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Year : 2021  |  Volume : 22  |  Issue : 1  |  Page : 66-69

Cutaneous Lesions Presenting as Recurrent Annular Erythema in a Child with Juvenile Myelomonocytic Leukemia, Coeliac Disease, and CALMs: The Myriad Manifestations of RASopathy

1 Department of Pediatrics, Shree Guru Gobind Singh Tricentenary Medical College and Hospital, Gurugram, Haryana, India
2 Department of Dermatology and STD, Shree Guru Gobind Singh Tricentenary Medical College and Hospital, Gurugram, Haryana, India
3 Department of Pathology, Shree Guru Gobind Singh Tricentenary Medical College and Hospital, Gurugram, Haryana, India

Date of Submission07-May-2020
Date of Decision17-May-2020
Date of Acceptance23-Jul-2020
Date of Web Publication31-Dec-2020

Correspondence Address:
Shikhar Ganjoo
Associate Professor, Department of Dermatology and STD, Shree Guru Gobind Singh Tricentenary Medical College and Hospital, Gurugram, Haryana
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpd.IJPD_79_20

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In neurofibromatosis type 1 (NF-1), a Ras-pathway mutation disorder both celiac disease and juvenile myelomonocytic leukemia (JMML) have been found in association. A 3-year-old male child presented to us with annular erythema and cafe-au-lait macules (>6 in number). On investigation, he was found to have JMML and celiac disease. A child with early manifestation of NF1 in association with JMML and celiac disease is an even rarer presentation.

Keywords: Annular erythema, coeliac disease, juvenile chronic myelomonocytic leukemia, neurofibromatosis

How to cite this article:
Sahoo B, Ganjoo S, Sawhney MP, Nagger S. Cutaneous Lesions Presenting as Recurrent Annular Erythema in a Child with Juvenile Myelomonocytic Leukemia, Coeliac Disease, and CALMs: The Myriad Manifestations of RASopathy. Indian J Paediatr Dermatol 2021;22:66-9

How to cite this URL:
Sahoo B, Ganjoo S, Sawhney MP, Nagger S. Cutaneous Lesions Presenting as Recurrent Annular Erythema in a Child with Juvenile Myelomonocytic Leukemia, Coeliac Disease, and CALMs: The Myriad Manifestations of RASopathy. Indian J Paediatr Dermatol [serial online] 2021 [cited 2021 Apr 22];22:66-9. Available from: https://www.ijpd.in/text.asp?2021/22/1/66/305816

  Introduction Top

Annular erythemas are characterized by annular, circinate, arcuate, or polycyclic lesions. These eruptions may occur secondary to a known cause such as erythema annulare centrifugum (EAC), erythema chronicum migrans (ECM), rheumatic fever, and lupus erythematosus or these may be idiopathic. Interestingly, juvenile myelomonocytic leukemia (JMML) has been associated with cutaneous lesions such as nonspecific maculopapular rash, neurofibromas, erythematous papules, and xanthogranulomas.[1],[2] The skin lesions of annular erythema preceding the clinical diagnosis of internal malignancy may occur in a rare setting. We describe a case with skin involvement as the presenting manifestation along with café-au-lait macules in a child with celiac disease without the diagnosis of internal malignancy at the time of onset.

  Case Report Top

A 3-year-old developmentally normal male child born to nonconsanguineous parents presented to the dermatology outpatient department of a tertiary care hospital with 1-month history of annular and arcuate skin eruptions. The cutaneous lesions were predominantly distributed over the front of the trunk [Figure 1], the proximal part of the upper limbs, and back of the trunk [Figure 2] and consisted of nonscaly erythematous concentric plaques with central clearing and raised well-defined borders. The lesions began as small papules with progressive peripheral spreading. One of the lesions on the back of the trunk attained a size as large as 15 cm diameter. The patient also gave a history of the disappearance of lesions at one site and appearance at others. The lesions were mildly itchy but otherwise asymptomatic. Systemic physical examination revealed mild pallor, multiple café-au-lait spots >6 in number, and size varying from 5 to 8 mm present since birth, generalized lymphadenopathy, and firm hepatosplenomegaly. Neurofibromas were absent. The rest of the systemic examination was unremarkable.
Figure 1: Lesions over the anterior trunk showing nonscaly erythematous concentric plaques with central clearing and raised well-defined borders

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Figure 2: Lesions over the posterior trunk showing morphologically similar lesions as [Figure 1] and plaque over the left scapular region attaining a diameter of 15 cm. Multiple café-au-lait macules can also be identified

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The total leukocyte count (TLC) at presentation was 90,000/cc. On further follow-up visits the TLC ranged from 25,300 to 90,000/cc. Hemoglobin level was 9 g% with a normal platelet count. Due to the simultaneous presence of fever, skin rash, and hepatosplenomegaly, we suspected it to be a case of Lyme's disease with ECM in leukemoid reaction. However, testing for  Borrelia burgdorferi Scientific Name Search i antibodies came out to be negative. Peripheral smear showed microcytic hypochromic anemia and immature myeloid cells-myelocytes, metamyelocytes, and myeloblasts [Figure 3]a and [Figure 3]b which constituted 10% of the total cells. Differential leukocyte count showed monocytosis with an absolute monocyte count of 13,500/cc. Platelets were normal in morphology and number.
Figure 3: (a) Peripheral blood smear at oil immersion ×100 showing a metamyelocyte. (b) Peripheral blood smear at oil immersion ×100 showing a myeloblast

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Since the child also had abdominal distention, recurrent diarrhea, and failure to thrive, a pediatric referral was sought. Workup revealed elevated tissue transglutaminase levels of 77.31 IU and duodenal biopsy revealed Marsh Stage 3b. A diagnosis of celiac disease was made.

Skin biopsy was done at a tertiary care center in India. Biopsy from a plaque on the back showed dense periappendageal, perivascular, and perineural infiltrate of atypical cells with opened up chromatin, irregular nuclear membrane, and small inconspicuous nucleoli. Few neutrophils and lymphocytes were also noted. There was evidence of karyorrhexis. The inflammation extended into the superficial portion of subcutis and invaded the wall of small blood vessels present in the subcutis. Spillover into the dermal interstitium was also seen. No epidermotropism was seen. Immunohistochemically, the cells were positive for CD4 with very few cells being labeled by CD3, CD5, CD7, CD8, and CD 10. The cells were negative for BCL 6, CD 20, and myeloperoxidase. The patient refused a repeat biopsy at our hospital.

Further workup done at our hospital, incluing bone marrow biopsy which revealed a hypercellular marrow with myeloid:erythroid ratio of 13:1. Among the myeloid series, myeloblasts (3%); promyelocytes and myelocytes (12%); neutrophils and band forms (50%); lymphocytes (6%); eosinophil precursors (7%); monoblasts and promonocytes (18%); and plasma cells (4%) were seen [Figure 4]. Few myeloid cells showing dysplastic features in the form of abnormal lobations and ring nucleus neutrophils were also seen. Erythroid series showing dyserythropoietic changes were observed. Megakaryocytes were normal. Based on the clinical and laboratory features, we considered the possibility of JMML. On further workup, an abnormal hemoglobin screen was done and showed adult hemoglobin to be 79% with elevated fetal hemoglobin value of 12.8%. BCR-ABL gene rearrangement (Philadelphia chromosome) by polymerase chain reaction (qualitative) was negative, thus ruling out chronic myeloid leukemia. Chest X-ray, endoscopy, computed tomography scan, and magnetic resonance imaging of the brain, echocardiography, slit-lamp examination, and fundoscopy were normal. Based on the revised WHO 2016 criteria, a diagnosis of JMML was performed. Neurofibromatosis type 1(NF1) gene testing could not be done due to the lack of facilities.
Figure 4: The bone marrow smear at ×10 shows a hypercellular marrow with myeloid predominance. Few myeloblasts and promyelocytes can be seen

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Parents were subsequently counseled about the prognosis of the disease and advised bone marrow transplantation at a higher center. Based on the classical appearance of the annular rash, EAC, ECM, erythema gyratum repens, erythema multiforme (EM), and annular erythema associated with anti-SSA (anti-Ro) and anti-SSB (anti-La) antibodies were considered. Although this association may be coincidental, the close temporal association prompts us to speculate that annular erythema, in this case, was a specific manifestation of JMML.

  Discussion Top

Many cutaneous manifestations of JMML have been reported in the literature. Most of these have been a nonspecific maculopapular rash, neurofibromas, erythematous papules that revealed the presence of Langerhans cell histiocytosis and xanthogranulomas.[1],[2] There are a few reports of skin involvement with leukemic cells in patients having JMML.[3] The description of these lesions varies from recurrent circinate plaques, indurated erythema with central clearing, annular erythema with induration, neutrophilic figurate erythema, and Sweet's syndrome.[4],[5] The lesion distribution is more common over the ears, hands, and feet. Skin involvement was the only presentation without the diagnosis of internal malignancy in a few of these patients at the time of onset of skin lesions.[6]

Ras-pathway mutations in the PTPN11, NRAS, KRAS, NF1, or CBL genes are present in leukemic cells of approximately 90% of patients of JMML.[6],[7] It has been well known that children with NF-1 are predisposed to develop JMML at a rate of 250–300 times higher than that of those who do not have NF-1. The NF-1 gene is a tumor suppressor gene whose gene product neurofibromin is GTPase-activating protein (GAP). It has been reasonably demonstrated that there is a selective decrease of NF1-GAP activity in bone marrow cells of children with NF and JMML.[7] The clinical features of NF1 appear over a period of time with café-au-lait macules being the first to appear in all children. Neurofibromas and Lisch nodules develop at a later age. Our child had multiple café-au-lait macules at presentation and we intend to follow-up the child for sequential development of clinical signs suggestive of NF-1. There have also been few previous reports of association of NF-1 with celiac disease.[8],[9],[10]

Our case revealed a history of disappearance of annular erythema lesions at one site and appearing at other sites over the course of several months. The relationship between leukemic annular infiltration of the skin and the course of JMML has not been clearly delineated. Giacaman et al. reported a 2-year history of migratory asymptomatic migratory lesions in an 8-year-old boy with Ras-associated autoimmune leukoproliferative disorder (RALD).[11] They explained the cutaneous involvement to be due to peaks in the production of monocytes delivered from the blood to the skin. Despite an extensive investigative workup, the authors found it difficult to differentiate between RALD and JMML in the patient.

However, we believe that the annular erythema may be a characteristic manifestation of JMML and may precede the development of JMML by months to years. Hence, it is vital to exclude it and follow-up all children presenting with annular erythemas for JMML.

To the best of our knowledge, this is the first case in which a possible NF1, celiac disease, and JMML have been reported together. We strongly believe the trigger to be NF1 gene mutation which is responsible for the disease complex in our patient in light of genetic undertones that all these diseases have.

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.

  References Top

Anzai H, Kikuchi A, Kinoshita A, Nishikawa T. Recurrent annular erythema in juvenile chronic myelogenous leukaemia. Br J Dermatol 1998;138:1058-60.  Back to cited text no. 1
Sires UI, Mallory SB, Hess JL, Keating JP, Bloomberg G, Dehner LP. Cutaneous presentation of juvenile chronic myelogenous leukemia: A diagnostic and therapeutic dilemma. Pediatr Dermatol 1995;12:364-8.  Back to cited text no. 2
Matsumoto K, Miki J, Matsuzaki S, Koike K, Saida T. Skin infiltration of juvenile myelomonocytic leukemia. J Dermatol 2004;31:748-51.  Back to cited text no. 3
Niemeyer CM, Flotho C. Juvenile myelomonocytic leukemia: Who's the driver at the wheel? Blood 2019;133:1060-70.  Back to cited text no. 4
Kitamura H, Kaneko T, Nakano H, Terui K, Ito E, Sawamura D. Juvenile myelomonocytic leukemia presenting multiple painful erythematous lesions diagnosed as Sweet's syndrome. J Dermatol 2008;35:368-70.  Back to cited text no. 5
Stiller CA, Chessells JM, Fitchett M. Neurofibromatosis and childhood leukaemia/lymphoma: A population-based UKCCSG study. Br J Cancer 1994;70:969-72.  Back to cited text no. 6
Shannon KM, O'Connell P, Martin GA, Paderanga D, Olson K, Dinndorf P, et al. Loss of the normal NF1 allele from the bone marrow of children with type 1 neurofibromatosis and malignant myeloid disorders. N Engl J Med 1994;330:597-601.  Back to cited text no. 7
Biagi F, Campanella J, Alvisi C, Versino M, Corazza GR. Unusual association of neurofibromatosis type 1 and coeliac disease in a single patient. Funct Neurol 2005;20:33-4.  Back to cited text no. 8
Işık İA, Akbulut UE. The coexistence of neurofibromatosis type I and celiac disease in a child. Turk J Gastroenterol 2018;29:522-3.  Back to cited text no. 9
Mones RL, Singh K, Fennoy I. The co-existence of celiac disease and neurofibromatosis type 1 in a child. J Gastroenterol Hepatol Endosc 2019;4:1061-2.  Back to cited text no. 10
Giacaman A, Bauzá Alonso A, Salinas Sanz JA, Dapena Díaz JL, Ramos Asensio R, Ferrés Ramis L, et al. Cutaneous involvement in an 8-year-old boy with Ras-associated autoimmune leucoproliferative disorder (RALD). Clin Exp Dermatol 2018;43:913-6.  Back to cited text no. 11


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]


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