BILATERAL ADRENOCORTICAL HYPERPLASIA IN CHILDREN WITH CUSHING’S SYNDROME
A. MUNRO NEVILLE AND T. SYMINGTON
Department of Pathology, Chester Beatty Research Institute, Institute of Cancer Research: Royal Cancer Hospital, Fulham Road, London
PLATES XL-XLIII
CUSHING’s syndrome is uncommon in childhood and the most frequent cause is said to be a malignant adrenocortical tumour (Guin and Gilbert, 1956; Heinbecker, O’Neal and Ackerman, 1957; Danowski, 1962). Neville and Symington (1967) noted that during the last few years bilateral adrenocortical hyperplasia was being recorded with increasing frequency in children. This study, which includes a review of Cushing’s syndrome in patients of 15 yr of age and under, focuses attention upon its occurrence in this age-group and collates the differences in the adrenal changes with those of adults.
MATERIALS AND METHODS
The material was prepared from adrenal glands or tumours removed surgically from 16 children with Cushing’s syndrome. The lesions were collected immediately from the operat- ing theatre, placed in polythene bags and kept on ice during transit to the laboratory. They were trimmed free of fat and adherent connective tissues and weighed.
The selected portions of tissues were processed as described previously (Neville and Symington, 1967). Some of the material was received from other centres as previously prepared paraffin-embedded blocks or as stained sections.
RESULTS
The pathological features of the adrenal glands removed at operation from 16 children, 12 of whom were 10 yr of age or over, are shown in table I.
Bilateral adrenocortical hyperplasia occurred in 12 patients; only the young- est, aged 3 mth (case 12, table I), had nodular hyperplasia. The average weight (4.57 g) of single glands showing simple hyperplasia fell within the normal adult range (mean 4.0 g, upper limit of normal 6.0 g; Studzinski, Hay and Symington, 1963). Fourteen of 20 glands weighed more than 4-0 g; none exceeded 6.0 g (table I).
Only four children had adrenocortical tumours (table I). Two have been classified as malignant on the basis of the histological features previously observed to occur in adrenal carcinomas (Symington and Jeffries, 1962; Neville and Symington, 1967). Case 15 (table I) developed pulmonary metastases 3 yr after removal of the primary tumour; case 16 (table I) remains well 3 yr post-operatively.
Macroscopic and microscopic appearances
Bilateral adrenocortical hyperplasia may be classified on gross examination as simple or nodular.
In simple hyperplasia the gland may be of normal adult size and have flattened edges (fig. 1), or possess rounded fuller contours when over 5.0 g in
| Adrenal lesion | Case no. | Age (yr) | Sex | Weight of adrenal glands or tumours (g) | |
|---|---|---|---|---|---|
| Left | Right | ||||
| Bilateral simple | 1 | 15 | F | 5-8 | 5.7 |
| hyperplasia | 2 | 15 | F | 5.0 | 2.6* |
| 3+ | 14 | F | 4.4 | 3.7 | |
| 4 | 12 | M | ... | ||
| 5+ | 12 | F | 3.8 | 2.8 | |
| 6 | 11 | F | 4.2 | 5.3 | |
| 7 | 11 | M | 5.2 | 5-4 | |
| 8 | 11 | M | 5.0 | 5-6 | |
| 9 | 11 | M | 4.5 | 5.0 | |
| 10 | 10 | M | 4.0 | 4.6 | |
| 11 | 7 | M | 5.5 | 3.3 | |
| Bilateral nodular hyperplasia | 12 | 3/12 | F | 1.0 | 3.0 |
| Adenoma | 13 | 15 | F | ... | 7.4 |
| 14 | 5 | M | 33.0 | ||
| Carcinoma | 15 | 15 | F | ... | 139-0 |
| 16 | 1 | M | ... | 165-0 | |
* Gland incomplete.
1 Plasma ACTH in case 3: 0-9 m.units per 100 ml (bioassay; normal: 0-1-0-3 m.units per 100 ml); and in case 5: 55 pg per ml (immunoassay; normal: 10-22 pg per ml).
weight. On section, the cortex consists of inner brown and outer yellow layers. Small yellow cortical nodules may be discerned on gross examination of many glands (fig. 1).
The typical histological appearances of bilateral simple hyperplasia in chil- dren are shown in fig. 2. The inner brown layer corresponds to a broadened compact-cell zona reticularis, which occupies about one-third to one-half the total cortical width; the outer yellow layer is represented by the clear-cell zona fasciculata. The dividing line between these zones is distinct and straight (fig. 2). The zona glomerulosa, frequently several cells in depth, is distributed
ADRENOCORTICAL HYPERPLASIA IN JUVENILE CUSHING’S SYNDROME
ADRENOCORTICAL HYPERPLASIA IN JUVENILE CUSHING’S SYNDROME
ADRENOCORTICAL HYPERPLASIA IN JUVENILE CUSHING’S SYNDROME
ADRENOCORTICAL HYPERPLASIA IN JUVENILE CUSHING’S SYNDROME
around the entire periphery of all glands and, in a few areas, extends in a tongue- like manner into the substances of the cortex (fig. 2).
All glands contain small microscopic nodules of clear cells, which lie in relation to the central vein or more peripherally in the cortex (fig. 3). Intimal proliferation and hyaline arteriosclerosis of the capsular arteries may be seen in such nodule-containing glands (fig. 4).
Bilateral nodular hyperplasia affected the cortex of a 3-mth-old infant (case 12; table I). The characteristic features are the presence of nodules, varying from a few millimetres to 2 cm in diameter, which are contiguous on some aspects with the remains of the ” foetal ” cortex and on others with the ” definitive ”
| Adrenal lesion | Number (and per- centage) of patients with this lesion |
|---|---|
| Hyperplasia | 56 (35) |
| Adenoma | 23 (14) |
| Carcinoma | 81 (51) |
* For bibliography, see review articles in the Reference list.
cortex, which shows simple hyperplasia. The nodules are composed of compact cells, which are smaller and have a higher nuclear-cytoplasmic ratio than cor- responding mature adult cells (fig. 5). Most of the attached cortex shows simple hyperplasia with similarly sized compact and clear cells (fig. 6), although some areas opposite nodules have not undergone hyperplasia (fig. 5). No zona glomerulosa is present in the “definitive ” cortex. Intimal proliferation and hyaline arteriosclerosis also affect the capsular arteries of these glands.
The macroscopic and microscopic appearances of functioning tumours and their related atrophic glands are identical with those fully discussed in previous reports (Symington and Jeffries; Neville and Symington, 1967).
DISCUSSION
The principal cause of Cushing’s syndrome in children has been reported to be adrenal tumours, 80 per cent. of which are malignant (Guin and Gilbert, 1956; Heinbecker et al., 1957). Bilateral adrenocortical hyperplasia was considered to occur in only 10 per cent. of children and, in a further 6 per cent. a pituitary tumour was present (Danowski, 1962). Because the adrenal changes in the children of this series (table I) did not substantiate these conclusions, a review of the incidence of the different adrenal lesions in children with Cushing’s syndrome was undertaken (table II).
One hundred and sixty examples were discovered; a complete bibliography for each of the pathological changes is appended in the reference section. Although carcinoma remains the commonest adrenal lesion (table II), chrono- logical arrangement of the reports confirms the recently observed increased
| Adrenal lesion | Number (and per- centage) of patients with this lesion |
|---|---|
| Simple hyperplasia | 38 (68) |
| Nodular hyperplasia | 15 (27) |
| Hyperplasia with "non- endocrine " tumours | 3 (5) |
| Case no. | Age (yr) | Sex | Weight of adrenal glands (g) | Reference | |
|---|---|---|---|---|---|
| Left | Right | ||||
| 1 | 8/52 | F | * | * | O'Bryan et al., 1964 |
| 2 | 11/52 | M | ... | ... | Lightwood, 1932 |
| 3 | 12/52 | F | 6.0 | 35.0 | Powell et al., 1955 |
| 4 | 3/12 | F | 2.5 | 12.0 | Marks et al., 1940 |
| 5§ | 3/12 | M | 4.7 | 4.3 | Klevitt et al., 1966 |
| 6 | 3/12 | F | 1.0 | 3.0 | Neville and Symington, 1967 Aarskog and Tverteraas, 1968 |
| 7§ | 3/12 | F | 1-0 | 1.5 | Loridan and Senior, 1969 |
| 8 | 4.5/12 | F | 3.5 | 2.7 | Perlmutter et al., 1962 |
| 9 | 7/12 | F | 2.5 | 3.0± | Loridan and Senior, 1969 |
| 10§ | 1 | F | ... | ... | Goldblatt and Snaith, 1958 |
| 11 | 3 | M | 7.1 | 6.7 | Loridan and Senior, 1969 |
| 12 | 8 | F | 4.7 | 5.3 | Chute, Robinson and Donohue, 1949 |
| 13 | 10 | M | (1 cm diam) | ... | Peterman, 1957 |
| 14§|1 | 14 | F | 5.5 | 4.0 | Meador et al., 1967 |
| 15§ | 15 | F | 16.2} | Mosier et al., 1960 | |
* Gland weight stated to be normal.
1 Weight of both glands.
į Gland weight at necropsy.
§ Slight or no response to ACTH infusion; no suppression with dexamethasone or 9x-fluoro- hydrocortisone.
|| Plasma ACTH <0.12 m.units per 100 ml (bioassay; normal: 0.1-0-3 m.units per 100 ml).
frequency of hyperplasia in children. This may be due to the better diagnostic techniques now available to detect the condition in children, who may be rela- tively asymptomatic (Schletter et al., 1967).
In children, as in adults, bilateral adrenocortical hyperplasia occurs in one of three forms (Neville and Symington, 1967): simple hyperplasia, nodular hyperplasia or hyperplasia associated with ” non-endocrine ” tumours that secrete ACTH or an ” ACTH-like ” peptide (table III). Of the 38 children with simple hyperplasia, nine had pituitary tumours. Nodular hyperplasia was diag- nosed in 15 (tables III and IV). Included in this category are several examples
| Adrenal lesion | Number of patients with this lesion who were | |||||
|---|---|---|---|---|---|---|
| males aged | females aged | |||||
| <1 yr | 1-8 yr | 9-15 yr | <1 yr | 1-8 yr | 9-15 yr | |
| Hyperplasia : | ||||||
| simple | 1 | 2 | 13 | 0 | 2 | 9 |
| with pituitary tumours | 0 | 0 | 6 | 0 | 1 | 2 |
| with " non-endocrine " | 1 | 1 | 1 | 0 | 0 | 0 |
| tumours nodular | 2+ | 1 | 1 | 8+ | 1 | 2 |
| Tumours: | ||||||
| adenoma | 2 | 3 | 2 | 8 | 7 | 1 |
| carcinoma | 3 | 13 | 6 | 9 | 41 | 9 |
* The sex of two children with hyperplasia in the review series was not stated.
t Both males and five females were 3 mth of age or less (see table IV).
previously considered to be bilateral adrenocortical adenomas or adenomas with attached hyperplastic glands (Lightwood, 1932; Marks, Thomas and Warkany, 1940; Powell, Newman and Hooker, 1955). Hyperplasia with so-called ” non- endocrine ” tumours was detected in three boys (table III); a thymoma, neuro- blastoma and islet-cell carcinoma were the sources of ACTH.
The different lesions exhibit different age and sex distributions. While adrenal tumours are commoner in females than males, they are detected in both sexes, particularly between 1 and 8 yr of age (table V). Simple hyperplasia tends to occur between 9 and 15 yr of age, especially at the time of puberty (table V). It seems to occur more frequently in boys in contrast with the incidence in adults (Neville and Symington, 1967). Nodular hyperplasia occurs particularly in children less than 3 mth of age and oftener in females. It may even commence in utero (O’Bryan et al., 1964; Loridan and Senior, 1969).
The pathological features of adrenocortical hyperplasia in children closely resemble those of adults, but there are several interesting differences.
In the present series, the mean weight (4.57 g) of the adrenal glands, removed at operation and showing simple hyperplasia, lies within the normal adult range. Because most patients were between 10 and 15 yr of age, such weights must be considered greater than normal. However, adrenal glands of normal weight can also occur in adults with Cushing’s syndrome (Neville and Symington, 1967).
Morphologically, the line dividing the hyperplastic zona reticularis from the zona fasciculata runs parallel to the capsule (fig. 2) and does not exhibit the undulations so typical of the adult hyperplastic gland. Collections of adipose cells are not found in the zona reticularis of the child gland, but are frequent in adults. The zona glomerulosa is always hyperplastic, present around the entire periphery of the gland in children (figs. 2 and 3) and sends into the cortex tongue-like projections that resemble the changes in the glands attached to adrenal tumours causing hyperaldosteronism with low plasma renin (Neville and Symington, 1966; Ferriss et al., 1970). Because aldosterone secretion in chil- dren with Cushing’s syndrome due to adrenal hyperplasia may be increased (Sobel and Taft, 1959; Schletter et al., 1967) or normal (case 7; table I) (Gold- blatt and Snaith, 1958; Chen, Kenny and Drash, 1969), the significance of glomerulosa hyperplasia remains obscure.
The final distinctive feature of the child gland in Cushing’s syndrome is the almost constant presence of cortical micronodules (fig. 3). Such nodules and the related capsular arteriopathy may be found in the adult with Cushing’s syndrome, but are less frequent.
The basic pathological features of nodular hyperplasia found in the 3-mth- old infant (case 12; table I) are similar to those described in the adult (Neville and Symington, 1967) (figs. 5 and 6). In contrast to adult examples, the com- ponent cells were smaller in size and had a higher nuclear-cytoplasmic ratio due to the hyperplasia involving the cells either of the ” definitive ” cortex early in its post-natal development or of the ” foetal ” cortex.
Several authors have reported nodular hyperplasia of the foetal cortex in infants with Cushing’s syndrome (Klevitt et al., 1966) or resemblance of the cells of the nodules to foetal cells (Powell et al., 1955). Others have observed the foetal cortex to be reduced in volume (O’Bryan et al.). In our case, the cells of the nodules were contiguous with those of the “foetal ” cortex and of the hyperplastic ” definitive ” cortex. Consequently, accurate identification of the nodule cell-type is not possible. We have recently examined a most interes- ting virilising adrenal tumour from a neonate, which appeared to arise from the foetal cortex and to be composed of cells morphologically similar to foetal cortical cells. Thus, this cell-type can play an aetiological role in some examples of neonatal hypercorticalism.
We believe that simple and nodular hyperplasia in adults and in children represent different morphological aspects and tissue responses to a similar disease process (Neville and Symington, 1967). The present study, which has shown that nodules of various sizes occur in all forms of adrenal hyperplasia causing Cushing’s syndrome, lends further support to this concept. Some con- sider the nodules to be autonomous and contributing to the disease (Kirschner, Powell and Lipsett, 1964; Meador et al., 1967; Choi, Werk and Sholiton, 1970).
If this were true, then the related cortex should be atrophic as is found in assoc- iation with all cortisol-secreting tumours (Neville and Symington, 1967). This appearance is never seen; all attached cortices are hyperplastic. Moreover, the arteriopathy of the capsular arteries of nodule-bearing adult and child adrenal glands (fig. 4) makes it likelier that the nodules are not aetiological lesions, but develop as local areas of cortical hyperplasia that come to fill ischaemic defects in the cortex (Dobbie, 1969). In our neonatal case, the areas of the definitive cortex that failed to undergo hyperplasia may have been caused by these vascular changes (fig. 5).
SUMMARY
The pathology of the adrenal glands removed from 16 children with Cushing’s syndrome is presented. Bilateral simple or nodular hyperplasia was found in 12; only two children had adrenal carcinomas. The morphological features of adrenal hyperplasia in children and adults are similar, but hyperplasia of the zona glomerulosa and intracortical micronodules are constant features in child glands. One hundred and sixty children are known to have suffered from Cushing’s syndrome; females were affected oftener than males. Bilateral hyperplasia occurred in 35 per cent. of children. Simple hyperplasia was found most frequently between 9 and 15 yr of age, whilst nodular hyperplasia usually was a disease of infancy. Tumours tended to occur between 1 and 8 yr of age.
The authors wish to express their appreciation and thanks to the following colleagues who sent material or made it available to them: Dr D. Aarskog, Dr D. J. Barry, Dr A. G. Cameron, Professor S. D. M. Court, Dr K. Griffiths, Professor J. W. Harman, Dr A. R. Horlen, Professor D. V. Hubble, Professor A. W. Kay, Professor T. D. V. Laurie, Mr W. B. Stirling, Dr J. Thompson, Professor J. P. M. Tizard and Dr G. Whyte.
These studies were supported by the Medical Research Council (grant G970/656/B).
REFERENCES
(G = General paper. R = Review paper on: A, adenoma; C, carcinoma; HNET, hyperplasia with ” non-endocrine ” tumour; HPT, hyperplasia with pituitary tumour; NH, nodular hyperplasia; SH, simple hyperplasia)
AARSKOG, D., AND TVERTERAAS, E. 1968. McCune-Albright’s syndrome following adrenal- ectomy for Cushing’s syndrome in infancy. J. Pediat., 73, 89. (R:NH)
ALBRIGHT, F., COPE, O., AND MALLORY, T. B. 1949. Carcinoma of adrenal. Case Records of Massachusetts General Hospital, no. 35481. New Engl. J. Med., 241, 874. (R:C) ALLIBONE, E. C., BAAR, H. S., AND CANT, W. H. P. 1947. Interrenal syndrome in childhood. Archs Dis. Childh., 22, 210. (R:C)
BAR-HAY, J., BENDERLY, A., AND RUMNEY, G. 1964. Treatment of a case of non-tumorous Cushing’s syndrome with o,p’DDD. Pediatrics, Springfield, 33, 239. (R:SH)
BARTSOKAS, S. 1947. A propos d’un cas de virilisme surrénal avec tumeur de la corticale surrénale et diabète insipide chez une fillette de 28 mois. Archs fr. Pédiat., 4, 266. (R:A)
BERARDINELLI, W., PAULINO, F., CARDIRO, J. G., AND ALBUQUERQUE, D. 1956. Sexual and somatic precocity with some features of Cushing’s syndrome in a 2 year old male. J. Clin. Endocr., 16, 674. (R:C)
BERDON, W. E., AND BAKER, D. H. 1969. Radiographic findings in adrenal disease in infants and children. N.Y. St. J. Med., 69, 2773. (R:A)
BERNHEIM, M., WERTHEIMER, D., GUINET, P., AND SUTET, J. 1954. Les syndromes d’hyper- fonctionnement cortico-surrénal d’origine tumorale chez l’enfant. Sem. Hôp. Paris, 30, 2597. (R:C)
BROSTER, L. R., ALLEN, C., VINES, H. W. C., PATTERSON, J., GREENWOOD, A. W., MARRIAN, G. F., AND BUTLER, G. C. 1938. In The adrenal cortex and intersexuality, London, p. 22. (R:C)
BURKINSHAW, J. H., O’BRIEN, D., AND PENDOWER, J. E. H. 1967. Cushing’s syndrome associated with an islet cell tumour of the pancreas in a boy aged 2 years. Archs Dis. Childh., 42, 525. (R:HNET)
CAHILL, G. F., MELICOW, M. M., AND DARBY, H. H. 1942. Adrenal cortical tumors: types of nonhormonal and hormonal tumors. Surg. Gynec. Obstet., 74, 281. (R:A)
CAHILL, G. F., AND ROBINSON, J. N. 1949. Androgenic symptom tumors of adrenal cortex in children; report of 4 cases. J. Urol., 61, 680. (R:C)
CERVINO, J. M., NAVARRO, A., FOLLE, J. A., MANARO, J. M., MAGGIOLO, J., DE DELFINO, E. Z., MUXI, F., AND BORGES, W. L. 1959. Syndrome de Cushing por carcinoma cortical en une nina de 34 meses. An. Fac. Med. Univ. Montevideo, 44, 36. (R:C)
CHEN, R., KENNY, F. M., AND DRASH, A. L. 1969. Cushing’s disease in a boy: serial steroid and growth hormone studies. Johns Hopkins Med. J., 125, 134. (R:SH)
CHOI, Y., WERK, E. E., JR, AND SHOLITON, L. J. 1970. Cushing’s syndrome with dual pituitary-adrenal control. Archs Intern. Med., 125, 1045. (G)
CHRISTY, N. P., LONGSON, D., AND JAILER, J. W. 1957. Studies in Cushing’s syndrome. I. Observations on the response of plasma 17-hydroxycorticosteroid levels to cortico- trophin. Amer. J. Med., 23, 910. (R:SH)
CHUTE, A. L., ROBINSON, G. C., AND DONOHUE, W. L. 1949. Cushing’s syndrome in children. J. Pediat., 34, 20. (R:NH)
CLEMENT, R., AND DEBAIN, M. 1942. Hirsutisme, hypertension artérielle, hémorragie méningée et cortico-surrénalome chez une fillette de quatre ans et demi. Bull. Mém. Soc. méd. Hôp. Paris, 58, 335. (R:C)
CLOUTIER, M. D., HAYLES, A. B., AND SPRAGUE, R. G. 1966. Pituitary tumor and Cushing’s syndrome. Report of a case of an adolescent male with cutaneous melanosis after adrenalectomy. Amer. J. Dis. Child., 112, 596. (R:HPT)
COLLETT, A. 1924. Genito-suprarenal syndrome (suprarenal virilism) in a girl one and a half years old, with successful operation. Amer. J. Dis. Child., 27, 204. (R:C)
COPINSCHI, G., NEVE, P., WOLTER, R., AND BASTENIE, P. A. 1969. Dwarfism caused by Cushing’s syndrome. Acta endocr., Copenh., 60, 446. (R:SH)
CROOKE, A. C., AND CALLOW, R. K. 1939. Differential diagnosis of forms of basophilism (Cushing’s syndrome), particularly by estimation of urinary androgens. Q. J. Med., 8, 233. (R:C)
DANOWSKI, T. S. 1962. In Clinical endocrinology, Baltimore, vol. 4, p. 154. (G)
DAVIES, D. M. 1953. Cushing’s syndrome in a child of 2} years. Proc. Roy. Soc. Med., 46, 307. (R:C)
DOBBIE, J. W. 1969. Adrenocortical nodular hyperplasia: the ageing adrenal. J. Path., 99, 1. (G)
FALK, W. 1953. Klinische Beiträge zum Cushing Syndrom im Kindesalter. Helv. paediat. Acta, 8, 216. (R:C)
FARBER, J. E., GUSTINA, F. J., AND POSTOLOFF, A. V. 1943. Cushing’s syndrome in children : review of literature and report of a case. Amer. J. Dis. Child., 65, 593. (R:C)
FERRISS, J. B., BROWN, J. J., FRASER, R., KAY, A. W., LEVER, A. F., NEVILLE, A. M., O’MUIRCHEARTAIGH, I. G., ROBERTSON, J. I. S., AND SYMINGTON, T. 1970. Hyper- tension with aldosterone excess and low plasma renin: preoperative distinction between patients with and without adrenocortical tumour. Lancet, 2, 995. (G)
FOLLIS, R. H., JR 1951. Pathology of osseous changes in Cushing’s syndrome in an infant and in adults. Bull. Johns Hopkins Hosp., 88, 440. (R:SH)
FORBES, A. P., AND ALBRIGHT, F. 1951. Comparison of 17-ketosteroid excretion in Cushing’s syndrome associated with adrenal tumor and with adrenal hyperplasia. J. Clin. Endocr., 11, 926. (R:HPT)
FORDYCE, A. D., AND EVANS, W. H. 1929. Suprarenal virilism. Report of 2 cases. Q. J. Med., 22, 557. (R:C)
GARRETT, R. A. 1951. Adrenal cortical carcinoma in children. J. Urol., 66, 477. (R:C) GELLIS, S. S., AND FEINGOLD, M. 1966. Congenital hemihypertrophy and adrenal carcinoma. Amer. J. Dis. Child., 111, 419. (R:C)
GILBERT, M. G., AND CLEVELAND, W. W. 1970. Cushing’s syndrome in infancy. Pediatrics, Springfield, 46, 217. (R:A)
GLANZMANN, E. 1948. Interrenale Syndrome im Kindesalter. Annls paediat., 171, 335. (R:C)
GOLDBLATT, E., AND SNAITH, A. H. 1958. A case of Cushing’s syndrome in an infant. Archs Dis. Childh., 33, 540. (R:NH)
GOLDSTEIN, A. E., RUBIN, S. W., AND ASKIN, J. A. 1946. Carcinoma of adrenal cortex with androgenital syndrome in children; complete review of literature and report of case with recovery in child 8 months of age. Amer. J. Dis. Child., 72, 563. (R:C)
GOLDSTEIN, H. M. 1949. Cushing’s syndrome due to tumor of adrenal cortex; report of case of an 11 month old infant with apparent operative cure. Amer. J. Dis. Child., 78, 260. (R:C)
GREENBLATT, R. B., MANAUTOU, J. M., ZIMMERMAN, A. M., AND LUCAS, W. T. 1957. Cushing’s syndrome in infancy. Amer. J. Dis. Child., 94, 691. (R:A)
GROB, M., PRADER, A., AND ZOLLINGER, H. U. 1953. Klassisches Cushing-Syndrom bei einem 4 jährigen Mädchen; Heilung nach Entfernung eines Nebennieren-karzinoms. Helv. paediat. Acta, 8, 202. (R:C)
GROSS, R. E. 1940. Neoplasms producing endocrine disturbances in childhood. Amer. J. Dis. Child., 59, 579. (R:C)
GRUMBACH, M. M., BONGIOVANNI, A. M., EBERLEIN, W. R., VAN WYK, J. J., AND WILKINS, L. 1955. Cushing’s syndrome with bilateral adrenal hyperplasia: study of plasma 17- hydroxycorticosteroids and response to ACTH. Bull. Johns Hopkins Hosp., 96, 116. (R:SH)
GUIN, GRACE H., AND GILBERT, ENID F. 1956. Cushing’s syndrome in children associated with adrenal cortical carcinoma: a case report with review of literature. Amer. J. Dis. Child., 92, 297. (G;R:C)
HAIN, A. M. 1947. Adrenal tumours and pseudo-hermaphroditism; a hormone study of cases. J. Path. Bact., 59, 267. (R:C)
HALL, D. T. 1954. Hormone-producing tumors of the adrenal cortex; review with a report of 2 cases. Amer. J. Surg., 88, 162. (R:A)
HARRISON, R. J., AND ABELSON, D. 1952. Carcinoma of adrenal cortex with endocrine manifestations; report of a case. Br. Med. J., 1, 303. (R:C)
HAUGEN, H. N., AND JENSEN, H. 1960. Diagnosis and surgical treatment of Cushing’s syndrome; a review of 16 cases. Acta med. scand., 168, 141. (R:SH)
HEINBECKER, P. 1944. Pathogenesis of Cushing’s syndrome. Medicine, Baltimore, 23, 225. (R:A,HPT)
HEINBECKER, P., O’NEAL, L. W., AND ACKERMAN, L. V. 1957. Functioning and non- functioning adrenal cortical tumors. Surg. Gynec. Obstet., 105, 21. (G;R:C)
HUBBLE, D. V., AND ILLINGWORTH, R. S. 1957. Adrenocortical hyperplasia in childhood. Archs Dis. Childh., 32, 285. (R:SH)
JACKSON, W. P. W., ZILBERG, B., LEWIS, B., AND MCKENZIE, D. 1958. Cushing’s syndrome in childhood; report of case of adrenocortical carcinoma with excessive aldosterone production. Br. Med. J., 2, 130. (R:C)
KENNEDY, C. M., AND LISTER, W. A. 1927. Case of suprarenal hypernephroma. Lancet, 2, 749. (R:C)
KENNY, F. M., STAVRIDES, A., VOORHESS, MARY L., AND KLEIN, R. 1967. Cushing’s syndrome associated with an adrenal neuroblastoma. A case in an infant with clinical, pathological
and adrenal cortical and medullary hormone excretion studies. Amer. J. Dis. Child., 113, 611. (R:HNET)
KEPLER, E. J., KENNEDY, R. L. J., DAVIS, A. C., AND WALTERS, W. 1934. Suprarenocortical syndrome and pituitary basophilism: presentation of 3 new cases. Proc. Staff Meet. Mayo Clin., 9, 169. (R:A)
KIEFER, J. H., AND BRONSTEIN, I. P. 1949. Adrenal cortical tumor : case reports. J. Urol., 62, 639. (R:A)
KIRSCHNER, M. A., POWELL, R. D., JR, AND LIPSETT, M. B. 1964. Cushing’s syndrome; nodular cortical hyperplasia of adrenal glands with clinical and pathological features suggesting adrenocortical tumor. J. Clin. Endocr., 24, 947. (R:NH)
KLEVITT, H. D., CAMPBELL, R. A., BLAIR, H. R., AND BONGIOVANNI, A. M. 1966. Cushing’s syndrome with nodular adrenal hyperplasia in infancy. J. Pediat., 68, 912. (R:NH) KOLFF, W. J., AND THIOOK, K. B. 1950. Hirsutism and virilism in 5 year old girl: remission following removal of adrenal carcinoma; recurrence after 34 years. J. Endocr., 10, 270. (R:C)
KRAUS, H., AND KRAINICK, H. G. 1958. Cushing’sches Syndrom bei einem eineinhalb Jahre alten Mädchen; Heilung nach Entfernung eines Nebennierenrindenadenoms. Dt. med. Wschr., 83, 321. (R:C)
KRIEGER, D. T., KRIEGER, H. P., AND SOFFER, L. J. 1964. Cushing’s syndrome associated with a suprasellar tumor. Acta endocr., Copenh., 47, 185. (R:HPT)
LAWRENCE, C. H. 1937. Adrenal cortical tumor; report of 4 cases. Ann. Intern. Med., 11, 936. (R:HPT)
LEVINE, S. Z., BARNETT, H. L., SHIBUYA, M., AND BARBER, J. K. 1956. Isosexual precocity in boys including a case of a gonadotrophin-producing teratoma. Adv. Pediat., 8, 53. (R:SH)
LIGHTWOOD, R. 1932. Tumour of suprarenal cortex in an infant of 18 weeks. Archs Dis. Childh., 7, 35. (R:NH)
LITTLE, A. A., JR 1936. Carcinoma of adrenal cortex. J. Pediat., 9, 62. (R:C)
LORIDAN, L., AND SENIOR, B. 1969. Cushing’s syndrome in infancy. J. Pediat., 75, 349. (R:NH)
MARIE, J., FÈVRE, M., SÉE, G., HÉBERT, S., AND WATCHI, M. J. 1955. Syndrome d’Apert- Cushing par tumeur maligne surrénale avec absence de la glande surrénale opposée. Sem. Hộp. Paris, 31, 282. (R:C)
MARKS, T. M., THOMAS, J. M., AND WARKANY, J. 1940. Adrenocortical obesity in children. Amer. J. Dis. Child., 60, 923. (R:NH)
MARSDEN, H. B., AND STEWARD, J. K. 1968. In Tumours of children, Berlin, p. 294. (R:C)
MEADOR, C. K., BOWDOIN, B., OWEN, W. C., AND FARMER, T. A., JR 1967. Primary adreno- cortical nodular dysplasia: a rare cause of Cushing’s syndrome. J. Clin. Endocr., 27, 1255. (R:NH)
MELICOW, M. M., AND CAHILL, G. F. 1950. Role of adrenal cortex in somato-sexual disturbances in infants and children: clinico-pathologic analysis. J. Clin. Endocr., 10, 24. (R:SH)
MELLGREN, J. 1945. The anterior pituitary in hyperfunction of the adrenal cortex; an anatomical study with special reference to Syndroma Morgagni and notes on prostatic hypertrophy. Acta path. microbiol. scand., Suppl. 60, p. 1. (R:C)
MOLTSCHANOFF, V. I., AND DAVYDOWSKI, I. V. 1930. Zur Klinik und Entstehungsweise des Hirsutismus. Virchows Arch. path. Anat. Physiol., 274, 606. (R:C)
MONTGOMERY, D. A. D., AND WELBOURNE, R. B. 1965. Adrenocortical carcinoma treated with o,p’DDD. Br. Med. J., 1, 1356. (R:C)
MOSIER, H. D., FLYNN, P. J., WILL, D. W., AND TURNER, R. D. 1960. Cushing’s syndrome with multinodular adrenal glands. J. Clin. Endocr., 20, 632. (R:NH)
NEFF, F. C., TICE, G., WALKER, G. A., AND OCKERBLAD, N. 1942. Adrenal tumor in female infant with hypertrichosis, hypertension, overdevelopment of external genitalia, obesity but absence of breast enlargement. J. Clin. Endocr., 2, 125. (R:A)
NEVILLE, A. M., AND SYMINGTON, T. 1966. Pathology of primary aldosteronism. Cancer, Philad., 19, 1854. (G)
NEVILLE, A. M., AND SYMINGTON, T. 1967. The pathology of the adrenal gland in Cushing’s syndrome. J. Path. Bact., 93, 19. (G;R:A,C,NH,SH)
O’BRYAN, R. M., SMITH, R. W., JR, FINE, G., AND MELLINGER, R. C. 1964. Congenital adrenocortical hyperplasia with Cushing’s syndrome. J. Amer. Med. Assoc., 187, 257. (R:NH)
PERLMUTTER, M., APFEL, A. Z., AVIN, J., HERMANN, H. B., AND KLEIN, E. A. 1962. Cushing’s syndrome in infancy: report of a case. Metabolism, 11, 946. (R:NH)
PETERMAN, M. G. 1957. Suprarenal tumor (Cushing’s syndrome). J. Pediat., 50, 59. (R:NH)
PICARD, R., HOREAU, J., KERNEIS, J., HARDY, M., GUINOT, W., AND RANGER, J. 1952. Tumeur cortico-surrénale chez un garçon de 14 ans avec hyperfolliculinisme. Confrontations cliniques et biologiques. Bull. Mém. Soc. méd. Hôp. Paris, 68, 72. (R:C)
POWELL, L. W., JR, NEWMAN, S., AND HOOKER, J. W. 1955. Cushing’s syndrome: report of a case in infant 12 weeks old. Amer. J. Dis. Child., 90, 417. (R:NH)
PUZYNSKI, D. L., AND BIEHUSEN, F. C. 1962. Adrenocortical adenoma with Cushing’s syn- drome and virilism in a 5 year old child. J. Pediat., 60, 836. (R:A)
QUINBY, W. C. 1933. Some dysfunctions caused by neoplasm, especially of adrenal gland. Trans. Amer. Assoc. Genito-urin. Surg., 26, 67. (R:C)
RIGGS, B. L., AND SPRAGUE, R. G. 1961. Association of Cushing’s syndrome and neoplastic disease: observations in 232 cases of Cushing’s syndrome and review of the literature. Archs Intern. Med., 108, 841. (R:HNET)
SCHLETTER, F. E., CLIFT, G. V., MEYER, R., AND STREETEN, D. H. P. 1967. Cushing’s syn- drome in childhood: report of two cases with bilateral adrenocortical hyperplasia showing distinctive clinical features. J. Clin. Endocr., 27, 22. (R:SH)
SCHWEIZER, F., SENET, O., AND LLAMBIÉS, A. 1930. Un case de hirsutismo. Archos argent. Pediat., 1, 550. (R:C)
SCOTT, H. W., JR, FOSTER, J. H., LIDDLE, G., AND DAVIDSON, E. T. 1962. Cushing’s syndrome due to adreno-cortical tumor: 11 year review of 15 patients. Ann. Surg., 162, 505. (R:A,C)
SILVER, H. K., AND GINSBURG, M. M. 1960. Cushing’s syndrome in an eight-year-old girl. Amer. J. Dis. Child., 100, 405. (R:SH)
SOBEL, EDNA H., LEE, C. M., JR, ESSELBORN, VIRGINIA M., AND CLARK, L. C., JR 1953. Functioning adrenal tumors in childhood; consideration of diagnosis, surgical approach and post-operative management. Amer. J. Dis. Child., 86, 733. (R:A)
SOBEL, EDNA H., AND TAFT, L. T. 1959. Cushing’s syndrome and suspected mental retardation in an 18 month old boy. Pediatrics, Springfield, 23, 413. (R:SH)
SOFFER, L. J., IANNACCONE, A., AND GABRILOVE, J. L. 1961. Cushing’s syndrome: a study of fifty patients. Amer. J. Med., 30, 129. (R:C,SH)
STATE, D. 1952. Surgery of tumors and hyperfunctioning states of adrenal glands. Surgery, St Louis, 32, 134. (R:SH)
STEINBACH, H. L., NOETZLI, M., AND OZONOFF, M. B. 1963. Small pituitary fossa in Cushing’s syndrome due to adrenal neoplasm. New Engl. J. Med., 269, 1286. (R:A)
STUDZINSKI, G. P., HAY, D. C. F., AND SYMINGTON, T. 1963. Observations on the weight of the human adrenal gland and the effect of preparations of corticotropin of different purity on the weight and morphology of the human adrenal gland. J. Clin. Endocr., 23, 248. (G)
SYMINGTON, T., AND JEFFRIES, R. 1962. In The human adrenal cortex, ed. by A. R. Currie, T. Symington and J. K. Grant, Edinburgh, p. 345. (G)
TALBOT, N. B., SOBEL, E. H., MCARTHUR, J. W., AND CRAWFORD, J. D. 1952. Functional endocrinology from birth through adolescence, Cambridge, Mass., p. 235. (R:C)
THURSBY-PELHAM, D. C., AND CROWE, G. G. 1961. Cushing’s syndrome in childhood due to adrenal hyperplasia. Br. Med. J., 2, 1536. (R:SH)
J. PATH .- VOL. 107 (1972)
TVERTERAAS, E., AND AARSKOG, D. 1963. Cushing’s syndrome in an infant. Acta pediat., Stockh., Suppl. 140, p. 140. (R:SH)
VAN DER BOGERT, F. 1933. Virilism and hypertension in infancy associated with adrenal tumor. J. Pediat., 3, 629. (R:C)
WALTERS, W., AND SPRAGUE, R. G. 1949. Hyperfunctioning tumors of adrenal cortex: study of 9 cases. J. Amer. Med. Assoc., 141, 653. (R:C)
WALTERS, W., WILDER, R. M., AND KEPLER, E. J. 1934. Suprarenal cortical syndrome with presentation of 10 cases. Ann. Surg., 100, 670. (R:C)
WEIDNER, M. G., AND TOWERY, B. T. 1956. Adrenocortical adenoma with Cushing’s syn- drome in infancy. Surgery, St Louis, 39, 492. (R:A)
WEISSE, K. 1947. Ein Cushing-Syndrom bei einem 20 monate alten Mädchen. Z. Kinder- heilk., 65, 9. (R:A)
WILKINS, L. 1957. The diagnosis and treatment of endocrine disorders in childhood and adolescence, Springfield, Ill., p. 378. (R:C)
WILKINS, L. 1962. Cushing’s syndrome and its puzzles. Archs Dis. Childh., 37, 1. (R:HPT) WILKINS, L., AND RAVITCH, M. M. 1952. Adrenocortical tumor arising in liver of 3 year old boy with signs of virilism and Cushing’s syndrome; report of case with cure after partial resection of right lobe of liver. Pediatrics, Springfield, 9, 671. (R:C)
WRIGHT, C. A. 1935. Pituitary basophilism; discussion of additional factors in relation to 4 cases. Med. Rec., N.Y., 141, 191. (R:HPT)