Somatotrophin‐induced acanthosis nigricans

SIR, Recombinant growth hormone (somatotrophin) can be given for the treatment of growth hormone de®ciency, in conditions of short stature such as Turner's syndrome, and in cases of short stature without a relative growth hormone de®ciency in children whose estimated ®nal height would be at the lower end of normal. In achondroplasia, somatotrophin levels are low±normal and insulin-like growth factor-binding protein (IGF-1) levels are low. Some of these patients respond to somatotrophin supplementation. The drug is thought to be well tolerated with few side-effects; however, its increasing use may uncover less common side-effects. We report a case of acanthosis nigricans developing in a 10-year-old boy with achondroplasia who had received long-term somatotrophin therapy. A healthy 10-year-old boy with achondroplasia had received 3±4 units of subcutaneous somatotrophin (Genotropin, Pharmacia & Upjohn Ltd, Milton Keynes, U.K.) weekly for 7 years. He was not overweight, had no other endocrine abnormalities and was on no other medication. There was no family history of acanthosis nigricans, autoimmune conditions or diabetes mellitus. One year into the treatment, non-scaly, asymptomatic hyperpigmentation was noted in a collar distribution over the nape of his neck (Fig. 1). Three years later similar changes were noted in the groin and axillae. By 7 years there was the characteristic dark velvety thickening of the skin in all three areas consistent with acanthosis nigricans. Other ̄exural sites, palms, soles and mucosal surfaces were uninvolved, and there were no papillomatoses. Investigations showed a normal full blood count, serum electrolytes, thyroid function tests, sex hormone pro®le, serum cortisol and adrenocorticotrophic hormone. An autoantibody screen was negative. IGF-1 was elevated at 1 ́9 IU/mL (normal range for adults: 0 ́5±1 IU/mL; prepubertal children: <0 ́5 IU/mL) and an oral glucose tolerance test con®rmed mild insulin resistance. Growth hormone stimulates the production of insulin-like growth factors (somatomedins), in particular IGF-1. High levels of IGF-1 are found in acromegaly and low levels in children with growth hormone de®ciency. Insulin and IGF-1 are similar peptides and either can bind to IGF-1 receptors. Activation of this receptor leads to the growth and differentiation of many different cell lines, including keratinocytes and ®broblasts. Excessive stimulation of keratinocytes and ®broblasts in the skin is thought to be the mechanism by which acanthosis nigricans develops. Overactive IGF-1 receptors are probably the ®nal common pathway for all situations where acanthosis nigricans develops. Acanthosis nigricans is therefore usually seen in hyperinsulinaemic states such as obesity, lipodystrophy, acromegaly, diabetes mellitus and insulinresistance syndromes, in the states of IGF-1 receptor dysfunction characterized in some insulin-resistance syndromes, or with excess stimulation of the IGF-1 receptor by paraneoplastic peptides or drugs such as corticosteroids, oral contraceptives, triazinate and fusidic acid. Cases of acromegaly with acanthosis nigricans have been described where the levels of growth hormone have been high, insulin resistance proven and acanthosis nigricans has improved with the removal of the growth hormone pituitary tumour. There is also one case of acanthosis nigricans developing in a woman receiving puri®ed pituitary extract, for the treatment of malignant melanoma, which would have contained growth hormone. This is the ®rst report of acanthosis nigricans developing following somatotrophin medication. One might have expected this to be commoner, but in keeping with other situations where acanthosis nigricans can be seen, it does not necessarily develop. In a study where IGF-1 was given to treat insulin-resistance syndromes, some cases with acanthosis nigricans improved when the insulin levels fell. This suggests that in some cases excessive IGF-1 receptor stimulation leads to receptor downregulation, therefore removing the growth stimulus to keratinocytes and ®broblasts. As most cases of reversible acanthosis nigricans improve rather than resolve, it should be considered as a potential long-term side-effect of somatotrophin supplementation.