Adult onset atopic dermatitis with secondary follicular mucinosis with cyclosporine induced spiny follicular hyperkeratosis and hair casts.

Secondary follicular mucinosis developing in adult patient with atopic dermatitis (AD) was observed on histology. Due to severity of disease, patient was started on oral cyclosporine 300 mg daily in 3 divided doses. Two weeks later patient started developing multiple spiny follicular keratoses mainly on face but also on extremities and trunk along with hair casts on scalp. Repeat biopsy from such keratotic lesions confirmed diagnosis spiny follicular hyperkeratosis (SFH). On investigations no evidence of multiple myeloma or any other malignancy was found. Cyclosporine was stopped and lesions cleared over 2 weeks. We report this case due to rare association of AD with follicular mucinosis and cyclosporine induced SFH with hair casts.

What was known?

1. Secondary follicular mucinosis is known to occur in variety of conditions.

2. Spiny follicular hyperkeratosis is a rare but characteristic paraneoplastic cutaneous manifestation of multiple myeloma.

3. SFH is also reported in association with chronic renal failure, Crohn's disease, hypovitaminosis A, HIV infection, lymphoma, other malignancies and rarely drugs like sorafenib and cyclosporine.

Introduction

Atopic dermatitis (AD) is a chronic relapsing eczematous skin disease characterized by pruritus and inflammation and accompanied by cutaneous physiological dysfunction, with a majority of the patients having a personal or family history of “atopic diathesis.”[12] Follicular mucinosis is a histopathological reaction pattern that has been described with many conditions apart from alopecia mucinosa.[34] It is rarely reported to occur with spongiotic or atopic dermatitis. Concurrent occurrence of follicular mucinosis and AD as observed in our case appears extremely rare.[4]

Our patient also developed multiple white colored follicular spiny keratoses with hair casts following cyclosporine therapy. Histology revealed orthokeratotic follicular plug and mild perifollicular lymphocytic infiltrate suggestive of spiny follicular hyperkeratosis (SFH). Patient was investigated for multiple myeloma (MM) but no evidence of it was found. Lesions of SFH cleared completely after stopping cyclosporine.

Occurrence of SFH following cyclosporine treatment also is very rare. After literature review we found only one similar case reported so far,[5] although 9 cases of sorafenib induced SFH are reported.[6]

Majority of cases reported are associated with MM however,[7] in our case no any underlying malignancy was detected.

Case Report

A 54 year-old female presented to us with multiple itchy red raised lesions over body and lichenified plaques over bilateral forearms with severe dryness of skin allover body developing gradually over last four years. Lesions used to get aggravated in winter season. She complained of lack of sleep due to severe itching and also of feeling depressed and emotional stress aggravating her disease. There was no any other significant medical history.

Examination revealed severe xerosis allover body, Hertoge's sign (loss of lateral eyebrows), bilateral Dennie-Morgan's folds and symmetric lichenified plaques on extensor aspect of both forearms and arms with multiple excoriated papulonodular lesions over abdomen and bilateral lower legs [Figure 1a and b, respectively]. Mucosal examination, palms, soles and nails appeared to be normal. A clinical diagnosis of adult onset AD was thought. Biopsy from forearm revealed orthohyperkeratosis, hypergranulosis, irregular epidermal hyperplasia and superficial perivascular lymphocytic infiltrate with occasional eosinophils [Figure 2a and b]. In addition to these, there were several hyperplastic follicles showing plenty of bluish-gray stringy mucin collected in large pools within the follicular epithelium in the same section [Figure 2a, c and d]. Based on clinicopathological correlation and using Hanifin and Rajka's criteria for atopic dermatitis[8] patient was diagnosed as adult onset AD with secondary follicular mucinosis. Her complete hemogram was normal except for 11 gm% hemoglobin. Serum IgE levels were marginally raised. No any other significant biochemical abnormality was detected. In view of affected quality of life patient was started on oral cyclosporine 5 mg/kg day in 3 divided doses after recording two normal baseline blood pressure readings along with potent topical steroids, moisturizers and oral antihistamines for pruritus. Two weeks later patient came back with multiple white colored spiny follicular keratoses developing allover body along with increased hair fall and hair casts. Lesions were most concentrated and prominent on chin and neck area [Figures 3, 4a and b].

Figure 1

(a) Lichenified plaque with excoriations on outer aspect of forearm. (b) Multiple excoriated prurigo nodularis like lesions over leg

Figure 2

(a) Skin biopsy from forearm plaque showing hyperkeratosis, epidermal hyperplasia with features of chronic eczematous dermatitis. Additionally some follicles studded with mucin are also seen. (H and E, ×40). (b) High power view showing hyperkeratosis, hypergranulosis, epidermal hyperplasia and superficial perivascular infiltrate. (H and E, ×100). (c) Hyperplastic follicles with mucin in infundibulam. (H and E, ×100). (d) Bluish stringy mucin is seen. (H and E, ×400)

Figure 3

Multiple white colored spiny hyperkeratoses seen over neck and chin area

Figure 4

Similar keratoses on outer arm and abdomen are seen

Examination revealed multiple whitish follicular keratoses up to 1 mm in diameter and up to 5 mm in length [Figure 5a]. Also there were numerous hair casts over scalp which were freely mobile along the shaft and mimicking pseudonits [Figure 5b]. A repeat biopsy including follicular keratoses was done from abdomen and a hair mount was examined. Histology revealed normal epidermis with dilated follicle containing compact orthokeratotic plug extending above surface with mild perifollicular lymphocytic infiltrate [Figure 6a-c]. Hair mount revealed loosely adherent whitish casts without any fungal elements [Figure 6d].

Figure 5

(a) Closer view of lesions on chin showing thick white spiny hyperkeratoses of variable diameter and length. (b) Multiple whitish hair casts on scalp hairs

Figure 6

(a) Biopsy from keratosis showing normal epidermis with dilated follicle containing orthokeratotic plug and perifollicular lymphocytic infiltrate (H and E, ×40). (b, c) High power view (H and E, ×100). (d) Hair mount showing loosely adherent casts on them without any fungi

Based on clinicopathological correlation a diagnosis of SFH with hair casts was made. With working diagnosis of SFH, we reviewed literature and found one case of cyclosporine induced follicular keratoses and strong association of SFH with MM. Accordingly cyclosporine was stopped and patient was investigated. There were no any signs or symptoms suggestive of MM or inflammatory bowel disease. Her total serum proteins, albumin: Globulin ratio, erythrocyte sedimentation rate, serum calcium, serum retinol level, repeat renal function tests, serum protein electrophoresis were all normal and no myeloma band was detected. Ultrasound of abdomen revealed no abnormality. Her radiograph of spine and scalp was also normal. Ear, nose and throat examination was also within normal limits. Both Kappa and Lambda light chains were also normal. Thus no any underlying malignancy was detected.

After three weeks of stopping cyclosporine all the skin lesions cleared [Figure 7] and 50% reduction in hair casts was noted. Thus a diagnosis of adult onset AD with cyclosporine induced SFH and hair casts was made. Patient is advised to take methotrexate 10 mg/week along with folic acid supplementation as an alternative to cyclosporine. Remaining medicines were continued as it is.

Figure 7

Complete clearance of lesion on stopping cyclosporine was seen. Compare with Figure 3

This is probably the first case of SFH from India and second case of cyclosporine induced SFH. Also we could not find report of secondary follicular mucinosis developing in adult onset AD.

Discussion

AD is a chronic relapsing eczematous skin disease. The exact etiology of AD is not known but various factors like heredity, environmental, dietary and immunological, etc., are involved in its causation. There is no laboratory “gold standard” for the diagnosis of AD and the definitive diagnosis of AD requires the presence of all three of the following features: Pruritus, typical morphology and distribution, and chronic and chronically relapsing course.[12] All three were present in our case.

Follicular mucinosis presents with solitary or grouped erythematous papules, nodules or plaques that may be indurated. Histopathologically, there is varying amounts of mucin accumulation within the follicular infundibula and the outer root sheath epithelium, accompanied by perifollicular lympho-histiocytic infiltrate. It is of two types, primary (idiopathic) and secondary variety. Primary form affects children and young adults usually and has a shorter duration with a benign course, while secondary form is more widespread and almost always a disease of adults. It has been associated with numerous conditions including lymphomas like mycosis fungoides, Hodgkin's disease, cutaneous B-cell lymphoma, syringolymphoid hyperplasia with cutaneous T cell lymphoma, inflammatory conditions like chronic discoid lupus erythematosus, alopecia areata, angiolymphoid hyperplasia, eosinophilic pustular folliculitis, spongitic dermatitis, lichen striatus, leprosy, sarcoidosis and growths such as verrucae and melanocytic nevi.[239]

Occurrence of follicular mucinosis in adult onset AD is unusual. Since it is a secondary follicular mucinosis, treatment of underlying condition only is needed .[2]

SFH has been described under several names, including spiny follicular keratoderma, hyperkeratotic spicules, filiform hyperkeratosis, parakeratotic horns, and follicular hyperkeratosis.[51011] SFH, although uncommon, is a characteristic paraneoplastic cutaneous manifestation of MM found mostly in white male patients. Other common associations reported include chronic renal failure, Crohn's disease, hypovitaminosis A, HIV infection, lymphoma, and other malignancies.[1112] No any such association was found in our case. Among the drugs, cyclosporine and sorafenib are reported to cause similar eruption.[56] Franck et al. reported 9 cases of sorafenib induced SFH.[6] Due to rarity of drug induced SFH cases in literature, it is difficult to make any conclusion regarding relationship between dose of the drug used and development of SFH.

Filliform palmoplantar hyperkeratosis, which is clinically close to this pattern, was reported in familial and sporadic forms but rarely in association with malignancies like renal, breast, rectal, eosophageal carcinomas and melanoma. In our case, palms and soles were spared by the eruption, corresponding to type IIb Zarour et al. classification.[13]

Various speculations regarding the pathogenesis of SFH include a possible alteration in normal keratinization or, a particular autoantibody activity in the monoclonal immunoglobulin modifying the keratinization process.[10] Bork et al. first showed that these follicular spicules contained myeloma dysprotein and cryoglobulins precipitating into the follicular infundibulum and stated that spicules were a clinical manifestation of cryoglobulinemia because they were localized to cold-exposed areas.[1011]

However, not all the reported cases have been associated with serum cryoglobulins, and not all showed spicules containing monoclonal dysprotein.[11] But, in our case lesions developed following cyclosporine intake and cleared after stopping it. Moreover, nose and other cold areas were not involved in our case.

Another characteristic feature in our case was development of hair casts simultaneously with cutaneous eruption and nearly 50% reduction on stopping cyclosporine was observed.

Interestingly, previous reports describe a resolution of the cutaneous lesions after treatment of the myeloma. A case of SFH marking relapse of MM is also reported. Thus although an uncommon entity, SFH should be recognized as a marker of progressive disease and this portends a dismal prognosis.[11] Thus, detailed history including drug intake and necessary investigations should be done to rule out malignancy, particularly MM in cases of SFH.

Various treatment modalities tried for SFH include adapalene gel, tretinoin cream, fluocinolone acetonide gel, and 12% lactic acid cream with minimal effect.[7] In our case lesions cleared completely on stopping cyclosporine without any additional topical therapy.

What is new?

1. Secondary follicular mucinosis occurring in adult onset AD is rare.

2. SFH with hair casts can occur due to variety of conditions and investigations to rule out underlying conditions should be done.

3. SFH with hair casts is a rare side effect of cyclosporine.