Adrenal function and MC1R gene analysis in a prepubertal girl with generalized hyperpigmentation: case report

Generalized hyperpigmentation (GHPT) of the skin may occur as a primary defect of pigmentation or in combination with other variable manifestations. It is visible in a number of diseases such as Addison’s disease (AD), haemochromatosis, porphyria cutanea tarda, scleroderma and neurofibromatosis, but it can also be associated with malignancy and the use of chemotherapeutics or it can be related to acanthosis nigricans in insulin resistance. Skin pigmentation depends on the differences in the amount, type and distribution of melanin produced during melanogenesis in skin melanocytes [1] and remains under the genetic control of more than 120 genes [2]. The most important one is the melanocortin 1 receptor (MC1R) gene [3] (OMIM ID: 155555) located on chromosome 16q24.3 and encoding for a 317-amino-acid G-protein coupled receptor. The MC1R receptor binds α-melanocyte-stimulating hormone (α-MSH) resulting in the activation of adenylyl cyclase, which produces cyclic adenosine monophosphate (cAMP). The increased cAMP concentration activates various intracellular molecular pathways, promotes melanin synthesis and increases the eumelanin to pheomelanin ratio [4]. MC1R receptor also binds ACTH, in this way contributing to the GHPT in AD. Upregulation of MC1R gene expression by UV radiation and α-MSH leads to enhancement of melanogenesis and melanin synthesis induction. Loss-of-function mutations in the MC1R gene are associated with fair skin, poor tanning, propensity to freckles and increased skin cancer risk due to a decrease in eumelanin synthesis and subsequently impaired protection against UV radiation [5-7]. To our knowledge, to date, no data are available considering gain-of-function mutations in the human MC1R gene which could lead to a constant activation of the MC1R receptor and subsequently cause GHPT. We present the case of a patient with a primary type of progressive GHPT in whom AD was suspected. An 11-year-old prepubertal girl with GHPT (Figures 1A-C) was born at term with normal birth weight and height and was first brought to our hospital at the age of 3 years with a suspicion of AD. She had a diffuse grey-brownish discoloration of the skin present since birth. Over the first few years of life she developed symmetrical hyperpigmentation most pronounced on her trunk and neck. Later, hyperpigmentation began to affect her hands and feet, and finally the whole body – sparing only the cheeks and finger tips. Her skin was very dry and atopic, and scars were not hyperCorresponding autor: Assoc. Prof. Marek Niedziela MD, PhD Department of Paediatric Endocrinology and Rheumatology Poznan University of Medical Sciences 27/33 Szpitalna St 60-572 Poznan, Poland Phone: +48 61 849 14 81 Fax: 48 61 848 02 91 E-mail: [email protected] Letter to the Editor