Growing pains: What do we know about etiology? A systematic review

Table 1 The main findings of included case-control and cohort studies

Ref.	Author	Subjects	Etiology	Results
[10]	Pavone et al (2011)	30 with growing were enrolled and prospectively followed up for 1 yr. Laboratory tests, including complete blood count, erythrocyte sedimentation rate, and serum calcium and phosphorus levels, were performed in all children	Family history	A family history of growing pains was positive in 20% of patients
[12]	Hashkes et al (2004)	In 44 children with growing pains and 46 healthy controls, pain thresholds were measured using a Fisher type dolorimeter with pressure applied to areas associated with increased tenderness in fibromyalgia, control points and anterior tibia	Lower pain threshold	Children with growing pains have more tender points and show lower pain thresholds if compared to healthy children. Growing pains might represent a non inflammatory pain syndrome in young children
[13]	Uziel et al (2010)	In the 44 previously studied children with growing pains and in 38 healthy controls, current status of growing pains and other pain syndromes were assessed by parental questionnaires. Pain threshold was also measured by using a Fisher-type dolorimeter	Lower pain threshold	The prognosis of growing pains is benign and with a tendency to self limitation. Growing pains might represent a pain amplification syndrome of early childhood
[14]	Oster et al (1972)	635 children were examined annually for five consecutive years or more. Of these, 185 experienced abdominal pain and/or headache for three consecutive years or more while 166 children never had experience of them. Questionnaires were sent to the parents in whom they were ask whether they experienced abdominal pain, headache and/or limb pains in childhood or at the time of investigation	Changes in vascular perfusion	A high prevalence of migraine headaches among children with growing pains have been reported. Recurring abdominal pain, migraine headaches and growing pains are strongly associated and might be part of a reaction pattern based on child’s constitution and domestic environment
[15]	Hashkes et al (2005)	11 patients with growing pains and 12 healthy controls underwent technetium-99 methylene diphosphate bone scans. The uptake in the blood pool phase, static images, and blood pool phase/static image ratio were measured in the right mid-tibia region (painful among patients with growing pains) and right mid-femur (non-painful). Measurements at painful and painless regions among growing pains children were done. Also children with or without growing pains were compared	Changes in vascular perfusion	There were no significant differences between children with growing pains and healthy controls in the blood pool, static images, and blood pool/static images in all localities. There were also no significant differences among painful regions and non-painful regions in children with growing pains. Growing pains are not associated with vascular perfusion changes in painful regions
[16]	Kaspiris et al (2016)	The syudy examined 276 children whose data were collected by using a combination of questionnaires, clinical examinations and medical charts of the children and the obstetric history of the mothers. 78 children presenting growing pains met Peterson’s criteria. The tibiofemoral angle and the intermalleolar distance were measured. The perinatal characteristics regarding gestational age, birth weight, length, head circumference, Apgar score, maternal infection, mode of delivery, use of medication and antenatal use of corticosteroids, alcohol or smoking during pregnancy which were based on the medical charts of the children and the maternal obstetrical history were recorded	Genu valgum and perinatal risk factors	Genu valgum severity was a significant factor for growing pains manifestation and increment in frequency and intensity. Perinatal factors including gestational age, Apgar score, head circumference and birth length or weight seemed to be important in growing pains’ onset. Conversely, antenatal corticosteroid treatment, increased maternal age and maternal smoking during pregnancy were not predictive of growing pains.
[17]	Kaspiris et al (2007)	The study included 532 children, aged 4 to 12 yr. 130 children presented growth pains. Children which had been breastfed were compared to those which were not	Breastfeeding	There is a statistically significant dependence between the presentation of pains and whether the child had been breastfed or not, as well as the duration of breastfeeding during infancy. However, in children with growing pains, breastfeeding does not affect the type or frequency of pain
[18]	Lee et al. (2015)	20 patients (seven boys, 13 girls), mean age 9.10 ± 2.32 yr, complaining of musculoskeletal pains in the lower extremities treated with custom made foot orthoses	Foot posture	Twenty children completed the study. Seventeen (75%) had overpronated feet. Significant improvements were noted after 1 and 3 mo in pain degree and frequency, and after 3 mo in balancing ability
[19]	Evans (2003)	8 children complaining of aching legs and with pronated foot posture were treated by wearing triplane wedges or orthoses	Foot posture	In-shoe wedges and foot orthoses are effective in the treatment of young children with growing pains and a pronated foot posture. A relationship between foot posture and growing pains is tenuously inferred
[20]	Evans and Scutter (2007)	180 children underwent foot posture measurements including navicular height, navicular drop, resting calcaneal stance position, foot posture index criteria FPI4 calcaneal inversion/eversion, FPI5 talo-navicular region, FPI6 medial longitudinal arch	Foot posture	No meaningful relationship between foot posture or functional health measures and leg pain in young children does exist
[21]	Viswanathan and Khubchandani (2008)	The study group consisted of 433 children. Joint hypermobility was assessed by using Beighton criteria Children were considered to have growing pains when fulfilling Petersons criteria	Hypermobility	Joint hypermobility and growing pains in schoolchildren are strongly associated. Joint hypermobility might play a role in the pathogenesis of growing pains
[22]	Friedland et al (2005)	In 39 children with growing pains, bone speed of sound was measured by quantitative ultrasound in both mid-tibial and radius bones. Patients’ findings were compared to norms of healthy controls	Reduced bone strenght	Bone speed of sound was significantly reduced in children with growing pains, especially in painful tibial regions. Growing pains might represent a local overuse (stress) syndrome
[23]	Uziel et al (2012)	In 39 previously studied children with growing pains, current growing pains status was assessed by parental questionnaires. Bone strength was measured by using quantitative ultrasound. Controls were normograms based on the measurement of bone speed of sound in 1085 healthy children	Reduced bone strenght	Pain improves parallel to the increase in bone strength. Growing pains might represent a local overuse syndrome
[24]	Qamar et al (2008)	100 children with growing pains were investigated for serum total calcium, inorganic phosphorus, alkaline phosphatase, vitamin D3 and parathormone levels. On the basis of serum vitamin D3 level, patients were divided into 3 groups; normal level of vitamin D3, vitamin D insufficiency, vitamin D deficiency	Hypovitaminosis D	Hypovitaminosis D might have a role in pathogenesis of growing pains. Children with unexplained limb pains should be tested for vitamin D status, and treated, if needed
[25]	Morandi et al (2005)	In 33 children affected by growing pains pain intensity was evaluated through a questionnaire using the Wong–Baker Faces Pain Rating Scale for pain assessment. Serum 25-OH-D, parathyroid hormone, and alkaline phosphatase levels were also measured. QUS measured both bone density and cortical thickness. After 3 and 24 mo of vitamin D supplementation, pain intensity and laboratory results were re-evaluated. After 24 mo, also QUS parameters we re-assessed	Hypovitaminosis D	After 3 mo of vitamin D supplementation, 25 OH-D levels increased while both parathyroid hormone levels and pain intensity decreased. After 24 mo, parathyroid hormone levels and pain intensity further decreased while QUS parameters improved. A relationship between growing pains, vitamin D levels and bone mineral status might exists
[26]	Vehapoglu et al (2015)	In 120 children with growing pains, serum 25(OH)D and bone mineral levels were evaluated at the time of enrollment. The pain intensity of those children with vitamin D deficiency was assessed by the pain VAS. After a single oral dose of vitamin D, the pain intensity was re measured at 3 mo. The 25(OH)D levels and VAS scores before and after oral vitamin D administration were compared	Hypovitaminosis D	Supplementation with oral vitamin D resulted in a significant reduction in pain intensity among those children affected by growing pains who also had hypovitaminosis D
[27]	Park et al (2015)	In 140 children with growing pains, levels of serum 25-(OH) D were measured.	Hypovitaminosis D	The high prevalence of vitamin D deficiency or insufficiency in Korean children with nonspecific lower-extremity pains, indicative the association between vitamin D deficiency and growing pains have been found
[28]	Insaf (2015)	36 child with growing pains underwent serum levels of vitamin D measurement at the time of presentation. Patients with low level of vitamin D were incorporated into a prospective cohort study and their pain intensity was measured utilizing a pain VAS. After a single oral or intramuscular dose of vitamin D given to those with low vitamin D levels, pain intensity was re measured at 1 mo. The vitamin D levels and (VAS) scores prior and then vitamin D treatment were compared	Hypovitaminosis D	Many children with growing pain had low vitamin D levels. Treatment with vitamin D resulted in diminishing pain severity in those children with growing pains which also had low vitamin D levels
[29]	Evans and Scutter (2004)	The prevalence of growing pains in children 4 to 6 yr of age in South Australia were reported. A survey of the parents of children, using a validated questionnaire previously developed for this purpose was used. The sample was systematic and randomized across rural and urban regions, with a total of 1445 valid responses achieved	Family history	Family history in growing pains have been reported
[30]	Champion et al (2012)	A twin family design study was applied to 88 pairs with at least one twin individual fulfilling criteria for growing pains. Questionnaires for history of growing pains and restless legs syndrome were completed for these twin pairs, their siblings and parents	Family history	Growing pains might have a genetic etiology and a genetic relationship with restless legs syndrome
[31]	Haque et al (2016)	Across sectional study included children from four kindergarten schools was carried out. Questionnaires were distributed among the children for indentifying children with limb pain which were selected for further history and clinical examination. Age and sex matched healthy children were selected as controls for comparison of risk factors	Family history	Obesity, over activity and especially family history were identified as growing pains’ risk factors
[32]	Naish and Apley (1951)	721 children and their mother were questioned regarding the occurrence of pains. Those children with a history satisfying the criteria were examined at the time and subsequently more fully. The assessment was particularly directed to history of pain, family and personal history and mentality whose assessment included school attainments, school and home behavior. Healthy children were questioned and examined in a similar manner as controls	Psychological disturbances	Few children ad an evident over-reaction to all forms of pain, accompanied by emotional instability. The mother’s emotional reactions were also excessive. Emotional disturbances were commoner in children with growing pains. Those children were frequently irritable, nervous, afraid of the dark and also suffering from bad dreams, nightmares, nocturnal enuresis or tics
[33]	Oberklaid et al (1997)	160 children with growing pains were compared with a group of 160 healthy controls. In assessing children’s behavior and temperament at home and school, mothers and teachers were ask to complete several questionnaires	Psychological disturbances	Children with growing pains were rated by their parents but not by their teachers as having different behavioral and temperamental if compared to healthy controls suggesting the psychological contribution to growing pains’ onset
[35]	Makay (2009)	-	Melatonin hormone	The author suggested that some activities including the child’s awakening and putting on lights by parents to see what is happening to the child might reduce pain by decreasing melatonin hormone levels
[36]	Lech (2002)	Electrolytes contents of hair taken from 173 children aged 1 to 15 yr and young people aged 16 to 18 yr with growing pains were measured, using the flame atomic absorption spectrometry method, and then compared with those of 108 normal, healthy children	Electrolytes contents	Increased levels of lead and zinc and decreased levels of copper were found in children suffering from growing pains if compared with controls. Magnesium levels for ill children were also enhanced, but in the youngest children, the levels were reduced. Mg/Pb and Mg/Zn ratios were lower and Zn/Cu were higher in the group of children suffering from growing pains than in the healthy children
[37]	Pathirana et al (2011)	33 children aged 5 to 12 yr with growing pains were compared to 29 healthy controls. Evidence for peripheral neuropathic disorder was tested by somatosensory testing involved threshold determination and/or response magnitude to non painful stimuli including touch, dynamic brush, cold, vibration, and deep pressure applied to limb and abdominal sites	Somatosensory disorder	Growing pains might be a regional pain syndrome with evidence of mild widespread disorder of somatosensory processing
[38]	Golding et al (2012)	Prenatal and postnatal diet, blood measures and variants in fatty acid desaturase genes that influence the metabolism of fatty acids were compared. The study included 1676 children with growing pains at age 8 and 6155 healthy controls	Fatty acids status	No evidence that ω-3 fatty acids status protects against the development of growing pains in childhood have been found
[39]	Ekbom (1975)	A family in which the mother has typical restless legs syndrome and also growing pains since her childhood was observed. Severe growing pains were also showed by her three sons	Restless legs syndrome	Growing pains and restless legs are different conditions
[40]	Rajaram et al (2004)	11 children with growing pains were interviewed with their parent to determine if their symptoms of growing pains also met criteria for restless legs syndrome. Those who met clinical criteria for Restless legs syndrome underwent polysomnography whose results were compared to those of 10 healthy controls	Restless legs syndrome	Some children with growing pains also meet diagnostic criteria for restless legs syndrome. A family history of restless legs syndrome have been found among those children
[43]	Evans et al (2018)	Foot arches, foot strength, joint mobility, vitamin D and iron levels were examined in 64 children with leg pain and in 13 healthy controls. Children with leg pain were divided into three groups: growing pains, restless legs syndrome, both syndromes are defined for the first time		Increased strength of ankle dorsiflexors and joint mobility were found to be predictive for all types of leg pain. Hypovitaminosis D was detected in 87% of the sample, and anaemia in 13%. Increased body weight, waist girth, and BMI were also found to be associated with leg pain

QUS: Quantitative ultrasound assessment; VAS: Visual analog scale.