Addisonian Pigmentation of the Oral Mucosa - Cutis

PEDIATRIC DERMATOLOGYSeries Editor: Camila K. Janniger, MDAddisonian Pigmentationof the Oral MucosaSamir S. Shah, MD; Catherine H. Oh, MD; Susan E. Coffin, MD, MPH; Albert C. Yan, MDCutaneous pigmentation is a hallmark of Addisondisease. When present, the hyperpigmentationgenerally localizes to sun-exposed surfaces.This case highlights a less well-recognizedcutaneous feature that is pathognomonic for thedisease: oral mucous membrane hyperpigmentation.We describe this unique type of discolorationin detail and contrast it with other forms oforal pigmentation.Cutis. 2005;76:97-99.Case ReportA 9-year-old girl presented with a 4-month historyof painless black patches on the tongue and gingiva.The patches had persisted despite treatment withoral fluconazole, which had been prescribed empiricallyfor presumed oral candidiasis. Results of a physicalexamination revealed scattered, asymptomatic,bluish-black macules on the dorsal surface of thetongue, the mucosal surface of the lower lip, and thehard palate (Figure). No cervical lymphadenopathywas noted. The patient’s medical history was notablefor a recent diagnosis of primary adrenal insufficiencyand Addison disease.Significant laboratory evaluation results includedfindings consistent with primary adrenal insufficiency:a nocturnal plasma cortisol level of 0.3 µg/dL(reference range, 2–10 µg/dL) and a corticotropinlevel of 1300 pg/mL (reference range, 9–52 pg/mL).Accepted for publication November 1, 2004.Drs. Shah, Coffin, and Yan are from the Department of Pediatrics,Children’s Hospital of Philadelphia, Pennsylvania. Dr. Oh is fromthe Department of Pediatrics, Jefferson University School ofMedicine, Philadelphia.The authors report no conflict of interest.Reprints: Albert C. Yan, MD, Pediatric Dermatology, Children’sHospital of Philadelphia, 34th St and Civic Center Blvd,Philadelphia, PA 19104 (e-mail: yana@email.chop.edu).Free thyroxine and thyrotropin levels were withinreference range.CommentAddison disease, a chronic primary insufficiency ofthe adrenal glands, results in both glucocorticoid andmineralocorticoid deficiency. Historically, tuberculosisaccounted for most cases of Addison disease. 1Autoimmune destruction of the adrenal glands, alsoknown as autoimmune adrenalitis, is now the mostcommon cause of Addison disease in both childrenand adults. 2,3 Autoimmune destruction of otherendocrine tissues can occur concurrently. Thesepolyglandular autoimmune syndromes are associatedwith hypoparathyroidism, pernicious anemia, andchronic mucocutaneous candidiasis (type 1); diabetesmellitus (type 2); or thyroiditis (type 3). 4 Type 3,however, consists of an autoimmune thyroiditissyndrome in the absence of Addison disease. 5Although most children (75%) presenting with isolatedAddison disease are boys, 6 type 1 autoimmune polyglandularsyndrome occurs equally in boys and girls. 2Other causes of Addison disease in children includetrauma and adrenocortical hemorrhage, which is mostcommonly associated with meningococcemia. 4Most of the symptoms arising from primaryadrenal insufficiency result in cortisol deficiency.Symptoms include fatigue, weakness, orthostasis,nausea, vomiting, weight loss, and anorexia. Commonpresenting symptoms seen in children includehypoglycemia, gastrointestinal disturbances, andprogressive peripheral weakness. Hyperpigmentationof the skin and mucosal surfaces, the most specificsign of Addison disease, occurs in up to 92% ofpatients. 7 This dyspigmentation may precede othermanifestations by up to 10 years. 8Pigmentation of the oral mucosa is consideredpathognomonic for Addison disease. This distinctivefinding can aid in distinguishing AddisonVOLUME 76, AUGUST 2005 97

Pediatric Dermatologydisease from other endocrinopathiesthat also may presentwith hyperpigmentation, such ashyperthyroidism. 9 The oral hyperpigmentedmacules of Addisondisease can be found diffusely onthe tongue, gingiva, buccalmucosa, and hard palate. Themacules tend to be blue-black orbrown and can be spotty orstreaked in configuration. Thepattern of pigmentation is usuallypatchy and can occasionally alternatewith leukodermic patterns.The hyperpigmentation ofAddison disease tends to producea generalized bronze appearancethat is more easily detectable infair-skinned children. In darkskinnedchildren, a similar increasein color may be mistaken for atan. Hyperpigmentation occursmost prominently at the flexures,sites of pressure and friction,palmar and plantar creases, andsun-exposed areas. It also mayresult in intensification of normallypigmented areas such as thegenitalia and areolae mammae. 6Scars also can exhibit hyperpigmentation,which only appears inscars acquired after the onset ofthe disease. Coexistence of pigmentedand uncolored scars mayaid in the precise dating of thedestructive process found in theadrenals. 8 Paradoxically, vitiligoalso may be seen in patients withAddison disease and may occurconcurrently with hyperpigmentation.Pigmentation of the vaginalmucosae and conjunctivaealso are frequently observed inaffected patients. 1Hyperpigmentation associatedwith Addison disease presumably occurs secondaryto overproduction of the pro-opiomelanocortinbyproduct -lipotropin, which is secreted in excessamounts concomitantly with corticotrophin fromthe pituitary gland because of the lack of feedbackinhibition seen in adrenal insufficiency states. 10Other conditions that lead to increased corticotropinproduction also may present with similarcutaneous hyperpigmentation, as seen in adrenoleukodystrophy(Siemerling-Creutzfeldt disease), 11Pigmentation of the tongue (A) and lower lip (B) in Addison disease.familial adrenocorticotropin unresponsiveness syndrome(familial glucocorticoid deficiency), 12 thymiccarcinoids, 13 and paraneoplastic corticotropin productionin the setting of underlying malignancy 14 ;however, oral pigmentation has not been specificallyreported in these cases.Adequate hormone replacement therapy typicallyresults in a decrease in the degree of cutaneouspigmentation, though oral pigmentation persistsindefinitely. 15 In this particular case, the patient’sAB98 CUTIS ®

Pediatric Dermatologyoral pigmentation did show modest improvementwith good hormonal control; however, when thepatient was noncompliant with hormonal therapy,her pigmentation worsened clinically. In someaffected younger children, the skin color may eventuallyreturn to normal with therapy.Differential DiagnosisDiagnoses that may mimic the oral pigmentationof Addison disease include: oral “black tongue”candidiasis, ethnic pigmentation, and reactions tocertain drugs. Black hairy tongue and black tonguecandidiasis are disorders believed to be caused byCandida albicans and occasionally Aspergillusspecies. These conditions are associated with longtermuse of antibiotics. Characterized by dense,black, bluish-black, or brown “matted” areas of thedorsal surface of the tongue, black tongue candidiasiscan be successfully eliminated by discontinuationor minimization of antibiotics, gentlebrushing of the tongue surface, and use of an oralantifungal agent. 16The most common pattern of ethnic or racial pigmentationis a band of pigment at the junction ofattached and alveolar mucosa. In contrast to Addisondisease, pigmentation on the tongue of those with skinof color is typically localized to the tips of isolated groupsof filiform papillae. 17 Such pigmentation, usually foundonly in persons with dark skin, also can be found asisolated pigmented patches in 5% of Caucasians.Drug-induced pigmentation can range frombrown (seen with oral contraceptives, cytotoxicagents, and some anticonvulsants) to yellow orblue-black (as seen with the antimalarial drugsquinacrine, chloroquine, and hydroxychloroquine).18 Long-term use of minocycline has beenassociated with a blue-gray staining of the tongue,gingival margins, palate, and pretibial surfaces.Patchy blue-black hyperpigmentation of the oralmucosa should cause suspicion of Addison disease,particularly if appropriate systemic signs are notedand if no other explanatory factors, such as concomitantcandidiasis, ethnic background, or drugs,are associated.REFERENCES1. Dunlop D. Eighty-six cases of Addison disease. BMJ.1963;3:887-891.2. Soderbergh A, Winqvist O, Norheim I, et al. Adrenalautoantibodies and organ-specific autoimmunity in patientswith Addison disease. Clin Endocrinol. 1996;45:453-460.3. Myhre AG, Undlien DE, Løvås K, et al. Autoimmuneadrenocortical failure in Norway. autoantibodies andhuman leukocyte antigen class II associations relatedto clinical features. J Clin Endocrinol Metab.2002;87:618-623.4. Baker JR Jr. Autoimmune endocrine disease. JAMA.1997;278:1931-1937.5. Spinner MW, Blizzard RM, Childs B. Clinical andgenetic heterogeneity in idiopathic Addison’s diseaseand hypoparathyroidism. J Clin Endocrinol Metab.1968;28:795-804.6. Oelkers W. Current concepts: adrenal insufficiency. N EnglJ Med. 1996;335:1206-1212.7. Hurwitz S. Clinical Pediatric Dermatology: A Textbook ofSkin Disorders of Childhood and Adolescence. 2nd ed.Philadelphia, Pa: WB Saunders Co; 1993.8. Forest MG. Adrenal steroid deficiency states. In:Brook CGD, ed. Clinical Paediatric Endocrinology. 3rded. Cambridge, England: Blackwell Science;1995:453-498.9. Banba K, Tanaka N, Fujioka A, et al. Hyperpigmentationcaused by hyperthyroidism: differences from the pigmentationof Addison disease. Clin Exp Dermatol.1999;24:196-198.10. Wiebke A, Allolio B. Adrenal insufficiency. Lancet.2003;361:1881-1893.11. Ropers HH, Burmeister P, Petrykowski W, et al.Leukodystrophy, skin hyperpigmentation, and adrenalatrophy: Siemerling-Creutzfeldt disease. transmissionthrough several generations in two families. Am J HumGenet. 1975;27:547-553.12. Berberoglu M, Aycan Z, Ocal G, et al. Syndrome of congenitaladrenocortical unresponsiveness to ACTH.report of six patients. J Pediatr Endocrinol Metab.2001;14:1113-1118.13. Gartner LA, Voorhess ML. Adrenocorticotrophic hormoneproducingthymic carcinoid in a teenager. Cancer.1993;71:106-111.14. Makita M, Maeda Y, Hashimoto K, et al. Acute lymphoblasticleukemia with large molecular ACTH production.Ann Hematol. 2003;82:448-551.15. Dummett CO. Systemic significance of oral pigmentationand discoloration. Postgrad Med. 1971;49:78-82.16. Wolf IJ. Black tongue moniliasis. Pediatrics. 1970;46:975.17. Leston JM, Santos AA, Varela-Centelles PI, et al. Oralmucosa: variations from normalcy, part II. Cutis.2002;69:215-217.18. Kleinegger CL, Hammond HL, Finkelstein MW. Oralmucosal hyperpigmentation secondary to antimalarialdrug therapy. Oral Surg Oral Med Oral Pathol Oral RadiolEndod. 2000;90:189-194.VOLUME 76, AUGUST 2005 99