XO mosaicism

XO mosaicism

THIRD PLENARY SESSION 88. The histogenesis of cardiac valves in the chick embryo tempted direct isolation and identification of acid mucopolysacch...

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88. The histogenesis of cardiac valves in the chick embryo

tempted direct isolation and identification of acid mucopolysaccharides present. At this time of chick embryo development, the majority of recoverable acid mucopolysaccharide present in the chick embryo was found to be located in the cardiac tube. It should be remembered, that at this stage cartilage centers have as yet not appeared. Da. SlSS~aAN. I am familiar with Dr. Gessner's work and it is of great interest to those of us interested in the embryology of the heart. Our analyses of valve development were begun on the fifth day of incubation, when the cardiac jelly becomes more restricted in its location and is already infiltrated with cells, which is 2 days after the stage of development at which Gessner performed his mucopolysaccharide identification.

Norman J. Sissman, ~ Stanford University School of Medicine, Palo Alto, Calif. Introduced by Norman Kretehmer Detailed description of the quantitative and qualitative aspects of the embryogenesis of normal heart valves is prerequisite to understanding the etiology of congenital valvular stenosis. Serial sections of the aortic, puhnonic, and mitral valves of chick embryos from Hamilton-Hamburger Stage 25 (5 days incubation) through hatching (21 days) and in the young mature chicken were stained histochemicaIly for collagen (C), elastic fibers (E), acid mueopolysaccharides ( A M P ) , periodic aeid-Schiff-positive material (P.A.S.), reticulin (R), and general nuclear and cytoplasmic constituents, and analyzed microscopically. Adult valves all have two distinct layers: the fibrous, which contains collagen, reticulin, AMP, and P.A.S.-positive material in longitudinal layers; and the spongy, comprised only loose A M P ground substance and scattered cells. The fibrous layer is located on the side of the valve subject to the highest pressure; i.e., the arterial face of the semilunar valves and the ventricular face of the atrioventricular valve. Changes occurring during embryogenesis are as follows: A M P is present diffusely throughout the valves from the earliest stage. Reticulin appears first at Stage 28 (5U2 days) and increases in amount and in degree of structural organization progressively. From Stage 34 (8 days, when septation is completed) on, there is continuing decrease in valve thickness and in cellular concentration. No collagen or elastic fibers are seen in the valves before hatching. The findings suggest that the nature and duration of helnodynamic pressures on the heart valves play an important role in the time of appearance and in the structure of connective tissue components in developing valves.

89. Hemophilia A in a phenotypically normal female with X X / X O mosaicism Gerald S. Gilchrist, ~ Denman Hammond, and John Melnyk,~ Childrens Hospital of Los Angeles and University of Southern California School of Medicine, Los Angeles, Calif. This is the first reported ease of severe antihemophilic globulin ( A H G ) deficiency in a heterozygous female with an X X / X O karyotype and represents the second occasion on which the abnormal karyotype has been detected in a phenotypically normal prepubertal female. O u r patient, a 6-year-old girl, has experienced excessive bruising and hemarthroses since infancy. A H G activity has ranged between 5 per cent and 7 per cent of normal. Pseudohemophilia has been excluded by normal bleeding times in all the family members and the patient's failure to exhibit a rise in A H G levels following an infusion of AHG-deficient plasma. Paternity could not be disputed on the basis of blood groups. Xg grouping failed to prove nondisjunction in the maternal X chromosome. Chromosome analysis of leukocyte and skin cultures revealed a bimodal distribution with approximately 20 per cent of the cells having only 45 chromosomes. If the degree of mosaicism in the AHG-producing cells is similar to that in the tissues analyzed, this, in itself, would not be sufficient to explain the severity of her deficiency. However, complete expression could result from inactivation of the majority of the normal X chromosomes in the X X cells as hypothesized by Lyon and Beutler.

DISCUSSION Dm ANDREW E. LOaINCZ, Department o[ Pediatrics, University o[ Florida, Gainesville, Fla. For the benefit of the few purists interested in connective tissue acid nmcopolysaccharides for whom the histochemical techniques for the identification of acid mucopolysaccharide are not specific enough, I would like to cite the work of Gessner and co-workers (Fed. Proc. 22: 194, 1963) who in our laboratory under direct vision dissected cardiac tubes from over 5,000 chick embryos incubated 3 days (to Hamburger Stage 17) and at-


Volume 67

Number 5

part 2


Dp,. L o r e s K. DIAMOND, Children's Hospital, .300 Longwood Ave., Boston, Mass. This is a very interesting paper and comes close to documenting what the authors claim, but there are still a few loopholes that ought to be closed in order to make sure that one is not dealing with a more common condition, an unusually severe yon Willebrand's disease, rather than a female hemophilia. Recent studies in our own and as well as in other clinics have revealed that yon Willebrand's disease is much more common than previously realized and this must be excluded in the patient reported here. We have recently surveyed more than 50 individuals and have found that the most sensitive test for the presence of von Willebrand's disease in a patient who has a low antihemophilic globulin level is the platelet adhesiveness test. This is always positive in patients with yon Willebrand's disease and even gives positive results in the asymptomatic relatives who are carriers of the condition. It seems possible that this patient could be an example of yon Willebrand's disease with the mother having the disease in milder form and the child and her brother in more severe form, since the AHF level of 5 per cent by our measurements would not be considered a severe deficiency and more typical of the von Willebrand's AHG deficiency. In addition, it might be worthwhile trying to procure enough serum or plasma from the patient to inject into another patient with yon Willebrand's disease, as a test of the stimulating effect, such as one would get with proved hemophilia A in a yon Willebrand's patient. The fact that the patient herself did not respond is not necessarily proof since some well-documented cases of yon Willebrand's disease do not respond typically on every occasion. At least these two loopholes would be worthwhile plugging in order to make sure that this unusual case you have worked up so well has all the characteristics of hemophilia A and not yon Willebrand's disease. DR. GILC~RIST. Thank you very much for your comments, Dr. Diamond. We shall certainly pursue this along those lines.t

90. Platelet studies in lViskottAldrich syndrome Howard A. Pearson, N. Raphael Shulman, ~ Frank A. Oski, * and Donald V. Eitzman, University of Florida College of Medicine, Gainesville, Fla., National IntThe patient and her mother have since been studied further and both have normal platelet adhesiveness using a modification of the method described by Hardisty and Hutton.





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M e d i c i n e , P h i l a d e l p h i a , Pa. The pathogenesis of the thrombocytopenia of Wiskott-Aldrich syndrome has been investigated in several patients. Eight survival studies using homologous platelets were normal in 3 patients and plasma-acid phosphatase levels were also normal suggesting no increased peripheral platelet destruction. Marrow aspirates from 3 patients showed many peculiar megakaryocytes. The nuclei of these cells showed pronounced fragmentation and karyorrhexis despite cytoplasm which showed no granularity or platelet formation. Prednisone and fresh plasma administrations were without beneficial effect in 2 patients. These studies indicate that the characteristic thrombocytopenia of Wiskott-Aldrich syndrome does not result from increased peripheral destruction as is usually the case in idiopathic thrombocytopenic purpura ( I T P ) . Rather the morphologic and thrombokinetic studies reported here suggest developmental or maturational factors to be involved. Similar mechanisms might conceivably be invoked to explain the eczema and susceptibility to infection which these children demonstrate. Although conventional therapy is without regular benefit, platelet transfusions may be confidently administered for hemorrhage or when surgery is necessary. DISCUSSION DR. WILLIAM KRIVIT,Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minn. 55455. We can confirm this work insofar as the survival of platelets is concerned. In our analysis, three different clinical syndromes have been compared: (1) amegakaryoeytic and sex-linked familial thrombocytopenia, (2) idiopathic thromboeytopenia, and (3) the Aldrich syndrome. There is agreement with Dr. Pearson's data that the survival in Aldrich syndrome is vastly different from ITP and similar to that of the patient with amegakaryocytosis. The pathogenesis is, therefore, as he has suggested, that of abnormality of production and not destruction of platelets. I would hasten to add that if the patients continue to receive more platelets, the survival of platelets will become shorter, and the effectiveness of the platelets would become less. Have you had any observations to indicate that the platelet transfusions become ineffective later on after multiple transfusions? One of our patients has developed an acquired hemolytic anemia. The other interesting problem is that the incidence of lymphoma or malignant reticulum disease is increased in Aldrich syndrome. It is my impression that the more foreign antigens these patients receive, such as immunizations, the higher the incidence of the lymphoma will be. Has your patient who developed the lymphoma (which occurrence we can also similarly collabo-