O'Neill JT

Lichen myxedematosus (LM), also called papular mucinosis, was first described by Dubreuilh1 in 1906 and later classified by Montgomery and Underwood2 in 1953. LMs are a group of localized or generalized papular eruptions of unknown etiology categorized as cutaneous mucinoses in which dermal mucin deposition is the distinctive histologic feature.3-5 LM has no relation to endocrine gland disorders, particularly thyroid disease.2,3,6 In their landmark paper, Montgomery and Underwood2 classified 4 clinical types of LM: (1) generalized lichenoid papular eruption, which is also called scleromyxedema, (2) discrete papular form, (3) localized to generalized lichenoid plaques, and (4) urticarial plaques and nodular eruptions that usually evolve into the generalized lichenoid form. In 2001, Rongioletti and Rebora6 updated the classification system. The articles by Montgomery and Underwood2 and Rongioletti and Rebora6 both agree with the existence of the discrete papular form, also called discrete papular LM (DPLM). According to Rongioletti and Rebora,6 DPLM has only been reported in the medical literature 8 times,1,2,7-12 This is unlike scleromyxedema, the most common type of LM, which has been documented in more than 110 cases.6 In this case report, we describe an interesting case of DPLM that was localized to the neck of our patient, and we review the English medical literature. 

Case Report

An 80-year-old black woman presented to our clinic with a 2-month history of a pruritic eruption localized to her neck. Multiple topical steroids and antihistamines had been used without any decrease in the eruption or the pruritus. The woman's medical history was significant for gastric cancer status post a partial gastrectomy 7 years prior, pseudotumor cerebri, hypertension, and osteoporosis. She is followed regularly for these conditions, which are stable. Her medications included acetazolamide, atenolol, nifedipine, rabeprazole sodium, fluoxetine, oxybutynin chloride, alendronate sodium, docusate calcium, and a multivitamin. Prior to the onset of this eruption, the patient had a change in the acetazolamide formulation, which was initially thought to be the culprit. Although she returned to the original formulation for longer than a month, she had no resolution of the symptoms. At that time, she sought evaluation in our clinic. On physical examination, multiple 2- to 4-mm discrete, flesh-colored shiny papules without scale were present over the patient's bilateral and posterior neck (Figure 1). Results of 2 punch biopsies showed splaying of the collagen with mucin present diffusely throughout the dermis. No increase in the number of fibroblasts was seen (Figure 2). Results of colloidal iron stain showed positive results in the papillary dermis and showed mucin mildly throughout the deep dermis (Figure 3), supporting the diagnosis of LM. Complete blood count, chemistry panel, liver function, thyrotropin, and serum protein test results were all within reference range. Pimecrolimus cream has been effective in treating our patient's pruritus. We have followed her for 14 months, and the lesions have remained localized to her neck, with continued normal thyrotropin and serum protein values.

Comment

In 2001, Rongioletti and Rebora6 revised the classification system of LM, categorizing it into 3 broad subsets: (1) generalized papular and sclerodermoid, (2) localized LM, and (3) atypical forms. The first subset, generalized papular and sclerodermoid, represents scleromyxedema. Diagnosis requires a generalized papular and sclerodermoid eruption, monoclonal gammopathy (paraproteinemia), no evidence of thyroid dysfunction, and a histologic triad of fibroblast proliferation, fibrosis, and mucin deposition.6 Scleromyxedema is associated with many systemic disorders that may include numerous organ systems.6,13 Although spontaneous resolution has been reported,14 scleromyxedema typically is a long-term and disfiguring disease6,13 associated with variable morbidity and mortality.15,16 The criteria for diagnosing the subset of localized LM requires a papular eruption, deposits of mucin with variable fibroblast growth, absence of paraproteinemia, and absence of thyroid dysfunction.6 There are 5 subtypes6: DPLM,2,7-9,17-21 acral persistent papular mucinosis (APPM),22-27 cutaneous mucinosis of infancy,28-31 self-healing papular mucinosis (SHPM),32-36 and nodular LM.37,38 All subtypes show small, firm, waxy papules limited to a few areas of the skin, which may coalesce and form nodules or plaques. DPLM can involve any site on the body. APPM exclusively involves both extensor surfaces of the distal upper extremities. Cutaneous mucinosis of infancy is a pediatric variant of DPLM or APPM. SHPM has spontaneous resolution. Nodular LM is characterized by a predominance of nodules.6 All subtypes except for SHPM typically persist long-term. Systemic symptoms were only reported in SHPM.32,33 In general, localized LM is self-limited and associated with a good prognosis.6 The histologic features of LM are summarized in Table 1.5 The pathology lies within the dermis for all types of this disease, and the epidermis is essentially normal.5 The types of LM can be distinguished from one another by 3 histologic clues: (1) mucin distribution pattern, (2) dermal level of mucin deposits, and (3) some extra findings.5 Differentiation can be additionally aided by observing the number of fibroblasts. Common mucin stains include colloidal iron, mucicarmine, and alcian blue at pH 2.5 (but not pH 0.5); common metachromatic mucin stains include toluidine blue, thionine, and methylene blue.3

DPLM is a subtype of localized LM.2,6 Although the lesions can involve any site, DPLM is typically distributed symmetrically to the trunk and limbs. The skin lesions have been described as a variable number of firm, smooth, waxy, or flesh-colored papules 2 to 5 mm in size. Normal serum protein and thyroid function test results verify the diagnosis of DPLM.6 Because Montgomery and Underwood2 originally defined LM as having no relation to any endocrine gland disturbance, we recommend additional random chemistry panel or fasting blood glucose laboratory tests if there is any question that a patient may have diabetes mellitus. Histologically, DPLM may have a diffuse or local pattern of mucin distribution involving the upper and mid reticular dermis. The involved dermis typically shows edema. The amount of fibroblast proliferation is variable. When compared with scleromyxedema, DPLM has no collagen deposition or sclerosis and a lesser amount of fibroblast proliferation.5-7 Some argue that DPLM and APPM are closely related variants.25,27 However, we believe that DPLM and APPM are distinct subtypes of localized LM. DPLM typically affects men (Table 2) and its lesions may be erythematous, larger, and include areas other than the distal upper extremities.4,23,24 In comparison, APPM has an overwhelming female-to-male ratio of 4.7:1.6 APPM also exclusively involves the back of the hands, extensor surface of the wrists, and sometimes the distal forearms.4,6,23 Histologically, APPM typically has more focal mucin deposits, which spare a subepidermal grenz zone, and a normal number of fibroblasts; DPLM has mucin deposits that are more diffuse (compared with APPM), have a variable number of increased fibroblasts, and have an irregular arrangement of collagen bundles.4-6,23

Table 2 summarizes the main features of the 10 DPLM cases reported in the English medical literature.2,7-9,17-21 Our criteria required there be no evidence of paraproteinemia, no history or laboratory evidence of any endocrine disease, no history of human immunodeficiency virus infection, histologic proof of dermal mucin deposits, and specific gross descriptions consistent with DPLM. It should be noted that only 4 of the 8 DPLM cases originally cited by Rongioletti and Rebora⁶ were included in Table 2. Four cases were excluded because 2 reports were written in French,1,12 1 report included a patient with diabetes mellitus,10 and another did not perform a necessary laboratory test to rule out thyroid disease.11 Other cases were excluded because they did not fulfill our criteria.39,40 Among the 10 DPLM patients summarized, 7 were men. The mean age of the group was 51.3 years. Only 3 of the 10 cases reported information on the patient's ethnicity: one was Caucasian,7 one was Asian,8 and our patient was African American. Nine of the 10 cases reported no evidence of paraproteinemia. The single case2 that did not report this finding was published before an association between LM and paraproteinemia was known in the 1960s.41 All 10 cases reported thyroid function test results within reference range. Only 3 of the 10 patients had symptomatic skin lesions, which were mainly pruritus. No systemic symptoms were noted. Three of the 10 patients had solitary skin lesions on areas other than the typical trunk and limbs. One patient had skin lesions only on his lumbar region, another had facial lesions, and our patient had lesions on her neck. Seven of the 10 patients had comorbid medical disorders, including hypertension, migraines, psoriatic erythroderma, psoriasis, seizures, gastric cancer in remission, pseudotumor cerebri, osteoporosis, and hepatitis C. Only hepatitis C was comorbid with more than one DPLM patient.17,20 This may be a coincidence because one patient developed DPLM after contracting hepatitis C,20, while the other patient developed it before contracting hepatitis C.17 Psychiatric illness was limited to depression and was found in 2 cases.20,21 No DPLM cases progressed to scleromyxedema, and none have been reported in the literature.5,6 DPLM rarely resolves on its own. Spontaneous resolution did not occur in any of the 10 reported DPLM cases, and only 2 patients were treated successfully. In Reynolds et al,18 the patient responded to therapy with intralesional corticosteroid injections and flurandrenolide-impregnated tape. In Kaymen et al,19 a patient was treated with a CO2 laser and postoperative intralesional corticosteroid injections. There was no growth after one year. All the other DPLM cases did not have effective therapy, lacked specific details of improvement, or did not report this information.2,7-9,17,20,21 Only Tay and Khoo,8 Enerback and Mobacken,9 and Kaymen et al19 commented on which therapies failed (oral thyroxine, topical corticosteroids, and shave excision, respectively). Our patient complained of persistent itching that did not respond to initial treatment with topical steroids and antihistamine medications. She later received pruritic relief with pimecrolimus cream therapy. However, the skin lesions remained. To our knowledge, this is the first report of pimecrolimus therapy in the treatment of pruritis secondary to DPLM. It is difficult to treat a rare disease such as DPLM when the pathogenesis is unknown, and many treatments have failed. Fortunately, DPLM and the other localized forms of LM are usually self-limited to the skin and have very little or no morbidity, leading some experts to believe that the disorder is unnecessary to treat.6 We believe that treatment is sometimes helpful. In our patient, the DPLM lesions were pruritic and located at a cosmetic area of the neck. The patient and dermatology staff decided to pursue a treatment plan. Therefore, even though localized LM lesions are typically benign, sometimes it is beneficial to treat them, especially if they cause irritating symptoms or cosmetic issues. 

Conclusion

DPLM is a rare variant of localized LM. DPLM can be diagnosed by a thorough history and physical examination; histologic proof of dermal mucin deposits; and ruling out other diseases with laboratory tests for serum protein, thyroid function, and, if the patient is at risk of diabetes mellitus, blood glucose levels. DPLM is a self-limited skin disease, and prognosis is generally good, but it typically persists long-term and may slowly progress. Treatment is usually unnecessary, but it may be recommended if the lesions are symptomatic or cause cosmetic issues. Unfortunately, few treatment plans have been shown to successfully treat DPLM. 

Lichen myxedematosus (LM), also called papular mucinosis, was first described by Dubreuilh1 in 1906 and later classified by Montgomery and Underwood2 in 1953. LMs are a group of localized or generalized papular eruptions of unknown etiology categorized as cutaneous mucinoses in which dermal mucin deposition is the distinctive histologic feature.3-5 LM has no relation to endocrine gland disorders, particularly thyroid disease.2,3,6 In their landmark paper, Montgomery and Underwood2 classified 4 clinical types of LM: (1) generalized lichenoid papular eruption, which is also called scleromyxedema, (2) discrete papular form, (3) localized to generalized lichenoid plaques, and (4) urticarial plaques and nodular eruptions that usually evolve into the generalized lichenoid form. In 2001, Rongioletti and Rebora6 updated the classification system. The articles by Montgomery and Underwood2 and Rongioletti and Rebora6 both agree with the existence of the discrete papular form, also called discrete papular LM (DPLM). According to Rongioletti and Rebora,6 DPLM has only been reported in the medical literature 8 times,1,2,7-12 This is unlike scleromyxedema, the most common type of LM, which has been documented in more than 110 cases.6 In this case report, we describe an interesting case of DPLM that was localized to the neck of our patient, and we review the English medical literature. 

Case Report

An 80-year-old black woman presented to our clinic with a 2-month history of a pruritic eruption localized to her neck. Multiple topical steroids and antihistamines had been used without any decrease in the eruption or the pruritus. The woman's medical history was significant for gastric cancer status post a partial gastrectomy 7 years prior, pseudotumor cerebri, hypertension, and osteoporosis. She is followed regularly for these conditions, which are stable. Her medications included acetazolamide, atenolol, nifedipine, rabeprazole sodium, fluoxetine, oxybutynin chloride, alendronate sodium, docusate calcium, and a multivitamin. Prior to the onset of this eruption, the patient had a change in the acetazolamide formulation, which was initially thought to be the culprit. Although she returned to the original formulation for longer than a month, she had no resolution of the symptoms. At that time, she sought evaluation in our clinic. On physical examination, multiple 2- to 4-mm discrete, flesh-colored shiny papules without scale were present over the patient's bilateral and posterior neck (Figure 1). Results of 2 punch biopsies showed splaying of the collagen with mucin present diffusely throughout the dermis. No increase in the number of fibroblasts was seen (Figure 2). Results of colloidal iron stain showed positive results in the papillary dermis and showed mucin mildly throughout the deep dermis (Figure 3), supporting the diagnosis of LM. Complete blood count, chemistry panel, liver function, thyrotropin, and serum protein test results were all within reference range. Pimecrolimus cream has been effective in treating our patient's pruritus. We have followed her for 14 months, and the lesions have remained localized to her neck, with continued normal thyrotropin and serum protein values.

Comment

In 2001, Rongioletti and Rebora6 revised the classification system of LM, categorizing it into 3 broad subsets: (1) generalized papular and sclerodermoid, (2) localized LM, and (3) atypical forms. The first subset, generalized papular and sclerodermoid, represents scleromyxedema. Diagnosis requires a generalized papular and sclerodermoid eruption, monoclonal gammopathy (paraproteinemia), no evidence of thyroid dysfunction, and a histologic triad of fibroblast proliferation, fibrosis, and mucin deposition.6 Scleromyxedema is associated with many systemic disorders that may include numerous organ systems.6,13 Although spontaneous resolution has been reported,14 scleromyxedema typically is a long-term and disfiguring disease6,13 associated with variable morbidity and mortality.15,16 The criteria for diagnosing the subset of localized LM requires a papular eruption, deposits of mucin with variable fibroblast growth, absence of paraproteinemia, and absence of thyroid dysfunction.6 There are 5 subtypes6: DPLM,2,7-9,17-21 acral persistent papular mucinosis (APPM),22-27 cutaneous mucinosis of infancy,28-31 self-healing papular mucinosis (SHPM),32-36 and nodular LM.37,38 All subtypes show small, firm, waxy papules limited to a few areas of the skin, which may coalesce and form nodules or plaques. DPLM can involve any site on the body. APPM exclusively involves both extensor surfaces of the distal upper extremities. Cutaneous mucinosis of infancy is a pediatric variant of DPLM or APPM. SHPM has spontaneous resolution. Nodular LM is characterized by a predominance of nodules.6 All subtypes except for SHPM typically persist long-term. Systemic symptoms were only reported in SHPM.32,33 In general, localized LM is self-limited and associated with a good prognosis.6 The histologic features of LM are summarized in Table 1.5 The pathology lies within the dermis for all types of this disease, and the epidermis is essentially normal.5 The types of LM can be distinguished from one another by 3 histologic clues: (1) mucin distribution pattern, (2) dermal level of mucin deposits, and (3) some extra findings.5 Differentiation can be additionally aided by observing the number of fibroblasts. Common mucin stains include colloidal iron, mucicarmine, and alcian blue at pH 2.5 (but not pH 0.5); common metachromatic mucin stains include toluidine blue, thionine, and methylene blue.3

DPLM is a subtype of localized LM.2,6 Although the lesions can involve any site, DPLM is typically distributed symmetrically to the trunk and limbs. The skin lesions have been described as a variable number of firm, smooth, waxy, or flesh-colored papules 2 to 5 mm in size. Normal serum protein and thyroid function test results verify the diagnosis of DPLM.6 Because Montgomery and Underwood2 originally defined LM as having no relation to any endocrine gland disturbance, we recommend additional random chemistry panel or fasting blood glucose laboratory tests if there is any question that a patient may have diabetes mellitus. Histologically, DPLM may have a diffuse or local pattern of mucin distribution involving the upper and mid reticular dermis. The involved dermis typically shows edema. The amount of fibroblast proliferation is variable. When compared with scleromyxedema, DPLM has no collagen deposition or sclerosis and a lesser amount of fibroblast proliferation.5-7 Some argue that DPLM and APPM are closely related variants.25,27 However, we believe that DPLM and APPM are distinct subtypes of localized LM. DPLM typically affects men (Table 2) and its lesions may be erythematous, larger, and include areas other than the distal upper extremities.4,23,24 In comparison, APPM has an overwhelming female-to-male ratio of 4.7:1.6 APPM also exclusively involves the back of the hands, extensor surface of the wrists, and sometimes the distal forearms.4,6,23 Histologically, APPM typically has more focal mucin deposits, which spare a subepidermal grenz zone, and a normal number of fibroblasts; DPLM has mucin deposits that are more diffuse (compared with APPM), have a variable number of increased fibroblasts, and have an irregular arrangement of collagen bundles.4-6,23

Table 2 summarizes the main features of the 10 DPLM cases reported in the English medical literature.2,7-9,17-21 Our criteria required there be no evidence of paraproteinemia, no history or laboratory evidence of any endocrine disease, no history of human immunodeficiency virus infection, histologic proof of dermal mucin deposits, and specific gross descriptions consistent with DPLM. It should be noted that only 4 of the 8 DPLM cases originally cited by Rongioletti and Rebora⁶ were included in Table 2. Four cases were excluded because 2 reports were written in French,1,12 1 report included a patient with diabetes mellitus,10 and another did not perform a necessary laboratory test to rule out thyroid disease.11 Other cases were excluded because they did not fulfill our criteria.39,40 Among the 10 DPLM patients summarized, 7 were men. The mean age of the group was 51.3 years. Only 3 of the 10 cases reported information on the patient's ethnicity: one was Caucasian,7 one was Asian,8 and our patient was African American. Nine of the 10 cases reported no evidence of paraproteinemia. The single case2 that did not report this finding was published before an association between LM and paraproteinemia was known in the 1960s.41 All 10 cases reported thyroid function test results within reference range. Only 3 of the 10 patients had symptomatic skin lesions, which were mainly pruritus. No systemic symptoms were noted. Three of the 10 patients had solitary skin lesions on areas other than the typical trunk and limbs. One patient had skin lesions only on his lumbar region, another had facial lesions, and our patient had lesions on her neck. Seven of the 10 patients had comorbid medical disorders, including hypertension, migraines, psoriatic erythroderma, psoriasis, seizures, gastric cancer in remission, pseudotumor cerebri, osteoporosis, and hepatitis C. Only hepatitis C was comorbid with more than one DPLM patient.17,20 This may be a coincidence because one patient developed DPLM after contracting hepatitis C,20, while the other patient developed it before contracting hepatitis C.17 Psychiatric illness was limited to depression and was found in 2 cases.20,21 No DPLM cases progressed to scleromyxedema, and none have been reported in the literature.5,6 DPLM rarely resolves on its own. Spontaneous resolution did not occur in any of the 10 reported DPLM cases, and only 2 patients were treated successfully. In Reynolds et al,18 the patient responded to therapy with intralesional corticosteroid injections and flurandrenolide-impregnated tape. In Kaymen et al,19 a patient was treated with a CO2 laser and postoperative intralesional corticosteroid injections. There was no growth after one year. All the other DPLM cases did not have effective therapy, lacked specific details of improvement, or did not report this information.2,7-9,17,20,21 Only Tay and Khoo,8 Enerback and Mobacken,9 and Kaymen et al19 commented on which therapies failed (oral thyroxine, topical corticosteroids, and shave excision, respectively). Our patient complained of persistent itching that did not respond to initial treatment with topical steroids and antihistamine medications. She later received pruritic relief with pimecrolimus cream therapy. However, the skin lesions remained. To our knowledge, this is the first report of pimecrolimus therapy in the treatment of pruritis secondary to DPLM. It is difficult to treat a rare disease such as DPLM when the pathogenesis is unknown, and many treatments have failed. Fortunately, DPLM and the other localized forms of LM are usually self-limited to the skin and have very little or no morbidity, leading some experts to believe that the disorder is unnecessary to treat.6 We believe that treatment is sometimes helpful. In our patient, the DPLM lesions were pruritic and located at a cosmetic area of the neck. The patient and dermatology staff decided to pursue a treatment plan. Therefore, even though localized LM lesions are typically benign, sometimes it is beneficial to treat them, especially if they cause irritating symptoms or cosmetic issues. 

Conclusion

DPLM is a rare variant of localized LM. DPLM can be diagnosed by a thorough history and physical examination; histologic proof of dermal mucin deposits; and ruling out other diseases with laboratory tests for serum protein, thyroid function, and, if the patient is at risk of diabetes mellitus, blood glucose levels. DPLM is a self-limited skin disease, and prognosis is generally good, but it typically persists long-term and may slowly progress. Treatment is usually unnecessary, but it may be recommended if the lesions are symptomatic or cause cosmetic issues. Unfortunately, few treatment plans have been shown to successfully treat DPLM. 

Lichen myxedematosus (LM), also called papular mucinosis, was first described by Dubreuilh1 in 1906 and later classified by Montgomery and Underwood2 in 1953. LMs are a group of localized or generalized papular eruptions of unknown etiology categorized as cutaneous mucinoses in which dermal mucin deposition is the distinctive histologic feature.3-5 LM has no relation to endocrine gland disorders, particularly thyroid disease.2,3,6 In their landmark paper, Montgomery and Underwood2 classified 4 clinical types of LM: (1) generalized lichenoid papular eruption, which is also called scleromyxedema, (2) discrete papular form, (3) localized to generalized lichenoid plaques, and (4) urticarial plaques and nodular eruptions that usually evolve into the generalized lichenoid form. In 2001, Rongioletti and Rebora6 updated the classification system. The articles by Montgomery and Underwood2 and Rongioletti and Rebora6 both agree with the existence of the discrete papular form, also called discrete papular LM (DPLM). According to Rongioletti and Rebora,6 DPLM has only been reported in the medical literature 8 times,1,2,7-12 This is unlike scleromyxedema, the most common type of LM, which has been documented in more than 110 cases.6 In this case report, we describe an interesting case of DPLM that was localized to the neck of our patient, and we review the English medical literature. 

Case Report

An 80-year-old black woman presented to our clinic with a 2-month history of a pruritic eruption localized to her neck. Multiple topical steroids and antihistamines had been used without any decrease in the eruption or the pruritus. The woman's medical history was significant for gastric cancer status post a partial gastrectomy 7 years prior, pseudotumor cerebri, hypertension, and osteoporosis. She is followed regularly for these conditions, which are stable. Her medications included acetazolamide, atenolol, nifedipine, rabeprazole sodium, fluoxetine, oxybutynin chloride, alendronate sodium, docusate calcium, and a multivitamin. Prior to the onset of this eruption, the patient had a change in the acetazolamide formulation, which was initially thought to be the culprit. Although she returned to the original formulation for longer than a month, she had no resolution of the symptoms. At that time, she sought evaluation in our clinic. On physical examination, multiple 2- to 4-mm discrete, flesh-colored shiny papules without scale were present over the patient's bilateral and posterior neck (Figure 1). Results of 2 punch biopsies showed splaying of the collagen with mucin present diffusely throughout the dermis. No increase in the number of fibroblasts was seen (Figure 2). Results of colloidal iron stain showed positive results in the papillary dermis and showed mucin mildly throughout the deep dermis (Figure 3), supporting the diagnosis of LM. Complete blood count, chemistry panel, liver function, thyrotropin, and serum protein test results were all within reference range. Pimecrolimus cream has been effective in treating our patient's pruritus. We have followed her for 14 months, and the lesions have remained localized to her neck, with continued normal thyrotropin and serum protein values.

Comment

In 2001, Rongioletti and Rebora6 revised the classification system of LM, categorizing it into 3 broad subsets: (1) generalized papular and sclerodermoid, (2) localized LM, and (3) atypical forms. The first subset, generalized papular and sclerodermoid, represents scleromyxedema. Diagnosis requires a generalized papular and sclerodermoid eruption, monoclonal gammopathy (paraproteinemia), no evidence of thyroid dysfunction, and a histologic triad of fibroblast proliferation, fibrosis, and mucin deposition.6 Scleromyxedema is associated with many systemic disorders that may include numerous organ systems.6,13 Although spontaneous resolution has been reported,14 scleromyxedema typically is a long-term and disfiguring disease6,13 associated with variable morbidity and mortality.15,16 The criteria for diagnosing the subset of localized LM requires a papular eruption, deposits of mucin with variable fibroblast growth, absence of paraproteinemia, and absence of thyroid dysfunction.6 There are 5 subtypes6: DPLM,2,7-9,17-21 acral persistent papular mucinosis (APPM),22-27 cutaneous mucinosis of infancy,28-31 self-healing papular mucinosis (SHPM),32-36 and nodular LM.37,38 All subtypes show small, firm, waxy papules limited to a few areas of the skin, which may coalesce and form nodules or plaques. DPLM can involve any site on the body. APPM exclusively involves both extensor surfaces of the distal upper extremities. Cutaneous mucinosis of infancy is a pediatric variant of DPLM or APPM. SHPM has spontaneous resolution. Nodular LM is characterized by a predominance of nodules.6 All subtypes except for SHPM typically persist long-term. Systemic symptoms were only reported in SHPM.32,33 In general, localized LM is self-limited and associated with a good prognosis.6 The histologic features of LM are summarized in Table 1.5 The pathology lies within the dermis for all types of this disease, and the epidermis is essentially normal.5 The types of LM can be distinguished from one another by 3 histologic clues: (1) mucin distribution pattern, (2) dermal level of mucin deposits, and (3) some extra findings.5 Differentiation can be additionally aided by observing the number of fibroblasts. Common mucin stains include colloidal iron, mucicarmine, and alcian blue at pH 2.5 (but not pH 0.5); common metachromatic mucin stains include toluidine blue, thionine, and methylene blue.3

DPLM is a subtype of localized LM.2,6 Although the lesions can involve any site, DPLM is typically distributed symmetrically to the trunk and limbs. The skin lesions have been described as a variable number of firm, smooth, waxy, or flesh-colored papules 2 to 5 mm in size. Normal serum protein and thyroid function test results verify the diagnosis of DPLM.6 Because Montgomery and Underwood2 originally defined LM as having no relation to any endocrine gland disturbance, we recommend additional random chemistry panel or fasting blood glucose laboratory tests if there is any question that a patient may have diabetes mellitus. Histologically, DPLM may have a diffuse or local pattern of mucin distribution involving the upper and mid reticular dermis. The involved dermis typically shows edema. The amount of fibroblast proliferation is variable. When compared with scleromyxedema, DPLM has no collagen deposition or sclerosis and a lesser amount of fibroblast proliferation.5-7 Some argue that DPLM and APPM are closely related variants.25,27 However, we believe that DPLM and APPM are distinct subtypes of localized LM. DPLM typically affects men (Table 2) and its lesions may be erythematous, larger, and include areas other than the distal upper extremities.4,23,24 In comparison, APPM has an overwhelming female-to-male ratio of 4.7:1.6 APPM also exclusively involves the back of the hands, extensor surface of the wrists, and sometimes the distal forearms.4,6,23 Histologically, APPM typically has more focal mucin deposits, which spare a subepidermal grenz zone, and a normal number of fibroblasts; DPLM has mucin deposits that are more diffuse (compared with APPM), have a variable number of increased fibroblasts, and have an irregular arrangement of collagen bundles.4-6,23

Table 2 summarizes the main features of the 10 DPLM cases reported in the English medical literature.2,7-9,17-21 Our criteria required there be no evidence of paraproteinemia, no history or laboratory evidence of any endocrine disease, no history of human immunodeficiency virus infection, histologic proof of dermal mucin deposits, and specific gross descriptions consistent with DPLM. It should be noted that only 4 of the 8 DPLM cases originally cited by Rongioletti and Rebora⁶ were included in Table 2. Four cases were excluded because 2 reports were written in French,1,12 1 report included a patient with diabetes mellitus,10 and another did not perform a necessary laboratory test to rule out thyroid disease.11 Other cases were excluded because they did not fulfill our criteria.39,40 Among the 10 DPLM patients summarized, 7 were men. The mean age of the group was 51.3 years. Only 3 of the 10 cases reported information on the patient's ethnicity: one was Caucasian,7 one was Asian,8 and our patient was African American. Nine of the 10 cases reported no evidence of paraproteinemia. The single case2 that did not report this finding was published before an association between LM and paraproteinemia was known in the 1960s.41 All 10 cases reported thyroid function test results within reference range. Only 3 of the 10 patients had symptomatic skin lesions, which were mainly pruritus. No systemic symptoms were noted. Three of the 10 patients had solitary skin lesions on areas other than the typical trunk and limbs. One patient had skin lesions only on his lumbar region, another had facial lesions, and our patient had lesions on her neck. Seven of the 10 patients had comorbid medical disorders, including hypertension, migraines, psoriatic erythroderma, psoriasis, seizures, gastric cancer in remission, pseudotumor cerebri, osteoporosis, and hepatitis C. Only hepatitis C was comorbid with more than one DPLM patient.17,20 This may be a coincidence because one patient developed DPLM after contracting hepatitis C,20, while the other patient developed it before contracting hepatitis C.17 Psychiatric illness was limited to depression and was found in 2 cases.20,21 No DPLM cases progressed to scleromyxedema, and none have been reported in the literature.5,6 DPLM rarely resolves on its own. Spontaneous resolution did not occur in any of the 10 reported DPLM cases, and only 2 patients were treated successfully. In Reynolds et al,18 the patient responded to therapy with intralesional corticosteroid injections and flurandrenolide-impregnated tape. In Kaymen et al,19 a patient was treated with a CO2 laser and postoperative intralesional corticosteroid injections. There was no growth after one year. All the other DPLM cases did not have effective therapy, lacked specific details of improvement, or did not report this information.2,7-9,17,20,21 Only Tay and Khoo,8 Enerback and Mobacken,9 and Kaymen et al19 commented on which therapies failed (oral thyroxine, topical corticosteroids, and shave excision, respectively). Our patient complained of persistent itching that did not respond to initial treatment with topical steroids and antihistamine medications. She later received pruritic relief with pimecrolimus cream therapy. However, the skin lesions remained. To our knowledge, this is the first report of pimecrolimus therapy in the treatment of pruritis secondary to DPLM. It is difficult to treat a rare disease such as DPLM when the pathogenesis is unknown, and many treatments have failed. Fortunately, DPLM and the other localized forms of LM are usually self-limited to the skin and have very little or no morbidity, leading some experts to believe that the disorder is unnecessary to treat.6 We believe that treatment is sometimes helpful. In our patient, the DPLM lesions were pruritic and located at a cosmetic area of the neck. The patient and dermatology staff decided to pursue a treatment plan. Therefore, even though localized LM lesions are typically benign, sometimes it is beneficial to treat them, especially if they cause irritating symptoms or cosmetic issues. 

Conclusion

DPLM is a rare variant of localized LM. DPLM can be diagnosed by a thorough history and physical examination; histologic proof of dermal mucin deposits; and ruling out other diseases with laboratory tests for serum protein, thyroid function, and, if the patient is at risk of diabetes mellitus, blood glucose levels. DPLM is a self-limited skin disease, and prognosis is generally good, but it typically persists long-term and may slowly progress. Treatment is usually unnecessary, but it may be recommended if the lesions are symptomatic or cause cosmetic issues. Unfortunately, few treatment plans have been shown to successfully treat DPLM. 

Keratosis punctata palmoplantaris (KPPP) is a rare genodermatosis with an autosomal-dominant pattern of inheritance. We report the case of a 61-year-old woman who presented with a long history of multiple symptomatic hyperkeratotic papules on the palms and soles. In addition, we review the literature and present the current classification of the heterogeneous group of punctate palmoplantar keratoses, the cutaneous and histologic findings, the differential diagnosis, the possible association with various anomalies including malignancies, and the various treatment options.

Case Report

A 61-year-old German woman whose medical history was significant only for osteoarthritis presented with a long duration of multiple hyperkeratotic papules on the palms and soles. The patient recalled the palmar lesions first appeared at approximately age 15 years. She denied any history of arsenic exposure. Her occupations included gardening and working as a housewife. All cancer screenings appropriate for her age, including mammography, fecal occult blood testing, colonoscopy, and Pap test, were current; no malignancies have been detected to date. Family history revealed 6 other relatives spanning 4 generations with similar lesions on the hands and soles (Figure 1). All family members in the pedigree were generally healthy without any reported history of malignancies. On examination, the patient had multiple 2- to 3-mm discrete keratotic papules over the palmoplantar surfaces that were confluent in areas involving the weight-bearing surface of her soles (Figures 2 and 3). The patient described some tenderness in these areas when standing and walking. Histologically, the keratotic papules revealed a compact hyperkeratotic plug with a slight depression in the underlying epidermis (Figure 4). No parakeratosis or cornoid lamellae were present. The patient was initially treated with daily salicylic acid 40% and urea 40% cream with some improvement of the hyperkeratosis. At follow-up one month later, daily tazarotene 0.1% gel was added, which resulted in further improvement and resolution of the pain after 3 months.

Please refer to the PDF to view the figures

Comment

The first description of keratosis punctata palmoplantaris (KPPP) was reported by Buschke and Fischer¹ in 1910. Three years later, Brauer² reported a family with clinically similar lesions that appeared to be hereditary. The disorder is thus often referred to as Buschke-Fischer-Brauer disease. Various synonyms have been used to describe this genodermatoses (Table 1).^3-7

Please refer to the PDF to view the table

Currently, the classification of palmoplantar keratodermas (PPKs) is based on clinical morphology, distribution of the lesions, histology, modes of inheritance, and, in some cases, molecular pathology.^3,8,9 The "simple" PPKs, which involve only the skin, can be divided into 3 types: diffuse, focal, and punctate. The punctate PPKs are subdivided into acquired and hereditary forms. Acquired forms include arsenical keratoses and keratosis punctata of the palmar creases. The hereditary forms of punctate PPKs include KPPP (type I punctate PPK, Buschke-Fischer-Brauer disease), spiny keratoderma (type II punctate PPK, porokeratosis punctata palmaris et plantaris), focal acral hyperkeratosis, and acrokeratoelastoidosis.^3,7,8

KPPP is transmitted as an autosomal-dominant trait with variable penetrance.^6-9 The lesions of KPPP develop over the palmoplantar surface between the ages of 12 to 30 years, with a peak incidence in the second decade, as was the case in our patient. Most reports suggest predominance in black patients with a roughly equal sex ratio overall.^4-7 The incidence in one large series is reported as 1.17 per 100,000 people.⁶ The primary lesions, which typically begin over the lateral edge of the digits, are slightly raised, sharply marginated, round to oval, skin-colored papules. The size of the lesions range between 2 to 20 mm. Over time and with repetitive trauma, the hyperkeratotic lesions become enlarged, turn more yellow-brown, and distribute irregularly over the entire palmoplantar surface. The plantar lesions may coalesce into a more diffuse pattern over the pressure points. The number of lesions per person may range from 1 to more than 40 papules, with an average in one study of 8.3.⁴ Removal of the deep central portion leaves a depression in which the original lesions will re-form during a period of weeks. The lesions may be accentuated with immersion in water.⁷

Most patients with KPPP are asymptomatic and are often diagnosed incidentally on examination; however, in some cases, symptoms of burning, pruritus, and pain hindering daily activities, such as walking or manual labor, have been noted.⁴ Hyperhidrosis is uncommon, but nail abnormalities such as longitudinal fissures, onychogryphosis, and onychomadesis are frequently reported.^4,10 The course of the disease is long-term, and spontaneous resolution has not been reported in the literature.

Histologic specimens from KPPP lesions reveal circumscribed compact columns of massive hyperkeratosis and a normal to mildly increased granular layer. There is usually a slight depression in the epidermis beneath the plug (Figure 4).⁴

Please refer to the PDF to view the Figure

The differential diagnosis of punctate keratoses of the palms and soles can be extensive (Table 2).^4,11-22 Following is a discussion of the clinical characteristics of the acquired and hereditary forms of primary punctate palmoplantar keratoses.

Please refer to the PDF to view the table

Arsenical keratoses are one of several cutaneous manifestations of long-term arsenic exposure. Sources of exposure to this toxic metal include well water, medicine, mining and smelting of various metals, and industrial pollution.^11-12 Drinking water contaminated with naturally high levels of inorganic arsenic is a significant problem in many parts of the world. For example, in Bangladesh and West Bengal, India, an estimated 79.9 million and 42.7 million inhabitants, respectively, are exposed to groundwater arsenic concentrations that far exceed the World Health Organization maximum permissible limit of 50 µg/L.¹² In both of these populations, the primary source of drinking water is from tube wells, which draw water from underground aquifers contaminated with geological sources of arsenic.¹² Arsenical keratosis is characterized by hyperkeratotic papules that typically develop over the palms and soles. The lesions may appear anywhere between 4 to 30 years after exposure and may degenerate into squamous cell carcinoma or, more rarely, basal cell carcinoma.^11-13 A detailed history is thus warranted if arsenic exposure is suspected. Associations with internal malignancies, including hepatic angiosarcoma, bronchial adenocarcinoma, bladder cancer, and nonmelanoma skin cancer, have been reported.^11-14

Keratosis punctata of the palmar creases appears to be predominantly found in the Afro-Caribbean population, but the prevalence is unclear, varying from 1.5% to 69% in different series.^4,15-17 The lesions are characterized by discrete, translucent, keratotic papules primarily in the palmar creases of the hands. They are usually asymptomatic but may be painful. Many authors suggest this disease is related to manual labor. No associations with malignancy have been reported.^4,5,15-17

Spiny keratoderma is an autosomal-dominant condition with an age of onset ranging from 12 to 59 years.^18-20 Clinical presentation is characterized by numerous tiny keratotic spines over the entire palmoplantar surfaces, resembling the spines of an old-fashioned music box.¹⁸ Histologically, these spines correspond to columnar parakeratosis resembling cornoid lamellae. This finding is absent in the KPPP form. The term spiny keratoderma was coined by Osman et al¹⁸ to distinguish this condition from porokeratosis, which is clinically and histologically a distinct entity. Confusion exists about whether or not the lesions of spiny keratoderma are a form of porokeratosis because previously designated names incorporated the term porokeratosis. The names punctate porokeratotic keratoderma, porokeratosis punctata palmaris et plantaris, and punctate porokeratosis of the palms and soles have been previously used to describe these spiny lesions.^18-20 The punctate variant of true porokeratosis is clinically characterized by discrete 1- to 2-mm seedlike hyperkeratotic plugs surrounded by a thin raised margin.^21-22 These lesions may be arranged linearly or may coalesce to form plaques, which are not observed with spiny keratoderma.²¹ The histologic hallmark of porokeratosis is the cornoid lamella, which consists of a thin column of parakeratotic cells extending through the surrounding orthokeratotic stratum corneum, an absent granular layer below the column of parakeratosis, and vacuolated or dyskeratotic cells at the base. Proper classification is needed because malignant degeneration has been reported with certain variants of porokeratosis.^18,21

Acrokeratoelastoidosis and focal acral hyperkeratosis are clinically similar entities and share an autosomal-dominant inheritance pattern. Clinical findings consist of 2- to 4-mm round to oval keratotic papules on the borders of the hands, feet, and wrists. The papules may be umbilicated in some cases and may become confluent in the center of the palms and soles. The lesions typically first develop in childhood or adolescence but may occur in adult life. Local hyperhidrosis may be present in acrokeratoelastoidosis but has not been reported for focal acral hyperkeratosis. These 2 entities are mainly distinguished histologically. Focal acral hyperkeratosis exhibits only hyperkeratosis, whereas acrokeratoelastoidosis has the additional finding of elastorrhexis. There have been no reported associations with malignancies.^3,23

Keratotic palmoplantar papules also are cutaneous manifestations of multisystem disorders such as Darier disease and Cowden disease.^24-25 Patients with these disorders typically have a multitude of other mucocutaneous and systemic findings to support these diagnoses. Histologically, the keratotic lesions of Darier disease are similar to that of KPPP in that hyperkeratosis is found in both. However, Darier disease also demonstrates follicular plugging, parakeratosis, and irregular acanthosis with papillomatosis.²⁴ The keratotic lesions of Cowden disease show nonspecific orthokeratosis, hypergranulosis, and acanthosis.²⁵ A thorough examination, family history, and histologic evaluation are all necessary to make an accurate diagnosis.

Various anomalies and diseases such as corneal opacities, spastic paralysis, epilepsy, oligophrenia, colonic adenocarcinoma, and gastroduodenal ulcers have been reported infrequently in association with KPPP8,^10,26-34; however, none were observed in our case.

As previously mentioned, KPPP is transmitted as an autosomal-dominant trait. The causative gene, however, has not been identified. Linkage to keratin gene clusters 12q and 17q has been excluded by Kelsell et al.²⁷ Various authors propose that the defect may lie in another gene involved in epithelial development and/or regulation in keratin expression (ie, genes responsible for structural proteins that are integral to keratin filament assembly and function).^7,8,10

Unlike diffuse and focal PPKs, the association of punctate PPKs with malignancies is not well established. To date, only 3 reports of inherited punctate PPK and malignancy have been published. Bennion and Patterson³³ reported a small kindred of 8 affected individuals; 2 developed adenocarcinoma of the colon and 1 developed adenocarcinoma of the pancreas. Interestingly, none of the family members without punctate keratoses developed cancer of any type. Ena et al³⁴ reported a family with 8 affected members, one of whom developed adenocarcinoma of the colon at 53 years of age. The statistical significance in these 2 studies is questionable due to the small number of subjects involved. Stevens et al³⁰ reported a larger kindred of more than 320 individuals spanning 4 generations. In this study, 10 of 43 adults with punctate PPK developed malignancies, including Hodgkin disease and renal, breast, pancreatic, and colon adenocarcinomas. Of the remaining 277 unaffected individuals, 6 developed malignancies.

Discovery of the causative gene(s) would serve at least 2 purposes: (1) it would provide insights into the possible association of punctate PPK and malignancy and (2) it may lead to an improved classification of the heterogeneous group of punctate PPKs.

Historically, KPPP was treated with mechanical debridement and topical keratolytics, which only provided temporary control. More recently, systemic retinoids have been used with improved results; however, relapse is reported with cessation of treatment. Baran and Juhlin³⁵ treated a patient with a disabling case of KPPP with etretinate 75 mg daily and observed significant clinical improvement after 3 weeks. The patient remained free from the hyperkeratoses with a maintenance dose of 50 mg daily; however, the lesions recurred when the dose was further decreased to 25 mg daily. Hesse et al³⁶ also treated a disabling case with acitretin, the active metabolite of etretinate, and observed similar success. Treatment with acitretin 30 mg daily resulted in significant, but incomplete, regression of the lesions after one month. Relapse occurred upon cessation of treatment; however, adequate control was maintained with 10 to 20 mg daily.

We chose to treat our patient with a trial of tazarotene 0.1% gel to minimize potential adverse reactions present with long-term use of oral retinoids. After 3 months of daily application of tazarotene, the hyperkeratotic lesions significantly diminished in size, and more importantly to the patient, the pain over the pressure areas resolved. Given our positive experience with tazarotene, topical retinoids may be a practical alternative for mild cases of KPPP. Long-term use is likely required for optimal control given the high relapse occurrence observed with cessation of oral retinoids.

Conclusion

In conclusion, we presented a case of KPPP in a patient with a strong family history supporting the autosomal-dominant inheritance pattern. The causative gene has not yet been identified, but its discovery would provide more insight into the possible association with malignancy and also may lead to an improved classification of the punctate PPKs. Punctate PPK has an extensive differential diagnosis and, if unrecognized, may be confused with common entities such as verrucae, leading to unnecessary frustration from multiple ineffective treatments. Multisystem conditions such as Darier disease and Cowden disease also must be considered when evaluating a patient with palmoplantar punctate keratoses. A full cutaneous examination, family history, and histologic evaluation are important components in making an accurate diagnosis. Treatment options include mechanical debridement, topical keratolytics, and topical and systemic retinoids. Maintenance therapy is required with all forms of treatment to prevent relapse. 

Keratosis punctata palmoplantaris (KPPP) is a rare genodermatosis with an autosomal-dominant pattern of inheritance. We report the case of a 61-year-old woman who presented with a long history of multiple symptomatic hyperkeratotic papules on the palms and soles. In addition, we review the literature and present the current classification of the heterogeneous group of punctate palmoplantar keratoses, the cutaneous and histologic findings, the differential diagnosis, the possible association with various anomalies including malignancies, and the various treatment options.

Case Report

A 61-year-old German woman whose medical history was significant only for osteoarthritis presented with a long duration of multiple hyperkeratotic papules on the palms and soles. The patient recalled the palmar lesions first appeared at approximately age 15 years. She denied any history of arsenic exposure. Her occupations included gardening and working as a housewife. All cancer screenings appropriate for her age, including mammography, fecal occult blood testing, colonoscopy, and Pap test, were current; no malignancies have been detected to date. Family history revealed 6 other relatives spanning 4 generations with similar lesions on the hands and soles (Figure 1). All family members in the pedigree were generally healthy without any reported history of malignancies. On examination, the patient had multiple 2- to 3-mm discrete keratotic papules over the palmoplantar surfaces that were confluent in areas involving the weight-bearing surface of her soles (Figures 2 and 3). The patient described some tenderness in these areas when standing and walking. Histologically, the keratotic papules revealed a compact hyperkeratotic plug with a slight depression in the underlying epidermis (Figure 4). No parakeratosis or cornoid lamellae were present. The patient was initially treated with daily salicylic acid 40% and urea 40% cream with some improvement of the hyperkeratosis. At follow-up one month later, daily tazarotene 0.1% gel was added, which resulted in further improvement and resolution of the pain after 3 months.

Please refer to the PDF to view the figures

Comment

The first description of keratosis punctata palmoplantaris (KPPP) was reported by Buschke and Fischer¹ in 1910. Three years later, Brauer² reported a family with clinically similar lesions that appeared to be hereditary. The disorder is thus often referred to as Buschke-Fischer-Brauer disease. Various synonyms have been used to describe this genodermatoses (Table 1).^3-7

Please refer to the PDF to view the table

Currently, the classification of palmoplantar keratodermas (PPKs) is based on clinical morphology, distribution of the lesions, histology, modes of inheritance, and, in some cases, molecular pathology.^3,8,9 The "simple" PPKs, which involve only the skin, can be divided into 3 types: diffuse, focal, and punctate. The punctate PPKs are subdivided into acquired and hereditary forms. Acquired forms include arsenical keratoses and keratosis punctata of the palmar creases. The hereditary forms of punctate PPKs include KPPP (type I punctate PPK, Buschke-Fischer-Brauer disease), spiny keratoderma (type II punctate PPK, porokeratosis punctata palmaris et plantaris), focal acral hyperkeratosis, and acrokeratoelastoidosis.^3,7,8

KPPP is transmitted as an autosomal-dominant trait with variable penetrance.^6-9 The lesions of KPPP develop over the palmoplantar surface between the ages of 12 to 30 years, with a peak incidence in the second decade, as was the case in our patient. Most reports suggest predominance in black patients with a roughly equal sex ratio overall.^4-7 The incidence in one large series is reported as 1.17 per 100,000 people.⁶ The primary lesions, which typically begin over the lateral edge of the digits, are slightly raised, sharply marginated, round to oval, skin-colored papules. The size of the lesions range between 2 to 20 mm. Over time and with repetitive trauma, the hyperkeratotic lesions become enlarged, turn more yellow-brown, and distribute irregularly over the entire palmoplantar surface. The plantar lesions may coalesce into a more diffuse pattern over the pressure points. The number of lesions per person may range from 1 to more than 40 papules, with an average in one study of 8.3.⁴ Removal of the deep central portion leaves a depression in which the original lesions will re-form during a period of weeks. The lesions may be accentuated with immersion in water.⁷

Most patients with KPPP are asymptomatic and are often diagnosed incidentally on examination; however, in some cases, symptoms of burning, pruritus, and pain hindering daily activities, such as walking or manual labor, have been noted.⁴ Hyperhidrosis is uncommon, but nail abnormalities such as longitudinal fissures, onychogryphosis, and onychomadesis are frequently reported.^4,10 The course of the disease is long-term, and spontaneous resolution has not been reported in the literature.

Histologic specimens from KPPP lesions reveal circumscribed compact columns of massive hyperkeratosis and a normal to mildly increased granular layer. There is usually a slight depression in the epidermis beneath the plug (Figure 4).⁴

Please refer to the PDF to view the Figure

The differential diagnosis of punctate keratoses of the palms and soles can be extensive (Table 2).^4,11-22 Following is a discussion of the clinical characteristics of the acquired and hereditary forms of primary punctate palmoplantar keratoses.

Please refer to the PDF to view the table

Arsenical keratoses are one of several cutaneous manifestations of long-term arsenic exposure. Sources of exposure to this toxic metal include well water, medicine, mining and smelting of various metals, and industrial pollution.^11-12 Drinking water contaminated with naturally high levels of inorganic arsenic is a significant problem in many parts of the world. For example, in Bangladesh and West Bengal, India, an estimated 79.9 million and 42.7 million inhabitants, respectively, are exposed to groundwater arsenic concentrations that far exceed the World Health Organization maximum permissible limit of 50 µg/L.¹² In both of these populations, the primary source of drinking water is from tube wells, which draw water from underground aquifers contaminated with geological sources of arsenic.¹² Arsenical keratosis is characterized by hyperkeratotic papules that typically develop over the palms and soles. The lesions may appear anywhere between 4 to 30 years after exposure and may degenerate into squamous cell carcinoma or, more rarely, basal cell carcinoma.^11-13 A detailed history is thus warranted if arsenic exposure is suspected. Associations with internal malignancies, including hepatic angiosarcoma, bronchial adenocarcinoma, bladder cancer, and nonmelanoma skin cancer, have been reported.^11-14

Keratosis punctata of the palmar creases appears to be predominantly found in the Afro-Caribbean population, but the prevalence is unclear, varying from 1.5% to 69% in different series.^4,15-17 The lesions are characterized by discrete, translucent, keratotic papules primarily in the palmar creases of the hands. They are usually asymptomatic but may be painful. Many authors suggest this disease is related to manual labor. No associations with malignancy have been reported.^4,5,15-17

Spiny keratoderma is an autosomal-dominant condition with an age of onset ranging from 12 to 59 years.^18-20 Clinical presentation is characterized by numerous tiny keratotic spines over the entire palmoplantar surfaces, resembling the spines of an old-fashioned music box.¹⁸ Histologically, these spines correspond to columnar parakeratosis resembling cornoid lamellae. This finding is absent in the KPPP form. The term spiny keratoderma was coined by Osman et al¹⁸ to distinguish this condition from porokeratosis, which is clinically and histologically a distinct entity. Confusion exists about whether or not the lesions of spiny keratoderma are a form of porokeratosis because previously designated names incorporated the term porokeratosis. The names punctate porokeratotic keratoderma, porokeratosis punctata palmaris et plantaris, and punctate porokeratosis of the palms and soles have been previously used to describe these spiny lesions.^18-20 The punctate variant of true porokeratosis is clinically characterized by discrete 1- to 2-mm seedlike hyperkeratotic plugs surrounded by a thin raised margin.^21-22 These lesions may be arranged linearly or may coalesce to form plaques, which are not observed with spiny keratoderma.²¹ The histologic hallmark of porokeratosis is the cornoid lamella, which consists of a thin column of parakeratotic cells extending through the surrounding orthokeratotic stratum corneum, an absent granular layer below the column of parakeratosis, and vacuolated or dyskeratotic cells at the base. Proper classification is needed because malignant degeneration has been reported with certain variants of porokeratosis.^18,21

Acrokeratoelastoidosis and focal acral hyperkeratosis are clinically similar entities and share an autosomal-dominant inheritance pattern. Clinical findings consist of 2- to 4-mm round to oval keratotic papules on the borders of the hands, feet, and wrists. The papules may be umbilicated in some cases and may become confluent in the center of the palms and soles. The lesions typically first develop in childhood or adolescence but may occur in adult life. Local hyperhidrosis may be present in acrokeratoelastoidosis but has not been reported for focal acral hyperkeratosis. These 2 entities are mainly distinguished histologically. Focal acral hyperkeratosis exhibits only hyperkeratosis, whereas acrokeratoelastoidosis has the additional finding of elastorrhexis. There have been no reported associations with malignancies.^3,23

Keratotic palmoplantar papules also are cutaneous manifestations of multisystem disorders such as Darier disease and Cowden disease.^24-25 Patients with these disorders typically have a multitude of other mucocutaneous and systemic findings to support these diagnoses. Histologically, the keratotic lesions of Darier disease are similar to that of KPPP in that hyperkeratosis is found in both. However, Darier disease also demonstrates follicular plugging, parakeratosis, and irregular acanthosis with papillomatosis.²⁴ The keratotic lesions of Cowden disease show nonspecific orthokeratosis, hypergranulosis, and acanthosis.²⁵ A thorough examination, family history, and histologic evaluation are all necessary to make an accurate diagnosis.

Various anomalies and diseases such as corneal opacities, spastic paralysis, epilepsy, oligophrenia, colonic adenocarcinoma, and gastroduodenal ulcers have been reported infrequently in association with KPPP8,^10,26-34; however, none were observed in our case.

As previously mentioned, KPPP is transmitted as an autosomal-dominant trait. The causative gene, however, has not been identified. Linkage to keratin gene clusters 12q and 17q has been excluded by Kelsell et al.²⁷ Various authors propose that the defect may lie in another gene involved in epithelial development and/or regulation in keratin expression (ie, genes responsible for structural proteins that are integral to keratin filament assembly and function).^7,8,10

Unlike diffuse and focal PPKs, the association of punctate PPKs with malignancies is not well established. To date, only 3 reports of inherited punctate PPK and malignancy have been published. Bennion and Patterson³³ reported a small kindred of 8 affected individuals; 2 developed adenocarcinoma of the colon and 1 developed adenocarcinoma of the pancreas. Interestingly, none of the family members without punctate keratoses developed cancer of any type. Ena et al³⁴ reported a family with 8 affected members, one of whom developed adenocarcinoma of the colon at 53 years of age. The statistical significance in these 2 studies is questionable due to the small number of subjects involved. Stevens et al³⁰ reported a larger kindred of more than 320 individuals spanning 4 generations. In this study, 10 of 43 adults with punctate PPK developed malignancies, including Hodgkin disease and renal, breast, pancreatic, and colon adenocarcinomas. Of the remaining 277 unaffected individuals, 6 developed malignancies.

Discovery of the causative gene(s) would serve at least 2 purposes: (1) it would provide insights into the possible association of punctate PPK and malignancy and (2) it may lead to an improved classification of the heterogeneous group of punctate PPKs.

Historically, KPPP was treated with mechanical debridement and topical keratolytics, which only provided temporary control. More recently, systemic retinoids have been used with improved results; however, relapse is reported with cessation of treatment. Baran and Juhlin³⁵ treated a patient with a disabling case of KPPP with etretinate 75 mg daily and observed significant clinical improvement after 3 weeks. The patient remained free from the hyperkeratoses with a maintenance dose of 50 mg daily; however, the lesions recurred when the dose was further decreased to 25 mg daily. Hesse et al³⁶ also treated a disabling case with acitretin, the active metabolite of etretinate, and observed similar success. Treatment with acitretin 30 mg daily resulted in significant, but incomplete, regression of the lesions after one month. Relapse occurred upon cessation of treatment; however, adequate control was maintained with 10 to 20 mg daily.

We chose to treat our patient with a trial of tazarotene 0.1% gel to minimize potential adverse reactions present with long-term use of oral retinoids. After 3 months of daily application of tazarotene, the hyperkeratotic lesions significantly diminished in size, and more importantly to the patient, the pain over the pressure areas resolved. Given our positive experience with tazarotene, topical retinoids may be a practical alternative for mild cases of KPPP. Long-term use is likely required for optimal control given the high relapse occurrence observed with cessation of oral retinoids.

Conclusion

In conclusion, we presented a case of KPPP in a patient with a strong family history supporting the autosomal-dominant inheritance pattern. The causative gene has not yet been identified, but its discovery would provide more insight into the possible association with malignancy and also may lead to an improved classification of the punctate PPKs. Punctate PPK has an extensive differential diagnosis and, if unrecognized, may be confused with common entities such as verrucae, leading to unnecessary frustration from multiple ineffective treatments. Multisystem conditions such as Darier disease and Cowden disease also must be considered when evaluating a patient with palmoplantar punctate keratoses. A full cutaneous examination, family history, and histologic evaluation are important components in making an accurate diagnosis. Treatment options include mechanical debridement, topical keratolytics, and topical and systemic retinoids. Maintenance therapy is required with all forms of treatment to prevent relapse. 

Keratosis punctata palmoplantaris (KPPP) is a rare genodermatosis with an autosomal-dominant pattern of inheritance. We report the case of a 61-year-old woman who presented with a long history of multiple symptomatic hyperkeratotic papules on the palms and soles. In addition, we review the literature and present the current classification of the heterogeneous group of punctate palmoplantar keratoses, the cutaneous and histologic findings, the differential diagnosis, the possible association with various anomalies including malignancies, and the various treatment options.

Case Report

A 61-year-old German woman whose medical history was significant only for osteoarthritis presented with a long duration of multiple hyperkeratotic papules on the palms and soles. The patient recalled the palmar lesions first appeared at approximately age 15 years. She denied any history of arsenic exposure. Her occupations included gardening and working as a housewife. All cancer screenings appropriate for her age, including mammography, fecal occult blood testing, colonoscopy, and Pap test, were current; no malignancies have been detected to date. Family history revealed 6 other relatives spanning 4 generations with similar lesions on the hands and soles (Figure 1). All family members in the pedigree were generally healthy without any reported history of malignancies. On examination, the patient had multiple 2- to 3-mm discrete keratotic papules over the palmoplantar surfaces that were confluent in areas involving the weight-bearing surface of her soles (Figures 2 and 3). The patient described some tenderness in these areas when standing and walking. Histologically, the keratotic papules revealed a compact hyperkeratotic plug with a slight depression in the underlying epidermis (Figure 4). No parakeratosis or cornoid lamellae were present. The patient was initially treated with daily salicylic acid 40% and urea 40% cream with some improvement of the hyperkeratosis. At follow-up one month later, daily tazarotene 0.1% gel was added, which resulted in further improvement and resolution of the pain after 3 months.

Please refer to the PDF to view the figures

Comment

The first description of keratosis punctata palmoplantaris (KPPP) was reported by Buschke and Fischer¹ in 1910. Three years later, Brauer² reported a family with clinically similar lesions that appeared to be hereditary. The disorder is thus often referred to as Buschke-Fischer-Brauer disease. Various synonyms have been used to describe this genodermatoses (Table 1).^3-7

Please refer to the PDF to view the table

Currently, the classification of palmoplantar keratodermas (PPKs) is based on clinical morphology, distribution of the lesions, histology, modes of inheritance, and, in some cases, molecular pathology.^3,8,9 The "simple" PPKs, which involve only the skin, can be divided into 3 types: diffuse, focal, and punctate. The punctate PPKs are subdivided into acquired and hereditary forms. Acquired forms include arsenical keratoses and keratosis punctata of the palmar creases. The hereditary forms of punctate PPKs include KPPP (type I punctate PPK, Buschke-Fischer-Brauer disease), spiny keratoderma (type II punctate PPK, porokeratosis punctata palmaris et plantaris), focal acral hyperkeratosis, and acrokeratoelastoidosis.^3,7,8

KPPP is transmitted as an autosomal-dominant trait with variable penetrance.^6-9 The lesions of KPPP develop over the palmoplantar surface between the ages of 12 to 30 years, with a peak incidence in the second decade, as was the case in our patient. Most reports suggest predominance in black patients with a roughly equal sex ratio overall.^4-7 The incidence in one large series is reported as 1.17 per 100,000 people.⁶ The primary lesions, which typically begin over the lateral edge of the digits, are slightly raised, sharply marginated, round to oval, skin-colored papules. The size of the lesions range between 2 to 20 mm. Over time and with repetitive trauma, the hyperkeratotic lesions become enlarged, turn more yellow-brown, and distribute irregularly over the entire palmoplantar surface. The plantar lesions may coalesce into a more diffuse pattern over the pressure points. The number of lesions per person may range from 1 to more than 40 papules, with an average in one study of 8.3.⁴ Removal of the deep central portion leaves a depression in which the original lesions will re-form during a period of weeks. The lesions may be accentuated with immersion in water.⁷

Most patients with KPPP are asymptomatic and are often diagnosed incidentally on examination; however, in some cases, symptoms of burning, pruritus, and pain hindering daily activities, such as walking or manual labor, have been noted.⁴ Hyperhidrosis is uncommon, but nail abnormalities such as longitudinal fissures, onychogryphosis, and onychomadesis are frequently reported.^4,10 The course of the disease is long-term, and spontaneous resolution has not been reported in the literature.

Histologic specimens from KPPP lesions reveal circumscribed compact columns of massive hyperkeratosis and a normal to mildly increased granular layer. There is usually a slight depression in the epidermis beneath the plug (Figure 4).⁴

Please refer to the PDF to view the Figure

The differential diagnosis of punctate keratoses of the palms and soles can be extensive (Table 2).^4,11-22 Following is a discussion of the clinical characteristics of the acquired and hereditary forms of primary punctate palmoplantar keratoses.

Please refer to the PDF to view the table

Arsenical keratoses are one of several cutaneous manifestations of long-term arsenic exposure. Sources of exposure to this toxic metal include well water, medicine, mining and smelting of various metals, and industrial pollution.^11-12 Drinking water contaminated with naturally high levels of inorganic arsenic is a significant problem in many parts of the world. For example, in Bangladesh and West Bengal, India, an estimated 79.9 million and 42.7 million inhabitants, respectively, are exposed to groundwater arsenic concentrations that far exceed the World Health Organization maximum permissible limit of 50 µg/L.¹² In both of these populations, the primary source of drinking water is from tube wells, which draw water from underground aquifers contaminated with geological sources of arsenic.¹² Arsenical keratosis is characterized by hyperkeratotic papules that typically develop over the palms and soles. The lesions may appear anywhere between 4 to 30 years after exposure and may degenerate into squamous cell carcinoma or, more rarely, basal cell carcinoma.^11-13 A detailed history is thus warranted if arsenic exposure is suspected. Associations with internal malignancies, including hepatic angiosarcoma, bronchial adenocarcinoma, bladder cancer, and nonmelanoma skin cancer, have been reported.^11-14

Keratosis punctata of the palmar creases appears to be predominantly found in the Afro-Caribbean population, but the prevalence is unclear, varying from 1.5% to 69% in different series.^4,15-17 The lesions are characterized by discrete, translucent, keratotic papules primarily in the palmar creases of the hands. They are usually asymptomatic but may be painful. Many authors suggest this disease is related to manual labor. No associations with malignancy have been reported.^4,5,15-17

Spiny keratoderma is an autosomal-dominant condition with an age of onset ranging from 12 to 59 years.^18-20 Clinical presentation is characterized by numerous tiny keratotic spines over the entire palmoplantar surfaces, resembling the spines of an old-fashioned music box.¹⁸ Histologically, these spines correspond to columnar parakeratosis resembling cornoid lamellae. This finding is absent in the KPPP form. The term spiny keratoderma was coined by Osman et al¹⁸ to distinguish this condition from porokeratosis, which is clinically and histologically a distinct entity. Confusion exists about whether or not the lesions of spiny keratoderma are a form of porokeratosis because previously designated names incorporated the term porokeratosis. The names punctate porokeratotic keratoderma, porokeratosis punctata palmaris et plantaris, and punctate porokeratosis of the palms and soles have been previously used to describe these spiny lesions.^18-20 The punctate variant of true porokeratosis is clinically characterized by discrete 1- to 2-mm seedlike hyperkeratotic plugs surrounded by a thin raised margin.^21-22 These lesions may be arranged linearly or may coalesce to form plaques, which are not observed with spiny keratoderma.²¹ The histologic hallmark of porokeratosis is the cornoid lamella, which consists of a thin column of parakeratotic cells extending through the surrounding orthokeratotic stratum corneum, an absent granular layer below the column of parakeratosis, and vacuolated or dyskeratotic cells at the base. Proper classification is needed because malignant degeneration has been reported with certain variants of porokeratosis.^18,21

Acrokeratoelastoidosis and focal acral hyperkeratosis are clinically similar entities and share an autosomal-dominant inheritance pattern. Clinical findings consist of 2- to 4-mm round to oval keratotic papules on the borders of the hands, feet, and wrists. The papules may be umbilicated in some cases and may become confluent in the center of the palms and soles. The lesions typically first develop in childhood or adolescence but may occur in adult life. Local hyperhidrosis may be present in acrokeratoelastoidosis but has not been reported for focal acral hyperkeratosis. These 2 entities are mainly distinguished histologically. Focal acral hyperkeratosis exhibits only hyperkeratosis, whereas acrokeratoelastoidosis has the additional finding of elastorrhexis. There have been no reported associations with malignancies.^3,23

Keratotic palmoplantar papules also are cutaneous manifestations of multisystem disorders such as Darier disease and Cowden disease.^24-25 Patients with these disorders typically have a multitude of other mucocutaneous and systemic findings to support these diagnoses. Histologically, the keratotic lesions of Darier disease are similar to that of KPPP in that hyperkeratosis is found in both. However, Darier disease also demonstrates follicular plugging, parakeratosis, and irregular acanthosis with papillomatosis.²⁴ The keratotic lesions of Cowden disease show nonspecific orthokeratosis, hypergranulosis, and acanthosis.²⁵ A thorough examination, family history, and histologic evaluation are all necessary to make an accurate diagnosis.

Various anomalies and diseases such as corneal opacities, spastic paralysis, epilepsy, oligophrenia, colonic adenocarcinoma, and gastroduodenal ulcers have been reported infrequently in association with KPPP8,^10,26-34; however, none were observed in our case.

As previously mentioned, KPPP is transmitted as an autosomal-dominant trait. The causative gene, however, has not been identified. Linkage to keratin gene clusters 12q and 17q has been excluded by Kelsell et al.²⁷ Various authors propose that the defect may lie in another gene involved in epithelial development and/or regulation in keratin expression (ie, genes responsible for structural proteins that are integral to keratin filament assembly and function).^7,8,10

Unlike diffuse and focal PPKs, the association of punctate PPKs with malignancies is not well established. To date, only 3 reports of inherited punctate PPK and malignancy have been published. Bennion and Patterson³³ reported a small kindred of 8 affected individuals; 2 developed adenocarcinoma of the colon and 1 developed adenocarcinoma of the pancreas. Interestingly, none of the family members without punctate keratoses developed cancer of any type. Ena et al³⁴ reported a family with 8 affected members, one of whom developed adenocarcinoma of the colon at 53 years of age. The statistical significance in these 2 studies is questionable due to the small number of subjects involved. Stevens et al³⁰ reported a larger kindred of more than 320 individuals spanning 4 generations. In this study, 10 of 43 adults with punctate PPK developed malignancies, including Hodgkin disease and renal, breast, pancreatic, and colon adenocarcinomas. Of the remaining 277 unaffected individuals, 6 developed malignancies.

Discovery of the causative gene(s) would serve at least 2 purposes: (1) it would provide insights into the possible association of punctate PPK and malignancy and (2) it may lead to an improved classification of the heterogeneous group of punctate PPKs.

Historically, KPPP was treated with mechanical debridement and topical keratolytics, which only provided temporary control. More recently, systemic retinoids have been used with improved results; however, relapse is reported with cessation of treatment. Baran and Juhlin³⁵ treated a patient with a disabling case of KPPP with etretinate 75 mg daily and observed significant clinical improvement after 3 weeks. The patient remained free from the hyperkeratoses with a maintenance dose of 50 mg daily; however, the lesions recurred when the dose was further decreased to 25 mg daily. Hesse et al³⁶ also treated a disabling case with acitretin, the active metabolite of etretinate, and observed similar success. Treatment with acitretin 30 mg daily resulted in significant, but incomplete, regression of the lesions after one month. Relapse occurred upon cessation of treatment; however, adequate control was maintained with 10 to 20 mg daily.

We chose to treat our patient with a trial of tazarotene 0.1% gel to minimize potential adverse reactions present with long-term use of oral retinoids. After 3 months of daily application of tazarotene, the hyperkeratotic lesions significantly diminished in size, and more importantly to the patient, the pain over the pressure areas resolved. Given our positive experience with tazarotene, topical retinoids may be a practical alternative for mild cases of KPPP. Long-term use is likely required for optimal control given the high relapse occurrence observed with cessation of oral retinoids.

Conclusion

In conclusion, we presented a case of KPPP in a patient with a strong family history supporting the autosomal-dominant inheritance pattern. The causative gene has not yet been identified, but its discovery would provide more insight into the possible association with malignancy and also may lead to an improved classification of the punctate PPKs. Punctate PPK has an extensive differential diagnosis and, if unrecognized, may be confused with common entities such as verrucae, leading to unnecessary frustration from multiple ineffective treatments. Multisystem conditions such as Darier disease and Cowden disease also must be considered when evaluating a patient with palmoplantar punctate keratoses. A full cutaneous examination, family history, and histologic evaluation are important components in making an accurate diagnosis. Treatment options include mechanical debridement, topical keratolytics, and topical and systemic retinoids. Maintenance therapy is required with all forms of treatment to prevent relapse.