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Betaxolol ophthalmic solution has been associated with periocular skin hyperpigmentation. We report a case of a woman with hyperpigmentation of the fingers associated with oral betaxolol. Based on case reports associated with the topical ophthalmic product, we believe the hyperpigmentation was likely caused by oral betaxolol.
OBJECTIVE: To quantify the 5-year risk of age-related macular degeneration (AMD) in eyes with different macular drusen characteristics (ie, size, type, location, and total area) or hyperpigmentation in a population-based cohort. METHODS: The Blue Mountains Eye Study examined 3654 residents during 1992-1994; 2335 (75.1% of survivors) were reexamined during 1997-1999. Retinal photographs were graded using the Wisconsin Age-Related Maculopathy Grading System. Incident AMD lesions were defined by development of neovascular AMD or geographic atrophy in eyes without these lesions at baseline (eyes at risk). Age-adjusted relative risks (RRs) were determined. Generalized estimating equation models were used to estimate odds ratios, adjusting for the correlation between eyes and other AMD risk factors. Main Outcome Measure Incidence of AMD. RESULTS: Of the 4634 eyes at risk, 52 (1.1%) developed neovascular or atrophic AMD lesions over 5 years. In right eyes, presence vs absence of the following macular signs predicted AMD: drusen that were 125 micro m or larger (13.9 vs 0.6%; age-adjusted RR, 5.7; 95% confidence interval [CI], 3.6-9.0), indistinct soft or reticular drusen (23.2% vs 0.4%; RR, 9.9; 95% CI, 6.4-15.4), total drusen area of half the disc area or more (31.4% vs 0.6%; RR, 13.5; 95% CI, 8.0-22.8), and hyperpigmentation (14.4% vs 0.5%; RR, 8.0; 95% CI, 5.4-11.9). After adjusting for age, sex, and smoking status, eyes with these signs at baseline had a high likelihood of developing AMD. Eyes with Age-Related Eye Disease Study categories 3 and 4 were 5 times more likely to develop AMD compared with eyes in categories 1 and 2. CONCLUSION: This study quantifies the 5-year risk of AMD in eyes with macular drusen and hyperpigmentation.
Generalized hyperpigmentation developed over 2 years in a 65-year-old woman. A diagnosis of pernicious anemia was made, and treatment with vitamin B12 led to complete reversion of her hyperpigmentation to normal. Literature pertinent to hyperpigmentation and its association with megaloblastic anemias is reviewed and several possible mechanisms are mentioned.
Dermatofibromas have an increased brownish color due to hyperpigmentation of the overlying skin. To determine paracrine factors involved in the epidermal hyperpigmentation, we have studied the expression of cytokines in lesional and nonlesional dermatofibroma skin at the transcriptional and protein levels using reverse transcription polymerase chain reaction and immunohistochemistry, respectively. The number of tyrosinase immuno-positive melanocytes in the pigmented dermatofibroma epidermis is significantly increased (2-fold) compared with nonlesional normal epidermis. Reverse transcription polymerase chain reaction analysis of mRNAs encoding stem cell factor and hepatocyte growth factor demonstrated that there is an accentuated expression of stem cell factor and hepatocyte growth factor transcripts in the lesional dermatofibroma dermis compared with the nonlesional dermis, although there is no difference in their expression between the lesional and nonlesional epidermis. In contrast, mRNA transcripts encoding endothelin-1, growth-related oncogene alpha, and basic fibroblast growth factor are not increased in lesional epidermis or in dermis relative to nonlesional skin. In parallel, immunohistochemical analysis using antibodies to stem cell factor and hepatocyte growth factor reveal a marked immunostaining in growing fibroblastic tumor cells in the dermatofibroma lesions with no detectable staining in the nonlesional dermis, but there is no difference in their immunostaining between the lesional and nonlesional epidermis. Interestingly, and consistent with the increased expression of stem cell factor in lesional dermatofibroma dermis, toluidine blue staining in the dermis revealed a 5-fold increase in the number of mast cells, an indication of their longevity or accumulation induced by stem cell factor. These findings suggest an important role of fibroblastic tumor cell-derived stem cell factor in the mechanism involved in the hyperpigmentation of the dermatofibroma epidermis.
Amiodarone (AD) induces photosensitivity in 75% of the patients treated with this drug. Phototoxic reactions can be experimentally elicited with UVA but not with UVB. The UVA-MED is significantly reduced after 12 months of treatment. The development of photosensitivity depends on the total dose of AD; 40 g is the minimal cumulative dose requirement. Under the regimens commonly used, photosensitivity can be expected after 4 months of continuous AD treatment and appears to be unrelated to the skin type. Photosensitivity gradually decreases and returns to normal between 4 and 12 months after the withdrawal of AD. AD-related hyperpigmentation develops after an average of 20 months of continuous AD treatment and a minimal total dose of 160 g AD in about 8% of the patients (mainly of skin type I). Electron microscopic examination of the sun-exposed skin of patients without AD discoloration shows pigment deposits similar to those already described in patients with AD hyperpigmentation in exposed and non-exposed skin. Light and electronmicroscopic examination of sun-exposed skin of both clinically photosensitive and non-photosensitive patients reveals perivascular inflammation even in the absence of a clinical rash. Reduplications of vascular basal laminae occur in sun-exposed skin of both patients with and without UVA photosensitivity but are absent from non-exposed skin. In one patient, followed for 33 months after drug withdrawal, massive AD-induced hyperpigmentation was found to be reversible.
A 26-year-old white woman had reticulate nonmelanocytic hyperpigmentation anomaly characterized by partially blanching red-brown papules and macules and a histologic picture of digitate epithelial budding proliferation with lightly pigmented rete ridges. Except for the classically described hyperpigmentation at the rete ridge tips, the patient has Dowling-Degos disease. This case of a reticulate nonmelanocytic hyperpigmentation anomaly is probably a variant of Dowling-Degos disease.
Pigmentary changes in mycosis fungoides are not rare. Although poikiloderma and hypopigmented skin lesions have often been reported in the literature, there are few cases of mycosis fungoides presenting as a hyperpigmented skin lesion. We present a 57-year-old Japanese male with mycosis fungoides whose skin lesions showed marked hyperpigmentation. The skin lesion initially appeared as an irregularly shaped itchy annular erythema with central pigmentation predominantly on his extremities. During our 5-year follow-up, these skin lesions gradually increased in size and number. The erythema extended peripherally and became elevated with marked hyperpigmentation. Histology revealed extreme elongation of the rete ridges with infiltration of atypical large lymphoid cells characteristic of mycosis fungoides and numerous melanin granules in both the epidermal melanocytes and dermal melanophages. Although the exact mechanism of the marked hyperpigmentation is one of the unique characteristics in mycosis fungoides, especially in non-white individuals.
Gingival hyperpigmentation may cause esthetic problems and embarrassment, especially in patients with a gummy smile. This report presents the use of the Nd:YAG laser for gingival depigmentation. Four cases, 3 females and 1 male, ages between 24 to 28 years old, presented with the same chief complaint of unesthetic gingiva caused by melanin hyperpigmentation. The Nd:YAG laser was set at 6 watts, 60 millijoules per pulse, and 100 pulses per second. The procedures were performed with contact mode in all pigmented areas by using a handpiece with a 320 microm diameter fiber optic. Ablation of the gingival hyperpigmented areas were accomplished without any bleeding complications or significant postoperative pain. Three to 4 weeks after the procedures, the hyperpigmented gingiva appeared healthy, pink, and firm. No recurrence of hyperpigmentation had been found in 11 to 13 months of follow-up. However, in delicate areas such as the marginal gingiva, the Nd:YAG laser should be used cautiously.
We described two members in a family with gastrointestinal stromal tumors (GISTs) without cutaneous hyperpigmentation. The patients were father and son who did not have cutaneous hyperpigmentation. Histological examination showed that these tumors were GISTs expressing CD34 and CD117. Tumor DNA extracted from paraffin-embedded specimens revealed somatic mutation with a deletion mutation at different codons in exon 11 of c-kit gene after direct sequencing analysis. No germline mutation was detected in DNA extracted from peripheral leukocytes obtained from the father and son. We propose that GISTs could be caused by sporadic somatic mutation in a family without germline mutation and hyperpigmentation.
Disorders of hyperpigmentation such as melasma and postinflammatory hyperpigmentation (PIH) are common, particularly among people with darker skin types. Hydroquinone (HQ) bleaching creams are considered the gold standard for treating hyperpigmentation. Recently, a new formulation of HQ 4% with retinol 0.15% entrapped in microsponge reservoirs was developed for the treatment of melasma and PIH. Microsponges were used to release HQ gradually to prolong exposure to treatment and to minimize skin irritation. The safety and efficacy of this product were evaluated in a 12-week open-label study. A total of 28 patients were enrolled, and 25 completed the study. Study end points included disease severity, pigmentation intensity, lesion area, and colorimetry assessments. Adverse events also were recorded. Patients applied the microentrapped HQ 4% formulation to the full face twice daily (morning and evening). A broad-spectrum sunscreen was applied once in the morning, 15 minutes after application of the test product. Patients were evaluated at baseline and at 4, 8, and 12 weeks. The microentrapped HQ 4%/retinol 0.15% formulation produced improvement at all study end points. Improvement in disease severity and pigmentation intensity was statistically significant at weeks 4, 8, and 12 compared with baseline (P<.001). Lesion area and colorimetry measurements also were significantly improved at each visit (P<.001). Microentrapped HQ 4% was well tolerated, with only one patient discontinuing because of an allergic reaction, which was not considered serious. In this open-label study, microentrapped HQ 4% with retinol 0.15% was safe and effective.
Thirty-two consecutive patients presenting with Graves' disease were divided into two groups, black (Group I) and non-black (Group II), and observed for the occurrence of hyperpigmentation. The overall incidence of hyperpigmentation in subjects with Graves' disease was 38 percent, with 12 of 14 Group I patients and 0 of 18 Group II patients demonstrating this finding. Serum thyroxine was higher in Group I than in Group II. We conclude that hyperpigmentation is common in black patients with Graves' disease.
Identification of foreign metallic substances that induce hyperpigmentation is now possible with the use of x-ray energy spectroscopy (XES), an ultrastructure, nondestructive technique that allows the correlation of the presence of foreign substances with localized tissue and cellular histological changes. This new analytic technique will be an innovative adjunctive technique in the practice of diagnostic pathology and dermatopathology. It is certain that further evaluation of hyperpigmentation will allow for better identification of possible etiological causes, especially in the evaluation of cutaneous hyperpigmentation secondary to metal toxicity.
Cutaneous hyperpigmentation resembling acanthosis nigricans developed in two patients with malignant brain tumors following chemotherapy with triazinate (Baker's Antifol), a folic acid antagonist. In both cases, the eruption resolved after the cessation of drug administration and reappeared after the reinstitution of triazinate therapy. A skin biopsy specimen from one patient showed microscopic changes consistent with those found in acanthosis nigricans. The other patient had a decreased serum folate level that returned to normal as the hyperpigmentation resolved. Folate may have a role in triazinate-induced acanthosislike hyperpigmentation.
An unusual pattern of zebra-like hyperpigmentation was observed in a black male infant with congenital defects that included an atrial septal defect, dextrocardia, auricular atresia, deafness, and growth retardation. The hyperpigmentation was strikingly linear and symmetrical and followed a dermatomal distribution, with involvement of the trunk and extremities. Results of histological, histochemical, and electron microscopic studies were normal except for an increase in the number of melanocytes in the bands of hyperpigmentation. This pigmentary anomaly appears to be transient and has faded to 50% of its original intensity. A review of the literature has not disclosed any similar cases.
BACKGROUND: Diltiazem hydrochloride is a commonly prescribed benzothiazepine calcium channel blocker for the treatment of cardiovascular disease. Recently, 8 cases of diltiazem-induced photodistributed hyperpigmentation occurring predominantly in elderly African American women were reported. Here, we report occurrence for the first time in a light-skinned African American woman and a Hispanic woman. We also report this finding in an African American man. Biopsy specimens of hyperpigmented areas were obtained for histopathologic evaluation and marker studies. Photospectrometry analysis for diltiazem was performed to analyze the photoabsorption properties of this drug. OBSERVATIONS: Routine laboratory examination results were normal in all patients. Serologic test results for antinuclear antibodies, including Sjögren antibodies anti-Ro (SS-A) and anti-La (SS-B), were negative. Histopathologic analysis of the skin biopsy specimens revealed a sparse lichenoid infiltrate, prominent pigmentary incontinence, and numerous melanophages in the dermis. There was no increase in dermal mucin suggestive of lupus. The mononuclear cells in the specimens were strongly positive for CD3, weakly positive for CD68, and either weakly positive or negative for CD79a. All specimens were negative for Alcian blue staining. Photospectrometry analysis of diltiazem showed an absorption range within the UV-B spectrum. CONCLUSIONS: Photospectrometry analysis revealed diltiazem could demonstrate a photosensitizing effect within the UV-B range. Discontinuation of therapy with diltiazem is the most effective modality in resolving hyperpigmentation. Avoidance of sun exposure and consistent use of sunscreens and sun-protective clothing are indicated for patients undergoing diltiazem therapy.
BACKGROUND AND OBJECTIVE: Cutaneous hyperpigmentations are well-documented, but nevertheless rare side-effects of high-dose or long-term minocycline therapy. The pigmental changes, may last for years, even though therapy has been abrogated. To date, no safe and effective therapy has been described to target this cosmetically disturbing sequela. STUDY DESIGN/MATERIALS AND METHODS: A 57-year-old female patient with extensive pigmental changes of the face due to long-term minocycline therapy was treated in eight consecutive sessions with the Q-switched Nd:YAG-laser (1,064-nm wavelength, 5- to 7-nsec impulse length). RESULTS: A 90% resolution of the pigmentation could be achieved after five treatments. After the last session the lesions were completely gone; no hypopigmentation scars, or other side-effects were observed. CONCLUSION: Treatment with the Q-switched Nd:YAG laser seems to be an effective, safe, and easily applicable strategy for the therapy of minocycline-induced hyperpigmentations.
Alkaptonuria, a rare autosomal-recessive disorder caused by mutations in the HGD gene and a deficiency of homogentisate 1,2-dioxygenase, is characterized by accumulation of homogentisic acid (HGA), ochronosis, and destruction of connective tissue resulting in joint disease. Certain medications have been reported to cause cutaneous hyperpigmentation resembling that of alkaptonuria. We present 5 such cases. Eighty-eight patients with a possible diagnosis of alkaptonuria were examined at the National Institutes of Health Clinical Center between June 2000 and March 2004. The diagnosis of alkaptonuria was confirmed or ruled out by measurement of HGA in the urine. Five patients with findings consistent with ochronosis, including pigmentary changes of the ear and mild degenerative disease of the spine and large joints, were diagnosed clinically as having alkaptonuria, but the diagnosis was withdrawn based on normal urine HGA levels. All 5 patients were women who had taken minocycline for dermatologic or rheumatologic disorders for extended periods. Minocycline-induced hyperpigmentation should be considered in the differential diagnosis of ochronosis. This could be of increased significance now that minocycline and other tetracyclines have been proposed as therapeutic options for rheumatoid arthritis, bringing a new population of patients with ochronosis and arthritis to medical attention with the potential, but incorrect, diagnosis of alkaptonuria.
A 56-year-old previously healthy man developed hyperpigmentation of the entire skin over the previous 6 months without any other signs of further impairment. Additionally, we found accentuated skin lines of the neck and intertriginous sites as well as cutaneous papillomatosis. Histological examinations, laboratory tests and technical diagnostics revealed the existence of both hereditary hemochromatosis and adenocarcinoma of the stomach. Simultaneous manifestation of hyperpigmentation as a result of hemochromatosis as well as malignant acanthosis nigricans as a paraneoplastic symptom in gastric cancer is very rare.