Case of Olmsted Syndrome with Essential Thrombocytosis Misdiagnosed as Acrodermatitis Enteropathica.

Olmsted syndrome is a rare genodermatosis. Palmoplantar keratoderma and periorificial keratodermic plaques are the most important clinical findings. Additional findings associated with a large number of systems may accompany such as teeth, nail deformities, alopecia, mental retardation, and bone-joint anomalies. Therefore, it is difficult to make a differential diagnosis from other palmoplantar keratodermas. It also needs to be differentiated from acrodermatitis enteropathica because of periorificial plaques. The absence of regression in lesions with zinc treatment excludes this disease. We present here an Olmsted syndrome case with essential thrombocytosis for the first time. Copyright:

Introduction

Olmsted syndrome was first reported by Olmsted in 1927 as a keratinization disorder.[1] Periorificial plaques and mutilating palmoplantar keratoderma (PPK) are hallmark clinical signs. In addition to the basic features, a wide variety of clinical findings may be present such as alopecia, tooth–nail deformities, osteoporosis, keratosis pilaris, mucosal anomalies, bone–joint abnormalities, mental retardation, eye problems, and ear disorders.[2] Olmsted syndrome is a rare genodermatosis. According to Pubmed researches, the total number of cases has just passed a hundred in 2018.[3] It is usually sporadic, but autosomal dominant (AD), autosomal recessive (AR), and X-linked forms have also been reported. AD forms are associated with TRPV-3 (Transient Receptor Potential Vanilloid 3), and X-linked recessive forms are associated with MBTPS-2 (Membrane-Bound Transcription Factor Protease Site 2) gene mutations.[456] In recent years, mutations in the PERP gene have also been reported in patients with Olmsted syndrome.[7] We would like to present an Olmsted syndrome case with alopecia, misdiagnosed as acrodermatitis enteropathica. Additionally, we report for the first time the association of essential thrombocytosis in a patient with Olmsted syndrome.

Case Report

A 39-year-old male patient having dry, scaly, red skin lesions of hands, feet, mouth, and anus was admitted to our department. He had a febrile illness with diarrhea when he was 8 months old. His hair started to fall out after this disease. By the age of five, all body hair was gone. The lesions on the hands and feet had started at 18 months. From then on, walking, equilibrium problems, and articulation disorders had begun. He was born of consanguineous marriage, at term, by normal vaginal delivery. The patient had two siblings, one female and one male. Family members, including parents, were healthy. The patient had a history of aggravating symptoms despite various treatments for acrodermatitis enteropathica, including zinc replacement since he was 1.5 years old. Dermatological examination revealed sharply marginated, erythematous hyperkeratotic plaques around the eyes, mouth, nose, anus, scrotum, and penis [Figures 1 and 2]. The patient also had bilateral, mutilating keratoderma extending from palmar surfaces to the dorsum of the hands with flexion deformities of the digits and generalized loss of hair. There were dystrophy and subungual hyperkeratosis in the nails and teeth deformities [Figures 1 and 3]. Laboratory tests revealed a platelet count of 716/microliter and JAK2 V6117F mutation. Bone marrow examination revealed cell-rich bone marrow (80% cellularity) and markedly increased megakaryopoiesis. With these findings, the patient was diagnosed with essential thrombocytosis. Serum zinc level was normal at 94 microgram/dl. Skin biopsy taken from the dorsum of the hand revealed severe hyperkeratosis, focal parakeratosis, hypergranulosis, and acanthosis [Figure 4]. A second biopsy taken from the perioral area revealed intracorneal pustule formation, psoriasiform acanthosis, and intense inflammatory infiltration of the papillary dermis [Figure 5]. Psychiatric examination revealed mild mental retardation. There was ectropion and dry eye on the eye examination. Walking disorders such as bending knees or making scissor-like movements with his legs and articulation disorders were assessed by the neurologist as cerebral palsy sequelae. The hearing was evaluated as normal. The patient was diagnosed with Olmsted Syndrome, given these clinical and histopathological findings. Systemic acitretin treatment (0.5 mg/kg/day) was initiated with emollients, topical salicylic acid, and corticosteroids, but only partial response was obtained.

Figure 1

Hyperkeratotic verrucous plaques around the eyes, nose, and mouth and loss of hair follicles in scalp, eyebrows, and eyelashes

Figure 2

Sharp-limited hyperkeratotic plaques around the anus, scrotum, and penis

Figure 3

Bilateral palmar keratoderma extending from palmar surfaces to dorsum of the hands with flexion deformities of the digits

Figure 4

Significant hyperkeratosis, acanthosis, and focal parakeratosis on the biopsy taken from dorsal aspect of the hand (HEX400)

Figure 5

Intracorneal pustule formation, hyperkeratosis, acanthosis, and dermal intense inflammation on the perioral biopsy (HEX400)

Discussion

Olmsted syndrome is a heterogeneous disease considering various genetic traits, accompanying clinical findings, and histopathological features. Hallmark findings are mutilating palmoplantar keratoderma and periorificial hyperkeratotic plaques.[7] Diagnosis is based on the clinical findings and exclusion of other causes of PPK. There are no characteristic histopathological findings. Genetic studies are helpful if they can be done. Olmsted syndrome has to be differentiated from other severe forms of PPK, such as Vohwinkel syndrome, Mal de Meleda, Papillon-Lefèvre syndrome, pachyonychia congenita, and Haim-Munk syndrome. Findings such as tooth–nail anomalies, alopecia, hearing loss, mental retardation, and bone–joint anomalies are found in varying degrees in these syndromes. Periorificial involvement helps distinguish other causes of PPK. But it can confuse with acrodermatitis enteropathica. Failure to respond to oral zinc therapy rules out the possibility of acrodermatitis enteropathica. Moreover, palmoplantar keratoderma is not a typical finding in patients with acrodermatitis enteropathica.[2]

Duchatelet et al.[4] reported the association of erythromelalgia and Olmsted syndrome for the first time in a young girl in 2014. Shortly after that, they reported the presence of erythromelalgia in two siblings with Olmsted syndrome. The common point of these cases was that they had TRPV3 mutation. They suggested that the TRPV3 cation channel plays a role in erythromelalgia pathogenesis in skin inflammation and nociceptive signals, and the coexistence of erythromelalgia and Olmsted syndrome is not coincidental.[8] We present here the first case of Olmsted syndrome reported with essential thrombocytosis. Essential thrombocytosis is a myeloproliferative disease characterized by vascular complications as a result of increased platelet count. Erythromelalgia is a well-known clinical manifestation of essential thrombocytosis. It occurs in approximately 6% of cases.[9] But, in our case there was no erythromelalgia. Platelet levels of patients who had previously been associated with erythromelalgia were not specified. Erythromelalgia may have been seen as a clinical sign of essential thrombocytosis in these patients. It is not clear whether essential thrombocytosis is a coincidental association or one of the heterogeneous clinical presentations of the disease in cases with Olmsted syndrome.

Progressive finger mutilations and squamous cell carcinomas arising from keratoderma cause morbidities in these patients.[10] Unfortunately, there is no definitive treatment. Topical treatments including emollients (white petrolatum), keratolytic agents (urea, salicylic acid), wet dressing, boric acid, tar, retinoid acid, shale oil, topical corticosteroids, and systemic retinoids (acitretin, etretinate), corticosteroids or methotrexate were used with poor to moderate relief.[5] In recent years, treatments such as sirolimus and erlotinib acting through epidermal growth factor receptor (EGFR) and Mammalian Target of Rapamycin (mTOR) signaling pathways have been found to be effective in the treatment of palmoplantar keratoderma. In keratinocytes, interaction of the TRPV-3 channel with EGFR leads to activation of the mTOR signaling pathway.[111213] In our case, we used oral acitretin and topical emollients, keratolytics, and corticosteroids. Our patient showed moderate improvement with this treatment.

This rare syndrome should be considered in the differential diagnosis of palmoplantar keratodermas and acrodermatitis enteropathica. In these patients, clinical evaluation of the presence of erythromelalgia and platelet cell count in the laboratory may be useful.

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Conflicts of interest

There are no conflicts of interest.