Prevalence And Contextual Factors Of Juvenile Fibromyalgia in A Population-Based Italian Sample Of Children And Adolescents Part 2

4. Discussion

To the best of our knowledge, this is the first study investigating the JFM prevalence in a large population-based sample of children and adolescents using the recent ACR criteria,  considering both versions of 2010 and 2016, as well as self-reported symptoms (minor criteria) of Yunus and Masi criteria.

Cistanche can act as an anti-fatigue and stamina enhancer, and experimental studies have shown that the decoction of Cistanche tubulosa could effectively protect the liver hepatocytes and endothelial cells damaged in weight-bearing swimming mice, upregulate the expression of NOS3, and promote hepatic glycogen synthesis, thus exerting anti-fatigue efficacy. Phenylethanoid glycoside-rich Cistanche tubulosa extract could significantly reduce the serum creatine kinase, lactate dehydrogenase, and lactate levels, and increase the hemoglobin (HB) and glucose levels in ICR mice, and this could play an anti-fatigue role by decreasing the muscle damage and delaying the lactic acid enrichment for energy storage in mice. Compound Cistanche Tubulosa Tablets significantly prolonged the weight-bearing swimming time, increased the hepatic glycogen reserve, and decreased the serum urea level after exercise in mice, showing its anti-fatigue effect. The decoction of Cistanchis can improve endurance and accelerate the elimination of fatigue in exercising mice, and can also reduce the elevation of serum creatine kinase after load exercise and keep the ultrastructure of skeletal muscle of mice normal after exercise, which indicates that it has the effects of enhancing physical strength and anti-fatigue. Cistanchis also significantly prolonged the survival time of nitrite-poisoned mice and enhanced the tolerance against hypoxia and fatigue.

Click on Covid Fatigue

【For more info:george.deng@wecistanche.com / WhatApp:8613632399501】

Although the 1990 ACR criteria were used to evaluate JFM prevalence in some target groups, they were never validated in the pediatric population. The 2010 ACR criteria,  designed for the diagnosis of FM in adults, were evaluated to be used for the diagnosis of JFM in adolescent females, with the Yunus and Masi criteria as the gold standard, with a  sensitivity of 89.4% and a specificity of 87.5%, suggesting that they can be applied to this population. Conversely, the 2016 ACR adult criteria have not been studied yet for use in the pediatric FM population.

Compared to the Yunus and Masi criteria, the 2010 ACR criteria have many advantages; in fact, they guarantee an easy and fast assessment of symptoms, and the exclusion of the tender points examination, which are not always present in the disease and are difficult to evaluate. Moreover, the absence of the tender points examination fosters the implementation of population studies on large samples such as ours, based on a self-compiled questionnaire to collect data instead of clinical evaluations carried out during medical examinations, which inevitably leads to a smaller numerousness.

The design of this study allows the comparison between different criteria for FM. Indeed, our results suggest that the 2010 preliminary criteria are more suitable for use in the pediatric population than the 2016 criteria, indicating that the assessment of the extent of somatic symptoms is helpful in this target group. 38 (0.5%) children met the 2010 ACR criteria, and only 4 (0.1%) the 2016 ACR criteria. Moreover, all the children who fulfilled the 2016 ACR criteria, also met the 2010 ACR criteria. Regarding Yunus and Masi criteria, for 46 (0.6%) children, 3 self-reported symptoms (minor criteria) have been referred;  however, the diagnosis of JFM must be confirmed by physical examination looking for the presence of at least 5 tender points.

According to 2010 ACR criteria, in our study, the prevalence of JFM is 0.5%, lower than those reported by other authors using the 1990 ACR criteria [12,13,16,17], and in a  retrospective study using the International Classification of Disease, ninth version (ICD IX) [14]. This variability may be due to racial and sociocultural differences between populations, as well as to the study design applied. Moreover, in comparing the prevalence described in different studies, the age range of the investigated sample has to be taken into account. In fact, in our study, the children/adolescents ranged between 1 and 17 years old, with a large group of children under the age of 8 (81.6%), which is different from previous studies which included only a 9 to 15 years old population. JFM  is rare among children younger than 9, and the average age of diagnosis in children and adolescents is around 13–15 years [3,6,18,19]. The statistically significant association we have found between age and positivity for the ACR criteria—either 2010 or 2016—confirms the above concerns. What seems to emerge is that the 2010 ACR criteria are more selective for the diagnosis of JFM than those of 1990.

Differently from other studies conducted in adult or pediatric populations [12,13,16,20],  the prevalence of JFM in our survey does not statistically differ between sexes, although it tends to be higher among females (according to the 2010 ACR criteria: 0.6% among females; 0.4% among males). These data agree with the progressive reduction of the female/male ratio in the incidence of FM in studies that do not use tender points as a criterion [21].

Almost all the symptoms investigated by our questionnaire (somatic symptoms of the ACR 2010 criteria and the Yunus and Masi questionnaire) were reported by our patients. Table 6 describes the percentage of symptoms detected among the children of our sample who met the 2010 ACR criteria in comparison with those described in a study by Wolfe (1990) conducted in adults, as well as in other surveys performed in children with JFM.

The rate of widespread pain is similar in all studies (93–100%). On the contrary, fatigue is more frequent in our work (94.7%) than that reported in the other studies;  in particular, it was much more frequent than that described by Siegel (62%), Eraso, and Gedalia (20–28%) [20,23], and slightly higher than those reported by Yunus (91%) and Wolfe (81%). Sleep disorders (68.4%), headaches (78.9%), and abdominal symptoms (26.2%)  tend to be as frequent as reported in the other studies. The exceptions were the percentage of sleep disturbances, which was higher in Siegel’s work (96%), and headache, which was lower in the studies by Wolfe and Yunus (53 and 58%, respectively). Instead, depression (57.9%) and anxiety (86%) are significantly more represented in our study than in the other surveys, especially concerning the Eraso and Gedalia studies.

Our data confirm that fatigue and depression are very common symptoms among patients with FM, supporting the particular prominence given in the 2010 and 2016 ACR  diagnostic criteria [3], together with sleep disorders, headache, and abdominal symptoms. In addition, cognitive symptoms, which are very frequent in our casuistry (difficulties in thinking and remembering: 36.8%; difficulties in studying: 63.2%), are relevant in the recent criteria [3] while they were not investigated in the other studies that used different criteria for JFM.

Subjective sensations such as soft tissue swelling, stiffness, and numbness are reported with a wide variability in frequency (Table 6), confirming the difficulty in detecting them in the pediatric population.

The variability in the prevalence of somatic symptoms reported by other authors, as well as the similarities and the differences concerning our data (Table 6), can be due to the diversity of the population studied (primarily, the age range), the items included into the questionnaires used as survey tools, and the methods for data collection (for example,  online questionnaire, telephone interview, face-to-face interview conducted in the clinic). Nonetheless, the studies confirm the multiplicity of symptoms in JFM and the complexity of its diagnosis.

As far as the multiplicity of symptoms is concerned, in our study, several symptoms appear to be very common, as follows (in order of frequency): dysmenorrhea (80% among females over 10 years), diarrhea/constipation (78.8%), muscle weakness in the legs (60.5%),  cold hands and feet (44.7%), itching (42.1%), chest pain (39.5%), nausea/heartburn (39.5%),  cramps (39.5%), mild fever (36.8%), shaking of the legs in bed (36.8%), shortness of breath (28.9%), tingling (28.9%), rash/hives (26.3%), palpitations (21.1%), and dizziness (21.1%). Moreover, all these symptoms are significantly more frequent among children who met the 2010 ACR criteria, with the exclusion of rash/hives.

Therefore, the data from our study do not allow us to be totally in agreement with the recommendation of Ting [17] concerning the removal of some items from the list of somatic symptoms such as chest pain, fever, cold hands and feet, and vomiting. On the other hand, we agree on the deletion of other items such as oral ulcers, loss of/change in taste, seizures, hearing difficulties, hair loss, painful urination, hives/welts, sun sensitivity,  and bladder spasms.

Pain is reported by 100% of children who met the 2010 ACR criteria; considering the severity, the mean WPI score was 4.5 (±1.5), a little lower than that reported by Ting [17] in 97 children with JFM using the 2010 ACR criteria (6.3 ± 1.6), and by Wolfe [2] in a sample of adults with FM (6.5 ± 2.3). The abdomen (52.6%) and legs (47% left and 52.6% right) are the areas where the pain was most frequently reported. These areas correspond perfectly to the most frequent painful sites reported by Yunus [6] who considers the joints of the limbs (knees and ankles) and does not take into consideration the abdomen. In this regard, we observe that among children for whom the diagnosis of JFM has been delayed, the pain in the lower limbs is often interpreted as “growing pains” [8,24].

According to our data, neck (31.6%), upper and lower back, upper arm, and chest (28.9%) are the body areas in which pain was reported for a greater number of children who met the 2010 ACR criteria, corresponding (in order of frequency) to elbows, lower and upper back, wrists, cervical spine, trapezius, and hands as reported in the Yunus study.

To our knowledge, only the study conducted by Ting has been performed among children using 2010 ACR criteria [17]; in that study, 47 girls aged 11–17 years (mean age 15.3)  recruited by the Rheumatology Clinic of Cincinnati were included. The SSS score calculated in our study is higher than that described by Ting (7.5 vs. 5.75), while WPI is lower (4.5 vs. 10.9) and symptom count is similar (12.5 vs. 14.4); in particular, in our sample, more children have mild and moderate levels of symptoms and fewer have severe ones. These differences may be due to the younger age of our group, as well as the study design: in our study, a population-based sample has been included while in that conducted by Ting,  the children have been enrolled in a Rheumatology Clinic.

Therefore, our results obtained using different criteria for FM (Yunus and Masi, 2010  and 2016 ACR criteria for FM) allow us to conclude, in agreement with Ting, that the 2010 ACR criteria offer a simplified means to diagnose a condition as complex as JFM. Compared to the previous classification criteria, these criteria have several advantages as they are based only on the 2010 questionnaire, which can be quickly filled in also by the parents and therefore easily used either in a clinical setting or in an epidemiological population-based study. Furthermore, the 2010 criteria, unlike the 1990 ACR criteria, include the assessment of a large number of important symptoms for the JFM diagnosis, as well as the severity of the main ones: fatigue, unrefreshing sleep, and cognitive symptoms. In the end, compared to the later 2016 criteria, our data indicate that the questionnaire based on the 2010 criteria, which includes multiple symptoms, is more comprehensive and gives more complete and useful information to diagnose JFM.

In this study, contextual factors of the children (relationship with peers, relationship with parents, school performance, and being bullied), previous painful traumatic situations (road accidents, injury in the leisure time, surgery), and contextual and clinical factors of the parents (cohabiting parents, to have diffuse pain, having had a diagnosis of fibromyalgia,  to use or have used psychotropic drugs) have also been investigated. Bivariate analysis revealed that JFM diagnosis according to the 2010 ACR criteria is significantly associated with most of the investigated variables. In particular, children who met the criteria for FM had significantly worse relationships with peers or with parents, had worse school performance,  have been more frequently bullied, were involved in leisure time accidents (with persistent pain),  and had surgeries. Moreover, their parents more frequently are not cohabitants, presented diffuse pain, had a diagnosis of fibromyalgia, or use or had used psychotropic drugs. The results confirm what has been reported by other authors.

Familial aggregation is a well-documented feature of FM [25,26]. Rosenblatt et al. (1997) [27]  studied 34 children with JFM aged 11 (±1) years and their mothers, observing a significant predominance of mothers with FM in the group of children with JFM (71%) compared to children with diffuse pain (30%) and asymptomatic children (0%). In addition, a significant correlation between polysomnographic indexes, sleep anomalies, and pain manifestations was present in children and their mothers.

Nelson et al. (2017) [28] studied 86 young adults with JFM and found that 37% of them reported a trauma history. JFM participants with and without a trauma history did not significantly differ for pain and physical functioning, but JFM participants with a trauma history were significantly more likely to have psychological comorbidities.

Hypermobility syndrome is a well-known clinical association of JFM [29]. The most probable hypothesis is that hyperlaxity leads to recurrent micro-trauma and occasional joint dislocation. The resulting recurrent peripheral pain may lead to the development of central sensitization and then JFM. Consistent with our results, in the study of Imbierowicz and Egle (2001) [30], the patients with FM, compared to patients with other pain disorders,  showed the highest score of childhood adversities. In addition to sexual abuse and physical maltreatment, the FM patients reported more frequently a poor emotional relationship with both parents, a lack of physical affection, experiences of parents’ physical quarrels, as well as alcohol or other problems of addiction of the mother, separation, and a poor financial situation before the age of seven.

Moreover, in the study by Schanberg et al. [31], parents of children with JFM reported multiple chronic pain conditions, including FM and their pain history, and the family environment correlated with the health status of adolescents with JFM.

Kashikar-Zuch et al. (2008) [32] detected JFM family relationships were characterized by higher levels of conflict, lower levels of cohesion, and less organizational structure than comparison families. Furthermore, mothers of adolescents with JFM reported significantly greater depressive symptoms than mothers of comparison peers.

In another work, Kashikar-Zuch et al. (2007) [33] assessed the peer relationships of adolescents with JFM and demonstrated that, from the perspective of peers, they are consistently rated as more sensitive/isolated than their healthy peers, having significantly fewer friends, fewer reciprocated friendships, and being less well-liked.

Multivariate analysis confirms the significant associations between some of the contextual factors investigated. In particular, the likelihood of meeting the 2010 ACR criteria was significantly higher for children older than 8 years old (OR: 2.42), among those who had injuries during their leisure time that caused persistent pain (OR: 6.49), whose parents (at least one) had a diagnosis of fibromyalgia (OR: 2.54) or had diffuse pain (OR: 9.09). On the contrary, relationships with peers and with parents, school performance, being bullied,  cohabiting parents, and the use of psychotropic drugs by parents were excluded during the stepwise procedure, probably due to collinearity with other variables.

This study has some limitations. First, a convenience sample has been included,  since the questionnaire was sent only to the parents of the children assisted by family pediatricians who joined the study. Moreover, the participation of the parents was voluntary. Therefore, we cannot exclude a selection bias for both—family pediatricians and parents—  that may have affected the results. Additionally, data were collected through an online self-reported questionnaire filled in by the parents to collect data regarding the health status of the children as well as their conditions. In this perspective, recall bias, lack of knowledge regarding mild symptoms of the children, and social desirability bias could have affected some of the results. On the other hand, the study design, in particular the use of an online self-reported questionnaire, allowed us to recruit a large sample size.

5. Conclusions 

Our study made it possible to calculate the prevalence of JFM in a large population-based sample of children and adolescents, using family pediatricians who used a telehealth medicine system based on a digital platform. Despite the many limitations,  the results provide some useful information for the diagnosis and the prevention of JFM. First, 2010 ACR criteria are confirmed as the more appropriate for children and adolescents, and the ease and quickness of use even by non-specialists move toward their applicability in pediatrician clinical practice, at least as an initial screening tool for JFM. Second, the analysis of contextual factors in the results suggests the need for family pediatricians to pay particular attention to the most important predictors of JFM, to prevent the syndrome or to anticipate the diagnosis.

In particular, we strongly advise family pediatricians not to underestimate children experiencing recurring pain that cannot be attributed to an organic cause. It is crucial to investigate whether these children exhibit any of the common symptoms associated with fibromyalgia, such as fatigue, sleep difficulties, headaches, or abdominal discomfort. We also recommend pediatricians inquire about the following factors: non-cohabitant parents, presence of diffuse pain, previous diagnosis of fibromyalgia, past or current use of psychotropic drugs, strained relationships with peers or parents, poor academic performance, history of bullying, involvement in leisure time accidents, and past surgeries.

This study also emphasizes the potential of implementing telehealth and digital platforms in providing proactive healthcare. These platforms enable patients to be questioned about their overall health, unveiling potential underdiagnosed conditions.

Finally, we hope further works on children suffering from chronic pain syndromes will provide pediatricians with tools to better diagnose and effectively treat this underserved population, prevent the unrecognition of JFM, and avoid the fast progression towards the more severe forms of FM in adulthood.

Author Contributions: Conceptualization, S.M.B., G.V.R. and C.L.; methodology, S.M.B., G.V.R., and C.L.; formal analysis, C.L.; investigation, S.M.B., and G.V.R.; data curation, C.L.; writing—original draft preparation, S.M.B., and C.L.; writing—review and editing, S.M.B., G.V.R., G.B. and C.L.;  supervision, G.B. All authors have read and agreed to the published version of the manuscript.

Funding: This research received no external funding. 

Institutional Review Board Statement: Not applicable due to the study design (observational nonprofit study cross-sectional study in which data are collected using an anonymous questionnaire voluntarily filled in by the parents of the children; parents were previously informed of the purpose of the study and agreed to participate; the link to the online questionnaire was diffused by the pediatricians of the children so the research team does not have the list of the parents; the collected data keep the anonymity of the respondents). The study was conducted according to the Helsinki Declaration, without risks for the participants.

Informed Consent Statement: Informed consent was obtained from all subjects involved in the study. Participants cannot be identified by the research group. 

Data Availability Statement: Data are available for scientific purposes upon request to the corresponding author. 

Acknowledgments: The authors would like to thank the pediatricians who joined the study: Lucietta Antonelli, Antonina Barreca, Emanuela Bonfigli, Domenico Capomolla, Domenico Cappellucci, Antonella Casani, Laura Cianciosi, Giuseppe Collacciani, Melina Cuzzucoli, Sergio Davi’, Liliana Di Giovine, Silvana Di Palma, Vittoria Dominijanni, Guido Donato, Maria Donnarumma, Maria Esposito, Saverio Ferraro, Antonio Gallese, Silvana Grasso, Salvatore Iasevoli, Eustachio Lapacciana, Mariangela Lepido, Maria Rosaria Maestro, Nunzia Maria Manzo, Giuseppe Marini, Umberto Muzii, Antonio Opallo, Ivana Orsini, Giovanni Pacciani, Salvatore Panasia, Antonietta Pascuzzi, Rita Antonina Paterra, Felice Petrelli, Antonino Putortì, Daniela Ranghieri, Anna Maddalena Renzi, Rosanna Rosa, Romano Rosati, Laura Saraceni, Maria Cristina Spada, Amedeo Spinelli, Nicola Pio Squadrone, Giuseppe Squazzini, Adalgisa Stendardo, Elisabetta Tarquini, Maria Tavano, and Antonio Valerioti. Moreover, the authors would like to thank Omar Loiudice, Arnaldo Campanella, and Daniela Di Luigi from Liver Pediatotem for their technical support.

Conflicts of Interest: The authors declare no conflict of interest.

References

1. Arnold, L.M.; Clauw, D.J.; McCarberg, B.H.; Fibro Collaborative. Improving the recognition and diagnosis of fibromyalgia. Mayo Clin. Proc. 2011, 86, 457–464. [CrossRef]

2. Wolfe, F.; Clauw, D.J.; Fitzcharles, M.A.; Goldenberg, D.L.; Katz, R.S.; Mease, P.; Russell, A.S.; Russell, I.J.; Winfield, J.B.; Yunus, M.B. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res. 2010, 62, 600–610. [CrossRef] 

3. Wolfe, F.; Clauw, D.J.; Fitzcharles, M.A.; Goldenberg, D.L.; Häuser, W.; Katz, R.L.; Mease, P.J.; Russell, A.S.; Russell, I.J.; Walitt, B. Revisions to the 2010/2011 fibromyalgia diagnostic criteria. Semin. Arthritis Rheum. 2016, 46, 319–329. [CrossRef] 

4. Wolfe, F.; Smythe, H.A.; Yunus, M.B.; Bennett, R.M.; Bombardier, C.; Goldenberg, D.L.; Tugwell, P.; Campbell, S.M.; Abeles, M.; Clark, P.; et al. The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum. 1990, 33, 160–172. [CrossRef] [PubMed] 

5. Kashikar-Zuck, S.; King, C.; Ting, T.V.; Arnold, L.M. Juvenile Fibromyalgia: Different from the Adult Chronic Pain Syndrome? Curr. Rheumatol. Rep. 2016, 18, 19. [CrossRef] 

6. Yunus, M.B.; Masi, A.T. Juvenile primary fibromyalgia syndrome. A clinical study of thirty-three patients and matched normal controls. Arthritis Rheum. 1985, 28, 138–145. [CrossRef] [PubMed] 

7. De Sanctis, V.; Abbasciano, V.; Soliman, A.T.; Soliman, N.; Di Maio, S.; Fiscina, B.; Kattamis, C. The juvenile fibromyalgia syndrome (JFMS): A poorly defined disorder. Acta Biomed. 2019, 90, 134–148. [CrossRef] [PubMed] 

8. Kashikar-Zuck, S.; Cunningham, N.; Sil, S.; Bromberg, M.H.; Lynch-Jordan, A.M.; Strotman, D.; Peugh, J.; Noll, J.; Ting, T.V.; Powers, S.W.; et al. Long-term outcomes of adolescents with juvenile-onset fibromyalgia in early adulthood. Pediatrics 2014, 133, e592–e600. [CrossRef] [PubMed] 

9. Walitt, B.; Fitzcharles, M.A.; Hassett, A.L.; Katz, R.S.; Häuser, W.; Wolfe, F. The longitudinal outcome of fibromyalgia: A study of 1555 patients. J. Rheumatol. 2011, 38, 2238–2246. [CrossRef] 

10. Kashikar-Zuck, S.; Zafar, M.; Barnett, K.A.; Aylward, B.S.; Strotman, D.; Slater, S.K.; Allen, J.R.; Lecates, S.L.; Kabbouche, M.A.; Ting, T.V.; et al. Quality of life and emotional functioning in youth with chronic migraine and juvenile fibromyalgia. Clin. J. Pain. 2013, 29, 1066–1072. [CrossRef] 

11. Kashikar-Zuck, S.; Johnston, M.; Ting, T.V.; Graham, B.T.; Lynch-Jordan, A.M.; Verkamp, E.; Passo, M.; Schiller, K.N.; Hashkes, P.J.; Spalding, S.; et al. Relationship between school absenteeism and depressive symptoms among adolescents with juvenile fibromyalgia. J. Pediatr. Psychol. 2010, 35, 996–1004. [CrossRef] 

12. Clark, P.; Burgos-Vargas, R.; Medina-Palma, C.; Lavielle, P.; Marina, F.F. Prevalence of fibromyalgia in children: A clinical study of Mexican children. J. Rheumatol. 1998, 25, 2009–2014. 

13. Buskila, D.; Press, J.; Gedalia, A.; Klein, M.; Neumann, L.; Boehm, R.; Sukenik, S. Assessment of nonarticular tenderness and prevalence of fibromyalgia in children. J. Rheumatol. 1993, 20, 368–370. [PubMed] 

14. Weir, P.T.; Harlan, G.A.; Nkoy, F.L.; Jones, S.S.; Hegmann, K.T.; Gren, L.H.; Lyon, J.L. The incidence of fibromyalgia and its associated comorbidities: A population-based retrospective cohort study based on International Classification of Diseases, 9th Revision codes. Clin. Rheumatol. 2006, 12, 124–128. [CrossRef] [PubMed] 

15. Sil, S.; Lynch-Jordan, A.; Ting, T.V.; Peugh, J.; Noll, J.; Kashikar-Zuck, S. Influence of family environment on long-term psychosocial functioning of adolescents with juvenile fibromyalgia. Arthritis Care Res. 2013, 65, 903–909. [CrossRef] [PubMed] 

16. Gerloni, V.; Ghirardini, M.; Fantini, F. Assessment of nonarticular tenderness and prevalence of primary fibromyalgia syndrome in healthy Italian school children. Arthritis Rheum. 1998, 41, S267. 

17. Ting, T.V.; Barnett, K.; Lynch-Jordan, A.; Whitacre, C.; Henrickson, M.; Kashikar-Zuck, S. 2010 American College of Rheumatology Adult Fibromyalgia Criteria for Use in an Adolescent Female Population with Juvenile Fibromyalgia. J. Pediatr. 2016, 169, 181–187.e1. [CrossRef] [PubMed] 

18. Kaufman, E.L.; Tress, J.; Sherry, D.D. Trends in Medicalization of Children with Amplified Musculoskeletal Pain Syndrome. Pain Med. 2017, 18, 825–831. [CrossRef] 

19. Lawrence, R.C.; Felson, D.T.; Helmick, C.G.; Arnold, L.M.; Choi, H.; Deyo, R.A.; Gabriel, S.; Hirsch, R.; Hochberg, M.C.; Hunder, G.G.; et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part. II. Arthritis Rheum. 2008, 58, 26–35. [CrossRef] 

20. Eraso, R.N.; Bradford, N.J.; Fontenot, C.N.; Espinoza, L.R.; Gedalia, A. Fibromyalgia syndrome in young children: Onset at age 10 years and younger. Clin. Exp. Rheumatol. 2007, 25, 639–644. 

21. Arnold, L.M.; Bennett, R.M.; Crofford, L.J.; Dean, L.E.; Clauw, D.J.; Goldenberg, D.L.; Fitzcharles, M.A.; Paiva, E.S.; Staud, R.; Sarzi-Puttini, P.; et al. AAPT Diagnostic Criteria for Fibromyalgia. J. Pain 2019, 20, 611–628. [CrossRef] [PubMed] 

22. Siegel, D.M.; Janeway, D.; Baum, J. Fibromyalgia syndrome in children and adolescents: Clinical features at presentation and status at follow-up. Pediatrics 1998, 101, 377–382. [CrossRef] [PubMed] 

23. Gedalia, A.; García, C.O.; Molina, J.F.; Bradford, N.J.; Espinoza, L.R. Fibromyalgia syndrome: Experience in a pediatric rheumatology clinic. Clin. Exp. Rheumatol. 2000, 18, 415–419. 

24. Uziel, Y.; Chapnick, G.; Jaber, L.; Nemet, D.; Hashkes, P.J. Five-year outcome of children with “growing pains”: Correlations with pain threshold. J. Pediatr. 2010, 156, 838–840. [CrossRef] [PubMed] 

25. Buskila, D.; Neumann, L.; Hazanov, I.; Carmi, R. Familial aggregation in the fibromyalgia syndrome. Semin. Arthritis Rheum. 1996, 26, 605–611. [CrossRef] [PubMed]

26. Arnold, L.M.; Hudson, J.I.; Hess, E.V.; Ware, A.E.; Fritz, D.A.; Auchenbach, M.B.; Starck, L.O.; Keck, P.E., Jr. Family study of  fibromyalgia. Arthritis Rheum. 2004, 50, 944–952. [CrossRef] 

27. Roizenblatt, S.; Tufik, S.; Goldenberg, J.; Pinto, L.R.; Hilario, M.O.; Feldman, D. Juvenile fibromyalgia: Clinical and polysomnographic aspects. J. Rheumatol. 1997, 24, 579–585. 

28. Nelson, S.; Cunningham, N.; Peugh, J.; Jagpal, A.; Arnold, L.M.; Lynch-Jordan, A.; Kashikar-Zuck, S. Clinical Profiles of Young Adults with Juvenile-Onset Fibromyalgia with and Without a History of Trauma. Arthritis Care Res. 2017, 69, 1636–1643. [CrossRef] 

29. Sendur, O.F.; Gurer, G.; Bozbas, G.T. The frequency of hypermobility and its relationship with clinical findings of fibromyalgia patients. Clin. Rheumatol. 2007, 26, 485–487. [CrossRef] 

30. Imbierowicz, K.; Egle, U.T. Childhood adversities in patients with fibromyalgia and somatoform pain disorder. Eur. J. Pain. 2003, 7, 113–119. [CrossRef] 

31. Schanberg, L.E.; Keefe, F.J.; Lefebvre, J.C.; Kredich, D.W.; Gil, K.M. Social context of pain in children with Juvenile Primary Fibromyalgia Syndrome: Parental pain history and family environment. Clin. J. Pain. 1998, 14, 107–115. [CrossRef] [PubMed] 

32. Kashikar-Zuck, S.; Lynch, A.M.; Slater, S.; Graham, T.B.; Swain, N.F.; Noll, R.B. Family factors, emotional functioning, and functional impairment in juvenile fibromyalgia syndrome. Arthritis Rheum. 2008, 59, 1392–1398. [CrossRef] [PubMed] 

33. Kashikar-Zuck, S.; Lynch, A.M.; Graham, T.B.; Swain, N.F.; Mullen, S.M.; Noll, R.B. Social functioning and peer relationships of adolescents with juvenile fibromyalgia syndrome. Arthritis Rheum. 2007, 57, 474–480. [CrossRef] [PubMed]

Disclaimer/Publisher’s Note: The statements, opinions, and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions, or products referred to in the content.

【For more info:george.deng@wecistanche.com / WhatApp:8613632399501】