# Clinical manifestations and management of pediatric granuloma annulare: a systematic review

Marie Albert, A Maruani, S Leducq

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## To cite this version:

Marie Albert, A Maruani, S Leducq. Clinical manifestations and management of pediatric granuloma annulare: a systematic review. The Journal of Pediatrics, 2023, 257, pp.113392. 10.1016/j.jpeds.2023.03.006. hal-04830431

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Distributed under a Creative Commons Attribution 4.0 International License
**Article Type:** Original Article

**Title:** Clinical manifestations and management of pediatric granuloma annulare:
a systematic review

**Short title:** Systematic review of pediatric granuloma annulare

**Authors and affiliations**

Marie Albert¹,², MD; Annabel Maruani¹,²,³, MD, PhD; Sophie Leducq¹,²,³, MD

¹Department of Dermatology and Reference Center for Rare Diseases and Vascular Malformations (MAGEC), CHRU Tours, Tours, France

²Unit of Pediatric Dermatology, CHRU Tours, Tours, France

³Universities of Tours and Nantes, INSERM 1246-SPHERE, 37000 Tours, France

**Corresponding author**

Dr Sophie Leducq, Department of Dermatology, CHRU Tours, Avenue de la République,
37044 Tours Cedex 9, France

Tel: +33 2 47 47 90 80

Fax: +33 2 47 47 82 47

Email: sophie.leducq@univ-tours.fr

**Conflict of interest:** None declared

**Funding:** None

**IRB approval status:** Not applicable

**Reprint requests:** Reprints not available from the authors

**Data sharing statement:** The datasets analyzed are available from the corresponding author on reasonable request.
**Manuscript word count:** 2271

**Summary word count:** 198

**References:** 27

**Figure:** 1

**Tables:** 3

**Supplemental file:** 3

**Prisma checklist**

**Keywords:** systematic review, granuloma annulare, therapeutic, management, diagnosis, epidemiology, pediatric dermatology
**Abstract**

*Objective*

To determine the clinical manifestations, management and outcomes of pediatric granuloma annulare.

*Study design*

We searched MEDLINE via PubMed, Latin American and Caribbean Health Sciences (LILACS) and EMBASE from inception to January 2021. We included all original reports of patients < 18 years old with a diagnosis of GA and all original reports describing any intervention, including topical or systemic drugs in these patients. Two authors independently extracted socio-demographics and clinical data of the study patients, and treatment used.

*Results*

Among the 2440 reports screened, 202 were included (836 patients). The mean age was 5.7 (SD 3.8) years and F:M ratio 1.3:1. Localized GA (n=384, 46.8%) and subcutaneous GA (n=353, 43.0%) were the most prevalent. The most affected site was lower limbs (n=272/568, 47.9%). Suspected triggering factors were mainly local trauma. Diabetes was associated in 22 (2.6%) patients. The rate of spontaneous remission was high (n=140/155, 90.3%), at a median delay of 12 months. The most frequent therapies were surgery and topical corticosteroids.

Recurrence was observed in 38.3% (n=168/439) of patients, whatever the treatment.

*Conclusions*

Pediatric GA frequently spontaneously resolves with a high recurrence rate. Hence, in asymptomatic forms, invasive therapies are not recommended as first-line treatment.
**Introduction**

Granuloma annulare (GA) is a benign inflammatory dermatosis of unknown etiology characterized by the appearance of annular, flesh-colored grouped papules, mostly affecting the extensor surfaces of lower and upper extremities (1,2). The diagnosis is usually based on physical examination and can be confirmed by histopathology examination. Four common variants of GA have been described: localized GA (LGA), subcutaneous GA (SGA), generalized GA (GGA) and perforating GA (PGA). Papular umbilicated GA is an unusual and rare variant (3). GA occurs in both adults and children but mainly in school-age children (4).

The differential diagnoses for LGA or GGA include dermatophyte infection, annular elastolytic giant cell granuloma, erythema annulare centrifugum, annular lichen planus, nummular eczema, sarcoidosis, annular lichenoid dermatitis and secondary syphilis (5-8).

SGA may be confused with rheumatoid nodules and a biopsy could be performed in case of atypical features (6,9). Although the pathogenesis of GA has not been entirely elucidated, several hypothesis based on histological features have been proposed (5,10,11). Multiple studies support a mechanism of delayed hypersensitivity reaction in which inflammatory cell activation leads to matrix degeneration and collagen synthesis. The presence of activated T-helper cells in the inflammatory infiltrate of GA corroborates this theory and implicates a cell-mediated immune response to various triggering factors (5,12).

GA remains a poorly understood condition and data are lacking and need to be clarified. We aimed to investigate the clinical manifestations, triggering factors, associated diseases and management of pediatric GA by performing a systematic review of all previously published cases in the scientific literature.
# Materials and methods

This systematic review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (Supplemental file 1) and was registered in the PROSPERO database (registration no.: CRD42021225903).

## *Search strategy and information sources*

We searched electronic databases, including MEDLINE via PubMed, Latin American and Caribbean Health Sciences (LILACS) and EMBASE from inception to January 2021 using the terms *child*, *infant* or *pediatric* combined with *granuloma annulare* or *granuloma annular*. We also searched the website ScienceDirect. Search terms were in English only.

## *Eligibility criteria*

We included all original reports of patients < 18 years old with a diagnosis of GA and all original reports describing any intervention, including topical or systemic drugs in these patients. We excluded patients with an uncertain diagnosis. No restriction on language was initially planned, but publications in non-Latin script languages were excluded.

## *Study selection strategy and data extraction*

Two authors (M.A. and S.L.) independently selected studies on the basis of their title and abstract and then examined the full texts of articles. The process selection and extraction were conducted in duplicate but separately. Duplicates were extracted, along with studies presenting the identical population in different articles. Then, these two authors extracted sociodemographic, clinical and management data. Any disagreements in article selection or data extraction were resolved by discussion with a third author (A.M.).

## *Statistical analyses*

Descriptive data are expressed as mean ± standard deviation (SD) or median and interquartile range (IQR) for quantitative data and number (%) for categorical data. Chi-square or Fisher exact test was used to analyze categorical outcomes. Student *t* test or Wilcoxon rank sum test
was used to analyze continuous outcomes. A two-sided p < 0.05 was considered statistically
significant. Statistical analyses were performed with R 4.0.2 (R Foundation for Statistical
Computing, Vienna, Austria). No methods were used to handle missing data.

Results

Characteristics of included reports

Our search strategy yielded 2440 studies; 371 articles underwent full-text review and 202 publications (836 children) met the inclusion criteria (Figure 1, online). Studies were published between 1957 and 2020: 37 reports were case series and 165 case reports. There were no trials or cohort studies. Populations ranged from 3 to 190, with a median of 5 (IQR 5.0-17.0).

Characteristics of included patients

Characteristics of included patients are in **Table I**. The mean (SD) age was 5.7 (3.8) years and 336 (42.6%) were boys (F:M ratio 1.3:1). All types of GA were represented, with most being LGA in 384/821 (46.8%) patients and SGA in 353/821 (43.0%) (missing data regarding type of GA for 15 patients).

Diabetes was reported in 22 (2.6%) patients. GA occurred before the diabetes diagnosis in 6 patients (median time 12 weeks, range 3-312); GA occurred at the same time as the diabetes diagnosis in 1 patient and after the diagnosis in 7 patients (median time 261 weeks, range 4-417). Among the 22 patients with diabetes, only 5 were asymptomatic and had diabetes diagnosed by blood screening; 7 patients were symptomatic (weakness, headaches, weight loss, polydipsia or polyuria) and the remaining patients had a history of diabetes without data on associated symptoms. Atopy was noted in 40 (4.8%) patients.

The most prevalent suspected triggering factors were local trauma (n=29, 3.5%) and
infections (n=22, 2.6%). Infections were diverse: viral infections in 7 patients (including
Epstein-Barr virus, rubella and varicella); upper respiratory-tract infection (n=7);
gastroenteritis, streptococcal pharyngitis, impetigo (n=2 each); and latent tuberculosis, oral
candidosis, otitis and isolated fever (n=1 each). Among the 15 patients with a vaccination
trigger, 10 had a bacille Calmette-Guerin vaccination preceding the GA. Two cases of
congenital GA were reported.

Characteristics of included patients by age

**Table II** shows the characteristics of patients according by age group: infants/toddlers < age 3 years, children 3 to 11 years old and adolescents ≥ 12 years old. Subcutaneous GA was more prevalent in infants/toddlers than others (n=50/71, 70.4%; p=0.025). In contrast, LGA was predominant in children (n=64/230, 27.8%) and adolescents (n=14/40, 35.0%, p=0.046). In all subgroups, the lower limb was the most frequent localization. Scalp involvement was more common in infants/toddlers than others (n=21/71, 29.6%; p<0.001), whereas hand involvement was more frequent in children than others (n=57/228, 25.0%; p=0.029).

Characteristics of included patients by GA subtype

Characteristics of patients by GA subtype are in **Table III**. Children with LGA were older
than those with GGA or SGA (mean age 7.5 vs 5.4 and 5.8 years, respectively, p=0.005).
Females were predominant in SGA, with 61.5% girls (n=169/275; p=0.026). The most
frequent localization in LGA was lower limbs (n= 64/146, 43.8%) and foot (n=51/146,
34.9%). Involvement of scalp was exclusively reported for SGA.

Diagnosis and management

For diagnosis, the most frequent examination was a skin sample for pathology examination,
obtained in 493 (59.0%) patients, and was mostly performed in GGA and SGA (93.6% and
93.1%, respectively) (Table III). Similarly, routine laboratory investigations were conducted
to find associated diseases in 326 (39.0%) patients and were performed mostly in GGA and
SGA (72.3% and 64.0%, respectively). Radiography, echography and MRI/CT were
exclusively performed in SGA. Data on treatments used for granuloma annulare were
available for 463 patients (missing data or no extractable data for 373 patients) (Figure 2 and
Table IV, online). Treatment was initiated in 265/463 (57.2%) patients and no treatment was
chosen for 198/463 (42.8%). Treatments observed in this review were predominantly surgery
(n=138) or topical corticosteroids (n=80). We found no difference in the efficacy of topical
corticosteroids regarding the potency class (Table IV (online)) (13). Associations of
treatments were used for only a few patients (n=11) are described in Table IV (online). The
efficacy of therapies is represented in Figure 2a and Table IV (online). Resolution outcomes
of these treatments by GA subtype are in Figures 2b, 2c and 2d.

Evolution

Complete spontaneous remission was achieved in 121/155 (78.1%) patients at a median of 12 months (IQR 3.0-12.0; data available for 110 patients), and partial spontaneous remission in 19/155 (12.3%) (Table I). A regression after biopsy was reported in 56/203 (27.6%) patients at a median of 1.75 months (IQR 1.0-3.75; data available for 22 patients). For the 265 patients with treatment, 195 (73.6%) showed complete resolution and 27 (10.2%) partial regression; 12 (4.5%) did not achieve resolution (n=30 [11.4%] patients with missing data for regression after treatment). Overall, 168/439 (38.3%, missing data for 397 patients) experienced recurrence regardless of the treatment received, with a median time to recurrence of 12 months [IQR 4-12] (data available for 69/168 patients). Recurrence was more frequent in SGA than LGA and GGA (46.5% vs 24.2 and 24.0, p<0.001) (Table III).

**Discussion**

Key results

To our knowledge, this is the first systematic review of focusing on clinical manifestations,
management and outcomes. The most common form was LGA, followed by SGA. Almost all
children were asymptomatic; however, pruritus was reported more frequently with GGA than other types and pain with SGA than other types. Most of the patients for whom no treatment was chosen as first-line therapy showed spontaneous remission at a median delay of 12 months. When a therapeutic approach was chosen, surgery or topical corticosteroids were the first-line treatments. Regardless of therapeutic approach, recurrence occurred in 38.3% of patients.

## Interpretation

Most of our results were consistent with the literature. In adults, GA occurs with a female predominance (F:M ratio 2:1) (10), whereas in children, Rapelanoro-Rabenja et al. reported a sex ratio of F/M of 1.3, which is close to our findings (14). However, we found LGA (46.8%) and SGA (43.0%) as the two most-reported subtypes. Most published data reported localized GA being the most common type, around 75% of patients and could be due to reporting bias as LGA is rather common and mostly not reported. Therefore, other findings can also be impacted by the unaligned prevalence of GA subtypes in this review (e.g. biopsy rate, recurrence rate).

Several associations have been reported for the development of GA in the literature (15). Diabetes, dyslipidemia, malignancies, local trauma, systemic infections, vaccination and thyroid disease are the most commonly reported associated conditions (10). Prevalence of comorbidities was very low in our study. No case of dyslipidemia was reported. Over the decades, the association of GA and diabetes mellitus has remained controversial (16,17). Kidd *et al.* suggested that glucose tolerance might be low in GA and that insulin resistance might exist (18). The latest studies suggested an association of GGA and diabetes in adults (12,19) but in children, small series failed to demonstrate homogenous results regarding a possible association. In our review, diabetes mellitus was observed in 2.6% of patients while the estimated prevalence of type 1 diabetes was 2.15 for 1000 youths in 2017 in United States and
approximately 1.3 for 1000 youths in France in 2015 (20,21). Diabetes mellitus was diagnosed with blood screening in only 5 in a cohort of 836 patients. Most diabetic children had a diagnosis based on typical symptoms (polyuria, polydipsia, weight loss) or already had diabetes at the time of GA.

In our review, a triggering factor was described for 12.9% of children; we found an association between previous infection, vaccination (mostly bacille Calmette-Guerin vaccination) or sun exposure with the onset of GGA. However, bites and stings were predominantly associated with LGA.

Although GA can be diagnosed clinically, histology was performed for most patients (59.0%), which may be related to publication bias. However, for SGA, a biopsy could be performed, mainly to rule out malignancy. As we observed in this review, treatment options vary. Evolution of the disease is unpredictable but mostly benign (22,23). Although the high rate of spontaneous remission we observed must be related to a publication bias (absence of spontaneous regression not described), therapy should be considered only in case of discomfort or symptoms.

We observed rapid resolution of GA after skin biopsy in almost one third of patients, which could suggest a cause-and-effect relation between GA resolution and skin biopsy as previously reported (24,25). Levin *et al*. suggested that biopsy or minor trauma could trigger resolution of GA by initiating a turnover of matrix proteins, neovascularization and wound healing (24).

Moreover, regardless of the therapeutic approach, recurrence occurred in more than one-third of cases, which was higher than previously reported (14,26). However, as reported in the Results section and stated before, missing data on GA recurrence (data on evolution were not available for almost half the patients) and the under-reporting of LGA may explain the high recurrence rate in our review.
Lastly, recurrence was more frequent in SGA than LGA and GGA. Therefore, invasive
 treatments such as surgery are not recommended, especially in the pediatric population.
Management for the generalized form of GA can be more challenging because lesions are less
 likely to self-resolve and can be resistant to treatment (11,27). In this review, phototherapy,
antimalarial drugs, dapsone and contrast-pulsed-laser were effective in small series and well
tolerated, which is mainly consistent with data regarding GGA treatments in adults (27). The
possible benefits of these treatments must be balanced with their side effects. Topical
treatments were often prescribed, but their efficacy was poor. However, conclusions regarding
the efficacy of topical corticosteroids are limited by the fact that many publications not
reporting the potency of topical corticosteroids used.

Limitations

Owing to the low prevalence of pediatric GA, one limitation of this review is that all the
included studies were case series and case reports. No randomized controlled trial was
included, so we could not perform a meta-analysis. Publication bias is another limitation
because only published articles were evaluated. Some large case series presented only pooled
data and did not allow for extracting individual data. Finally, for some variables, data were
not reported in articles and were considered as missing.

Conclusions

From this systematic review of pediatric GA, we suggest obtaining a blood glucose profile
only in patients with symptoms suggesting diabetes or those with risk factors (family history
of diabetes or personal history of obesity/hypertension). For asymptomatic GA, no treatment
should be proposed. Treatment should be considered for symptomatic patients and can
include topical treatment for LGA, surgery for SGA or systemic treatments for GGA resistant
to local treatment. Patients and parents should be informed of the risk of recurrence,
especially with SGA.
**Acknowledgements**

The authors thank Mrs Virginie Rochereau, librarian, University of Tours, for her technical
assistance by collecting the selected studies identified in the electronic databases via the
Interlibrary Loan. A detail of the articles identified via the Interlibrary Loan is available from
the corresponding author on request.

**Abbreviations used**

GA, granuloma annulare

GGA, generalized granuloma annulare

LGA, localized granuloma annulare

PGA, perforating granuloma annulare

SGA, subcutaneous granuloma annulare
References

1. Lemont H, Simon W. Granuloma annulare. Case reports of superficial and deep forms. J Am Podiatr Med Assoc 1987; 77:82-85.

2. Radcliffe Crocker. Granuloma annulare. Br J Dermatol 1902; 14:1-9.

3. Patrizi A, Gurioli C, Neri I. Childhood granuloma annulare: a review. G Ital Dermatol Venereol 2014; 149:663-674.

4. Patrizi A, Neri I, Guerrini V, Marini R, Fiorillo L. Granuloma annulare: clinical and laboratory findings in a pediatric group of patients. Acta Derm Venereol 1996; 76:326-8

5. Smith MD, Downie JB, DiCostanzo D. Granuloma annulare. Int J Dermatol 1997; 36:326-333.

6. Ben Mously R, el Euch D, Chakroun R, Mokni M, Cherif F, Azaïz M, et al. Le granulome annulare: à propos de 18 observations. Tunis Med 2003; 81:495-498.

7. Hogan P. Annular skin lesions with a smooth surface. Aust Fam Physician 1998; 27:1133-1134.

8. Muhlbauer JE. Granuloma annulare. J Am Acad Dermatol 1980; 3:217-230.

9. Argent JD, Fairhurst JJ, Clarke NM. Subcutaneous granuloma annulare: four cases and review of the literature. Pediatr Radiol 1994; 24:527-529.

10. Piette EW, Rosenbach M. Granuloma annulare: Pathogenesis, disease associations and triggers, and therapeutic options. J Am Acad Dermatol 2016; 75:467-479.

11. Thornsberry. Etiology, diagnosis, and therapeutic management of granuloma annulare: an update. Am J Clin Dermatol 2013; 14:279-290.

12. Yun JH, Lee JY, Kim MK, Seo YJ, Kim MH, Cho KH, et al. Clinical and pathological features of generalized granuloma annulare with their correlation: A retrospective multicenter study in Korea. Ann Dermatol 2009; 21:113-119.
13. World Health Organization (WHO). Who model prescribing information: drugs used in skin diseases. classification of topical corticosteroids, 2017. Available: http://apps.who.int/medicinedocs/en/d/Jh2918e/32.html

14. Rapelanoro-Rabenja F, Maleville J, Taïeb A. [Localized granuloma annulare in children: outcome in 30 cases]. Arch Pédiatrie 1995; 2:1145-1148.

15. Barron DF, Cootauco MH, Cohen BA. Granuloma annulare. A clinical review
Lippincotts Prim Care Pract. 1997; 1:33-39.

16. Spicuzza L, Salafia S, Capizzi A, Vitaliti G, Rotolo N, Leonardi S, et al. Granuloma annulare as first clinical manifestation of diabetes mellitus in children: a case report. Diabetes Res Clin Pract 2012; 95:e55-57.

17. Almazan E, Roh YS, Belzberg M, Qin CX, Williams K, Choi J, et al. Comorbidities associated with granuloma annulare: A cross-sectional, case-control study. Med Basel Switz 2020; 7:e53.

18. Kidd GS, Graff GE, Davies BF, McDermott MT, Aeling JL, Hofeldt FD. Glucose tolerance in granuloma annulare. Diabetes Care 1985; 8:380-384.

19. Barbieri JS, Rosenbach M, Rodriguez O, Margolis DJ. Association of granuloma annulare with type 2 diabetes, hyperlipidemia, autoimmune disorders, and hematologic malignant neoplasms. JAMA Dermatol 2021; 9:e211805

20. Lawrence JM, Divers J, Isom S, Saydah S, Imperatore G, Pihoker C, et al. Trends in prevalence of type 1 and type 2 diabetes in children and adolescents in the US, 2001-2017 JAMA. 2021; 326:717-727.

21. Briet C, Piffaretti C, Fosse S, Denis P, Allix I, Campagna A, et al. Épidémiologie du diabète de type 1 et de ses complications. Rev Prat 2018; 68:607-610.

22. Terziroli Beretta-Piccoli B, Mainetti C, Peeters M-A, Laffitte E. Cutaneous granulomatosis: a comprehensive review. Clin Rev Allergy Immunol 2018; 5:1-20.
54:131-146.

23. Dahl MV. Granuloma annulare: long-term follow-up. Arch Dermatol 2007; 143:946-947.

24. Levin NA, Patterson JW, Yao LL, Wilson BB. Resolution of patch-type granuloma annulare lesions after biopsy. J Am Acad Dermatol 2002; 46:426-429.

25. Hashizume H, Umayahara T. Case of granuloma annulare resolving after repetitive pricking. J Dermatol 2013; 40:761-762.

26. Martinon-Torres F, Martinon-Sanchez JM, Martinon-Sanchez F. Localized granuloma annulare in children: A review of 42 cases. Eur J Pediatr 1999; 158:866.

27. Lukács J, Schliemann S, Elsner P. Treatment of generalized granuloma annulare – a systematic review. J Eur Acad Dermatol Venereol 2015; 29:1467-1480.
**Figures legend**

**Figure 1 (online)**

Flow chart of included reports.

**Figure 2.**

(a) Therapies for pediatric granuloma annulare (with number of patients treated)

(b) Therapies for generalized granuloma annulare (with number of patients treated)

(c) Therapies for localized granuloma annulare (with number of patients treated)

(d) Therapies for subcutaneous granuloma annulare (with number of patients treated)

*For each treatment, resolution outcomes (complete efficacy, partial, none or worsening) and missing data are represented in percentage (from 0 to 100). Treatments reported for only one patient are not represented in Figure 2. Patients with no data on subtype on GA are not represented in Figures 2b, c and d.*
**Supplemental file**

**Table IV online.** Therapies for granuloma annulare.

**Supplemental file.** References of included studies