Physical, Mental, and Social Problems of Adolescent and Adult Patients with Achondroplasia

Matsushita, Masaki; Kitoh, Hiroshi; Mishima, Kenichi; Yamashita, Satoshi; Haga, Nobuhiko; Fujiwara, Sayaka; Ozono, Keiichi; Kubota, Takuo; Kitaoka, Taichi; Ishiguro, Naoki

doi:10.1007/s00223-019-00518-z

Cited by 39 publications

(68 citation statements)

References 29 publications

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“…The early onset of SSS in this study is consistent with other studies [7][8][9]18], but is in marked contrast to the average statured population, where symptoms rarely present before 60 years of age [6]. Healthcare professionals managing individuals with achondroplasia must be aware of this, so as not to overlook or neglect symptoms of spinal stenosis.…”

Section: Discussionsupporting

confidence: 90%

“…The prevalence of SSS in our study is much higher than reported in commonly cited studies of achondroplasia [10][11][12][13], but consistent with a recently published study from Japan [18]. However, none of these studies have described how SSS was defined.…”

Section: Discussionsupporting

confidence: 89%

“…We have not found prevalence rates reported in unselected achondroplasia populations [14], and our clinical experience indicates that the prevalence of SSS is much higher. Several studies have also found a decline in physical health in individuals with achondroplasia during the fourth decade, including a high prevalence of pain [15][16][17][18]. However, the relationship between SSS and physical functioning has not been investigated in detail.…”

Section: Introductionmentioning

confidence: 99%

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High prevalence of symptomatic spinal stenosis in Norwegian adults with achondroplasia: a population-based study

Fredwall

Steen

Vries

et al. 2020

Orphanet J Rare Dis

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Background: Symptomatic spinal stenosis (SSS) is a well-known medical complication in achondroplasia. The reported prevalence of SSS is 10 to 30%, an estimate based on small studies or selected populations. No population-based studies exist currently. Furthermore, the relationship between SSS and physical functioning has not been investigated in detail. The aims of this study were to describe the prevalence of SSS in Norwegian adults with achondroplasia, and to explore the impact of SSS on physical functioning. Methods: This was a population-based study on Norwegian community-dwelling adults with genetically confirmed achondroplasia. Prevalence of SSS was defined by clinical symptoms, and confirmed by imaging or surgical reports. Physical functioning was assessed by walking capacity (6-min walk test), hand strength (Grippit), and activities of daily living (the Health Assessment Questionnaire, HAQ). Pain was assessed by pain site locations and intensity (Numeric Rating Scale, NRS). Results: In total, 50 participants were included (27 males, 23 females). Median age was 41 years (range 16 to 87 years), 34 (68%) had SSS. The estimated median age at first symptom onset was 33 years (95% confidence interval (CI) 29 to 43 years), range 10 to 67 years. The majority had multiple spinal levels affected. The walking distance was 110 m shorter in the SSS group (95% CI − 172 to − 40 m) as compared with the non-SSS group (p < 0.01). There was no considerable difference in hand strength between the two groups. Mean HAQ scores (0-3) for walking and hygiene were significantly higher in the SSS group, reflecting more activity limitations. Mean differences were 0.9 (95% CI 0.3 to 1.4, p < 0.01) and 0.6 (95% CI 0.2 to 1.0, p < 0.01). Pain intensity (NRS 0-10) was also significantly higher in the SSS group with a mean difference of 3.2 (95% CI 0.6 to 5.6, p = 0.02). Conclusions: SSS was highly prevalent in Norwegian adults with achondroplasia, with symptom onset at young age, and multiple spinal levels affected. The presence of SSS was associated with reduced walking distance, activity limitations, and more pain. The findings underline the importance of thorough assessment and monitoring of SSS in achondroplasia, including a formal assessment of physical functioning.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

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High prevalence of symptomatic spinal stenosis in Norwegian adults with achondroplasia: a population-based study

Fredwall

Steen

Vries

et al. 2020

Orphanet J Rare Dis

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“…Common medical complications include delayed motor and speech development in children (Hunter, Bankier, Rogers, Sillence, & Scott Jr., 1998;Ireland et al, 2010;Ireland et al, 2011;Ireland et al, 2012), otolaryngeal problems such as otitis media associated with hearing loss (Afsharpaiman, Sillence, Sheikhvatan, Ault, & Waters, 2011;Hunter et al, 1998;Tunkel et al, 2012), respiratory dysfunction including obstructive sleep apnea (Afsharpaiman et al, 2011;Hunter et al, 1998) spinal stenosis and compression (Hunter et al, 1998;Shirley & Ain, 2009), and dental malocclusions (Hunter et al, 1998). Furthermore, these medical complications can cause significant pain and diminish physical function and quality of life (Alade et al, 2013;Dhiman et al, 2017;Gollust, Thompson, Gooding, & Biesecker, 2003;Mahomed, Spellmann, & Goldberg, 1998;Matsushita et al, 2019). Mortality rates are elevated in individuals with achondroplasia at all ages due to an increased risk of sudden death in young children attributed to brainstem compression resulting from foramen magnum stenosis and greater mortality risk in adulthood related to cardiovascular disease, neurological complications, and accidents (Hashmi et al, 2018;Hecht, Francomano, Horton, & Annegers, 1987;Simmons, Hashmi, Scheuerle, Canfield, & Hecht, 2014;Wynn, King, Gambello, Waller, & Hecht, 2007).…”

mentioning

confidence: 99%

Birth prevalence of achondroplasia: A systematic literature review and meta‐analysis

Foreman

Kessel²,

Hoorn³

et al. 2020

American J of Med Genetics Pt A

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Achondroplasia is a genetic disorder that results in disproportionate short stature. The true prevalence of achondroplasia is unknown as estimates vary widely. This systematic literature review and meta‐analysis was conducted to better estimate worldwide achondroplasia birth prevalence. PubMed, Embase, Scielo, and Google Scholar were searched, complemented by manual searching, for peer‐reviewed articles published between 1950 and 2019. Eligible articles were identified by two independent researchers using predefined selection criteria. Birth prevalence estimates were extracted for analysis, and the quality of evidence was assessed. A meta‐analysis using a quality effects approach based on the inverse variance fixed effect model was conducted. The search identified 955 unique articles, of which 52 were eligible and included. Based on the meta‐analysis, the worldwide birth prevalence of achondroplasia was estimated to be 4.6 per 100,000. Substantial regional variation was observed with a considerably higher birth prevalence reported in North Africa and the Middle East compared to other regions, particularly Europe and the Americas. Higher birth prevalence was also reported in specialized care settings. Significant heterogeneity (Higgins I2 of 84.3) was present and some indication of publication bias was detected, based on visual asymmetry of the Doi plot with a Furuya‐Kanamori index of 2.73. Analysis of pooled data from the current literature yields a worldwide achondroplasia birth prevalence of approximately 4.6 per 100,000, with considerable regional variation. Careful interpretation of these findings is advised as included studies are of broadly varying methodological quality.

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“…ACH is caused by activating mutations in FGFR3 encoding the fibroblast growth factor receptor 3, which is a negative a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 regulator of longitudinal bone growth [1,2]. In addition to severe short stature, neurological complications associated with stenosis of the foramen magnum and spinal canal, such as gait disturbance, leg paralysis, hydrocephalus, and central hypopnea, exacerbate patients' quality of life [3].…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and safety after once and twice a day doses of meclizine hydrochloride administered to children with achondroplasia

et al. 2020

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Achondroplasia (ACH) is the most common short-limbed skeletal dysplasia caused by activating mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. We identified that meclizine hydrochloride inhibited FGFR3 signaling in various chondrocytic cells and promoted longitudinal bone growth in mouse model of ACH. Meclizine has safely been used for more than 50 years, but it lacks the safety data for repeated administration and pharmacokinetics (PK) when administered to children. We performed a phase Ia study to evaluate the PK and safety of meclizine administered orally to ACH children. Twelve ACH children aged from 5 to younger than 11 years were recruited, and the first 6 subjects received once a day of meclizine in the fasted condition, subsequent 6 subjects received twice a day of meclizine in the fed condition. Meclizine was well tolerated in ACH children with no serious adverse events. The mean C max , T max , AUC 0-24h , t1/2 during 24 hours in the fasted condition were 130 ng/mL, 1.7 hours, 761 ng�h/mL, and 8.5 hours respectively. The simulation of repeated administration of meclizine for 14 days demonstrated that plasma concentration apparently reached steady state around 10 days after the first dose both at once a day and twice a day administration. The AUC 0-10h of the fasting and fed condition were 504 ng�h/mL and 813 ng�h/mL, respectively, indicating exposure of meclizine increased with the diet. Although higher drug exposure was confirmed in ACH children compared to adults, a single administration of meclizine seemed to be well tolerated.

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Physical, Mental, and Social Problems of Adolescent and Adult Patients with Achondroplasia

Cited by 39 publications

References 29 publications

High prevalence of symptomatic spinal stenosis in Norwegian adults with achondroplasia: a population-based study

High prevalence of symptomatic spinal stenosis in Norwegian adults with achondroplasia: a population-based study

Birth prevalence of achondroplasia: A systematic literature review and meta‐analysis

Pharmacokinetics and safety after once and twice a day doses of meclizine hydrochloride administered to children with achondroplasia

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