A novel mutation of the human luteinizing hormone receptor in 46XY and 46XX sisters.

We report a novel homozygous mutation of the LH receptor (LHR) gene in three siblings: two 46XY and one 46XX. The 46XY siblings presented with female external genitalia, primary amenorrhea, and lack of breast development. Hormonal evaluation revealed a markedly elevated LH level with a low testosterone level, which failed to increase after human CG stimulation. Enzymatic deficiencies of testosterone biosynthesis were eliminated as possible etiologies. Histologic analysis of the inguinal gonads in a 46XY sibling revealed no Leydig cells; Sertoli cells, spermatogonia, and primary spermatocytes were seen. The 46XX sibling had female external genitalia, normal breast development, and primary amenorrhea. Hormonal analyses showed markedly elevated LH levels and low plasma 17 beta-estradiol levels. Genetic analysis of the LHR revealed a homozygous missense mutation at exon 11 of the LHR gene. Guanine was replaced by adenine (GAA-->AAA), resulting in a substitution of lysine for glutamic acid (glu) at amino acid position 354 of the receptor. This mutation is located in the extracellular domain adjacent to the first transmembrane helix of the LHR. Glutamic acid at position 354 of the LHR has been highly conserved throughout evolution. Functional analysis of the LHR mutation, using an in vitro mutagenesis-transfection assay, demonstrated complete loss of function, indicated by the lack of cAMP production after human CG stimulation in transfected human embryonic kidney 293 cells. Screening of family members demonstrated heterozygosity for the mutation, indicating autosomal recessive inheritance. Delineation of the specific genetic defect in this family confirms recent reports that a single mutation in the LHR gene causes male pseudohermaphroditism in 46XY subjects and primary amenorrhea in 46XX subjects. More importantly, it also defines a new region of the LHR molecule that is critical for biologic activity.

5 alpha-reductase-2 gene mutations in the Dominican Republic.

Male pseudohermaphroditism due to 5 alpha-reductase deficiency was clinically and biochemically described in a large Dominican kindred of 23 families with 38 affected subjects in 1974. Recently, the 5 alpha-reductase-2 gene defect in the large Dominican kindred was found to be due to a single base substitution of thymidine (TGG) for cytosine (CGG) on exon 5 of the 5 alpha-reductase-2 gene, causing a tryptophan replacement of arginine at amino acid 246 (R246W) of the enzyme. In the present report, affected subjects from four additional Dominican families were studied to determine whether they carried the same 5 alpha-reductase-2 gene defect as the large kindred, suggesting a common ancestry for the gene defect within this small country. Using single strand conformational polymorphism and DNA sequencing, two other mutations of the 5 alpha-reductase-2 gene were found in affected subjects from two of the four families. A point mutation on exon 2 of the 5 alpha-reductase-2 gene, in which substitution of adenine (GAC) for guanine (GGC) caused an aspartic acid replacement of glycine at amino acid 115 (G115D), was demonstrated in one of these families, and a substitution of adenine (AGT) for guanine (GGT) on exon 3 causing a serine replacement for glycine at amino acid 183 (G183S) was detected in the other family. Affected subjects from the two remaining families demonstrated the same exon 5 mutation of the 5 alpha-reductase-2 gene as previously detected in the large Dominican kindred. The phenotypic and biochemical characteristics of the male pseudohermaphrodites were similar regardless of the genetic defect, except that one affected subject (C-VI-2) with the same exon 5 mutation as the large Dominican kindred had much more facial and body hair. Thus, the identification of multiple mutations in the 5 alpha-reductase-2 gene in male pseudohermaphrodites from the Dominican Republic demonstrates a lack of common ancestry, as had been previously postulated.

The biochemical and phenotypic characterization of females homozygous for 5 alpha-reductase-2 deficiency.

The biochemical and physiologic manifestations of decreased 5 alpha-dihydrotestosterone (DHT) in females are characterized. Three females from the large Dominican kindred with 5 alpha-reductase-2 deficiency were identified as homozygous for a point mutation (R246W, C-->T) on exon 5 of the 5 alpha-reductase-2 gene by single strand DNA conformational polymorphism analysis and DNA sequence analysis. Body hair was decreased; there was no history of acne. Despite delayed menarche, all were fertile, and two had twins. Urinary 5 beta/5 alpha C19 and C21 steroid metabolite ratios were elevated. Plasma testosterone was normal to elevated, with low DHT, resulting in an increased testosterone/DHT ratio. 3 alpha,5 alpha-Androstanediol glucuronide was low. Menstrual cycle profiling performed in two subjects showed ovulatory gonadotropin peaks. Sebum production was normal. 5 alpha-Reductase-2-deficient homozygotic females demonstrate the importance of DHT in the physiology and pathophysiology of body hair growth. Normal sebum implies regulation by the 5 alpha-reductase-1 isoenzyme. Delayed puberty suggests involvement of 5 alpha-reductase-2 in menarche at the hypothalamic/pituitary and/or ovarian level. As two had nonidentical twins, DHT and/or the DHT/estradiol ratio may regulate follicular development, with lower levels permitting more than one dominant follicle per cycle and higher levels impairing follicular development and ovulation. Thus, females with 5 alpha-reductase-2 deficiency highlight a role for DHT in hirsutism and/or menstrual disorders.

Distribución de colesterol, trigliceridos y lipoproteinas plasmaticas en dominicanos sanos: estudio retrospectivo de 1980 a 1990 en una población comprendida entre 20 y 79 años / Cholesterol tryglicerides and lipoproteines in the plama of healthy Dominicans : retrospective study form 1980 to 1990 in a population between 20 to 79 years old

Se estudiaron 551 pacientes entre 20 y 79 años de edad, los que fueron divididos por sexo y en grupos de 5 años. Hubo 309 hombres y 242 mujeres. Los grupos fueron también subdivididos en fumadores y no fumadores así como hijos y no hijos de padecederos de enfermedad coronaria. Se les tomó sangre para medir en el suero triglicéridos, colesterol total y fraccionado. El valor promedio de trigliceridos en la población masculina fue de 157 mg/dL mientras en la femenina fue de 123.9 mg/dL. El valor promedio de colestrol en la población masculina fue de 208mg/dL y en la femenina de 206 mg/dL. El valor promedio para las HDL en la población masculina fue de 40.7 mg/dL y en la femenina 44.7 mg/dL. Para las LDL el valor promedio en la población masculina fue de 133.5 mg/dL y para la femenina 134.9 mg/dL. La relación de riesgo fue mayor en la población masculina (5.6) en la relación con la femenina (5.0). De los 551 pacientes 53 resultaron ser hipertrigliceridémicos para un 9.3 por ciento con niveles superior a 250 mg/dL de trigliceridos. De estos 38 fueron masculinos y 15 femeninos. De los 551 pacientes, 141 o sea 23.8 por ciento tenían hipercolesterolemia con colestrol por encima de 240 mg/dL. De estos 71 correspondieron al sexo masculino y 60 al femenino. Un total de 161 pacientes (29.2 por ciento ) preentó hipoalfalipoproteinemia o sea un nivel de HDL de 35 mg o menos. De estos 112 pertenecían al sexo masculino y 49 al sexo femenino. Un total de 140 pacientes (25.4 por ciento ) presentaron hiperbetalipoproteinemia, esto es, niveles de LDL superiores a 160 mg/dL. De estos 74 correspondieron al sexo masculino y 66 al femenino. En la población fumadora masculina los niveles de HDL fueron mas bajos que en la no fumadora, 36.6 versus 42.4 mg/dL respectivamente. En la población famenina estos valores fueron para las fumadoras 40.4 y para las no fumadoras 45.8 mg/dL. No hubo relación con las variables y el factor hereditario de enfermedad coronaria

Fiebre reumatica en niños menores de 5 años: revisión clínica de 20 años (1969-1989); Hospital Infantil Dr. Robert Reid Cabral, Santo Domingo / Rheumatic fever in children under 5 year old: clinical review of 20 years (1969-1989) : Hospital Infantil Dr. Robert Reid Cabral, Santo Domingo

En un período de 20 años encontramos 121 casos de fiebre reumática en niños menores de 5 años para un 0.62 por ciento de los pacientes registrados en el departamento de cardiología del hospital. Un 83.5 por ciento de ellos presentaron manifestaciones de carditis y 19.8 por ciento manifestaciones de artritis

Prevencion de la endocarditis infecciosa en ninos cardiopatas. / Prevention of the infectious endocarditis in children with cardiopathies

Se comenta sobre la importancia de la prevencion de la endocarditis infecciosa en ninos con cardiopatias, estableciendose los criterios aceptados para su realizacion