X-chromosome abnormalities ingonadal dysgenesis: DNA replication of structurally abnormal X-chromosomes; relation to thyroid disease

X-chromosome abnormalities ingonadal dysgenesis: DNA replication of structurally abnormal X-chromosomes; relation to thyroid disease

Volume 65 Number6 Part 2 important new syndrome. More attention is being paid to salt-wasting syndromes in infancy, and there has been progress made ...

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Volume 65 Number6 Part 2

important new syndrome. More attention is being paid to salt-wasting syndromes in infancy, and there has been progress made in the last few years. In 1957 we described (Cheek and Perry: Arch. Dis. Childhood 33: 252, 1958) an infant whose case I think illustrates another form of this condition and differentiation is important as I shall explain. O u r patient presented with the same clinical picture of salt depletion and shock with hyponatremia and hyperkalemia and without renal a b n o r m a l i t y - - b u t , unlike your patient, our patient had resistance to mineral corticoid. O t h e r aspects of adrenal function were normal and we concluded that the renal tubule was insensitive to aldosterone. Administration of sodium chloride reversed the clinical picture while desoxycorticosterone, in contrast to its result in your patient, was ineffective. I believe this distinction is important in terms of emergency therapy and subsequent reports by Drs. Donnell, Litman, and Roldan of Los Angeles (A. M. A. J. Dis. Child. 97: 813, 1959) and Dr. Lelong and associates of Paris emphasized the increased level of aldosterone in the urine. I believe the occurrence of a second variety of infantile salt wasting with failure to produce aldosterone will cause confusion from the point of clinical diagnosis. I wonder whether Dr. Gautier would like to draw any further comparisons between these two syndromes which are so much alike and which must also be separated from adrenal hyperplasia with salt wasting? DR. GAUTIER. We are well aware of the type of patient described first by Dr. Cheek. O u r patient presented a similar clinical picture but was completely different in regard to the cause of the salt loss. Both the patients unresponsive to saltretaining steroids and the patients unable to produce enough aldosterone seem to improve clinieally from the age of 1 or 2 years on. We do not know yet what is the essence of the improvement in the patients with hypoaldosteronism. Is it that they become able to produce more salt-retaining steroids, aldosterone, or its precursors, or that they just obtain more sodium from their food? DR. ROBERT t~. GREENBERO, Department of

Pediatrics, Stanford University, School of Medicine, Pa[o Alto, Calif. As an extension of the comments of Dr. Cheek, we are studying a child similar to ones previously studied by Dr. Cheek and Dr. George Donnell, in that the child presented with hyponatremia, hyperkalemia, and resistance to the sodium-retaining effects of exogenously administered D O C A or 9-alpha fluorohydrocortisone. This child improved spontaneously in ability to maintain a normal serum sodium and exhibit adequate growth; even when improved, however, she is still completely resistant to the sodium-retaining effects of mineralocortieoids when administered exogenously. W h e n one combines these observations with the interesting point from Dr. Migeon's group, namely, that the aldosterone secretion rate appears to be similar in young infants as compared to that of adults, it seems likely that mechanisms for sodium reabsorption which are independent of the action of steroids may be more significant than previously considered. Has your child shown any lessening of the adverse

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clinical effects when taken off steroids ? This is a question related to inquiring further about the potential importance of non-steroid-dependent sodium reabsorptive mechanisms as age progresses. DR. GAUTIER. Our patient has not yet been taken off steroids. When he was suffering salt depletion, he was finally able to achieve sodium balance, at the cost of dehydration a n d hyponatremia. He was not totally deprived of saltretaining steroids, so that the importance of n o n steroid-dependent sodium reabsorption mechanisms was difficult to assess. He had a low glomerular filtration rate, judged from endogenous creatinine clearance, which, together with hyponatremia, produced a low filtered amount of sodium, a circumstance which favors sodium reabsorption.

16. X-chromosome abnormalities in gonadal dysgenesis: D N A replication oJ structurally abnormal X-chromosomes; relation to thyroid disease Melvin M. Grumbach and Akira Morlshima, ~ Columbia University and Babies Hospital, New York, N. Y. Two prepubertal females with features of gonadal dysgenesis and diffuse goiters were found to have structurally abnormal X-chromosomes. One patient developed thyrotoxicosis associated with circulating thyroid antibodies at 8~2 years of age (radioactive iodine uptake was not suppressed by tri-iodothyronine). Rare somatic interphase nuclei contained an abnormally small sex chromatin body. Blood and skin were used for karyotypic analyses. I n both tissues, X O / X X R mosaicism was found (X ~ denoting a self-perpetuating monocentric ring chromosome derived from an X ) . Studies of DNA replication using tl3-thymidine showed that the X ~ was invariably the late labeling X, an observation consistent with the preferential heterochromatinization of heteromorphic X's we reported previously (Proc. Nat. Aead. Sc. 49: 581, 1963). X g blood group studies suggest that X ~ is derived from the maternal X. The second patient, a sex chromatin-positive 10-year-old glrl with a firm goiter, was euthyroid but had a discrepancy between protein-bound iodine and butanol-extractable iodine and a high titer of circulating antibodies to thyroglobulin. Chromosome studies revealed 2 n ~ 4 6 , and an XX-isochromosome sex chromosome constitution. Biopsy of the thyroid gland of these two patients showed Hashimoto's thyroidids. A third patient, a 13-year-old girl with X O / X X / X X X mosaicism and goitrous hypothyroidism has a high titer of circulating thyroid antibodies. The available data suggest: (1) an increased frequency of Hashimoto's thyroiditis in juvenile patients with various types of X-chromosome abnormalities, especially heteromorphic X's; (2) an increased frequency of thyroid antibodies in unaffected relatives; (3) the fact that a

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Society for Pediatric Research

genetic predisposition to develop thyroid autoantibodies in a parent is associated either directly or indirectly with an increased occurrence of chromosome errors in their offspring, especially X-chromosome abnormalities. DISCUSSION DR. S. D. FRASleR, UCLA School o[ Medicine, Los Angeles, Call/. May I ask what the incidence of Hashim3to's thyroiditis is in your entire population of patients with gonadal dysgenesis? DR. MORISmMA. I should like to answer this question by dividing the patients with the syndrome of gonadal dysgenesis into two categories: those with sex chromatin-negative interphase nuclei and those with sex chromatin-positive pattern. We have not found Hashirnoto's thyroiditis in a group of 65 patients with sex chromatin-negative gonadal dysgenesis and an X O sex chromosome constitution. The three patients reported upon here were from a group of fifteen individuals with sex chromatin-positive gonadal dysgenesis we have studied so far.

17. Excessive concurrence of Wilms' tumor with aniridia, hemihypertrophy, and other congenital dejects Robert W. Miller, ~ Joseph F. Fraumeni, Jr., § and M i r i a m D. Manning, ~ Epidemiology Branch, National Cancer Institute, Bethesda, Md. Introduced by Donald Pinkcl Knowledge of the excessive concurrence of leukemia and mongolism in the same patient has contributed to current hypotheses concerning the etiology of leukemia. To afford a similar opportunity in the study of Wihns' tumor, the medical charts of 440 children with this neoplasm were reviewed in a search for the excessive occurrence of specific congenital malformations. The observed numbers of each anomaly were compared with expected values based on data from large-scale surveys. Among patients with Wilms' tumor the frequency of' aniridia (6 cases) was 1:73 as compared with the usual at-birth frequency of 1:50,000. The existence of a syndrome was suggested by the finding that 3 children had Wilms' tumor, aniridia, small head circumference with mental retardation, and cataracts or glaucoma. Three other children with Wilms' tumor had congenital hemihypertrophy, an anomaly which despite its rarity has previously been described in 13 children with Wilms' tumor, 4 with adrenal tumors, and 3 with hepatoblastoma. Among the 223 boys with Wilms' tumor, 5 had hypospadias as compared with 0.6 expected, and 11 had undescended testes as compared with 3.3 cases expected. Four children had horseshoe kidneys, 5 had duplications of the kidney or ureter, and 9 had other anomalies of the urinary tract. Although

December 1964

aniridia and congenital hemihypertrophy apparently have different etiologies and different mechanisms, they are alike in having a teratogeniconcogenic effect on the genitourinary tract. Further research concerning the origins of any one of the diseases in the constellation associated with Wihns' tumor should provide insight into the genesis of the others. DISCUSSION DR. GUNNAR B. STICKLER,Mayo Clinic, Rochester, Minn. I wonder if you ran across patients with bilateral Wilms' tumors in your series. I recall in two instances associated abnormalities like mental retardation and small head circumference. DR. MILLER. As I recall, in the cases presented here with mental retardation, the tumors were unilateral. We did not make a special attempt to relate laterality of the tumor to the malformations observed. DR. ANGELO M. DI GEORGE,St. Christopher's

Hospital {or Children, 2600 N. Lawrence St., Philadelphia 33, Pa. Dr. Miller and the audience might be interested in our recent experiences with this fascinating association of anomalies and neoplasms. Our interest in this association was first aroused about two years ago when we saw a 3-year-old boy with cryptorchidism who also had aniridia, cataracts, and glaucoma. He was mentally retarded and had had a Wilms' tumor removed at 2~2 years of age, This boy has since died; the testes were intra-abdominal with a gonadoblastoma in one of them. Our curiosity was further aroused by a second patient with aniridia and cataracts who is a male pseudohermaphrodite. This second patient has an XY karyotype and showed ambiguous external genitals. He is essentially a hypospadic, cryptorchid male with a rudimentary vagina and other Miillerian duct remnants. We elected to rear the child as a femaIe. After the publication of Dr. Miller's paper (New England J. Med. 270: 922, 1964), it occurred to us that this patient (who was now 2 years old) might be harboring a Wilms' tumor. While we were contemplating calling the patient in for an intravenous pyelogram, the family pediatrician called to inform me that the child was in his office and she had an abdominal mass. This proved, of course, to be a Wilms' tumor. There is no history of aniridia in either of these families. We then inquired of our ophthalmologist, who had seen both of these children, if we knew of other young children with aniridia. He readily recalled another aniridic child living in another city whom he had not seen in a year or so. When the local urologist was called and asked to examine this child for a Wilms' tumor, he was flabbergasted, since he had already removed a Wilms' tumor from the child at 2 years of age. In Dri Miller's collected cases there are patients with aniridia and Wilms' tumor and there are patients with aniridia and genital abnormalities. Our first two patients are of particular in-