Institute of Endocrinology and Metabolic Diseases, Zapata y D, Havana 4, Cuba
FAMILIAL CUSHING’S SYNDROME By Bartolomé Arce, Manuel Licea, Santiago Hung and Rubén Padrón
ABSTRACT
Cushing’s syndrome has been demonstrated in four of seven siblings with clinical manifestations appearing around puberty in three of the four siblings. The only other associated findings in these cases were short stature and disturbed carbohydrate metabolism. Adenomatous hyperplasia of the adrenal glands was demonstrated in 3 of the patients, and a viril- izing adrenal carcinoma in the fourth sibling. The pathogenesis of the adrenocortical disorders in these siblings is discussed.
Adrenal diseases with familial occurrences have been reported in the literature. In congenital adrenal hyperplasia, the genetic origin seems to be unquestion- able (Bongiovanni 1958), but also in other diseases, e. g. pheochromocytoma (Carman & Brasher 1960; Cushman 1962) primary aldosteronism (Motulsky & Epstein 1969; Ballard et al. 1964) and Addison’s disease (Heggarty 1968; Frey et al. 1973); a familial appearance has been reported.
Cushing’s syndrome has been described in connection with a disorder of probable genetic origin, Ehler-Danlos syndrome (Aguirre et al. 1968). A possible genetic basis was suggested for both diseases.
This paper reports the occurrence of Cushing’s syndrome in four siblings. To our knowledge, this is the first report of this kind.
PATIENT MATERIAL
Four siblings, two females and two males were studied. A genealogical survey of both branches of the family was undertaken to identify any manifestation of adrenal hyper- function in other relatives.
Case 1
J. G., a 13 year old boy had noted the onset of symptoms of obesity at the age of 10. Three months later, asthenia, pelvic girdle pain, dyspnoea and progressive obesity had developed. Physical examination revealed a moonface, a cervical hump, purple striae and slight generalized skin pigmentation (Fig. 1). The patient was 136 cm in height, 75 kg in weight, and had a blood pressure of 170/130 mmHg. The funduscopic and visual field examinations were normal. Skull radiographs were normal and no enlargement of the sella turcica was noted. The electrocardiogram was within normal limits. Bone radiographs disclosed severe osteoporosis of the spine with vertebral compressions of the lumbar region.
Retroperitoneal insufflation of air demonstrated enlarged adrenal glands which, however, could not be seen on pyelograms and arteriograms.
The results of laboratory examinations included: a decreased oral glucose tolerance test; and a slight elevation of urinary 17-ketosteroids (Gray et al. 1969) and 17-keto- genic steroids (Schöller 1962), 19 and 32 mg/24 h, respectively.
Bilateral total adrenalectomy was performed and the patient placed on replacement therapy with hydrocortisone and deoxycorticosterone acetate (DOCA).
The results of histopathological examination included: adrenal glands weighing 7 g each and measuring 5 x 3 x 2 cm; as well as numerous cortical nodules from 3 mm to 1.5 cm in diameter in both glands, some of which were encapsulated, and composed of cells with central to somewhat excentric nuclei and clear eosinophilic cytoplasm similar to the cells of the reticular and fascicular zones. The hyperplastic internodal cortex revealed large cells with giant bizarre hyperchromatic nuclei; clear and vacuo- lated or eosinophilic cytoplasm; and, lipochromic pigment (Figs. 2 and 3).
Clinical course. - Within the first post-operative year the patient grew 11 cm (147 cm) in height and lost 17 kg in weight. The purple striae had disappeared, and blood pressure was normal at 130/70 mmHg. The face appeared normal. Moreover the onset of puberty occurred. The vertebrae showed marked re-calcification as shown by the radiograms. The glucose tolerance test was normal. Urinary 17-KS and 17-OH (Appleby et al. 1955) were 2.6 and 4.5 mg/24 h, respectively.
Eight years post-operatively the patient was still in complete remission. Puberty had developed normally. At the time of writing this report (1977), the patient, now aged 29, is still well while on daily replacement therapy with cortisone acetate and DOCA.
Case 2
J. G., a 32 year old man was noted at the age of 27 to have a retinal detachment and subsequent loss of vision in the left eye. Despite surgical intervention, the same condition resulted in visual impairment of the right eye one year later. On re-admission for further ophthalmic surgery he developed a hypertensive crisis with a persistent elevation of his blood pressure. Severe obesity was also noted.
Physical examination revealed obesity of the face and trunk, a moonface, a cervical hump, and abdominal purple striae. He weighed 91 kg, was 167 cm in height, and had a blood pressure of 200/130 mmHg. Funduscopic examination disclosed almost complete retinal detachment in the left eye and lower segment detachment in the right eye.
The results of laboratory examination included: a decreased oral glucose tolerance test; normal findings in the chest radiograph, pyelogram and arteriogram; skull radio- graphs were normal with no enlargement of the sella turcica; and the vanilmandelic acid level was normal. The mean values for 17-ketosteroids and 17-OH were 7.3 and 12 mg/24 h, respectively. ACTH stimulation, dexamethasone suppression (2 and 8 mg) or metyrapone tests produced no significant variation in the steroid levels. The cir- cadian rhythm for urinary 17-OH was 2.4 mg (7 a. m .- 3 p. m.), 5.2 mg (3 p. m .- 11 p. m.), and 2.8 mg (11 p. m .- 7 a. m.); and, the circadian rhythm for plasma cortisol (according to Mattingly (1962) and Martin & Martin (1968) modified in our laboratory) was 28 and 21 ug/100 ml of plasma at 8 a. m. and 5 p. m., respectively.
The left adrenal gland was removed. It weighed 9.5 g, had numerous cortical nodules and showed similar histological findings as noted in Case 1.
The clinical manifestations of Cushing’s syndrome persist at present while the pa- tient awaits operation for removal of the right adrenal gland.
Case 3
M. G., a 15 year old young woman was found to have had since the age of 10 marked obesity and growth arrest. At the age of 11, she had the onset of pubarche
and thelarche, and developed acne of the face and neck, hypertension and progressive obesity. Physical examination revealed a moonface, moderate hypertrichosis, and a marked dorsal kyphosis. She was 145 cm in height, 70 kg in weight, and had a blood pressure of 140/110 mmHg (Fig. 4).
The results of laboratory examination included: a decreased oral glucose tolerance test; and mean values for 17-KS and 17-OH were 9 and 14 mg/24 h, respectively. Neither ACTH stimulation nor dexamethasone suppression (2 and 8 mg) or metyrapone tests produced any significant alteration in the levels of 17-OH.
Funduscopic and visual field examinations were normal, as were the radiographs of the skull. There was no enlargement of the sella turcica. Arteriograms of the adrenals were normal.
Six months later, the characteristics of Cushing’s syndrome had developed further, and her blood pressure was now 150/120 mmHg. The right adrenal gland was removed.
The histopathological examination revealed an adrenal gland weighing 6 g with numerous yellowish cortical nodules, from 0.2 to 1 cm in diameter. The histological findings were similar to those in Case. 1.
Clinical course. - There was a marked remission of clinical signs of Cushing’s syn- drome and menarche occurred within 6 months after adrenalectomy. Eight months later, oligomenorrhoea and hypomenorrhoea developed. Subsequently amennorrhoea devel- oped with the re-appearance of Cushing’s syndrome. The results of adrenal function tests were similar to those at the time of first admission. The left adrenal gland was removed. The histological findings were similar to those of the contralateral gland.
Case 4
A. G., a 15 year old young women developed amenorrhoea at the age of 14 after having had a normal puberty at the age of 12. Six months later, the patient demon- strated progressive asthenia and anorexia, severe hirsutism and acne. On physical examination, the liver was palpable 9 cm below the arcus and a tumour mass was palpable in the left hypochondrium. She had an enlarged clitoris, purple striae over the abdomen, and typical Cushing facies. She was 40 kg in weight, 148 cm in height, and had a blood pressure of 140/80 mmHg (Fig. 5).
+
+
+
+
+
+
- GOITER
- EPILEPSY
+
13
16
19
2ª
17
21
32
33
30
?
CUSHING
IEEM-66-77
+
₹ DEAD
Fig. 6. Genealogical study of 4 generations.
The results of laboratory examinations included: a glutamic pyruvic transaminase of 129 units (normal value 4-16); an alkaline phosphatase of 26 Bodansky units (normal value < 5); a total bilirubin of 12.4 mg (direct: 5.96 mg); and, a decreased glucose tolerance. Other liver function tests were normal and, the prothrombin time was 18 seconds (normal 12 seconds). The mean values of 17-KS and 17-OH were 365 and 43 mg/24 h, respectively, and the dehydroepiandrosterone (DHA) was 83 mg/24 h (Drosdowsky 1962).
Funduscopic and visual field examinations were normal, as were the radiographs of skull, sella turcica and long bones. An abdominal radiograph disclosed a tumourous mass below the lower pole of the left kidney, and a pyelogram showed the tumour slightly raising the kidney. A colon contrast enema disclosed a downward-forward displacement of the splenic angle and left half of the transverse colon. Laparoscopy revealed a retroperitoneal tumour and marked uterine and ovarian hypoplasia.
At exploratory laparotomy with operative cholangiography no obstruction of extra- hepatic biliary ducts was noted but a collapsed gallbladder was observed. The ovaries were hypoplastic and there was moderate splenomegaly. A large non-resectable and highly vascularized cystic tumour (15 x 20 cm) infiltrating the retroperitoneal spaces and transverse mesocolon was seen. The pancreas was reduced to a sheet due to tumour compression. A biopsy taken from the tumour mass unfortunately could not be used for histological examination. The patient died 2 months later in a state of cachexia. An autopsy was not possible in this case.
Summary of main data
A four-generation genealogical study of both branches of the family revealed no other case of adrenal hyperfunction (Fig. 6). The only other familial endocrinological disease noted was a simple goitre in the father.
In all these patients there was disturbed carbohydrate metabolism. Spinal column osteoporosis occurred in 2 patients with adenomatous hyperplasia. Arteriograms were normal in the 3 patients with adrenocortical hyperplasia; a pyelogram revealed a left retroperitoneal tumour in the fourth patient. Hormone determinations proved valuable in the latter case since both glucocorticoid metabolites and androgenic steroids were markedly elevated. Complete adrenal functional autonomy was demonstrated in 2 pa- tients with adrenal hyperplasia and in the one with adrenal tumour.
COMMENTS
Endocrine syndromes with familial appearance have been reported previously (Danowski et al. 1962). Koch & Tiwisina (1959) compiled all published cases of familial acromegaly, and there have been reports of familial hyperthy- roidism (Vague et al. 1958) toxic thyroid adenomas (Martin & Fisher 1945) primary hyperparathyroidism, alone or associated with polyadenomatosis (Frohner & Walgamot 1954; Danowski et al. 1962), pheochromocytoma (Car- man & Brashner 1960; Cushman 1962; Cone 1960), male precocious puberty (Beas et al. 1962) and all the variants of adrenal enzymatic defects (Bongio- vanni 1961; Green et al. 1960). The genetic character of the familial poly- adenomatosis seems to be well established (Wermer 1963; Ballard et al. 1964).
It was associated with adrenal alterations in 37.6 % of the cases (Ballard et al. 1964), and in two families, one member of whom had Cushing’s syndrome (Schmid et al. 1961). On the other hand, we have found no reference of more than one case of Cushings’ syndrome within one and the same family (Lehman 1968).
The presence of Cushing’s syndrome in our four siblings leaves little margin for the possibility of a casual event. On the contrary, it supports the idea of a common and possibly genetic origin, although none of the known previous family members demonstrated any signs of adrenal disease. The clinical mani- festations appeared around puberty in three of the four siblings.
Three of our patients had an adenomatous hyperplasia with functional adrenal autonomy demonstrated in two cases, whereas the fourth patient pre- sented a malignant tumour with a virilizing syndrome.
It has been suggested that the genesis of endocrine tumours stem from an anomalous and continuous stimulus by the corresponding trophic hormone. At the first stage the pathological action leads to functional hyperplasia. The process may be arrested at this point or continues to a second stage with deeper more marked cellular changes to the extent of producing an adenomatous hyperplasia or even an adenomatous tumour. If this stimulus continues the tumour may degenerate into a carcinoma.
If this hypothesis is applied to our cases, their common stimulus would be an anomalous ACTH hyperproduction, that led to adenomatous hyperplasia in three, and even further more in the fourth patient, to produce an adrenal carcinoma. Methods for the measurement of ACTH in the blood were not available in our laboratory at that time.
Although it was impossible to obtain a specimen of the tumour, the clinical signs and hormone results taken together with the fatal outcome of the case, provide sufficient evidence to consider the tumour a virilizing adrenal car- cinoma.
The present report serves the purpose of pointing to a possible familial pathogenic origin of Cushing’s syndrome.
ACKNOWLEDGMENT
We wish to express our appreciation to Professor Rolf Luft and Dr. Mark A. Belsey, for the review of the manuscript and valuable suggestions.
REFERENCES
Aguirre J., Cabre F., Cruz C. & Garrido M .: Rev. clin. esp. 108 (1968) 395. Appleby J. I., Norymberski J. J. & Stubbs R. D .: Biochem. J. 60 (1955) 453. Ballard H. S., Frame B. & Hartsock R. J .: Medicine (Baltimore) 43 (1964) 481.
Beas F., Zurbrogg R. P., Leibow S. G., Patton R. G. & Gardner L. I .: J. clin. Endocr. 22 (1962) 1095.
Bongiovanni A. M .: Pediatrics 21 (1958) 1031.
Bongiovanni A. M .: J. clin. Endocr. 21 (1961) 860.
Carman C. T. & Brasher R. E .: New Engl. J. Med. 263 (1960) 419.
Cone T. E .: Amer. J. Dis Child. 100 (1960) 781.
Cushman P .: Amer. J. Med. 32 (1962) 352.
Danowski T. S., Mateer F. M. & Longabaugh E. E .: Acta med. scand. 172 (1962) 559.
Drosdowsky M. In: Jayle M. F., Ed. Analyse des Steroides Hormonaux, Vol. II. Masson et Cie. Paris (1962) 64.
Frey H. M. M., Vogt J. H. & Nerup J .: Acta endocr. (Kbh.) 72 (1973) 401.
Frohner R. N. & Walgamot J. C .: Ann. intern. Med. 40 (1954) 765.
Gray C. H., Baron D. N., Brooks R. V. & James V. H. T .: Lancet 1 (1969) 124.
Green O. C., Migeon C. J. & Wilkins L .: J. clin. Endocr. 20 (1960) 929.
Heggarty H .: Brit. med. J. 1 (1968) 559.
Koch G. & Tiwisina T .: Ärztl. Forsch. 13 (1959) 489.
Lehman W. In: Becker P. E., Ed. Genetica Humana, Vol. III. Toray, Barcelona (1968) 250.
Martin L. & Fisher R. A .: Quart. J. Med. 14 (1945) 207.
Martin M. M. & Martin A. L. A .: J. clin. Endocr. 28 (1968) 137.
Mattingly D .: J. clin. Path. 15 (1962) 374.
Motulsky A. G. & Epstein C. J. In: Williams R. H., Ed. Tratado de Endocrinología. Salvat, Barcelona (1969) 1150.
Schmid J. R., Labhart A. & Rossier P. H .: Amer. J. Med. 31 (1961) 343.
Schöller R. In: Jayle M. F., Ed. Analyse des Steroides Hormonaux, Vol. II. Masson et Cie. Paris (1962) 137.
Vague J., Codaccioni J. L. & Legré M .: Folia endocr. 11 (1958) 1.
Wermer P .: Amer. J. Med. 35 (1963) 205.
Received on April 22nd, 1977.