina S / Effect of hydroxyurea on hemoglobin S

Previous studies have determined the laboratory alterations, clinical efficacy and toxicity profile associated with hydroxyurea (HU) therapy in patients with severe sickle cell anemia. We report the efficacy of HU treatment in the prevention of vaso-occlusive crises in an 11-years-old boy with severe sickle cell disease. The number of vaso-occlusive crises, hospital days and blood transfusions in the year before HU treatment were compared with the same parameters at 6, 12, 24, 36 and 72 months of treatment. A decrease in the frequency of vaso-occlusive crises, blood transfusions and days spent in hospital were demonstrated during the HU treatment period compared to the same period before hand. The clinical and laboratory response to HU was dramatic in this severely affected patient, allowing him a normal schooling and social life. The adverse effects observed were not serious and reversed after transient discontinuation of HU. We conclude that long-term chronic treatment with HU for seriously ill sickle cell patients appears feasible, and devoid of any major toxicity

Beta talasemia mayor en la Argentina / [Beta thalassemia major in Argentina]

An analysis of beta thalassemia major patients seen at Hospital Juan P. Garrahan was carried out in order to determine the characteristics and outcome of the population. From August 1987 to July 2000, 45 patients were admitted (27 males-18 females). The most common beta globin gene defects were C-39 (30.7

). alpha globin genes were normal in 42 patients, 1 patient had triplicate and cuadriplicate alpha globin genes and 2 patients were not analyzed. Six patients of 5 families were heterozygous for -158G gamma mutation. Allogeneic stem cell transplantation was performed in 7 patients, with an identical sibling. Transfusion-related infections and alloantibodies were detected in 6.7

patients. Growth assessment showed no significant difference in the stature of girls compared to the reference population, but 5 boys had short stature. There is a tendency to short trunk. Growth velocity was normal at prepubertal age. No X-ray lesions related to desferrioxamine were observed. Delayed puberty and hypogonadotropic hypogonadism were found in 35.7

and abnormalities in GH/IGF-I axis in 12.5

of the patients. Impaired glucose tolerance was found in 2 patients. No patient developed diabetes mellitus, thyroid or adrenal insufficiency. One patient had cardiac complications. Forty-two patients are alive and 3 died (cardiac failure 1, central nervous system bleeding 1, sepsis 1). We conclude that beta thalassemia major, originated mainly from Italian immigrants, has a cumbersome treatment and is severely hindered by the lack of adequate economic resources in our patients.