Study selection

Our initial searches identified 4,149 citations. All were from electronic databases, except for ten studies identified through grey literature. After we removed duplicates from different databases, we retained 3,903 potentially relevant articles for further assessment. After reading titles and abstracts, 87 articles were retrieved as full text for further assessment. After screening the full texts, we included 53 clinical studies with one further publication. We excluded 32 studies after reviewing the full papers. The reasons for exclusion are listed in the PRISMA flow diagram (Fig. 1). The total number of included studies is 53 with one further publication, and from these 11 contributed to meta-analysis.

Eight of the included studies were published only as an abstract [26,27,28,29,30,31,32,33], and five studies as theses [34,35,36,37,38]. The remainder of the included studies (n = 40) was published as full-text articles [5, 6, 24, 39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74]. One study [75] was published as full-text with an additional publication in abstract format [76]. When information regarding risk of bias or other aspects of methods was unavailable, we attempted to contact study authors for additional information.

Study characteristics

Tables 1 and 2 summarize the key characteristics from those studies that reported at least one patient-important or economic outcome. Regarding study design, four were case series [26, 34, 35, 73], 24 cross-sectional studies [5, 6, 24, 29, 36,37,38, 40, 45, 48, 50,51,52,53,54, 56, 58, 60, 61, 66, 69, 70, 72, 75], and 25 case reports [27, 28, 30,31,32,33, 39, 41,42,43,44, 46, 47, 49, 55, 57, 59, 62,63,64,65, 67, 68, 71, 74].

Table 1 LATAM ACH studies evaluating patient-important or economic burden outcomes not accountable for the meta-analysis
Table 2 LATAM ACH studies evaluating patient-important or economic burden outcomes accountable for the meta-analysis

Twenty-four of the included studies were conducted in Brazil [5, 24, 26,27,28,29,30,31,32,33,34, 36, 38,39,40, 45, 49, 57, 63, 66, 67, 69, 74, 75], nine in Argentina [44, 50,51,52,53,54, 56, 64, 73], five in Colombia [42, 48, 58, 68, 71], four in Mexico [35, 37, 41, 59], three in Chile [46, 47, 61], three in Cuba [43, 60, 65], one each in Dominican Republic [55], in Paraguay [62], in Venezuela [72], and in Puerto Rico [70]. Only one article [6] was a multicenter cross-sectional study, which involved nine countries (i.e., Argentina, Bolivia, Brazil, Chile, Colombia, Ecuador, Paraguay, Uruguay, and Venezuela) [6]. Sample sizes from these studies ranged from four [61] to 357 patients [53]. Study participants ranged in age, from a mean age of 3.07 [56] to 40.24 [40] years (Tables 1 and 2).

The type of burden outcome most frequently reported among the cross-sectional and case series studies was nervous system disorders (28.66%, n = 8) [5, 29, 34, 37, 56, 70, 72, 73], followed by spinal issues including stenosis, compression and associated pain (25.00%, n = 7) [34, 35, 37, 40, 56, 70, 73], and then ear, nose, throat and speech disorders (21.42%, n = 6) [5, 37, 40, 56, 70, 75]. The majority of the cross-sectional, case series, and case reports studies (86.36%, n = 38) reported only on patient-important outcomes (Tables 1 and 2).

Additional file 2: Table S2 describes study characteristics related to LATAM countries only from those that reported other than patient-important or economic outcome. Ten studies [36, 45, 48, 50,51,52,53,54, 60, 61] evaluated in addition to burden outcomes, such factors as mutations in the fibroblast growth factor receptor 3 gene [48, 61]; growth velocity [52, 54]; and body proportions references [53].

Additional file 3: Table S3 describes the burden outcomes on 25 LATAM case reports studies. With regards the case reports studies, the majority (68.0%, n = 17) [27, 28, 30, 39, 42, 44, 46, 47, 49, 55, 57, 59, 62,63,64,65, 68] assessed some physical comorbidities such as apnea [59, 68], lower back and leg pain [49], and obesity [65]. Ten case report studies evaluated other outcomes such as hemorrhoidectomy [63] and vesicostomy for neurogenic bladder [59]. Only one study [49] reported on environmental burden (i.e., difficulty getting on the bus because of the distance from the sidewalk to the step and the height of the steps).

Risk of bias assessment

Figure 2 and Additional files 4, 5: Tables S4 and S5 describe the risk of bias assessment. In the cross-sectional studies (Fig. 2, panel A), at least one of the following domains of sample size, statistical significance, statistics methods, or demographic data were rated as “high risk of bias” in 13 studies (54.16%) [5, 24, 29, 37, 38, 40, 56, 58, 66, 69, 70, 72, 75]. In the case series studies (Fig. 2, panel B), only two domains (i.e., clear description of both patient’s history and post-intervention clinical condition) were rated as “high risk of bias” in three studies (75.00%) [34, 35, 73].

Fig. 2
figure2

Risk of bias assessment of the included studies. a Cross-sectional studies. b Case series studies

Outcomes

The results were pooled from studies that reported available data. Therefore, out of 54 included studies [5, 6, 24, 26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76], only 11 [5, 29, 34, 37, 40, 56, 66, 70, 72, 73, 75, 76] were used for the quantitative analysis described below as they presented available data (Table 2).

Mortality

The pooled proportion for mortality (i.e., sudden death [37] and death due to respiratory complications [56, 72]) was 15% [95% CI 1.0E−3 to 0.47; I2 = 82.9%, p = 0.0029] from three studies [37, 56, 72] with a total of 99 patients (Fig. 3). There was significant statistical heterogeneity in the analyses.

Fig. 3
figure3

Pooled analysis of proportions for burden outcomes in LATAM ACH patients. a Mortality. b Cardio-respiratory-metabolic disorders. c Nervous system disorders. d Ear, nose, throat and speech disorders. e Spinal issues including stenosis, compression and associated pain. f Psychosocial complications. g Others

Cardio-respiratory-metabolic disorders

The pooled proportion for cardio-respiratory-metabolic disorders was 17% [95% CI 0.04 to 0.37; I2 = 90.3%, p < 0.0001] from four studies [5, 37, 56, 75, 76] with a total of 230 patients (Fig. 3). There was significant statistical heterogeneity in the analyses. The outcomes used to calculate the mean or median of the cardio-respiratory-metabolic disorders among the studies included in the analysis were: adenotonsillectomy [5]; apnea followed by death [37]; pneumonia [56]; apnea index slightly and moderately increased [75]; desaturations during sleep [75]; and apnea [75]. There was no outcome directly related to cardiac to be included in this category.

Nervous system disorders

The pooled proportion for nervous system disorders was 18% [95% CI 0.07 to 0.33; I2 = 84.6%, p < 0.0001] from six studies [5, 29, 37, 56, 72, 73] with a total of 262 patients (Fig. 3). There was significant statistical heterogeneity in the analyses. A sensitivity analysis excluding case series studies from the cross-sectional studies yielded results that were consistent with the primary analysis of 27% [95% CI 0.09 to 0,50; I2 = 87.2%, p < 0.0001] from five studies [5, 29, 37, 56, 72] with a total of 165 patients (Fig. 4). There was no statistically significant difference between the primary analysis (i.e., all the studies) and the sensitivity analysis (i.e., only cross-sectional studies), as their CIs overlapped. The outcomes used to calculate the mean or median of the nervous system disorders among the studies included in the analysis were: hydrocephalus [5, 37]; convulsive crises [72]; epilepsy [5]; paresthesias and paresias [37]; hypotonia [37]; neurological manifestations [56]; decompressive surgery of foramen magnum [56]; mental retardation [72]; and neurological problems [73].

Fig. 4
figure4

Sensitivity analysis excluding case series studies from the cross-sectional studies for burden outcomes in LATAM ACH patients. Panel A: Nervous system disorders. Panel B: Spinal issues including stenosis, compression and associated pain.

Ear, nose, throat and speech disorders

The pooled proportion for ear, nose, throat and speech disorders was 32% [95% CI 0.18 to 0.48; I2 = 73.4%, p = 0.0046] from five studies [5, 37, 40, 56, 75, 76] with a total of 183 patients (Fig. 3). There was significant statistical heterogeneity in the analyses. The outcomes used to calculate the mean or median of the ear, nose, throat and speech disorders among the studies included in the analysis were: hearing loss [5, 56, 75]; recurrent otitis media [37, 56, 75]; required surgical treatment (i.e., placement of ventilation tubes) [37]; delay in speech development [56]; hypotonia [56]; hypertrophy of adenoids [75]; snoring; tonsillectomy; and thickening of the tympanic membrane [75].

Spinal issues including stenosis, compression and associated pain

The pooled proportion for spinal issues including stenosis, compression and associated pain was 24% [95% CI 0.07 to 0.47; I2 = 91.3%, p < 0.0001] from five studies [34, 37, 40, 56, 73] with a total of 235 patients (Fig. 3). There was significant statistical heterogeneity in the analyses. A sensitivity analysis excluding case series studies from the cross-sectional studies yielded results that were consistent with the primary analysis of 17% [95% CI 0.01 to 0.45; I2 = 93.4%, p < 0.0001] from three studies [37, 40, 56] with a total of 194 patients (Fig. 4). There was no statistically significant difference between the primary analysis (i.e., all the studies) and the sensitivity analysis (i.e., only cross-sectional studies), as their CIs overlapped. The outcomes used to calculate the mean or median of the spinal disorders among the studies included in the analysis were: osteopenia or osteoporosis [40]; posterior laminectomy [37]; craniocervical compression [34, 37, 56, 73]; spinal compression requiring laminectomy [56]; spinal cord liberation alone [73]; anterior arthrodesis plus posterior instrumented arthrodesis [73]; anterior arthrodesis, associated with fibular grafting followed by posterior simple arthrodesis [73]; posterior arthrodesis instrumented with pedicular screws [73].

Psychosocial disorders

The pooled proportion for psychosocial complications was 19% [95% CI 0.02 to 0.48; I2 = 80.8%, p = 0.0054] from three studies [5, 66, 70] with a total of 66 patients (Fig. 3). There was significant statistical heterogeneity in the analyses. The outcomes used to calculate the mean or median of the psychosocial disorders among the studies included in the analysis were: depression [5], perception of their body image [66], and mild somatization [70].

Descriptive analysis

Four studies [38, 58, 69, 75, 76] reported on economic burden outcomes. Gomez et al., 2017 [58] reported on the adaptation of shoes for the ACH patients and the costs associated with the anthropometric and baropodometric analyses of the foot. This study addressed the design of a footwear system that fulfills form, function and usage of eight persons with ACH patients. The most relevant information was that footwear should have a low heel (about 2 cm) as there is a greater risk of falling due to the instability associated with wearing higher heels (7 1⁄2 cm and above), considering the lower center of gravity for ACH patients; however, patients want to have comfort and elegant heels and shoes (Table 1).

The Lima, 2019 [38] study sought to identify the consequences of stigmatization on social life, including work. The results indicate that people with ACH experience humiliation and disrespect due to associations made with the stereotype built about them. The authors found this stereotype is commonly used by comedians for entertainment purposes (Table 1).

Medeiros et al., 2017; Medeiros et al., 2019 [75, 76] and Rocha & Wagner, 2018 [69] describe the challenges associated with physical activities (Table 1). Patients reported that while physical activities can be difficult to perform [75, 76], though the regular practice of physical activity improves their self-esteem and confidence which in turn contributes to their sense of social inclusion [69].

None of the included studies reported on the following patient-important outcomes: suicide attempts, and suicide rates; impact of the disease on caregivers, such as health-related quality of life, activities of daily living, work productivity, education, employment, social, and so forth; and social adaptation challenges. Furthermore, none of the included studies reported on the following economic burden outcomes: limitation of physical access to transportation modalities; and adaptation to standard transport equipment.

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