Rishabh Kumar Chauhan, Saumya Sankhwar, Ruchika Tripathi, SS Pandey
Department of Dermatology and Venereology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India

Correspondence Address:
Saumya Sankhwar
Department of Dermatology and Venereology, Institute of Medical Sciences, Banaras Hindu University, Varanasi – 221 005, Uttar Pradesh
India

Sir,

A 9-year-old pair of monozygotic twin sisters, born of spontaneous, full-term normal vaginal delivery, visited the dermatology outpatient department of Sir Sunderlal Hospital, Banaras Hindu University, Varanasi, with the absence of body and scalp hair since birth. There was no history of consanguinity in parents. Parents were using various homemade remedies for the condition, on-and-off, including ayurvedic treatment, since 1 year of age. Some hairs appeared on the scalp one year later and they were persistent [Figure 1] and [Figure 2]a. Examination revealed small, discrete, spiny papules with follicular plugging, present on normal looking skin on the body [Figure 2]b. Oral mucosa, teeth, nails, palms and soles were found to be normal. There was no history of photophobia. Ophthalmic examination revealed no abnormal findings. Routine hematological and other laboratory studies were within normal limits. Hair microscopy was done to rule out hair shaft defects.

Figure 1: Female twins with follicular papules and some hair on the scalp Click here to view

Figure 2 Click here to view

Histopathological examination of the hairy areas such as the scalp and extensor aspect of the left forearm showed sparse superficial perivascular and periappendageal lymphocytic infiltrates with no epidermal changes. Some of the follicular infundibula were dilated and plugged with orthokeratotic corneocytes while others showed mild spongiosis. There was dense perifollicular fibroplasia in some follicles and the terminal follicles were reduced in number on the scalp skin [Figure 3] and [Figure 4]. Based on these clinical and histopathological findings, these cases were diagnosed as keratosis follicularis spinulosa decalvans.

Figure 3: Perifollicular fibroplasia and lymphocytic infiltrate (arrowheads) in other fields on scalp histopathology (H and E, ×100) Click here to view

Figure 4: Dilated follicular infundibula plugged with orthokeratotic corneocytes and perivascular, periappendageal lymphocytic infiltrate on scalp histopathology (H and E, ×400) Click here to view

Keratosis follicularis spinulosa decalvans is a rare, X-linked, hereditary disorder of keratinization, characterized by the involvement of the skin and eyes. Keratosis follicularis spinulosa decalvans was first described as an X-linked dominant disorder.^[1] However, in some cases, an autosomal dominant and sporadic inheritance have also been reported. The term was first used by Siemens in 1926, who described some individuals from a Bavarian family who presented with follicular papules on the face, trunk and extremities with partial loss of hairs; thus, the disease is also known as Siemens syndrome.^[1] Genetic studies in Dutch and English families have showed connection with the Xp21.2-p22 gene.^[2] When the inheritance pattern is X-linked, males are predominantly affected and females are mostly carriers. Females with severe forms of the disease have also been reported. These cases either had an autosomal dominant pattern of inheritance or some were sporadic in onset. A theory of non-random X-inactivation (process of  Lyonization ^{More Details}) was proposed in cases with sporadic onset.^[3] As there is no positive family history and since the disease is rare and present in female twins, our case likely has either an autosomal dominant inheritance or heterogeneous transmission with sporadic inheritance, which is one of the four reported patterns of inheritance in literature.^[4] Our patients also had the characteristic cutaneous and histological features of keratosis follicularis spinulosa decalvans. However, there were no other associated abnormalities such as ocular changes, deafness, physical and mental retardation, hypoplastic nails and palmoplantar keratoderma, as described in literature.^[3],[4] Moreover, the presence of scarring alopecia on the scalp [Figure 2]a and the lack of ophthalmological abnormalities differentiate it from ichthyosis follicularis alopecia and photophobia syndrome, where there is nonscarring alopecia and photophobia that presents either at birth, in infancy or in early childhood.^[3] Furthermore, in this case, while there was complete alopecia at birth, some hairs appeared on the scalp with time that are still persisting; which helped to differentiate this from the condition- congenital atrichia with papules, where there is permanent and complete alopecia by the first few months of life and no hair regrowth occurs with the passage of time.^[5] Clinically, our patients did not have any bony pain or deformities and there was no decreased muscle tone and the levels of alkaline phosphatase, serum calcium and vitamin D were within normal limits, thus ruling out rickets. Other differentials such as lichen spinulosus and lichen planopilaris were excluded on the basis of histopathological findings.

There is no specific treatment for this disorder. However, drugs such as isotretinoin and dapsone have been tried; emollients, topical corticosteroids and keratolytic agents can be used for symptomatic relief.^[3] Although it is a rare genodermatosis, keratosis follicularis spinulosa decalvans should always be considered in all cases of hyperkeratosis with alopecia. Genetic counseling is needed in some cases and the treatment should be started as early as possible so as to retard and minimize sequelae such as cicatrization.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the legal guardian has given his/her consent for images and other clinical information to be reported in the journal. The guardian understands that names and initials will not be published and due efforts will be made to conceal patient identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Siemens HW. Keratosis follicularis spinulosa decalvans. Arch Derm Syphilol (Berlin) 1926;151:384.
2.	Oosterwijk JC, Nelen M, van Zandvoort PM, van Osch LD, Oranje AP, Wittebol-Post D, et al. Linkage analysis of keratosis follicularis spinulosa decalvans, and regional assignment to human chromosome Xp21.2-p22.2. Am J Hum Genet 1992;50:801-7.
3.	Maheswari UG, Chaitra V, Mohan SS. Keratosis follicularis spinulosa decalvans: A rare cause of scarring alopecia in two young Indian girls. Int J Trichology 2013;5:29-31.
4.	Castori M, Covaciu C, Paradisi M, Zambruno G. Clinical and genetic heterogeneity in keratosis follicularis spinulosa decalvans. Eur J Med Genet 2009;52:53-8.
5.	Yip L, Horev L, Sinclair R, Zlotogorski A. Atrichia with papular lesions: A report of three novel human hairless gene mutations and a revision of diagnostic criteria. Acta Derm Venereol 2008;88:346-9.

Indu Kumari¹, Satyendra Kumar Singh¹, Rishabh Kumar Chauhan¹, Satyendra Kumar Kaushal^2
1 Department of Dermatology and Venereology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
² Department of Microbiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India

Correspondence Address:
Dr. Satyendra Kumar Singh
Department of Dermatology and Venereology, Institute of Medical Sciences, Varanasi, Uttar Pradesh – 221 005

Fusarium species are known to cause disseminated cutaneous lesions in immunocompromised patients. Some cases of fusariosis are reported in patients infected with the human immunodeficiency virus. There are two reports in such patients with systemic comorbidities like lymphoma, neutropenia and infective port-a-catheter. Another reported patient had systemic fusariosis, without skin involvement. Diagnosis and treatment of cutaneous fusariosis is difficult and resistance to antifungals is a problem. Our patient was at an advanced human immunodeficiency virus infection stage with disseminated cutaneous fusariosis, without any systemic involvement, who responded completely to oral itraconazole.

Keywords: Disseminated, Fusarium, human immunodeficiency virus, itraconazole

Introduction

Fungal infections cause cutaneous lesions either directly or are metastatic in immunocompromised patients. Fusarium species are common plant pathogens that cause localized and disseminated infection (in immunocompromised and neutropenic patients). Majority of patients (72%–91%) have cutaneous lesions (primary or metastatic).^[1] Diagnosis of disseminated cutaneous infection is difficult. The treatment is quite unsatisfactory due to the variable susceptibility of the pathogen to antifungals and the lack of supporting evidence. We herein report a rare case of disseminated cutaneous fusariosis, without systemic involvement, in a patient infected with the human immunodeficiency virus, who responded successfully to itraconazole.

Case Report

A 40-year-old farmer presented with multiple, painless, raised skin lesions with pus discharge, which were of one-and-a-half months ^‘ duration. Lesions began to appear on the face and progressed to both his arms and thighs over a period of 1 week. He was earlier diagnosed to be infected with the human immunodeficiency virus, with CD4 T-lymphocyte count of 38 cells/μL, and was on highly active antiretroviral therapy from an antiretroviral therapy center for the past 6 months.

The patient was afebrile with no other systemic complaints. On examination, his body mass index was 18.88 kg/m ^[2]. Multiple erythematous and tender papules and nodules with central crusting and necrosis were present on the face, neck, and bilaterally on arms and on thighs extending to the knees [Figure 1]. Trunk, distal extremities, palms, soles and mucosae were spared. There was no history of trauma and no clinically apparent onychomycosis or any breach in the skin other than the lesions present. Clinically, the possibility of cryptococcosis (common opportunistic infections in human immunodeficiency virus patients) and ecthyma gangrenosum were considered. Lymph nodes examination revealed no significant enlargement.

Figure 1 Click here to view

On hematological investigation, no significant abnormality was found. Blood culture was negative for any bacterium or fungus. All other possible systemic involvements were ruled out by appropriate tests, mainly computed tomography of the chest, x-rays of the paranasal sinuses and abdominal ultrasonography. Skin biopsy from a nodule on the arm revealed pseudoepitheliomatous hyperplasia and intraepidermal granulomas with giant cells. Periodic acid–Schiff staining was positive for spores and short fungal hyphae. An additional sample of the excised nodule was sent for microbiological examination.

A 10% potassium hydroxide wet mount of tissue revealed septate, hyaline and branched fungal hyphae. The specimen was cultured on two sets of Sabouraud dextrose agar, incubated at 37°C and 25°C. After 4 days of incubation, a heavy growth of fungal colonies was seen at 25°C in the form of a white and cotton obverse and orange reverse suggestive of Fusarium [Figure 2]. Growth was observed on successive subcultures performed on potato dextrose agar. Lactophenol cotton blue mount showed septate, branched hyphae producing microconidia (oval small 2–4 × 4–8 μm with 1–2-celled reniform conidia singly and in clusters) and many branched conidiophores with phialides producing 2–4 × 11–60 μm multiseptate (3–4), sickle or boat-shaped macroconidia typical of Fusarium solani [Figure 3]. Later, another tissue sample was sent for repeat isolation of fungus in order to confirm the species.^[2]

Figure 2 Click here to view

Figure 3 Click here to view

Minimal inhibitory concentrations and minimal effective concentration were determined following the microdilution method recommended by Clinical and Laboratory Standards Institute document M38-A2 with minor changes.^[3] Fluconazole, amphotericin-B and terbinafine were ineffective in inhibiting growth of F. solani. Among sensitive drugs, itraconazole, ketoconazole and voriconazole had minimal inhibitory concentration 90 of 2 μg/ml each [Figure 4].^[4],[5],[6]

Figure 4: Minimal inhibitory concentrations by microdilution method in round-bottomed 96-well microdilution tray Click here to view

Our patient was prescribed itraconazole 200 mg twice daily and response was seen in 2 weeks, with complete subsidence of lesions in 1½ months, leaving postinflammatory hyperpigmentation and scarring [Figure 5]. Itraconazole was continued at a tapered dose of 100 mg twice daily for a further 3 months.

Figure 5 Click here to view

Discussion

Fusarium species are ubiquitous soil saprophytes and plant pathogens that may cause infections in humans, in localized, locally invasive and disseminated forms. Fusarium species now represent the second most common mold causing opportunistic infections in immunocompromised patients.^[7]F. solani was the most frequent, followed by Fusarium oxysporum, Fusarium verticillioidis and Fusarium moniliforme among 12 species associated with infection.^[8]

Skin involvement represents a frequent manifestation (>50%) of infection by Fusarium species and is also the most common source of diagnostic material. Distinct patterns of skin involvement exist, depending on the immune status of the host.^[9] Sampathkumar and Paya classified the cutaneous lesions into three groups: violaceous nodules with central necrosis, ecthyma gangrenosum-like and target lesions.^[10] In immunocompromised patients, skin lesions evolve rapidly over a short period of time and can involve any site, with predominance in the extremities.

The principal portal of entry for Fusarium species is the airways, followed by skin at the site of tissue breakdown (trauma, burns and onychomycosis) and foreign bodies (keratitis in contact lens wearers). Other sources are tap and hospital water system. The fact that we could not establish the entry portal of the fungus in our patient might be explained by the fact that skin breakdown may precede infection by up to 1 year.^[9]

Disseminated infections occur when two or more noncontiguous sites are involved.^[9] Immunocompromised patients with prolonged and profound neutropenia (hematologic diseases) and/or severe T-cell deficiency (allogenic hematopoietic stem cell transplantation) and high-dose corticosteroid therapy are at the highest risk.^[1],[9] So far, disseminated cutaneous fusariosis in human immunodeficiency virus-positive patients is very rarely known. In a review published in 2002, out of 259 patients with fusariosis, 232 (90%) patients were immunocompromised. Skin involvement was seen in 181 (70%) patients and was more common in immunocompromised group (72% vs. 52%).^[9] Out of 232 patients, only two were human immunodeficiency virus positive of which one had an infected port-a-catheter and other patient had non-Hodgkin’s lymphoma with neutropenia.^[11],[12] Another case was reported in human immunodeficiency virus patient without skin involvement and neutropenia in 2013.^[13] Hence, we state that this is the first reported case of isolated disseminated cutaneous fusariosis and the third case of disseminated fusariosis in a human immunodeficiency virus infected patient [Table 1].

Table 1: Cases of disseminated fusariosis in human immunodeficiency virus patients Click here to view

The most frequent pattern of disseminated disease is a combination of cutaneous lesions and positive blood cultures with or without involvement of other sites.^[8] Interestingly, in a previous review among patients with positive blood culture, skin lesions preceded fungemia in 11 patients by a median of 5 days, occurred on the same day (4 patients) and did not appear until after the diagnosis of fungemia was made (3 patients).^[8] In this case, the blood culture was negative for Fusarium similar to a previous review where 78 (52.7%) patients had blood cultures negative for Fusarium species.

Different patterns of susceptibility of different Fusarium species exist and there is not enough data documenting a correlation between minimal inhibitory concentrations and the clinical outcome. Amphotericin B has been used as the first-line drug but resistance to it has been reported and even our case was found to be resistant to it.^[14] Newer antifungal triazole agents are available for Fusarium species including itraconazole, voriconazole and posaconazole. Susceptibility to itraconazole has been shown in some reports but at higher minimal inhibitory concentration which is even higher for F. solani.^[15],[16] The results of itraconazole against localized fusariosis have been documented but rarely against disseminated cutaneous fusariosis. This variable susceptibility to these drugs poses a great problem for the physicians.

Our case of disseminated cutaneous fusariosis is being reported for the first time and is unique since the cause of immunocompromised state is only human immunodeficiency virus without any associated neutropenia, concomitant malignancy or any systemic involvement. Moreover, the excellent response of Fusarium to itraconazole is worth reporting.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initial will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Boutati EI, Anaissie EJ. Fusarium, a significant emerging pathogen in patients with hematologic malignancy: Ten years’ experience at a cancer center and implications for management. Blood 1997;90:999-1008.
2.	Hafizi R, Salleh B, Latiffah Z. Morphological and molecular characterization of Fusarium Solani and F. Oxysporum associated with crown disease of oil palm. Braz J Microbiol 2014;44:959-68.
3.	Clinical and Laboratory Standards Institute. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Filamentous Fungi: Approved Standard M38-A. Wayne, PA, USA: CLSI; 2008.
4.	Alastruey-Izquierdo A, Cuenca-Estrella M, Monzón A, Mellado E, Rodríguez-Tudela JL. Antifungal susceptibility profile of clinical Fusarium spp. Isolates identified by molecular methods. J Antimicrob Chemother 2008;61:805-9.
5.	Espinel-Ingroff A, Boyle K, Sheehan DJ.In vitro antifungal activities of voriconazole and reference agents as determined by NCCLS methods: Review of the literature. Mycopathologia 2001;150:101-15.
6.	Guilhermetti E, Takahachi G, Shinobu CS, Svidzinski TI. Fusarium spp. As agents of onychomycosis in immunocompetent hosts. Int J Dermatol 2007;46:822-6.
7.	Vennewald I, Wollina U. Cutaneous infections due to opportunistic molds: Uncommon presentations. Clin Dermatol 2005;23:565-71.
8.	Nucci M, Anaissie E. Fusarium infections in immunocompromised patients. Clin Microbiol Rev 2007;20:695-704.
9.	Nucci M, Anaissie E. Cutaneous infection by Fusarium species in healthy and immunocompromised hosts: Implications for diagnosis and management. Clin Infect Dis 2002;35:909-20.
10.	Sampathkumar P, Paya CV. Fusarium infection after solid-organ transplantation. Clin Infect Dis 2001;32:1237-40.
11.	Eljaschewitsch J, Sandfort J, Tintelnot K, Horbach I, Ruf B. Port-a-cath-related Fusarium oxysporum infection in an HIV-infected patient: Treatment with liposomal amphotericin B. Mycoses 1996;39:115-9.
12.	Guarro J, Nucci M, Akiti T, Gené J. Mixed infection caused by two species of Fusarium in a human immunodeficiency virus-positive patient. J Clin Microbiol 2000;38:3460-2.
13.	Esnakula AK, Summers I, Naab TJ. Fatal disseminated Fusarium infection in a human immunodeficiency virus positive patient. Case Rep Infect Dis 2013;2013:379320.
14.	Pereira GH, de Angelis DA, Brasil RA, dos Anjos Martins M, de Matos Castro e Silva D, Szeszs MW, et al. Disseminated amphotericin-resistant fusariosis in acute leukemia patients: Report of two cases. Mycopathologia 2013;175:107-14.
15.	Arikan S, Lozano-Chiu M, Paetznick V, Nangia S, Rex JH. Microdilution susceptibility testing of amphotericin B, itraconazole, and voriconazole against clinical isolates of Aspergillus and Fusarium species. J Clin Microbiol 1999;37:3946-51.
16.	Carrillo-Muñoz AJ, Quindós G, Ruesga M, Brió S, del Valle O, Rodríguez V, et al. Activity of itraconazole against clinical isolates of Aspergillus spp. and Fusarium spp. determined by the M38-P NCCLS method. Rev Esp Quimioter 2001;14:281-5.

Dermoscopy of a rare case of linear syringocystadenoma papilliferum with a review of the literature

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