Are You Confident of the Diagnosis?
What you should be alert for in the history
The lesions usually appear soon after birth and progress during childhood. After puberty, the lesions may remain stable or regress partially.
Characteristic findings on physical examination
Progressive symmetric erythokeratoderm (PSEK) is characterized by well-demarcated hyperkeratotic plaques on erythematous bases symmetrically distributed on the extremities, buttocks, and occasionally face, with the trunk often spared. Variable palmoplantar keratoderma may be present. Diffuse, erythematous palmoplantar keratoderma may be observed in half of the patients. We present homozygous twin sisters with well-demarcated erythematous, hyperkeratotic plaques on both palmar and dorsal hands (Figure 1, Figure 2).
Expected results of diagnostic studies
Histopathology is usually nonspecific. It may demonstrate orthokeratosis, a well-preserved granular layer, psoriasiform hyperplasia and a sparse perrivascular infiltrate of lymphocytes in the upper dermis. Electron microscopy may reveal many swollen, vacuolated mitochondria around nuclei of keratinocytes.
Diagnosis is established on the clinical manifestations. Serologic tests and imaging studies are of no diagnostic value. Gene sequencing and mutation analysis have been done in pedigrees and sporadic cases. A frameshift mutation within the loricrin gene on chromosome 1q21 has been identified in a Japanese family with PSEK and mutilating palmoplantar keratoderma. A missense mutation in GJB4 gene has been identified in two independent patients with PSEK.
PSEK and erythrokeratodermia variabilis have many overlapping features: both are inherited as an autosomal dominant trait, both usually present within the first year of life, and both have well-defined erythema. But they have long been regarded as distinct entities in that the lesions of erythrokeratodermia variabilis change continuously in size and pattern with changes in ambient temperature, distress and mechanical pressure. Diffuse palmoplantar keratoderma is characterized by diffuse hyperkeratosis of palms and soles without erythematous bases, extending to the dorsal aspects; sometimes the lesions involve the shins, knees and elbows, making the differentiation difficult.
Pytiriasis rubra pilaris can be distinguished by its perifollicular papules. Psoriasis can be differentiated by the typical scale, and the well-preserved granular layer in PSEK is an important feature the differentiation from psoriasis.
Who is at Risk for Developing this Disease?
PSEK is predominantly inherited as an autosomal dominant trait; some sporadic cases and autosomal recessive inheritance have also been described. PSEK is rare, but there has been no study on the accurate prevalence. Both sexes are equally affected. PSEK has been described in all ethnic groups.
What is the Cause of the Disease?
PSEK is usually inherited in an autosomal dominant pattern with incomplete penetrance and variable expressivity. PSEK is a genetically heterogeneous disorder. Two causal mutations in genes encoding loricrin and connexin have been documented. A frameshift mutation within the loricrin gene on chromosome 1q21 was identified in a Japanese family with PSEK and mutilating palmoplantar keratoderma.
The missense mutation G12D in GJB4 gene encoding Connexin 30.3 has been identified in two independent patients with PSEK and three paients with erythrokeratodermia variabilis in one study. However, no mutation in this gene has been found in other pedigrees or sporadic cases with PSEK. A novel locus on chromosome 21q11.2-21q21.2 in a Chinese family was identified, but no responsible gene has been found to date.
The pathophysiology of PSEK is not yet clear. Loricrin is a major structural component of the cornified cell envelop of the epidermis, participating in the formation of keratohyalin granules. Connexins, preferentially expressed in the keratinocytes of the upper epidermis are thought to take part in intercellular communication of keratinocytes. Mutations of the loricrin and connexin genes may disturb the epidermal differentiation. The molecular basis of PSEK in patients who do not carry the identified mutations remains elusive.
Systemic Implications and Complications
No systemic implications and complications have been described.
The treatment is mainly symptomatic and the goal is to diminish hyperkeratosis and decrease discomfort. Treatment options are summarized in Table I.
|Keratolytics: urea, ammonium lactate, tars, salicylic acid|
|Retinoids: acitretin, etretinate, isotretinoin|
|Psoralen plus ultraviolet A (PUVA)|
Optimal Therapeutic Approach for this Disease
Emollients can be used singly or in combination with other treatment for preserving hydration of epidermis. Retinoids such as tazatotene 0.1 cream have a promising effect in diminishing hyperkeratosis. Keratolytics and corticosteroids, such as 10% urea cream, urea cream containing hydrocorticosteroid, 10-20% salicytic acid ointment and 0.1% tretinoin ointment, are usually used with variable success. Combinations of emollients with retinoids or with keratolytics are preferred.
Retinoids are the treatment of choice for generalized PSEK. Improvement was observed in several PSEK patients. Recurrence occurred when retinoids were discontinued. Side effects limit the long-term use. Acitretin is the preferred oral retinoid and is usually initiated at a dose of 1-2 mg/kg daily and etretinate at 0.5 mg/kg daily. Pregnancy is an absolute contraindication. Alcohol consumption must be avoided as it causes acitretin to be metabolized to etretinate, which can be detected in the serum 3 years after cessation of acitretin. Liver and kidney function, cholesterol and triglycerides should be monitored monthly.
Oral H1 antihistamines, such as hydroxyaine, can relieve the pruritus.
Psoralen plus ultraviolet A (PUVA) therapy was used in the treatment of a boy with PSEK with a good result.
PSEK patients receiving oral retinoids should be followed up regularly for monitoring treatment effectiveness and adverse effects at monthly intervals. When an obvious improvement is achieved, the retinoids should be tapered to a maintenance dose. Topical emollients can be used liberally. Alternative treatments should be considered if the effect is minimal or the adverse effects outweigh the benefits.
The patient and family members should be informed about the following: PSEK is a chronic skin disorder without other organ involvement and developmental defects; the skin lesions may progress during childhood, then usually remain stable; regression may occur occasionally. Optimal treatments can control the skin lesions. Genetic counselling should be available.
Unusual Clinical Scenarios to Consider in Patient Management
Topical vitamin D3 analogues (calcipotriol, tacalcitol) have been widely used for psoriasis. Local irritation is the most frequent side effect. Few systemic side effects have been documented. Although there are no previous reports of the use of vitamin D3 analogues for PSEK, the fact that active vitamin D3 modulates proliferation and differentiation of epidermal keratinocytes indicates a potential therapeutic effect for PSEK.
What is the Evidence?
Niemi, KM, Kanerva, L. “Histological and ultrastructural study of a family with erythrokeratoderma progressiva symmetrica”. J Cutan Pathol. vol. 20. 1993. pp. 242-9. (This reference demonstrated a family with 4 members with clinical phenotype of PSEK. Multiple morphological changes were found on histological and ultrastructural study.)
Ishida-Yamamoto, A, Mcgrath, JA, Lam, H, Iizuka, H, Friedman, RA, Christiano, AM. “The molecular pathology of progressive symmetric erythrokeratoderma: a frameshift mutation in the loricrin gene and pertubations in the cornified cell envelop”. Am J Hum Genet. vol. 61. 1997. pp. 581-9. (This reference demonstrated an insertion of a C following nucleotide 709 resulting in a framshift which changes the terminal 91 amino acids into missense amino acids.)
van Steensel, MA, Oranje, AP, van der Schroeff, JG, Wagner, A, van Geel, M. “The missense mutation G12D in connexin30.3 can cause both erythrokeratodermia variabilis of Mendes da Costa and progressive symmetric erythrokeratodermia of Gotton”. Am J Med Genet A. vol. 149A. 2009. pp. 657-61. (The same mutation in the GJB4 gene was found in two patients with PSEK and three patients with EKV. The five patients had the same allelic haplotype. The authors concluded the same GJB4 mutation might cause either EKV or PSEK phenotype.)
Akman, A, Masse, M, Mihci, E, Richard, G, Christiano, AM, Balle, BJ. “Progressive symmetrical erythrokeratoderma: report of a Turkish family and evaluation for loricrin and connexin gene mutations”. Clin Exp Dermatol. vol. 33. 2008. pp. 582-4. (This reference reported the first Turkish patient with PSEK. No mutation of the loricrin, connexin 31 and connexin 30.3 genes was identified. The results underline the genetic heterogeity of erythrokeratodermia.)
Wei, S, Zhou, Y, Zhang, TD, Huang, ZM, Zhang, XB, Zhu, HL. “Evidence for the absence of mutations at GJB3, GJB4 and LOR in progressive symmetrical erythrokeratodermia”. Clin Exp Dermatol. vol. 36. 2011. pp. 399-405. (No mutations were found in GJB3, GJB4 and LOR genes in 25 patients with PSEK. The results supported that PSEK is a disorder distinct from EKV.)
Cui, Y, Yang, S, Gao, M, Zhou, WM, Li, M, Wang, Y. “Identification of a novel locus for progressive symmetric erythrokeratodermia to a 19.02-cM interval at 21q11.2-21q21.2”. J Invest Dermatol. vol. 126. 2006. pp. 2136-9. (A novel locus for PSEK was identified.)
Matsumoto, K, Muto, M, Seki, S, Saida, T, Horiuchi, N, Takahashi, H. “Loricrin keratodermia: a cause of congenital ichthyosiform erythroderma and collodion baby”. Br J Dermatol. vol. 145. 2001. pp. 657-60. (Mutations in loricrin gene have been identified in a group of hereditary keratoma.)
Tamayo, L, Ruiz-Maldonado, R. “Oral retinoid (RO-109359) in children with lamellar ichthyosis, epidermolytic hyperkeratosis and symmetrical progressive erythrokeratodermia”. Dermatologica. vol. 161. 1980. pp. 305-14. (Oral retinoid showed dramatic effect in treating five patients with PSEK.)
Nazzaro, V, Blanchet-Bardon, C. “Progressive symmetric erythrokeratodermia. Histological and ultrastructural study of patient before and after treatment with etretinate”. Arch Dermatol. vol. 122. 1986. pp. 434-40. (Twenty-five patients with PSEK were treated with tretinate and considerable clinical improvement was observed.)
Levi, L, Benerggi, M, Crippa, D, Sala, GP. “Gottron's erythroderma congenitalis progressiva symmetrica”. Hautarzt. vol. 33. 1982. pp. 605-8. (Both aromatic retinoid and PUVA had effect; results with PUVA were better.)
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