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Table of Contents 
Year : 2022  |  Volume : 67  |  Issue : 1  |  Page : 79-84
What can we learn from a tortuous diagnosis and treatment experience for a child with PAPA syndrome? A case report

1 Department of Pediatrics, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, PR China
2 Department of Gastroenterology, Peking University Third Hospital, Beijing, PR China
3 Department of Pediatrics, Guangzhou First People's Hospital, Guangzhou Medical University; Department of Pediatrics, Guangzhou First People's Hospital, School of Medicine, South China University Of Technology, Guangzhou, PR China

Date of Web Publication19-Apr-2022

Correspondence Address:
Li Yu
Department of Pediatrics, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou
PR China
Shengyou Yu
Department of Pediatrics, Guangzhou First People's Hospital, Guangzhou Medical University; Department of Pediatrics, Guangzhou First People's Hospital, School of Medicine, South China University Of Technology, Guangzhou
PR China
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijd.ijd_277_21

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How to cite this article:
Tan J, Zhang T, Hao Z, Wang L, Feng S, Yu L, Yu S. What can we learn from a tortuous diagnosis and treatment experience for a child with PAPA syndrome? A case report. Indian J Dermatol 2022;67:79-84

How to cite this URL:
Tan J, Zhang T, Hao Z, Wang L, Feng S, Yu L, Yu S. What can we learn from a tortuous diagnosis and treatment experience for a child with PAPA syndrome? A case report. Indian J Dermatol [serial online] 2022 [cited 2023 Dec 8];67:79-84. Available from:

Dear editors,

Pyogenic arthritis, pyoderma gangrenosum (PG) and acne (PAPA) syndrome is an autosomal dominant disease caused by heterozygous mutations in PSTPIP1 gene located on chromosome 15 encoding CD2-binding protein 1 (CD2BP1), presenting with recurrent cutaneous and articularlesions.[1] In most cases, the recurrent, aseptic, and erosive arthritis is the earliest symptom that occurrs in childhood, and commonly affects the joints of hands, elbows, knees, and ankles to varying degrees of severity. However, the severity of arthritis will spontaneously decrease in adolescence, but simultaneously, the cutaneous lesions will get worse, manifesting as severe nodular cystic acne and PG, which can also be found in adulthood.[2]

Currently, the literature on PAPA syndrome is very scarce. Herein, we retrospectively report the clinical data of a patient diagnosed with PAPA syndrome caused by a mutation in PSTPIP1 gene in order to improve the physicians' understanding of PAPA syndrome further.

   Case Presentation Top

A nine-year-old boy was diagnosed with PAPA syndrome at the Department of Pediatrics, Guangzhou First People's Hospital in August 2020. He was complaining of multiple joints swelling and pain accompanied by limited mobility in the whole body for 7 years.

The treatment process before diagnosis was confirmed

As shown in [Table 1], in September and October 2013, he successively experienced painful swelling of left ankle and knee, accompanied by limited mobility and low-degree fever without any obvious causes. Hence, he has been presented to local hospital twice, and pyogenic arthritis was considered. After joint incision and drainage, he recovered well and joint pus culture was negative. Moreover, a large number of lymphocytes and plasma cells, as well as few neutrophils and eosinophils were found in the pathological examination [Figure 1]. In June 2015, he was presented with skin pustules, mostly on the left lower extremity, waist, and right cheeks, accompanied by itching and suppuration [Supplement materials 1 and 2], and the topical glucocorticoid was effective [Figure 2]a and [Figure 2]b. In August 2016, his left ankle swelled again and he was treated with cefotaxime as well as joint incision and drainage. During the operation, a large amount of purulent secretions were found subcutaneously, and also to deep fascia, but the periosteum was intact. In April 2017, his right ankle began to swell, and the pathological examination showed fibrovascular hyperplasia, multinucleated giant cells (MGCs), and infiltration of a large number of acute and chronic inflammatory cells in the biopsy tissue. Necrosis with granulation tissue hyperplasia was considered. Afterwards, he was given cefotaxime and six times of free skin-flap successively [Figure 2]c and [Figure 2]d.
Figure 1: Early symptoms of this patient: (a) shows swollen left knee; (b) shows the suppuration and swelling of right ankle; (c) shows the suppuration and swelling of left ankle; (d and e) are the results of pathological examination after the incision and drainage of left knee in October 2013, which suggested that there were a large number of lymphocytes, plasma cells, and a small number of neutrophils and eosinophils in the joint fluid

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Figure 2: (a and b) show the skin lesions in recovery period in 2015, among which A is knee and B is hip site; (c and d) show postoperative recovery period after ankle incision and drainage; (e and f) are the joint scar tissue period during follow-up in 2019; (g and h) are scar recovery period during follow-up in 2020

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Table 1: The process of diagnosis and treatment before the diagnosis was confirmed

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Laboratory examinations and genetic test

Blood routine examination showed normal white blood cell count 8.7 × 109/L and normal neutrophil ratio 65.6%. Serological examination revealed elevated CRP 6.2 mg/L (normal, <5 mg/L), negative anti-nuclear antibody, negative anti-dsDNA antibody, negative anti-keratin antibody, and negative anti-perinuclear factor antibody. The blood biochemical analysis showed that: ESR: 13 mm/h, IL-6: 5.97 Pg/ml, and the levels of TNF-a, IL-1, IL-2, and IL-4 were slightly elevated. Additionally, in September 27, 2017, the serum zinc level of this patient was 4.5 mg/L (normal, for children aged 0–16: 3.7-7.3 mg/L) and the MRP8/14 was 890.2 ng/mL.

In August 2017, the genetic test results suggested a heterozygous mutation in PSTPIP1 gene: c.748G>A(p.E250K), but the genetic tests of his parents and younger brother were negative. Given the patient's history of cutaneous lesions and articular involvement, the abnormal genetic testing, and the nomal serum levels of zinc and MRP8/14, the diagnosis of PAPA syndrome was made [Figure 3].
Figure 3: The genetic detection of this patient. (a) is the outcome of this genetic detection, which shows heterozygous mutations in PSTPIP1 gene: c.748G > A (p.E250K). (b) is the Genome Atlas

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The treatment process after diagnosis was confirmed

After the diagnosis was confirmed, there were still new swollen joints. Especially, when the symptoms were obvious, the serum levels of CRP, ESR, IL-1, IL-6, and TNF-a increased apparently. As shown in [Figure 4], from September 2017 to mid-January 2018, although he was given totally five times of tocilizumab (5 mg/kg) and three times of IVIG 10 g (400 mg/kg), the joint swelling still repeated, and the levels of IL-6, TNF-a, and IL-1, which were frequently monitored during this period, were still high.
Figure 4: This figure contains a total of 23 columns and three rows of grids (23*3). Each column of grids represents the time point of each follow-up of the patient from September 2017 to August 2020 (or after the diagnosis was confirmed). The grids in the first row represent the joint symptoms at each follow-up, and the grids in the 2nd and 3rd rows (combination: 2nd + 3rd rows) represent the chemotherapy regimens at each follow-up. As shown in the figure, the dividing line between each of the two columns of grids corresponds to each time interval between the patient's two follow-up. The meaning of each color is also indicated clearly in the figure. The severity of symptoms at each follow-up and the time interval between each follow-up can indirectly reflect the effect of the previous chemotherapy regimens

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Therefore, since the end of January 2018, the therapeutic regime has been adjusted, and as of February 2019, the patient has been treated with infliximab (5 mg/kg) for nine times, after which the interval between each episode of joint swelling has been slightly prolonged, but new articular lesions still appeared. In March 2019, the anakinra was started to be used for 10 consecutive months, and no joint symptoms appeared after that [Figure 2]e and [Figure 2]f. Since January 2020, due to the pandemic of COVID-19, he has not returned to Hong Kong to purchase anakinra, but there has not been a recurrence of joint swellings during that period. In April 2020, he started to take 20 mg prednisolone acetate orally at 8 o'clock each morning, and not only the symptoms were controlled, but also the IL-1, IL-6 and TNF-α values were generally rehabilitated to normal levels. In August 2020, he started to take 25 mg thalidomide orally once a night. Now, the child is in stable condition and has no new joint swellings. The follow-up is still underway [Figure 2]g and [Figure 2]h.

   Discussion Top

Due to abnormal innate immunity and infiltration of immune cells in bones, followed by differentiation and activation of osteoclasts, the aseptic inflammation of bones in patients with PAPA syndrome appeared, often accompanied by skin inflammation, but no pathogenic evidence was found in etiologic test and histopathological examination.[3],[4]

Holzinger et al.[5] found that the genetic cause for Hz/Hc was also a single amino acid substitution in the y-domain of PSTPIP1 (E/K) either at position p.E250 (13/14 of patients) or p.E257. Therefore, we cannot distinguish between Hz/Hc and PAPA syndrome only by genetic tests. Clinically, Hz/Hc is distinguished from PAPA syndrome based on the presence of a severe course and early-onset disease, hepatosplenomegaly, and failure to thrive. In terms of laboratory parameters, the patients with Hz/Hc have significantly higher MRP8/14 and zinc serum levels than the patients with PAPA syndrome. It is necessary for patients with undefined autoinflammatory syndromes and significant skin inflammation (or pyoderma gangrenosum) to be tested for the serum MRP8/14 levels. In our study, the patient's serum MRP8/14 and zinc levels were normal. Thus, we ruled out the possibility of Hz/Hc.

At present, novel IL-1 and TNF-α receptor antagonists have made successful progress in the treatment of PAPA syndrome. For example, TNF-α receptor antagonists such as etanercept, adalimumab, and infliximab have obvious effects on PAPA syndrome, and anakinra, a kind of short-acting IL-1 receptor antagonist (IL-1Ra), can alleviate the joint symptoms efficiently.[6] In addition, kanazumab, a long-acting fully human anti-IL-1β monoclonal antibody, can relieve joint pain and swelling quickly and long-lastingly.[7] In this case report, the child was treated with tocilizumab and infliximab in succession at an early stage, but the clinical manifestations were still repeated. Therefore, since March 2019, the treatment has been adjusted to anakinra (300 mg qd), after which the joint symptoms did not appear again. Anakinra, a recombinant naturally-occurring non-glycosylated form of IL-1Ra, can inhibit the activities of IL-1α and IL-1β.[8],[9] However, the main shortage of anakinra is its short half-life (4–6 hours). So patients need to be injected daily, which often causes the injection site painful and poor patient compliance.[10]

However, due to the pandemic of COVID-19, the child didn't receive anakinra for 3 months, therefore, since April 2020, the therapeutic schedule has been adjusted to oral prednisolone acetate and thalidomide. Thalidomide is a derivative of glutamate with immunomodulatory and anti-inflammatory effects, and it is mostly used for children's rheumatic diseases, which are effective unlike other drugs, mainly including systemic lupus erythematosus, Behcet syndrome, juvenile idiopathic arthritis, and so on. However, the literature on patients with PAPA syndrome using thalidomide were very scarce. According to a guideline from Asia-Pacific Society of Medical Bioimmunology in 2020,[11] thalidomide can be used when other drugs are ineffective or unsuitable due to some objective reasons and restrictions. In our case, the patient has been using thalidomide so far, and his condition is stable without any adverse events, which can provide reference value for other cases in the future.

Our study shows PAPA syndrome is prone to be misdiagnosed and mistreated easily. For example, patients treated with early antibiotics and multiple surgical procedures were not cured and so they were transferred to many hospitals for further diagnosis and treatment. We have summarized the reasons for misdiagnosis: (1) PAPA syndrome is a rare disease, and many clinicians do not have a deep understanding of it and are lacking of experience in diagnosis and treatment; (2) This case was caused by mutations in genes, which made it difficult to obtain relevant clues from the family history.

In conclusions, genetic test should be performed as soon as possible for suspected autoinflammatory diseases so as to avoid unnecessary surgical treatment and achieve precise treatment. Additionally, the serum levels of zinc and MRP8/14 can help us to distinguish between PAPA syndrome and Hz/Hc.

Ethics approval and consent to participate

This study was approved by Ethics Committee of Guangzhou First People's Hospital. The Committee's reference number is W2020-003. Written informed consent was obtained from all participants.

Declaration of patient consent

This was approved by Ethics Committee of Guangzhou First People's Hospital.

List of Abbreviations

APTT: Activated partial thromboplastin time; CD2BP1: CD2 binding protein 1; ECG: Electrocardiogram; ESR: Erythrocyte sedimentation rate; FIB: Fibrinogen; Hz/Hc: Hypercalprotectinemia and hyperzincemia; MGCs: Multinucleated giant cells; NLRP3: Nucleotide oligomerization domain-like receptor protein 3; NOMID: Neonatal onset multi-system inflammatory disease; PAPA: Pyogenic arthritis, pyoderma gangrenosum and acne; PG: Pyoderma gangrenosum; PSTPIP1: Proline-serine-threonine phosphatase interacting protein 1; PT: Prothrombin time; TT: Thrombin time; UCG: Ultrasonic cardiodiagram.


We acknowledge all medical staff who participated in this study.

Financial support and sponsorship

This study was funded by the Science Fundation of Guangzhou First People's Hospital (No. M2019020), Guangzhou Planned Project of Science and Technology (No.202102080447), and GuangZhou General Science and Technology Project of Health and Family Planning (No.20211A011016).

Conflicts of interest

There are no conflicts of interest.

   References Top

Wise CA, Gillum JD, Seidman CE, Lindor NM, Veile R, Bashiardes S, et al. Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder. Hum Mol Genet 2002;11:961-9.  Back to cited text no. 1
Smith EJ, Allantaz F, Bennett L, Zhang D, Gao X, Wood G, et al. Clinical, molecular, and genetic characteristics of PAPA syndrome: A review. Curr Genomics 2010;11:519-27.  Back to cited text no. 2
Maitrepierre F, Marzano AV, Lipsker D. A unified concept of acne in the PAPA spectrum disorders. Dermatology 2020;1-8. doi: 10.1159/000509874. Online ahead of print.  Back to cited text no. 3
Martinez-Rios C, Jariwala MP, Highmore K, Duffy KW, Spiegel L, Laxer RM, et al. Imaging findings of sterile pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome: Differential diagnosis and review of the literature. Pediatr Radiol 2019;49:23-36.  Back to cited text no. 4
Holzinger D, Fassl SK, de Jager W, Lohse P, Röhrig UF, Gattorno M, et al. Single amino acid charge switch defines clinically distinct proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated inflammatory diseases. J Allergy Clin Immunol 2015;136:1337-45.  Back to cited text no. 5
Genovese G, Moltrasio C, Garcovich S, Marzano AV. PAPA spectrum disorders. G Ital Dermatol Venereol 2020;155:542-50.  Back to cited text no. 6
Tofteland ND, Shaver TS. Clinical efficacy of etanercept for treatment of PAPA syndrome. J Clin Rheumatol 2010;16:244-5.  Back to cited text no. 7
Goldbach-Mansky R, Dailey NJ, Canna SW, Gelabert A, Jones J, Rubin BI, et al. Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition. N Engl J Med 2006;355:581-92.  Back to cited text no. 8
Demidowich AP, Freeman AF, Kuhns DB, Aksentijevich I, Gallin JI, Turner ML, et al. Brief report: Genotype, phenotype, and clinical course in five patients with PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne). Arthritis Rheum 2012;64:2022-7.  Back to cited text no. 9
Lazaros G, Imazio M, Brucato A, Vassilopoulos D, Vasileiou P, Gattorno M, et al. Anakinra: An emerging option for refractory idiopathic recurrent pericarditis: A systematic review of published evidence. J Cardiovasc Med (Hagerstown) 2016;17:256-62.  Back to cited text no. 10
Yang S, Zhao D, Du Y, Wu Y. 5th of recommendations series of experts on clinical practice hot issues of children's immune related diseases-Advice on the application of thalidomide in the immune diseases in children[J]. Chinese Journal of Practical Pediatrics,2020,35:431-4. (in Chinese). Available from:  Back to cited text no. 11


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

  [Table 1]


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