Amyloidosis cutis dyschromica is a rare form of primary cutaneous amyloidosis without systemic involvement and characterized by asymptomatic, progressive hyper- and hypopigmentation. We present the first case of a patient with amyloidosis cutis dyschromica diagnosed previously elsewhere as having Addison disease with generalized hyperpigmentation of the skin. This case suggests that in patients presenting with asymptomatic cutaneous dyschromia a skin biopsy for histopathological examination should be considered.
- ACD —
- amyloidosis cutis dyschromica
- PCA —
- primary cutaneous amyloidosis
Characteristic skin signs can be helpful in clinical differential diagnostic approaches. Dermatological findings can occur as part of a systemic disease or of a skin disorder. Primary cutaneous amyloidosis (PCA) is defined as cutaneous amyloidosis in the absence of other systemic and dermatological manifestations. Amyloidosis cutis dyschromica (ACD) is a rare form of PCA. The main cutaneous feature is generalized hyper- and hypopigmentation. To date only 49 cases have been described. Hereby we report, to our knowledge, the first patient with ACD assessed elsewhere as having hyperpigmentation due to primary adrenal insufficiency.
A 9-year-old boy from Libya presented with asymptomatic hyperpigmentation beginning on the trunk (Fig 1 A and C) and progressing over almost the whole body including the nails (Fig 1B). Hair, teeth, and oral mucosa were unaffected. Systemic examination was normal. The patient was born to healthy consanguineous parents. There were no family members with similar symptoms. The patient had no history of photosensitivity or inflammatory skin disease.
Hyperpigmentation appeared initially after a febrile infection with vomiting and diarrhea at the age of 1 year. Primary adrenal insufficiency was suspected and the patient received hormone substitution therapy with hydrocortisone, initially intravenously and over the next years orally. No substitution of mineralocorticoids was performed.
Because the skin abnormalities did not improve during hormone therapy, laboratory evaluation of adrenal function was performed at the age of 8 years and revealed normal glucocorticoid and mineralocorticoid secretions. For further investigation, a skin biopsy was taken revealing hyperkeratosis, mild acanthosis, moderate irregular elongation of rete ridges with focal fusion, and mild focal hydropic degeneration of the basal layer. The papillary dermis revealed deposition of amyloid (confirmed by positive Congo red staining) as globules and mild superficial perivascular infiltrates of lymphocytes and melanophages.
Hormone substitution was discontinued thereafter. One year later, the patient presented to our hospital for further diagnostic workup. Laboratory evaluations including whole blood cell count, serum electrolytes, urine analysis, renin, adrenal androgens, adrenal, pancreatic and thyroid antibodies, cortisol, and corticotropin 24-hour profiles, as well as corticotropin-releasing hormone stimulation test, were completely normal.
Abdominal ultrasonography did not reveal any pathology. In dermatologic consultation, the skin findings were described as mottled hyper- and hypopigmentation. Based on the clinical findings and histopathological reevaluation of the skin biopsy, the diagnosis of ACD was established. Primary adrenal insufficiency was excluded. Photoprotection and a follow-up examination of adrenal function after 1 year were recommended.
Primary adrenal insufficiency, or Addison disease, describes a condition of deficient production of adrenal cortical hormones. Patients present with nonspecific symptoms such as fatigue, malaise, abdominal pain, weight loss, nausea, and vomiting.1 Hypotension and hyperpigmentation are typical physical signs.
In Addison disease, hyperpigmentation, resulting from elevated cosecretion of corticotropin and melanocyte stimulating hormone, presents as uniform pigmentation. Hyperpigmentation usually precedes other symptoms of the disease and occurs at the extensor surfaces, elbows, knees, acral skin creases, at preexistent nevi and areas of scarring formed after the onset of the disease. Darkening of the areola, scrotal region, lips, and oral mucosa, as well as pigmentation of the linea alba and longitudinal lines in the nails can appear.2 Sites that are exposed to sunlight and pressure are prominently affected.
In addition, patients having Addison disease may present other manifestations of autoimmune endocrinopathies, such as hypoparathyroidism, pernicious anemia, and vitiligo.
PCA is a chronic pruritic skin disorder with characteristic amyloid deposits in the papillary dermis. ACD, a rare form of PCA, was described by Morishima3,4 and is characterized by the presence of the following features:
Reticular hyperpigmentation with hypopigmented macules almost all over the body;
Little or no itching;
Onset before puberty; and
Focal subepidermal amyloid deposition.
Our patient fulfilled all these criteria. Laboratory and radiologic findings did not reveal any abnormalities indicating systemic amyloidosis.
The pathogenesis of ACD is unknown to date. A hypersensitivity to damage by UV-B light with possible DNA repair defects has been suggested.3 However, there are reported cases of no history of sun exposure and skin findings being pronounced in nonsun-exposed skin areas.5,6 The occurrence of familial cases and prepubertal onset suggest a genetic etiology of the disorder,6–8 but the molecular basis has not been identified so far.
In our case, initially described as hyperpigmentation, the skin findings revealed reticulate hyperpigmentation with hypopigmented spots, indicating a dyschromia.
On one hand, there are numerous differential diagnoses of acquired hyperpigmentation including amyloidosis (Fig 2). In ACD dyschromia is present. Dyschromia is the coexistence of macular hyper- and hypopigmentation. In Addison disease, hyperpigmentation is the sole dermatological finding. In addition, the distribution of pigmentary changes in Addison disease is characteristic as it includes the mucous membranes, palmoplantar skin, and the acral skin creases, a finding not reported in ACD. The skin findings in our patient did not reveal uniform hyperpigmentation, but dyschromia and the pigmentary alterations affected the whole body including the nails but leaving hair, teeth, and oral mucosa unaffected.
On the other hand, several differential diagnoses of dyschromatosis may be considered: dyschromatosis universalis hereditaria, xeroderma pigmentosum, poikilodermalike amyloidosis, macular amyloidosis, and other rare forms of cutaneous amyloidosis.3,6,9
ACD can be differentiated histologically from dyschromatosis universalis hereditaria. Clinically, xeroderma pigmentosum may have similar dyspigmentation, but reveals marked photosensitivity and evidence of actinic damage beginning in infancy and early childhood, as well as evidence of development of skin cancers during the first decade of life. Poikilodermalike amyloidosis is associated with photosensitivity, short stature, blister formation, and palmoplantar hyperkeratosis.3,8
Several therapeutic options for ACD are reported, such as topical corticosteroids, keratolytics, dimethyl sulfoxide, UV-B and psoralen–UV-A phototherapy, dermabrasion, capsaicin, and CO2 laser. However, success is limited. Photoprotection and systemic acitretin treatment seem to have the most promising results.6,11,12
In pediatric patients with acquired pigment abnormalities, there should be a detailed examination of the skin, nails, and mucosa, paying attention to the distribution and morphology of any pigment change. All accompanying symptoms should be taken into consideration as well. In patients presenting pigment abnormalities including both hyperpigmented and hypopigmented lesions in the absence of other symptoms, histopathological examination of a skin biopsy may point the way ahead. If focal amyloid deposits in papillary dermis are substantiated and systemic amyloidosis is excluded, the diagnosis of ACD is confirmed.
- Accepted November 7, 2016.
- Address correspondence to Oya Kuseyri, MD, Department of General Pediatrics and Division of Pediatric Endocrinology and Diabetes, University Children’s Hospital Heidelberg, Im Neuenheimer Feld 430, D-69120 Heidelberg, Germany. E-mail:
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
- Copyright © 2017 by the American Academy of Pediatrics