Familial male pseudohermaphroditism

Familial male pseudohermaphroditism (MPH) due to 17, 20-desmolase deficiency is rare. Here we present two siblings with MPH possibly due to 17, 20-desmolase deficiency. The first patient presented with unambiguous female external genitalia and hypergonadotrophic hypogonadism. Chromosomal analysis revealed 46 XY. Ultrasound evaluation of pelvis revealed gonads in the inguinal canal, and no uterus. These findings were confirmed on laparotomy. Histology revealed the gonads to be testes. The second patient had ambiguous genitalia (perineoscrotal hypospadias, bifid scrotum with palpable gonads) with a 46 XY chromosomal pattern. Both patients had high plasma 17-hydroxy progestrone (17 OHP), low normal dehydro epiandrosterone sulphate (DHEAS) and low plasma testosterone. Plasma testosterone and DHEAS showed no response to ACTH or HCG. These features are compatible with the diagnosis of 17, 20-desmolase deficiency.     

Unusual Lack of the Epitope Recognized by OKT4 on the Helper/Inducer T Lymphocytes

Lack of the epitope recognized by OKT4 monoclonal antibody on the helper/inducer T lymphocytes in a 14-year-old boy with IgA nephritis is described. The lymphocytes reacted normally with OKT3 /Leu4 and OKT8/αLeu2a monoclonal antibodies but not with OKT4 monoclonal antibody. Studies with other monoclonal antibodies (αLeu3a, OKT4A, OKT4B, OKT4C, OKT4D) which also identify the helper/inducer T lymphocyte subset revealed that cells of this population were present in normal numbers among the lymphocytes of the peripheral blood. Staining with OKT4 plus αLeu3a in normal persons indicated that T4 antigen is present on a small population of lymphocytes which lack Leu3a antigen. Further, the intensity of staining of the majority of cells in the subpopulation is increased when these two fluorescienated antibodies are used together. In this patient neither this small OKT4⁺ Leu 3a^- population nor the cells bearing the Leu3a antigen showed OKT4 staining. The findings in the surface marker analysis of E+ OKT8- peripheral lymphocytes which were achieved by panning of the patient's peripheral cells indicated the existence of a population of E⁺OKT8^- peripheral lymphocytes which were achieved by panning of the patient's periphera cells indicated the existence of a population of E⁺ (4A⁺4B⁺4C4D⁺)αLeu3al⁺ ly mphocytes in this patient. Lymphocyte responses to PHA, ConA and PWM, however, were all within normal range. Further, this patient had normal serum immunoglobulin levels and exhibited no symptoms or signs of immunodeficiency. These findings indicate that the patient under study has functionally normal helper/inducer T lymphocytes which lack the epitope recognized by OKT4 monoclonal antibody.     

Germ cells and ova in dysgenetic gonads of a 46-XY female dizygotic twin.

The frequency of germ cell neoplasms in girls with 46-XY gonadal dysgenesis suggests that germ cells may persist in the dysgenetic gonads for many years. A phenotypic female infant with a karyotype of 46-XY in blood, skin, and gonads had a few ova in primordial follicles and numerous germ cells in her dysgenetic gonads at the age of 3 months. At 3 years and 10 months of age her gonads contained no primordial follicle and the only remaining germ cells were in a gonadoblastoma. We propose that germ cells are lost from dysgenetic gonads much more rapidly than from normal gonads, but that the rate of loss in patients with a karyotype of 46-XY may be less than the rate of loss in patients with a karyotype of 45-XO.     

Cerebrospinal fluid evaluation in neonates: comparison of high-risk infants with and without meningitis.

Results of CSF examinations from 117 high-risk neonates were reviewed. The mean CSF cell count was 8.4 cells/mm3 and the range was 0 to 32 cells/mm.3 Approximately 60% of the CSF WBC were polymorphonuclear leukocytes. Average CSF protein concentrations were 90 mg/dl (range, 20-170 mg/dl) in term and 115 mg/dl (range, 65-150 mg/dl) in preterm infants. The average CSF glucose was 81% of the blood glucose value in term and 74% in preterm infants. Comparison of these CSF findings with those from 119 infants with bacterial meningitis revealed that there was considerable overlapping of values, but only one of the 119 infants with meningitis had a completely normal initial CSF examination. The decision to initiate antimicrobial therapy in neonates with suspected meningitis must be based on total evaluation of the patient.     

CHEMICAL PATHOLOGY OF KRABBE''S DISEASE

ABSTRACT: Svennerhotai, L., Håkansson, G. and Vanier, M. Th. (Department of Neurochemistry, Psychiatric Research Centre, University of Göteborg, Göteborg, Sweden). Chemical pathology of Krabbe's Disease. IV. Studies of galactosylceramide and lactosylceramide β-galactosidases in brain, white blood cells and amniotic fluid cells. Acta Paediatr Scand, 64: xxx, 1975.–Galactosylceramide β-galactosidase and lactosylceramide β-galactosidase activities were investigated in normal human brain, leukocytes and amniotic fluid cells. The enzymatic assays were performed on brains from 11 patients with Krabbe's disease, on leukocytes from 16 patients and 18 obligate heterozygotes, and on amniotic fluid cells from 9 foetuses at risk. The brain enzyme was solubilized from a 900 g-100000 g pellet. With this enzyme preparation a profound deficiency of galactosylceramide β-galactosidase activity in brain, approximately 1 % of that in age-matched controls was shown. The lactosylceramide β-galactosidase activity of brain was also strongly reduced, but not to the same extent as the other β-galactosidase. Galactosylceramide β-galactosidase activity in leukocytes from patients with Krabbe's disease was generally less than 5 % of that in age-matched controls, and there was no overlap between the patients and the obligate heterozygotes. Carrier detection by the leukocyte enzyme was, however, not possible, because of considerable overlap between heterozygotes and normal controls. The lactosylceramide β-galactosidase activity was only moderately reduced in leukocytes, but strongly reduced in cerebral tissue from patients with Krabbe's disease. The changes in the glycolipid pattern of cerebral tissue, recently described by us in patients with Krabbe's disease, offers an explanation to the serious glycolipid β-galactosidase deficiency in CNS.     

Immunologic study of the age-related loss of activity of six enzymes in the red cells from newborn infants and adults--evidence for a fetal type of erythrocyte phosphofructokinase.

Blood from 10 normal healthy adults and cord blood from 8 healthy full term infants were infiltrated through a mixture sulfoethylethycellulose-Sephadex G 25 in order to eliminate the platelets and the leukocytes. Then the erythrocytes were fractionated into young and old cells by centrifugation in microhematocrit tubes. The enzyme activity and the immunologic reactivity of glucose phosphate isomerase (EC.5.3.1.9), phosphoglycerate kinase (EC.2.7.2.3), pyruvate kinase (ec.2.7.1.40), glucose 6-phosphate dehydrogenase (EC. 1.1.1.49), and 6-phosphogluconate dehydrogenase (EC.1.1.1.44) were measured in every fraction. As previously reported, the enzyme activities were far higher in cord blood than in adult blood red cells; nevertheless, the age-related loss of enzyme activity was similar in both cord and adult blood. The decrease of the enzyme activity of glucose phosphate isomerase and phosphoglycerate kinase in old cells was singly associated with a lowered concentration of the enzyme-related antigen; by contrast, the age-related decrease of the enzyme activity of pyruvate kinase, glucose-6-phosphate dehydrogenase, and 6-phosphogluconate dehydrogenase was associated with both a lowered concentration of the enzyme-related antigen and a lowered "molecular specific activity" (i.e., a lowered ratio of enzyme activity to enzyme-related antigen concentration). This phenomenon was especially marked for pyruvate kinase, which had a molecular specific activity in old cells that was 68% of that in young cells. Phosphofructokinase had a lower enzyme activity in cord blood erythrocytes than in adult blood erythrocytes; the difference was especially important in old cells from infants in which phosphofructokinase activity was 53% of that in old cells from adults. Phosphofructokinase from old cells of full term infants and from unfractionated cells from two premature infants (21 and 32 weeks of gestation) was less neutralized by anti-muscle phosphofructokinase serum and more inhibited by ATP than the enzyme from adult blood erythrocytes.     

Glycogenosis II: Comparative Biochemical and Electron Microscopic Studies on Infantile and Late Onset Patients

Acid α-glucosidase was studied in mixed leukocytes, lymphocytes, fibroblasts and livers from patients with glycogenosis II. This enzyme was deficient in all specimens from an infantile type patient, whereas there was a higher residual activity of this enzyme in a late onset patient, when 4-methylumbelliferyl-α-glucopyranoside and maltose were used as substrates. The hydrolytic activity toward glycogen in the liver of the late onset patient was as low as in the early onset patient. Km and thermostability were identical for the latter patient and the controls. The neutral enzyme was normal in both patients. Complementation of the enzyme activity was not demonstrated in the fused cells of these two patients, suggesting the allelic gene mutation on the same locus. There was no difference in the ultrastructure of fibroblasts from both patients.     

A Sterile 21, X Chinese Hamster

Abstract A Chinese hamster with a single X chromosome was found in 23 off-spring from crosses between a male heterozygous for T(1;3)8Idr translocation and karyologically normal females. All karyotypes of cells from various tissues of this animal were 21, X. The animal had an external genitalia generally characteristic to the female but no typical proestrous and estrous figure was found in the vaginal smear, and the animal showed no indication of pregnancy by any crosses. On autopsy, two gonads were found. Microscopically, there were some large fluid-filled cysts and many follicle-like bodies in the cortex of both gonads, but no mature follicle containing an oocyte was observed. The XO conditions in the Chinese hamster are compared with those of other mammals.     

Activation of NKT Cells by IL 15 Plus GM CSF Stimulation and Its Cytotoxicity to Neuroblastoma Cells

Ｎｅｕｒｏｂｌａｓｔｏｍａ (ＮＢ)ｉｓｔｈｅｍｏｓｔｃｏｍｍｏｎｍａｌｉｇ ｎａｎｔｔｕｍｏｒｏｆｔｈｅｓｙｍｐａｔｈｅｔｉｃｎｅｒｖｏｕｓｓｙｓｔｅｍｉｎｃｈｉｌ ｄｒｅｎ .Ｔｈｅｌｏｎｇ ｔｅｒｍｓｕｒｖｉｖａｌｉｓｌｏｗｗｉｔｈｆｒｅｑｕｅｎｔｒｅ ｃｕ     

An unusual case of T-cell lymphoproliferative disorder.

A 54-year-old woman with epigastric pain had leukocytosis of 73,000/microliter consisting mainly of atypical lymphoid cells with convoluted and cleaved nuclei resembling Sézary cells; the bone marrow aspirate was nondiagnostic. Skin biopsy was unremarkable. The patient also had hypercalcemia and hemolysis with a positive direct Coombs' test, both of short duration. The arterial oxygen tension was decreased, but there was no demonstrable lung pathology. The patient subsequently developed rapidly enlarging lymphadenopathy. Lymph node biopsy was interpreted as "undifferentiated pleomorphic lymphoma." Immunologic functional studies revealed that the majority of the peripheral blood atypical lymphoid cells from involved lymph nodes formed rosettes with sheep erythrocytes. The lymphadenopathy regressed transiently after the administration of chemotherapy and the white blood cell count decreased from a maximum of 385,000/microliter to 3,500/microleter, at which point the arterial oxygen tension returned to normal. The unusual features of this patient are discussed in light of the known characteristics of the various types of T-cell lymphorpoliferative disorders.     

Significance of polymorphonuclear leukocytes in CSF of bacteremic children

A retrospective study was performed of 32 bacteremic children not receiving preadmission antibiotic therapy who had a diagnostic lumbar puncture for analysis of cerebrospinal fluid at the time of initial evaluation for an acute illness. In each instance, the CSF contained polymorphonuclear leukocytes without pleocytosis. Of these 32 bacteremic patients, 88% had a CSF differential cell count with 20% or fewer polymorphonuclear cells, and greater than 90% had glucose and protein concentration within the range of normal limits. All patients had a Gram-stained smear of CSF which revealed no organisms. In no instance was a CSF culture positive for a bacterial pathogen. In the bacteremic child not pretreated with antibiotics, cerebrospinal fluid which contains total white blood cell, glucose, and protein concentrations within limits of normal, a differential cell count with 20% or fewer polymorphonuclear leukocytes, and Gram-stained smear which reveals no organisms is not indicative of risk for bacterial meningitis.     

Myeloperoxidase deficiency as a cause of recurrent infections

Myeloperoxidase (MPO) deficiency is a common hereditary leukocyte function defect. A two year old girl with MPO-deficiency suffered from recurrent skin infections. No MPO-activity was detectable in leukocytes of her peripheral blood smears, while NBT reduction and chemotactic activity was normal. The quantitative enzyme determination in leukocyte sonicates confirmed the total MPO-deficiency in the girl's leukocytes and a partial MPO-deficiency in the cells of her mother. The patient leukocytes demonstrated also an impaired chemiluminescence.     

Gonadal Pathology in Triploidy

There are numerous reports describing the pathology of the fetus and placenta in triploidy. Although gonadal pathology is described in many of these reports, consistent changes have not been noted nor is it clear whether genital ambiguity can be considered part of the triploid phenotype. We present a case of triploidy of probable diandric origin, in which there were dysgenetic gonads with abnormal seminiferous tubules, nodules of undifferentiated stroma, and focal absence of the tunica albuginea. As this finding was distinctly unusual in our experience of triploid gonadal pathology, we reviewed the gonadal histology in 51 fetal and infant triploids examined in our autopsy/embryopathology laboratory. The gonads were compared to age-matched normal controls to determine if there was a specific gonadal pathology associated with triploidy and if there was any correlation of this pathology with parental origin of the triploidy. Our review of the triploid gonads indicated that while minor, nonspecific changes were not uncommon, overtly dysgenetic gonads, as observed in the index case, are rare. Received June 2, 1999; accepted November 5, 1999.     

An unusual case of T-cell lymphoproliferative disorder

A 54-year-old woman with epigastric pain had leukocytosis of 73,000/μ1 consisting mainly of atypical lymphoid cells with convoluted and cleaved nuclei resembling Sézary cells; the bone marrow aspirate was nondiagnostic. Skin biopsy was unremarkable. The patient also had hypercalcemia and hemolysis with a positive direct Coombs' test, both of short duration. The arterial oxygen tension was decreased, but there was no demonstrable lung pathology. The patient subsequently developed rapidly enlarging lymphadenopathy. Lymph node biopsy was interpreted as “undifferentiated pleomorphic lymphoma.” Immunologic functional studies revealed that the majority of the peripheral blood atypical lymphoid cells from involved lymph nodes formed rosettes with sheep erythrocytes. The lymphadenopathy regressed transiently after the administration of chemotherapy and the white blood cell count decreased from a maximum of 385,000/μ1 to 3,500/μ1, at which point the arterial oxygen tension returned to normal. The unusual features of this patient are discussed in light of the known characteristics of the various types of T-cell lymphoproliferative disorders.     

Aplastic presentation of acute lymphoblastic leukemia: evidence for cellular inhibition of normal hematopoietic progenitors

Childhood acute lymphoblastic leukemia (ALL) may rarely present with blood and bone marrow findings suggestive of aplastic anemia. Although numerous examples of ALL presenting with this phenomenon have been reported, there is no accepted explanation for the pathogenesis of this preleukemic hypoplasia. We report a case of a child with ALL whose initial presentation was characterized by pancytopenia and bone marrow hypoplasia and who had repeated episodes of pancytopenia at times of systemic relapse. In vitro coculture experiments demonstrated that the leukemic cells from this patient were inhibitory for the growth of myeloid, erythroid, and megakaryocytic progenitor cells from normal peripheral blood. This inhibitory effect exhibited a dose-dependent relationship with the number of added lymphoblasts and persisted when the lymphoblasts were irradiated to prevent leukemic cell growth. Inhibitory activity was not present in media conditioned by the growth of the patient's lymphoblasts, nor was it present in lymphoblasts from three other children with ALL with similar immunophenotype but without marrow aplasia. These data suggest that the aplastic presentation of ALL may be attributable to inhibitory properties intrinsic to the leukemic cells rather than to other host factors.     

Immune response to herpes simplex virus in patients with recurrent herpes labialis. II. Relationship between interferon production and cytotoxic responses

The relationship between the development of cytotoxic cellular immune response to herpes simplex virus type I (HSV-1)-infected autologous cells and the production of interferon (IFN) was studied using in vitro secondary sensitization of peripheral blood leukocytes in subjects with recurrent herpes labialis (RHL) and in normal controls without any history of recurrent herpes labialis. There was a significant discordance between optimal HSV-1 antigen dose required for induction of peak cytotoxic responses and for maximal activity of IFN. Moderate IFN activity (6-100 U/ml) was demonstrated in all HSV-1 antigen-stimulated peripheral blood leukocytes collected from subjects during both acute and convalescent phase of RHL. However, only 50% of seropositive controls and no seronegative controls exhibited detectable IFN activity, when stimulated with HSV-1 antigen, although such in vitro stimulation resulted in maximal virus-specific cell-mediated cytotoxicity. A correlation of virus specific cytotoxic activity to HSV-1 and IFN production (r = 0.38, p less than 0.05) was less marked than that of cytotoxic activity to K562 (natural killer-sensitive target cells) and IFN titer (r = 0.48, p less than 0.01). Furthermore significant reverse correlations between cytotoxicity against HSV-1-infected autologous cells and a titer of gamma-IFN was observed in samples with high cytotoxic activity. These observations suggest that gamma-IFN produced by HSV immune T cell may also act as an autoregulatory factor against the production of cytotoxic cellular activity against HSV-1-infected autologous cells.     

Chemical pathology of krabbe's disease. IV. Studies of galactosylceramide and lactosylceramide BETA-galactosidases in brain, white blood cells and aminotic fluid cells.

Galactosylceramide beta-galactosidase and lactosylceramide beta-galactosidase activities were investigated in normal human brain, leu-kocytes and amniotic fluid cells. The enzymatic assays were performed on brains from 11 patients with Krabbe's disease, on leukocytes from 16 patients and 18 obligate heterozygotes, and on amniotic fluid cells from 9 foetuses at risk. The brain enzyme was solubilized from a 900 g-100000 g pellet. With this enzyme preparation a profound deficiency of galactosylceramide beta-galactosidase activity in brain, approximately 1% of that in age-matched controls was shown. The lactosylceramide beta-galactosidase activity of brain was also strongly reduced, but not to the same extent as the other beta-galactosidase. Galactosylceramide beta-galactosidase activity in leukocytes from patients with Krabbe's disease was generally less than 5% of that in age-matched controls and there was no overlap between the patients and the obligate heterozygotes. Carrier detection by the leukocyte enzyme was, however, not possible because of considerable overlap between heterozygotes and normal controls. The lactosylceramide beta-galactosidase activity was only moderately reduced in leukocytes, but strongly reduced in cerebral tissue from patients with Krabbe's disease. The changes in the glycolipid pattern of cerebral tissue, recently described by us in patients with Krabbe's disease, offers an explanation to the serious glycolipid beta-galactosidase deficiency in CNS.     

Deficiency of NADPH oxidase activity in chronic granulomatous disease.

NADPH oxidase activity was examined in paired 27,000 x g granule fractions isolated from normal polymorphonuclear leukocytes from patients with chronic granulomatous disease. At 0.17 mM NADPH, the oxidase activity was not measurable in normal resting cells but was activated by phagocytosis.This activation was absent in CGD cells. At higher levels of NADPH, activity was present in cells from patients with CGD, although it was lower than normal, and no difference in activity was found between resting and phagocytizing cells. Granule fractions from phagocytizing normal cells exhibited higher than granule fractions from resting normal cells at all levels of NADPH. These results suggest that NADPH oxidase activity is defective in chronic granulomatous disease, and further that the defect is not the absence of the enzyme but rather a failure to activate it.     

Biochemical studies in a patient with subacute neuropathic Gaucher disease without visceral glucosylceramide storage

Autopsy samples were obtained from a 12.5-year-old girl who died with a neurologic disorder consisting of myoclonus, myoclonic epilepsy, spasticity, strabismus, and mild mental retardation but no hepatosplenomegaly. Studies in leukocytes, cultured skin fibroblasts, brain, liver, and spleen of this patient revealed glucosylceramide beta-glucosidase (EC 3.2.1.45, glucocerebrosidase) activity about 10% of controls, and well in the range found in samples from Gaucher disease patients. Extraction of the lipids from liver and spleen with chloroform-methanol (2:1) did not show accumulation of glucosylceramide or other lipid. Examination of the lipids in brain by high performance liquid chromatography revealed the presence of glucosylceramide, which is not found in brain samples from controls. Pathologic examination of the liver and spleen revealed no evidence of Gaucher disease. The brain showed many degenerative lesions and loss of neurons. There was no complementation of glucocerebrosidase activity when the cells from this patient were hybridized with cells from patients with Type 1 or Type 2 Gaucher disease. The reason for the lack of glucosylceramide storage in the liver and spleen has not been determined.     

XY/XO mosaicism in a child with feminime phenotype manifesting internal genital ambiguity

A 18 year old patient presented with a female phenotype and no signs of sexual maturation. The leukocyte karyotype was XY. At laparotomy, there was no uterus and the gonadal streaks had a XY/XO mosaicism. There were rudiments of fallopian tubes and epididymis. Histologic examination of the gonads showed foci of Leydig and Sertoli cells.