Medical genetics
IL36RN mutation causing generalized pustular psoriasis in a Palestinian patient Yael Renert-Yuval1, MD, Liran Horev1,2, MD, Sofia Babay2, RN, Spiro Tams3, MD, Yuval Ramot1,2, MD, MSc, Abraham Zlotogorski1,2, MD, and Vered Molho-Pessach1,2, MD
1 Department of Dermatology, HadassahHebrew University Medical Center, Jerusalem, Israel, 2Center for Genetic Diseases of the Skin and Hair, HadassahHebrew University Medical Center, Jerusalem, Israel, and 3Faculty of Medicine, Palestinian Al Quds University, Abu Dis, Palestinian Authority
Correspondence Vered Molho-Pessach, MD Department of Dermatology Hadassah-Hebrew University Medical Center Jerusalem 9112001, Israel E-mail: [email protected]
Abstract Deficiency of interleukin-36 (IL-36) receptor antagonist (DITRA; OMIM 614204) is a rare autoinflammatory disorder characterized by periodic fever associated with a generalized erythematous and pustular skin rash. A 6-year-old Arab-Palestinian boy presented with a history of periodic fever and unremitting, erythematous, scaly skin rash accompanied by widespread pustules that had been present since the age of one month. The patient’s skin lesions were compatible with generalized pustular psoriasis. Sequence analysis revealed a homozygous nonsense mutation, c.28C>T (p.Arg10X) in the IL36RN gene. The patient improved with oral methotrexate in combination with oral and topical corticosteroids. The molecular basis for DITRA has only recently been identified, and the mutation spectrum for this disorder in many populations is still obscure. This paper reports the presence of the c.28C>T mutation in an Arab-Palestinian patient and thus represents the first description of this mutation in a non-Japanese subject.
Conflicts of interest: None. Funding: None
866
Introduction
Case Report
Deficiency of interkeukin-36 (IL-36) receptor antagonist (DITRA; OMIM 614204) is a form of generalized pustular psoriasis (GPP) caused by mutations in the IL36RN gene, located at chromosome 2q13. DITRA is a rare, life-threatening, autoinflammatory autosomal recessive disease. It is characterized by recurrent episodes of generalized scaly erythematous rash with disseminated pustules, associated with high-grade fever and elevated levels of C-reactive protein (CRP) and leukocytosis.1–3 Other phenotypes of the IL36RN mutation include related pustular disorders,4 palmoplantar pustulosis,5 acrodermatitis continua of Hallopeau,6 and acute generalized exanthematous pustulosis.7 Histology shows spongiform pustules, acanthosis and parakeratosis, and an abundance of CD3+ and CD8+ T cells and macrophages.1 Here, we report the first patient of Arab-Palestinian origin with typical clinical features of GPP. Genetic analysis revealed a homozygous IL36RN mutation, c.28C>T, so far described only in patients of Japanese origin.8–10
A 6-year-old Arab-Palestinian boy of consanguineous parents had suffered from a widespread pustular and scaly erythematous rash since the age of one month. This rash was episodically accompanied by attacks of high fever and malaise, with no obvious source of infection. The previous three generations of the family showed no history of psoriasis or similar symptoms. The subject had two brothers with no dermatological illness. Previous treatments for his skin disorder had included topical and systemic steroids in combination with cyclosporine, none of which were effective. The patient had significantly retarded growth, attributed in part to long-term steroid use. He weighed 16 kg and measured 110 cm in height, both of which were below the third percentile. Physical examination revealed the widespread presence of scaly erythematous plaques with pinhead pustules involving the scalp, face, extremities, torso, and buttocks (Fig. 1a,b). The palms and soles were also affected. Nail pitting was observed. Marked hypertrichosis was noted, most likely
International Journal of Dermatology 2014, 53, 866–868
ª 2014 The International Society of Dermatology
Renert-Yuval et al.
IL36RN mutation and generalized pustular psoriasis
(a)
Figure 1 (a) Clinical examination of a 6-year-old Arab-Palestinian boy shows erythematous plaque with numerous pustules affecting the shins. (b) Scales on the scalp are apparent. (c) Genetic analysis of the IL36RN gene in DNA from peripheral blood demonstrates the mutation c.28C>T in a homozygous state in the patient and heterozygously in the mother and father
(b)
(c)
caused by prolonged treatment with cyclosporine and systemic steroids. Plain radiographs of the hand demonstrated a delayed bone age. A complete blood count demonstrated anemia and leukocytosis with a normal cell differential; however, during febrile episodes the patient’s white blood cell count increased to 23,000/ll with neutrophilia of 92%. An elevated CRP level was also seen. Biochemistry results were within normal limits. Urine and blood cultures were both sterile, and no source of infection was identified. Skin biopsy demonstrated parakeratosis, spongiosis, and psoriasiform acanthosis. Clusters of neutrophils were observed in the stratum corneum and upper epidermis. Perivascular monocytic infiltrate was noted. Genetic analysis revealed a homozygous nonsense mutation, c.28C>T (p.Arg10X), of the IL36RN gene (Fig. 1c). The parents were found to be heterozygous for the mutation. In order to avoid the chronic use of systemic steroids, the patient’s dose was gradually decreased. In addition, cyclosporine treatment was replaced by methotrexate at a dose of 3.75 mg once per week. Under this treatment, the patient progressed ª 2014 The International Society of Dermatology
Medical genetics
towards a good general condition, and his skin partially improved. Discussion The findings presented here support the diagnosis of DITRA, a genetically distinct form of GPP. Clinical and morphological parameters do not distinguish DITRA from non-DITRA GPP. Therefore, this diagnosis must be made with particular care in occasional patients who present with GPP or its variants and with no family history. In the present patient, the early onset of disease, parental consanguinity, and resistance to therapy aroused the suspicion of DITRA. Molecular analysis enables the clinician to reach a rapid diagnosis and provides a tool with which to screen other family members for carrier status. To date, nine different mutations in the IL36RN gene have been reported, mainly in Japanese patients but also in DITRA patients of other origins. The c.28C>T (p.Arg10x) mutation, which leads to a premature termination codon, has been described only in Japanese patients and was International Journal of Dermatology 2014, 53, 866–868
867
868
IL36RN mutation and generalized pustular psoriasis
Renert-Yuval et al.
considered to represent a Japanese hot spot mutation in this gene.8–10 Its presence in an Arab-Palestinian family implies that it is located in a hot spot in the IL36RN gene, and not in only a certain population. At present, there is no definitive or generally accepted treatment for this disease, and the various treatments or combinations of treatments for psoriasis are usually provided. DITRA is an autoinflammatory disease in which the damage is caused by excessive expression of IL-1 family proteins in the skin.1,2,5 Increased awareness of this distinct type of GPP caused by mutations in IL36RN is of major importance for future potential therapy directed at the IL36RA protein.
3 Cowen EW, Goldbach-Mansky R. DIRA, DITRA, and new insights into pathways of skin inflammation: whats in a name? Arch Dermatol 2012; 148: 381–384. 4 Setta-Kaffetzi N, Navarini AA, Patel VM, et al. Rare pathogenic variants in IL36RN underlie a spectrum of psoriasis-associated pustular phenotypes. J Invest Dermatol 2013; 133: 1366–1369. 5 Onoufriadis A, Simpson MA, Pink AE, et al. Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis. Am J Hum Genet 2011; 89: 432–437. 6 Abbas O, Itani S, Ghosn S, et al. Acrodermatitis continua of Hallopeau is a clinical phenotype of DITRA: evidence that it is a variant of pustular psoriasis. Dermatology 2013; 226: 28–31. 7 Navarini AA, Valeyrie-Allanore L, Setta-Kaffetzi N, et al. Rare variations in IL36RN in severe adverse drug reactions manifesting as acute generalized exanthematous pustulosis. J Invest Dermatol 2013; 133: 1904–1907. 8 Kanazawa N, Nakamura T, Mikita N, et al. Novel IL36RN mutation in a Japanese case of early onset generalized pustular psoriasis. J Dermatol 2013; 40: 1–3. 9 Sugiura K, Takeichi T, Kono M, et al. A novel IL36RN/ IL1F5 homozygous nonsense mutation, p.Arg10X, in a Japanese patient with adult-onset generalized pustular psoriasis. Br J Dermatol 2012; 167: 699–701. 10 Farooq M, Nakai H, Fujimoto A, et al. Mutation analysis of the IL36RN gene in 14 Japanese patients with generalized pustular psoriasis. Hum Mutat 2013; 34: 176–183.
Medical genetics
Acknowledgment The authors thank the patient and his family for their participation in this study and for their permission to publish clinical photographs. References 1 Marrakchi S, Guigue P, Renshaw BR, et al. Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis. N Engl J Med 2011; 365: 620–628. 2 Almeida de Jesus A, Goldbach-Mansky R. Monogenic autoinflammatory diseases: concept and clinical manifestations. Clin Immunol 2013; 147: 155–174.
International Journal of Dermatology 2014, 53, 866–868
ª 2014 The International Society of Dermatology
IL36RN mutation causing generalized pustular psoriasis in a Palestinian patient Yael Renert-Yuval1, MD, Liran Horev1,2, MD, Sofia Babay2, RN, Spiro Tams3, MD, Yuval Ramot1,2, MD, MSc, Abraham Zlotogorski1,2, MD, and Vered Molho-Pessach1,2, MD
1 Department of Dermatology, HadassahHebrew University Medical Center, Jerusalem, Israel, 2Center for Genetic Diseases of the Skin and Hair, HadassahHebrew University Medical Center, Jerusalem, Israel, and 3Faculty of Medicine, Palestinian Al Quds University, Abu Dis, Palestinian Authority
Correspondence Vered Molho-Pessach, MD Department of Dermatology Hadassah-Hebrew University Medical Center Jerusalem 9112001, Israel E-mail: [email protected]
Abstract Deficiency of interleukin-36 (IL-36) receptor antagonist (DITRA; OMIM 614204) is a rare autoinflammatory disorder characterized by periodic fever associated with a generalized erythematous and pustular skin rash. A 6-year-old Arab-Palestinian boy presented with a history of periodic fever and unremitting, erythematous, scaly skin rash accompanied by widespread pustules that had been present since the age of one month. The patient’s skin lesions were compatible with generalized pustular psoriasis. Sequence analysis revealed a homozygous nonsense mutation, c.28C>T (p.Arg10X) in the IL36RN gene. The patient improved with oral methotrexate in combination with oral and topical corticosteroids. The molecular basis for DITRA has only recently been identified, and the mutation spectrum for this disorder in many populations is still obscure. This paper reports the presence of the c.28C>T mutation in an Arab-Palestinian patient and thus represents the first description of this mutation in a non-Japanese subject.
Conflicts of interest: None. Funding: None
866
Introduction
Case Report
Deficiency of interkeukin-36 (IL-36) receptor antagonist (DITRA; OMIM 614204) is a form of generalized pustular psoriasis (GPP) caused by mutations in the IL36RN gene, located at chromosome 2q13. DITRA is a rare, life-threatening, autoinflammatory autosomal recessive disease. It is characterized by recurrent episodes of generalized scaly erythematous rash with disseminated pustules, associated with high-grade fever and elevated levels of C-reactive protein (CRP) and leukocytosis.1–3 Other phenotypes of the IL36RN mutation include related pustular disorders,4 palmoplantar pustulosis,5 acrodermatitis continua of Hallopeau,6 and acute generalized exanthematous pustulosis.7 Histology shows spongiform pustules, acanthosis and parakeratosis, and an abundance of CD3+ and CD8+ T cells and macrophages.1 Here, we report the first patient of Arab-Palestinian origin with typical clinical features of GPP. Genetic analysis revealed a homozygous IL36RN mutation, c.28C>T, so far described only in patients of Japanese origin.8–10
A 6-year-old Arab-Palestinian boy of consanguineous parents had suffered from a widespread pustular and scaly erythematous rash since the age of one month. This rash was episodically accompanied by attacks of high fever and malaise, with no obvious source of infection. The previous three generations of the family showed no history of psoriasis or similar symptoms. The subject had two brothers with no dermatological illness. Previous treatments for his skin disorder had included topical and systemic steroids in combination with cyclosporine, none of which were effective. The patient had significantly retarded growth, attributed in part to long-term steroid use. He weighed 16 kg and measured 110 cm in height, both of which were below the third percentile. Physical examination revealed the widespread presence of scaly erythematous plaques with pinhead pustules involving the scalp, face, extremities, torso, and buttocks (Fig. 1a,b). The palms and soles were also affected. Nail pitting was observed. Marked hypertrichosis was noted, most likely
International Journal of Dermatology 2014, 53, 866–868
ª 2014 The International Society of Dermatology
Renert-Yuval et al.
IL36RN mutation and generalized pustular psoriasis
(a)
Figure 1 (a) Clinical examination of a 6-year-old Arab-Palestinian boy shows erythematous plaque with numerous pustules affecting the shins. (b) Scales on the scalp are apparent. (c) Genetic analysis of the IL36RN gene in DNA from peripheral blood demonstrates the mutation c.28C>T in a homozygous state in the patient and heterozygously in the mother and father
(b)
(c)
caused by prolonged treatment with cyclosporine and systemic steroids. Plain radiographs of the hand demonstrated a delayed bone age. A complete blood count demonstrated anemia and leukocytosis with a normal cell differential; however, during febrile episodes the patient’s white blood cell count increased to 23,000/ll with neutrophilia of 92%. An elevated CRP level was also seen. Biochemistry results were within normal limits. Urine and blood cultures were both sterile, and no source of infection was identified. Skin biopsy demonstrated parakeratosis, spongiosis, and psoriasiform acanthosis. Clusters of neutrophils were observed in the stratum corneum and upper epidermis. Perivascular monocytic infiltrate was noted. Genetic analysis revealed a homozygous nonsense mutation, c.28C>T (p.Arg10X), of the IL36RN gene (Fig. 1c). The parents were found to be heterozygous for the mutation. In order to avoid the chronic use of systemic steroids, the patient’s dose was gradually decreased. In addition, cyclosporine treatment was replaced by methotrexate at a dose of 3.75 mg once per week. Under this treatment, the patient progressed ª 2014 The International Society of Dermatology
Medical genetics
towards a good general condition, and his skin partially improved. Discussion The findings presented here support the diagnosis of DITRA, a genetically distinct form of GPP. Clinical and morphological parameters do not distinguish DITRA from non-DITRA GPP. Therefore, this diagnosis must be made with particular care in occasional patients who present with GPP or its variants and with no family history. In the present patient, the early onset of disease, parental consanguinity, and resistance to therapy aroused the suspicion of DITRA. Molecular analysis enables the clinician to reach a rapid diagnosis and provides a tool with which to screen other family members for carrier status. To date, nine different mutations in the IL36RN gene have been reported, mainly in Japanese patients but also in DITRA patients of other origins. The c.28C>T (p.Arg10x) mutation, which leads to a premature termination codon, has been described only in Japanese patients and was International Journal of Dermatology 2014, 53, 866–868
867
868
IL36RN mutation and generalized pustular psoriasis
Renert-Yuval et al.
considered to represent a Japanese hot spot mutation in this gene.8–10 Its presence in an Arab-Palestinian family implies that it is located in a hot spot in the IL36RN gene, and not in only a certain population. At present, there is no definitive or generally accepted treatment for this disease, and the various treatments or combinations of treatments for psoriasis are usually provided. DITRA is an autoinflammatory disease in which the damage is caused by excessive expression of IL-1 family proteins in the skin.1,2,5 Increased awareness of this distinct type of GPP caused by mutations in IL36RN is of major importance for future potential therapy directed at the IL36RA protein.
3 Cowen EW, Goldbach-Mansky R. DIRA, DITRA, and new insights into pathways of skin inflammation: whats in a name? Arch Dermatol 2012; 148: 381–384. 4 Setta-Kaffetzi N, Navarini AA, Patel VM, et al. Rare pathogenic variants in IL36RN underlie a spectrum of psoriasis-associated pustular phenotypes. J Invest Dermatol 2013; 133: 1366–1369. 5 Onoufriadis A, Simpson MA, Pink AE, et al. Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis. Am J Hum Genet 2011; 89: 432–437. 6 Abbas O, Itani S, Ghosn S, et al. Acrodermatitis continua of Hallopeau is a clinical phenotype of DITRA: evidence that it is a variant of pustular psoriasis. Dermatology 2013; 226: 28–31. 7 Navarini AA, Valeyrie-Allanore L, Setta-Kaffetzi N, et al. Rare variations in IL36RN in severe adverse drug reactions manifesting as acute generalized exanthematous pustulosis. J Invest Dermatol 2013; 133: 1904–1907. 8 Kanazawa N, Nakamura T, Mikita N, et al. Novel IL36RN mutation in a Japanese case of early onset generalized pustular psoriasis. J Dermatol 2013; 40: 1–3. 9 Sugiura K, Takeichi T, Kono M, et al. A novel IL36RN/ IL1F5 homozygous nonsense mutation, p.Arg10X, in a Japanese patient with adult-onset generalized pustular psoriasis. Br J Dermatol 2012; 167: 699–701. 10 Farooq M, Nakai H, Fujimoto A, et al. Mutation analysis of the IL36RN gene in 14 Japanese patients with generalized pustular psoriasis. Hum Mutat 2013; 34: 176–183.
Medical genetics
Acknowledgment The authors thank the patient and his family for their participation in this study and for their permission to publish clinical photographs. References 1 Marrakchi S, Guigue P, Renshaw BR, et al. Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis. N Engl J Med 2011; 365: 620–628. 2 Almeida de Jesus A, Goldbach-Mansky R. Monogenic autoinflammatory diseases: concept and clinical manifestations. Clin Immunol 2013; 147: 155–174.
International Journal of Dermatology 2014, 53, 866–868
ª 2014 The International Society of Dermatology
