Cushing’s syndrome should be considered in any child with obesity in combination with short stature, as children with simple obesity tend to be tall whereas hypercortisolaemia stunts growth. The elevated circulating androgens seen in Cushing’s syndrome, particularly in adrenal adenomas, can result in apparent puberty and virilization without gonadal enlargement (pseudoprecocious puberty). Contrary to earlier reports, bone age is normal in 80% of children with Cushing’s syndrome as although androgens accelerate bone maturation, with a consequent loss of linear growth potential, hypercortisolaemia appears to delay maturation.
The specific features that may be present on examination include inappropriate axillary or pubic hair, penile enlargement, scrotal pigmentation, and clitoral hypertrophy. Acne vulgaris can develop in children of any age. These features of hyperandrogenism are likely to be more pronounced with androgen- secreting adrenal tumours, but also occur with ACTH- dependent Cushing’s syndrome. Primary or secondary amenorrhoea may be a feature in girls. Blood pressure is often mildly or moderately elevated, but diabetes mellitus is very unusual. School performance can suffer and psychiatric and emotional symptoms may occur.
Aetiology
The distribution of causes in childhood is different from that encountered in adults; there is a male predominance in Cushing’s dis ease. Fetal- and neonatal- onset Cushing’s syndrome have been described, but the diagnosis remains exceptionally rare until ap proximately 8 years of age. Under 2 years of age, adrenal carcinoma accounts for 80% of cases of Cushing’s syndrome, of which 80% occur in females.
Investigation in childhood
Cushing’s syndrome presenting in childhood is rare. Any child with weight gain and growth failure should be investigated but, as described earlier, the presenting symptoms may vary. The investigative algorithm is as described for adults, and experience shows that it is not necessary to alter the dose of dexamethasone or CRH used in adults. Although more technically challenging in children, inferior petrosal sinus sampling is, as in adults, vital for localizing the source of ACTH secretion.
Treatment
The principles of treatment of hypercortisolaemia are the same in children as in adults. Ketoconazole is preferable to metyrapone in children, as the former lowers, rather than increases, circulating androgen levels, but both are safe. Transsphenoidal surgery achieves remission in the majority of children with Cushing’s dis ease. Pituitary radiotherapy is reserved for surgical failures, or those whose surgery is impossible because of the small size of the pituitary fossa; however, when required it controls ACTH secretion more promptly in children than in adults with Cushing’s disease, but residual pituitary function requires close monitoring to ensure normal pubertal development and growth. Growth hormone deficiency occurs early after radiotherapy in children, but may recover in some.
Once hypercortisolaemia has been controlled, the management of growth and puberty is a major challenge. Glucocorticoids both inhibit growth hormone secretion and induce epiphyseal insensitivity to growth hormone action, and correction of hypercortisolaemia is a prerequisite to re- establishing linear growth. Adrenal androgen- induced pseudoprecocious puberty causes premature true gonadotropin- dependent puberty, and hence, even once adrenal androgen secretion has been controlled, bone age will continue to advance and potential for linear growth to diminish. These factors can be regulated by the combined use of gonadotropin- releasing hormone analogues to inhibit gonadotropin secretion and control puberty, and growth hormone treatment to induce linear growth. With effective treatment of hypercortisolaemia and careful management of puberty and growth, children with Cushing’s syndrome will achieve a normal final height (Figure 1).
Fig1. Growth charts of two children with Cushing’s disease treated with pituitary irradiation. GHT, growth hormone therapy; RT, radiotherapy; M, mother’s height; F, father’s height. Reproduced with permission from Johnston L. Grossmann AB, Plowman PN, Besser GM, Savage MO. Clinical Endocrinology, 1998; 48: 663– 7.
