GENETIC ASPECTS of PEDIATRIC ENDOCRINOLOGY Summary of a Round Table

GENETIC ASPECTS OF PEDIATRIC ENDOCRINOLOGY Summary of a Round Table

By Lytt I. Gardner, M.D., Ira M. Rosenthal, M.D., and Richard J. Feinberg, M.D. Department of Pediatrics, State University of New York, College of Medicine at Syracuse (L.l.G.) and Department of Pediatrics, University of illinois (1MB. and R.J.F.)

Introductory Remarks of this group of patients represents in- DR. GARDNER: Historically pediatricians henited disease. As is obvious from the syn- have been in the vanguard of the social and dromes we will take up in this endocrine scientific forces improving the health and round table, nearly every one of tllese well-being of their patients-the children of conditions is genetically determined, that this country. Indeed, we have the heavy is to say, the result of a mutation which responsibility of carrying on the proud tra- has taken place in the human hereditary dition of our professional great-grandfather, material. Dr. Abraham Jacobi, who came to these With this “load of mutations” to deal witil shores in the aftermath of the German in our pediatric services, naturally any pub- Revolution of 1848, and who eventually lie health measures to prevent further in- rose to the presidency of the American crease in the mutation rate are very muc Medical Association.1 As the pioneer in in order. It is now common knowledge that American pediatrics, Jacobi never failed to ionizing radiations, in the form of x-rays, let his position be known on controversial fall-out radiation, etc., cause an increase in issues. His intuitive Jeffersonian grasp of the mutation rate. This has been carefully the democratic process facilitated his role quantitated in a number of animal forms, in the early development of pediatrics here. and a straight-line relationship has been Jacobi’s coat has, in a sense, fallen upon found to exist between total radiation and our shoulders, and American pediatrics mutation rate. The more radiation there is, must continually be on the alert to live up the more mutations occur.2 to what he would have expected of us. Our colleagues in roentgenology have Therefore let me come directly to the become acutely aware of this problem, and problem at hand. As we know, the relative are making great efforts to reduce the x-ray number of children with congenital defects exposure of patients to the absolute mini- in our hospitals is very much greater than mum. Public health laws are restricting the 25 years ago. Recently in our hospital we use of x-ray apparatus to trained personnel. tabulated the cases over a 5-month period, So there is good reason to think that prog- and found that 30% of the pediatric in- ress is being made to reduce human cx- patients were there because of congenital posure to x-rays and to medically used defects. This apparent increase is almost radioisotopes. certainly due in large part to the reduc- There is one other source of human cx- tion in patients with infectious disease, but posure to radiation about which something the figure of 30% still must remind us that could be done, and that is the radiation the care of children with congenital de- exposure brought on by fall-out from the fects is a field of major importance in mod- testing of nuclear bombs. Unfortunately cnn pediatrics. How many of these defects little progress has been made in reducing are genetically determined is not known human exposure to this form of radiation. for sure, but certainly a considerable pant Russia has just resumed a series of tests,

Presented at the Annual Meeting of the American Academy of Pediatrics, October 20, 1958. ADDRESS: (L.I.G.) 766 Irving Avenue, Syracuse 10, New York. PEDIATRICs, August 1959

330

Downloaded from www.aappublications.org/news by guest on September 29, 2021 AMERICAN ACADEMY OF PEDIATRICS - PROCEEDINGS 331 which means that we are still playing this participated in these calculations have em- Alphonse-Gaston game of genetic roulette. phasized the large uncertainties and diffi- The relevance of this increase in radiation culties involved in estimates of genetic (and therefore increase in mutation rate) damage. Nevertheless there is little doubt to the field of pediatric and child care can of the general nature of the conclusion. be immediately seen from the following. The problem is now mostly one of inter- Dr. J. F. Crow, Professor of Genetics at pretation. It is understandable that the miii- the University of Wisconsin, has estimated tary mind would take the point of view that if tile world’s population is exposed that the genetic casualties are only a very to 0.1 roentgen per person over a single small aspect of the whole weapons testing period of 30 years, there will be produced program. a total of 80,000 gross defects in the living On the other hand, because the cost of children of future generations.3 In additon these “casualties” is measured in helpless lle estimated a total of 700,000 lethal mu- infants and children, the pediatrician is tations (i.e., deaths) for future generations liable to take a very different point of view. as a result of this irradiation. Dr. Linus We are the custodians of an ancient precept Pauling, Professor of Chemistry at the Cali- that holds all life to be important, that fornia Institute of Technology, recalculated heeds the words of Maimonides, the physi- these data on the basis of a 1958 estimate cian : “Thy eternal providence has ap- of fall-out radioactivity. Dr. Pauling con- pointed me to watch over the life and health eluded that if the present rate of testing of Thy creatures.” It is said that the present were continued, each such year would result situation is a philosophic dilemma. If this in 8,000 gross defects in the living children be so we are equipped with a rich tradi- of future generations (or a total of 240,000 tion to exert a force for the benefit of hu- produced by a 30-year period of testing).4 manity. It must be noted that the foregoing calcula- Hypopituitarism tions refer only to the immediate radiation produced by the relatively short-lived iso- DR. ROSENTHAL: The diagnosis of hypo- topes of a bomb explosion. This is, in a pituitanism originating in childhood is reia- sense, the first phase of genetic damage tively easy in the patient over 20 years of caused by weapons testing.5 age. The diagnosis is more difficult in The second phase of genetic damage ap- younger children, and careful differentia- pears to be caused by the effect on the tion must be made from primordial dis- hereditary material of the long-lived iso- turbance of growth, constitutional delay tope, C4. This isotope has an average life in rate of growth, and growth failure see- of 8,000 years. During all this period of ondary to serious organic disease. The time the human hereditary material is presence of a severe delay in bone age, irradiated, and the mutations thereby pro- normal body symmetry, and evidence of duced are permanently inherited.6’ ‘ The secondary hypoadrenalism and hypothyroid- most recent publication of the Atomic ism may aid in early diagnosis. Some pa- Energy Commission estimates that the C’4 tients present evidence of a pituitary tu- produced from bombs alone to date (ex- mon, although in most instances the cause eluding the current U.S.S.R. series) might of hypopituitanism is not known. Increased cause 100,000 gross genetic defects in the sensitivity to insulin and abnormal exere- living infants and children of future genera- tion of a standard water load may help in tions.7 A very much larger number of the early establishment of the diagnosis genetic lethals (fetal, neonatal and child- of hypopituitanism. A good clinical method hood deaths) were estimated from this C14 for the assay of growth hormone is badly irradiation. All the agencies which have needed.

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The recent demonstration by Raben8 of 14 years. The average age of onset was 9 stimulation of the growth of a hypopituitary years. The youngest child was 18 months. dwarf over a period of 10 months, by the The tumor was confined to one adrenal in intramuscular injection of iluman growth 16 cases and involved both adrenals in hormone t\V() or three times a week, is of 7 cases. In seven cases the tumor was great interest. Other workers have also not in tile adrenal. In four cases the tumors demonstrated pilysiologic effects of human were in tile adrenal and also in an extra- growth hormone in man. Human growth adrenal site. The disease may be familial. hormone is not available for general clini- The presacral injection of air may localize cal use. It is unlikely that it will become the tumor; the test may be misleading and available in tile near future. Animal growth in these patients carries a definite risk. hormones appear to be of no value in the In the management of these patients be- treatment of human patients. fore surgery the oral administration of Regi- Treatment for hypopituitanism should tine#{174}(phentolamine) may be useful in the not be instituted unless tile diagnosis is control of the hypertension until definitive definitely established. Treatment before the surgery is performed. In those rare cases normally expected age of puberty, as sug- in which both adrenal glands are involved gested by some workers, is not recom- with tumor, bilateral adrenalectomy may be mended. For males of pubertal age, treat- necessary. Appropriate preoperative mcdi- ment with testosterone enanthate (200 mg) cation and postoperative adrenal contico- intramuscularly each month is recom- steroid substitute therapy are indicated. mended. For females of pubertal age, oral DR. GARDNER: It should also be men- treatment with methyl testosterone (10 mg tioned that removal of a pheochromocytoma daily) and with a suitable estrogen is recom- may result in prolonged hypotensive shock mended. Fairly good sexual development even when a constant infusion of norepi- should result from this therapy, although nephnine is provided. Dr. Robert E. Green- the patients obviously remain infertile. For berg and I have recently described such a psychologic reasons, treatment at the usual case in our report of the eighth known af- age of puberty, as recommended recently fected kindred. In this family, father and by Martin and Wilkins,9 is suggested in- son were both affected. The father showed stead of treatment at a later age which was severe hypotension after removal of a left- previously recommended. It is doubtful, sided pheocllromocytoma in spite of nor- however, that therapy with its resulting epinephnine therapy. His son, age 3% years, growth spurt causes any increase in height also had a left-sided pheochromocytoma re- over that which would have eventually moved, but interestingly enough the child been attained without treatment. did not exhibit postoperative hypotension. DR. GARDNER: Hypopituitarism has DR. KEAGY, ALTOONA, PA. : Will essential causes which sometimes can be readily hypertension respond to Regitine#{174}? demonstrated. We should be aware of the DR. GARDNER: Usually not. But the surest possibility of a suprasellar cyst. Roentgeno- way to diagnose plleochromocytoma is by grams of the skull in this syndrome will measurement of catechol amines in the usually demonstrate calcification in the urine. Figure 1 shows a typical Regitine#{174} suprasellar region and/or flattening of the response in a case of proven pheochromoey- sella. toma. Primary aldostenonism may also be a cause of unexplained hypertension. The Pheochromocytoma serum potassium levels are usually low,

DR. ROSENTHAL: Cone, Allen and Pear- although occasional values may be normal. sont#{176}in a recent review of the literature Conn recommends that a series of serum were able to find 34 cases of pheochromoey- potassium levels sllOuld be done before toma reported in children under the age of ruling out primary aldosteronism.

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REGITINE 2MG.IV

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MINUTES FIG. 1. Positive I1egitinet test in a 3’3i2-year-old boy with pheochromocytonia as (lescribed l)y Greenberg and Gardner.”

Familial Goitrous Cretinism other less common biochemical abnormali- DR. ROSENTHAL: The symptoms of hypo- ties responsible for goitrous cretinism. In thyroidism do not differ in goitrous cretin- the diagnosis of goitrous cretinism second- ism from those of sporadic athyreotic crc- any to a lack of oxidative enzyme, the dis- tinism. A more suitable designation for change of trapped P3-iodide from the thy- goitrous cretinism is cretinism caused by roid gland by potassium thiocyanate is a biochemical abnormality in the synthesis of useful test. More elaborate diagnostic meth- thyroid hormones. In goitrous cretinism tile ods are necessary to establish tile metabolic goiter usually develops later in childhood. block in other cases. Goitrous cretinism appears to be genetic DR. STANLEY STEINBERG, WASHINGTON, in origin. D.C. : Can tile measurement of protein- In goitrous cretinism the radioiodine up- bound and butanol-extractable iodine be take of the thyroid gland may be elevated done with accuracy in a small hospital? or in the normal range. The protein-bound DR. GARDNER: Unless the local laboratory iodine in blood serum is usually low but facilities are unusually excellent, it is nec- may be normal or even elevated. Goitrous ommended that these determinations be cretinism, according to Stanbury, can result sent to laboratories which make a specialty from one of several biochemical abnormali- of these measurements. ties in tile synthesis of thyroxin. The thyroid DR. KEAGY, ALTOONA, PA. : Does the bone gland may lack the oxidative enzyme so age respond to thyroid therapy? tilat, while it can trap iodine, it cannot pro- DR. GARDNER: Yes, improvement in bony duce iodotyrosine. The thyroid gland may maturation occurs very readily under thy- lack the enzyme which causes coupling of noid treatment. But bone age may not be iodotyrosines to form iodothyronines. The used alone to judge adequacy of therapy, gland may lack the enzyme dehalogenase because one may find normal bone ages so that monoiodotyrosine and diiodotyrosine in a child who is not being treated with escape into the blood and insufficient thy- sufficient thyroid. roid hormone is produced. There are also DR. JOAN BRADY, Rocia&rm Co., N.Y.:

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Does the cholesterol level go up in a hypo- Intersexuality thyroid child who is not treated? DR. ROSENTHAL: vIale pseudohenmaph- DR. GARDNER: For reasons not cleanly roditism results from failure of the fetal understood, untreated hypothyroid infants testis to cause male differentiation. Female in the first year of life do not show elevated pseudohenmaphnoditism results from par- serum cholesterol values. Figure 2 shows tial vinilization of the fetus by androgens this point very strikingly. It can be seen produced by its own adrenals or derived that after 1 year of age there is a matura- from the mother. In true hermaphnoditism, tion of the cholesterol metabolic defect, the pathogenesis is failure of normal differ- with abnormally increased values in cvi- entiation of one or both gonads in accord- dence. anee with the genetic sex. Most cases of DR. J. DICK, LEVITTOWN, N.Y. : Would gonadal dysgenesis (previously known as you comment on the so-called metabolic ovarian agenesis) appear to result from insufficiency syndrome? early degeneration of the fetal testes, so DR. GARDNER: In my opinion the syn- that the fetus (like Jost’s rabbit fetuses drome of “metabolic insufficiency” as ap- which were castrated in utero), develops as plied to children is a figment of medical female. Some cases of testicular dysgenesis semantics and has no existence in fact. appear to result from abnormal diffenentia-

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Fic. 2. Concentrations of cholesterol in plasnia of infants and children with untreated hypothyroidism. The failure of the young hypothyroid infants to show increased values for serum cholesterol is obvious. The open circles represent previously treated children who had not received thyroid therapy for 6 weeks or longer.

Downloaded from www.aappublications.org/news by guest on September 29, 2021 AMERICAN ACADEMY OF PEDIATRICS - PROCEEDINGS 335 tion of the undifferentiated gonads into had been used in cases of threatened or testes in individuals of female genetic sex. habitual abortion. It is important that all Pathogenetically these cases appear to be pediatricians be aware of this syndrome. related to true hermaphroditism. In cases of hermaphroditism the diag- As a result of the work of Barr and his nosis should be established as early as colleagues, it is now possible to determine possible so that definitive sex assignment the genetic sex of an hermaphrodite. By can be made after a consideration of all buccal mucosal smear or by skin biopsy, factors involved. The nature of the internal a chromatin mass can be detected in the and external genitalia are of prime im- nucl& of a high percentage of the cells of portance in this regard. The development those of female genetic sex, but not in the of gender role is dependent in large part cell nuclei of those of male genetic sex. upon assigned sex. Change of sex assign- Individuals with a high percentage of cells ment is particularly undesirable after tile with tilese chromatin masses are called age of 18 months, and should be avoided chromatin positive, and those whose cells unless there are extraordinary circum- do not have tile chromatin mass are called stances. cilromatin negative. This test for genetic In gonadal dysgenesis, the presence of sex is simple to perform and is useful in the understature, pterygium colli and other diagnosis of clinical cases of intersexuality. anomalies may suggest the diagnosis. It Careful attention must be paid to the must be remembered that female patients proper preparation of smears and biopsies with the pterygium syndrome may not in order to avoid errors. necessarily have gonadal dysgenesis. i’sIale pseudohermaphrodites are sex It is emphasized that the vinilization of chromatin negative. Female pseudoher- females with vinilizing adrenal hyperplasia, mapilrodites are either chromatin positive or due to a congenital defect in the synthesis negative. Most cases of gonadal dysgenesis of hydrocortisone by the adrenal, may not are chromatin negative. Many eases of be present at birth but have its onset in testicular dysgenesis are chromatin posi- childhood. These cases can be differentiated tive. from cases of adrenal tumor by the method In the diagnosis of hermaphnoditism con- of Gardner and Migeon.13 The urinary cx- sideration must be given to the nature of eretion of 17-ketosteroids is depressed by the genitalia, the character of the gonads, the administration of cortisone or one of the genetic sex, the secondary sex char- its analogs in vinilizing adrenal hyperplasia actenistics and the gender role. The deter- but not in vinilizing adrenal tumor. The mination of the urinary excretion of 17- eases of tumor usually excrete excessive ketosteroids and of pregnanetniol are most amounts of dehydro-epiandrosterone. useful in tile diagnosis of vinilizing adrenal Unless the sodium-losing form of eon- hyperplasia. Exploratory laparotomy and genital adrenal hyperplasia is recognized gonadal biopsy are necessary for diagnosis and treated vigorously in infancy there is in the cases of hermaphroditism but should a high mortality. The diagnosis is particu- not be necessary for diagnosis in the eases larly difficult in male infants, because there of female pseudohermaphrodites secondary is no genital abnormality at an early age. to congenital adrenal hyperplasia. Vigorous treatment with intramuscular Wilkins et al.12 have recently shown that cortisone, sodium chloride, and desoxycorti- female pseudohermaphnoditism may result costerone acetate is recommended. After from mascuiinization of the female fetus the needs for desoxycorticosterone are de- as a result of the administration of certain termined, infants can be conveniently main- pnogestins to the mother during gestation. tamed on the drug by injection of desoxy- The drugs involved, among which were corticosterone tnimethylacetate approxi- 17-ethinyltestosterone and progesterone, mately every 4 weeks as an alternative to

Downloaded from www.aappublications.org/news by guest on September 29, 2021 336 ENDOCRINOLOGY the insertion of pellets of desoxycorticos- periodic fever.14 These paroxysmal episodes terone acetate. During the second year of are characterized by high fever, pains in life desoxycorticosterone can be discon- the abdomen and head, hypotension, flush- tinued in most instances, but it must be ad- ing of ears and face, and prostration. It ministered to maintain electrolyte homeo- now appears that endogenous liberation of stasis in an occasional patient. By the see- etiocholanolone is responsible for the par- ond year of life cortisone or one of its oxysms of periodic fever in this subvariant analogs should be administered orally. In of vinilizing adrenal hyperplasia.15 case of stressful circumstances this dose of cortisone should be increased and if neces- Bioassay of Insulin sary administered parenterally. Cortisone DR. FEINBERG: Several methods of assay- must be continued throughout life in these ing insulin in blood and other body fluids patients. have been proposed. There is described be- With proper psychologie preparation, low a method at present under study, based elitonidectomy and plastic reconstruction of on an immunologic principle. the genitalia may be performed in females In this immunologic method an antiserum with vinilizing adrenal hyperplasia without to insulin is prepared by immunizing guinea fear of causing psychologic disturbances. pigs to insulin. Insulin antigen for the test In some instances clitonidectomy may be is prepared by adsorbing insulin on tannic avoided by early treatment with cortisone. acid-treated sheep erythrocytes. This con- Normal sexual maturity and fertility may vents the ordinary sheep erythnocyte into a be expected if treatment is started early. cell coated with the specific antigen, in this If treatment with cortisone is started late case insulin. in childhood when the bone age is already All sena used in the test are heated at advanced, isosexual true precocious puberty 56#{176}Cfor 30 minutes to inactivate comple- should be anticipated as a result of therapy. ment, and adsorbed with washed sheep Virilizing Adrenal Hyperplasia erythrocytes in order to remove any non- specific antisheep agglutinins. Serial dilu- DR. GARDNER: Although Dr. Rosenthal tions are made in Houssay cat serum in order has already touched on some of the prob- to eliminate any insulin in the system other lems of the female with this syndrome, a than tilat from the patient’s serum or on few general remarks about the classification the sensitized sheep erythrocytes. The anti- of the syndrome would seem to be in order. insulin guinea pig serum is then added, and Roughly, there are five categories into which the system incubated. If insulin is present this syndrome can be divided: in the serum being assayed, it will neutral- 1) First there is the usual type, which ize the antibody. The sheep erythrocytes simply shows the results of vinilization, on which insulin has been adsorbed are without excessive sodium loss or other eom- then added. If there remains free antibody, plications. This type may be either congen- hemagglutination will occur. If insulin in ital or postnatal. the serum being tested has neutralized all 2) Secondly there is the so-called “salt- or part of the antibody, hemagglutination loser,” which is the patient with vinilization will be completely or partially inhibited. described above plus crises of excessive The amount of insulin in the serum can sodium loss. thus be estimated. 3) Thirdly there is the type showing vinilization plus hypoglycemia. Acknowledgment 4) A fourth type shows vinilization plus hypertension. The authors are indebted to Dr. Daniel S. 5) Lastly, a newly described fifth sub- Rowe who assisted in the preparation of type shows virilization plus episodes of this material for publication.

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REFERENCES 1958. 1 . Truax, R. : The Doctors Jacobi. Boston, 10. Cone, T. E., Jr., Allen, M. S., and Pear- Little, 1952. son, H. A. : Pheochromocytoma in chil- 2. Russell, W. L., Russell, L. B., and Kelli’, dren : report of three familial cases in E. M. : Radiation dose rate and muta- two unrelated families. PEDIATRICS, 19: tiOll frequency. Science, 128 : 1546, 1958. 44, 1957. 1 1 . Greenberg, R. E., and Gardner, L. I.: 3. Crow, J. F. : Genetic effects of radiation. Bull. Atom. Sc., 14:19, 1958. Pheochromocvtoma in father and son: report of the eighth known affected 4. Pauling, L. : No More War! New York, kindred. Clin. Endocninol. and Metab., Dodd, 1958, p. 71. J. 5. Report of the United Nations Scientific 19:351, 1959. Committee on the Effects of Atomic 12. Wilkins, L., Jones, H. W., Jr., Holman, Radiation, Suppl. No. 17 (A/3838). New G. H., and Stempfel, R. S., Jr. : Mascu- York, Columbia Univ. Press, 1958. linization of the female fetus associated 6. Pauling, L. : Genetic menace of tests: with administration of progestins during views regarding potential danger from gestation: non-adrenal female pseudo- carbonh4 reaffirmed (Letter to the Edi- hermaphrodism. J. Cliii. Endocrinol. and ton). The New York Times, May 16, Metab., 18:559, 1958. 1958. 13. Gardner, L. I., and Migeon, C. J. : Urinary 7. Totter, J. R., Zelle, M. H., and Hollister, dehvdroisoandrosterone in hyperadreno- H. : The biological hazard to man of corticism : influence of cortisone, hydro- carbonl4 from nuclear weapons, Docu- cortisone and ACTH. J. Clin. En- ment WASH-1008. Washington, D.C., docninol. and Metab., 12:1117, 1952. Division of Biology and Medicine, 14. Gonzales, R. F., and Gardner, L. I. : Con- Atomic Energy Commission, Sept., genital adrenal hvperplasia with epi- 1958. sodes resembling histamine poisoning. 8. Raben, M. S. : Treatment of a pituitary PEDIATRICS, 17:524, 1956. dwarf with human growth hormone 15. Gardner, L. I., and Migeon, C. J. : Un- (Letter to the Editor). J. Clin. Endocninol. usual plasma 17-ketosteroid pattern in a and Metab., 18:90, 1958. boy with congenital adrenal hyperplasia 9. Martin, M. M., and Wilkins, L. : Pituitary and periodic fever (Letter to the Editor). dwarfism: diagnosis and treatment. J. J. Clin. Endocrinol. and Metab., 19:266, Clin. Endocninol. and Metab., 18:679, 1959.

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Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 1959 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

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