|Year : 2020 | Volume
| Issue : 3 | Page : 187-190
Palmo-plantar keratoderma with debilitating pruritus
Vandana Kataria, Chander Grover, Deepika Pandhi
Department of Dermatology and STD, University College of Medical Sciences and Guru Teg Bahadur Hospital, Delhi, India
|Date of Submission||03-Jan-2020|
|Date of Decision||10-Feb-2020|
|Date of Acceptance||14-Apr-2020|
|Date of Web Publication||30-Jun-2020|
Dr. Chander Grover
Department of Dermatology and STD, University College of Medical Sciences and Guru Teg Bahadur Hospital, Dilshad Garden, Delhi-110095, Delhi
Source of Support: None, Conflict of Interest: None
We describe two siblings with diffuse, mutilating palmo-plantar keratoderma suggestive of Olmsted syndrome, with significantly compromised quality of life in the form of inability to walk and grasp objects. This was accompanied by severe pruritus and erythromelalgia-like symptoms. The keratoderma responded to acitretin therapy but there was paradoxical worsening of burning and pruritus which were further disabling. The poor response to medical and phototherapy in relieving these symptoms is described.
Keywords: Acitretin, erythromelalgia, Olmsted syndrome, pseudoainhum
|How to cite this article:|
Kataria V, Grover C, Pandhi D. Palmo-plantar keratoderma with debilitating pruritus. Indian J Paediatr Dermatol 2020;21:187-90
|How to cite this URL:|
Kataria V, Grover C, Pandhi D. Palmo-plantar keratoderma with debilitating pruritus. Indian J Paediatr Dermatol [serial online] 2020 [cited 2021 May 6];21:187-90. Available from: https://www.ijpd.in/text.asp?2020/21/3/187/288501
| Introduction|| |
Olmsted syndrome (OS) is a rare disorder of keratinization, first described in 1927 as a combination of congenital palmoplantar keratoderma (PPK) with periorificial hyperkeratosis. It typically presents in early childhood with a wide clinical spectrum of features including diffuse alopecia, digital constriction, onychodystrophy, linear hyperkeratotic follicular streaks, oral leukokeratosis, acral hyperhidrosis, ichthyotic lesions, joint laxity, absent premolar teeth, high-frequency hearing loss, and sclerosing cholangitis., Debilitating pruritus and pain are lesser described symptoms. The gene responsible for most cases is transient receptor potential vanilloid-3(TRPV3), which is a thermosensible cation nonselective channel, activated by temperature and chemical ligands, predominately expressed in keratinocytes, and in sensory neurons. OS is a heterogeneous syndrome with variable clinical features and mutations within TRPV3, causing both typical and atypical OS cases.
Debilitating pruritus affects around 16% of OS cases, with pain and itch being major morbidities leading to insomnia and poor walk and grasp. Both these can be particularly severe with erythromelalgia-like symptoms leading to acute flares of hyperalgesia, severe itch, erythema, vasodilatation, and warmth. Such dysesthetic patients with allodynia also have an increased sensitivity to thermal and mechanical stimuli with features suggestive of a neuropathic pain, even though no cause can be identified.
We present two siblings with clinical features suggestive of OS and complaints of pruritus and dysesthesia. Suboptimal response to acitretin therapy, along with paradoxical worsening of symptoms, is described.
| Case Report|| |
Two brothers, aged 15 (patient 1) and 13 years (patient 2), products of a nonconsanguineous parentage ( first and second in order of birth), presented with painful hyperkeratotic lesions and fixed flexion deformities affecting palms and soles. They had intense pruritus (worse on cold exposure), burning, malodourous erosions, fissuring, and erythema. Keratoderma was progressive with constriction bands, auto-amputation of digits, and inability to walk; however, there was no history of periorificial lesions, generalized scaling or dryness, patchy hair loss, premature loss of dentition, dysphagia, seizures, or focal neurological deficit. Both children achieved age-appropriate developmental milestones, and neither parents nor the two younger siblings had any similar lesions [Figure 1].
|Figure 1: Pedigree chart of two generations showing two children with diffuse palmo-plantar keratoderma|
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On examination, both brothers were undernourished with normal intelligence and psychomotor development. A mutilating PPK with inability to walk, or use hands, disuse atrophy of legs, and stunted growth was noted. There was diffuse, malodorous, waxy yellow hyperkeratosis, with sharp demarcation at the line of Wallace [Figure 2]a, [Figure 2]b, [Figure 2]c. Fixed flexion contractures, acro-osteolysis, auto-amputation of toes, and pseudoainhum were present. Hyperkeratotic scaly papules on bilateral knees and elbows and hypertrichosis were seen. Patient 1 also had dolichocephaly, prognathous jaw, high-arched palate, kyphoscoliosis, pectus carinatum, and hypermobile joints. Both children had evidence of florid rickets clinically as well as radiographically. Delayed puberty with absence of secondary sexual characters and low testicular volume (<4 ml) was noted in both patients.
|Figure 2: (elder brother): Bilateral palms (a) and soles (b) diffuse malodorous waxy yellow hyperkeratosis with violaceous, erythematous margins and sharp demarcation at the line of Wallace. Sparing of dorsum and knuckles of both hands with fixed flexion deformity and contracture is seen. Acroosteolysis, auto-amputation of right fifth toe, and pseudoainhum in the second and third toe of the right foot can be seen. (c) (younger brother): Bilateral soles showing diffuse malodorous waxy yellow hyperkeratosis with sharp demarcation at the line of Wallace and sparing of dorsum and knuckles. Auto-amputation of the left fifth toe was seen. Both the hands were completely normal|
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Histopathology showed nonepidermolytic epidermal hyperplasia with marked hyperkeratosis, mild acanthosis, papillomatosis, focal parakeratosis, hypergranulosis, and superficial perivascular inflammatory infiltrate. Hematological and biochemical investigations were normal except for moderate Vitamin D deficiency. Imaging of hands and feet showed diffuse osteopenia, cupping and fraying at the metaphyseal region. Based on the findings, a diagnosis of OS was entertained, even though confirmatory mutational analysis (TRPV 3) could not be done due to resource constraints.
The use of topical keratolytics (salicylic acid) with potent steroid and white petrolatum produced unsatisfactory response; hence, they were started on acitretin (0.5 mg/kg). There was partial improvement over 6 weeks, enabling them to walk with appropriate foot wear [Figure 3]a and b]; however, paradoxically, pruritus and burning worsened. These were not responsive to additional modalities including paroxetine (6 mg), amitriptyline (25 mg three times a day), and trial of ultraviolet (UV)-A therapy (0.5 J/cm2) for over 2 weeks. Despite multiple interventions, there was no improvement in visual analog scale for pruritus, with a score of 10 at baseline and score of 9 after 4 weeks of treatment in both the patients. After continuing acitretin (0.5 mg/kg) for further 8 weeks, the patients were lost to follow-up.
|Figure 3: (a and b) Response to acitretin (after 6 weeks of treatment) showing a decrease in keratoderma and improvement in grip and walking (a [elder brother], b [younger brother])|
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| Discussion|| |
OS is a rare, congenital disorder of keratinization, characterized by sharply circumscribed, transgradient PPK and periorificial keratotic plaques, often leading to flexural contractures and spontaneous amputation as seen in our patients. The first case described by Olmsted was an 8-year-old child. Later, Poulin et al. expanded the spectrum by describing onychodystrophy, universal alopecia, leukokeratosis of tongue, hyperextensibility of joints, and absence of premolar teeth. Familial cases, similar to our patients, had been described by Atherton et al. and Cambiaghi et al. From India, Dogra et al. described a case of OS with hypotrichosis in an 8-year-old boy who had massive palmo-plantar keratoderma and keratotic plaques periorally and at elbows and knees. Systemic complications including congenital deafness, mental retardation, osteoporosis, squamous cell carcinoma, and malignant melanoma, have also been reported.
Most described cases have been sporadic, though familial cases with varying modes of inheritance have also been described., Recently, the gene responsible has been identified as TRPV3 affected by a number of de novo autosomal dominant mutations and one autosomal recessive mutation.
Although a genetic analysis could not be performed for our patients, due to resource constraints, the clinical features were consistent with previous cases of OS described in literature.,,,,, Cheng et al. described an atypical family with OS with absence of periorificial keratoderma and alopecia in three affected individuals from a three-generation Chinese family. Additional clinical signs in the proband included cone-shaped fingers and sclerodactyly-like appearance overlapping with Huriez syndrome (symmetric, focal PPK, with acute flares of warmth-elicited pain and itching). There were no pathogenic sequence alterations in KRT1, GJB2, LOR, and SLURP1 g enes even though TRPV3 sequencing revealed an identical heterozygous mutation. In the absence of mutational analysis, primary features in our patients point toward OS, Vohwinkel's syndrome, or Mal de Meleda More Details. However, clinical features against the latter two include a mutilating nonepidermolytic PPK with pseudoainhum, autoamputation, onychodystrophy, and normal hearing (not in favor of Vohwinkel's) and absence of a foul smell, lingual defects, or syndactyly (features against Mal de Meleda).
Interestingly, pruritus is reported in around 16% of OS patients, which was the prominent and most debilitating feature in our patients. TRPV3 belongs to a superfamily of thermo-sensitive transient receptor potential cation channels, which gets activated at 33°C, thus playing a role in warm sensation among patients with OS. Ion channels serve many functions, including transport of ions and water, control of electrical excitability, and regulation of ionic homeostasis. TRPV3 is mainly expressed in keratinocytes, hair follicles, brain, and spinal cord. The mutant TRPV3 might function in a dominant-positive manner to increase the constitutive TRPV3 activity and elevate Ca2+ in keratinocytes, leading to severe keratoderma and intolerable itch.
Systemic retinoids have been considered the most effective and promising treatment modality for keratoderma, improving clinical signs and quality of life. Our patients also responded well in terms of a significant reduction in keratoderma, enabling them to walk; however, pruritus and burning worsened with the thinning of skin. These symptoms are particularly severe in a minority of OS patients, like ours, associated with erythromelalgia-like features and acute flares of hyperalgesia, erythema, vasodilatation, and warmth of legs and extremities. Debilitating pruritus and burning in both hands and feet was the most challenging part of management in our patients as there was no significant therapeutic response to escalating doses of antihistamines, tricyclic antidepressants, and selective serotonin reuptake inhibitors and worsening with acitretin and UVA therapy. For patients with severe pain, especially erythromelalgia-like or neuropathic symptoms, anti-inflammatory drugs, anticonvulsants (carbamazepine, gabapentin, and pregabalin), tricyclic antidepressants (amitriptyline and nortriptyline), and opioid analgesics (tramadol) have been reported effective. However, they produced suboptimal response at best, in our patients. Debulking surgery followed by skin grafting has also been tried in some patients with flexion contractures, but recurrence has been noted.
| Conclusion|| |
Since the first descriptions of OS, the spectrum of associated clinical features has been expanding, making its diagnosis challenging. Unfortunately, currently available drugs are nonspecific and poorly effective in the management of morbidities other than keratoderma. Identification of molecular basis may permit the development of targeted therapeutic strategies such as TRPV3 antagonists.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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