Table 1.
XLH-related manifestations and surgeries reported in the included research studies
| Publication information | Patient population | Data on manifestations, surgeries and pain | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Reference | Publication type(s) | Sample size | Female, n (%) | Average age, years | Average height, cm; weight, kg; BMI, kg/m2; and body fat, % | XLH-specific treatment, n (%) | Manifestations reported (% of total sample experiencing manifestation) | Surgeries reported (% of total sample with history of surgery) | Pain medication (% of total sample who had received pain medication) |
| Berndt et al. (1996) [23] | Journal article | 23 | 19 (83%) | Median, 29 | Mean height (range), women 152.4 (140–171), men 157 (144–168) | Vitamin D and phosphate at last investigation, 8 (35%); vitamin D and phosphate ever, 19 (83%); never been treated, 4 (17%) | Impaired joint mobility (100%), mild scoliosis (78%), dental problems (61%), enthesopathy (48%), fractures (39%), nephrocalcinosis (35%), hyperparathyroidism (13%) | Orthopaedic surgery (57%) | NR |
| Chaussain-Miller et al. (2003) [17] | Journal article | 16a | 12 (75%) |
Mean (range), 37 (28–52) |
NR | No therapy or phosphate and vitamin D until adulthood, 7 (44%); Phosphate and vitamin D (replaced when available with 1α-hydroxy vitamin D3) from infancy, 9 (56%) | Dental abnormalities (100%)b | NR | NR |
| Che et al. (2015/2016) [10, 46]; Briot et al. (2014) [47] | Journal article [10] and conference abstracts [46, 47] | 52 | 37 (71%) | Mean (SD), 42 (13) | NR | Phosphate supplements, 31 (65%); vitamin D 29 (59%); vitamin D analogues 32 (67%) at the time of the study | Pain (90%), osteoarthritis (85%), enthesopathy (64%), fracture (36%) | Lower limb surgery (64%) |
Analgesics (31%), NSAIDs (24%) |
| Chesher et al. (2018) [34] | Journal article | 59c | 40 (68%) | Median (range), 37 (17–79 | Median height (IQ range), women 153 (146–156), men 162 (158–168); median BMI (IQ range), women 27.6 (24.8–33.7), men 25.3 (23.5–30.2) | Phosphate supplements and vitamin D analogues, 40 (68%) | Hip/knee joint disease (32%), degenerative ankle/foot joint disease 12%), Achilles enthesopathy (10%), dental abnormalities (63%), hearing loss (14%), renal disease (42%) | At least one osteotomy (42%), knee replacement (5%), hip replacement (3%) | NR |
| Connor et al. (2015) [20] | Journal article | 52 | 34 (65%) | Mean (SD), 39 (14) | Participants with height Z-score < − 2, 36 (70%); mean BMI (SD), 33.9 (9.2); mean body fat (SD), 35.1 (11.5) | 0% of adult life with treatment (phosphate and vitamin D analogues or high-dose vitamin D), 8 (15%); > 0% to < 100% of adult life with treatment, 27 (52%); 100% of adult life with treatment, 17 (33%) | Impaired mobility (18%), severe dental disease (62%) | At least one osteotomy (65%) | Any pain medication (73%) |
| Davies et al. (1984) [39] | Journal article | 22a | 10 (45%) | Mean (range), 38 (18–75) | NR | NR | Hearing loss (55%), vertigo (32%), tinnitus (36%) | NR | NR |
| Harrison et al. (1976) [44] | Journal article | 7c | 5 (71%) | Mean (range), 24 (17–30) | Mean height (range), 150 (125–160) | Vitamin D therapy at time of study, 2 (29%); vitamin D therapy ever, 5 (71%); phosphate supplements, 0 (0%) | Osteomalacia (100%), skeletal deformities (71%) | NR | NR |
| Insogna et al. (2018) [12]; Portale et al. (2018) [48] | Journal article [12] and conference abstract [48] | 134 | 87 (65%) | Mean (SD), 40 (12) | Mean height (SD), 152 (10.7); mean height Z-score (SD), −2.3 (1.3); mean height percentile (SD), 6.8 (12.5); mean BMI (SD), 30.3 (7.6) | Phosphate and vitamin D metabolites or analogues ever, 121 (90%); phosphate alone, 4 (3%); vitamin D metabolites or analogues alone, 6 (5%) | Enthesopathy (99%), severe paind (72%), osteoarthritis (63%), nephrocalcinosis (55%), fracture/pseudofracture (52%) | Orthopaedic surgery (69%) | Any pain medication (68%), any opioid (22%) |
| Javier et al. (2013) [49] | Conference abstract | 43 | 32 (74%) | Average (range), 42 (21–80) | NR | Most patients did not receive XLH-specific therapy (some younger patients were treated during childhood) | Pain (60%), fatigue (58%) | NR | Analgesics (~ 50%) |
| Nakamura et al. (2017) [27] | Journal article | 22e | 12 (55%) | Mean (range), 32 (19–65) | Mean height (range), women 149 (138–162), men 156 (141–162) | Phosphate and vitamin D analogues, 16 (73%); vitamin D analogues alone, 5 (23%) | Nephrocalcinosis (68%), hypertension (27%), hyperparathyroidism (23%), chronic renal dysfunction (9%) | NR | NR |
| Reid et al. (1989) [36] | Journal article | 22 | 16 (73%) | Mean (range), 40 (20–66) | Mean height (range), women 147 (128–162), men 158 (140–168); mean weight (range), women 70.5 (47.2–104.6), men 70.2 (57.8–97.2) | Phosphate and vitamin D or vitamin D analogues at time of study or 1 month before, 6 (27%); phosphate and vitamin D or vitamin D analogues ever, 14 (64%); vitamin D alone ever, 4 (18%) | Osteomalacia (100%), dental problems (91%), joint pain (82%), genu varum (77%), osteoarthritis (55% of patients aged < 30 years; 80% of patients aged ≥ 30 years), limitation in joint movements (46%), pseudofracture (45%), gait disturbance (32%), bone pain (36%), enthesopathy (33% of patients aged < 30 years; 100% of patients aged ≥ 30 years), muscle weakness (27%), difference in leg length of ≥ 2 cm (23%), scoliosis (14%), fracture (9%), spinal stenosis (5%) | Osteotomy (64%) | NR |
| Ruppe et al. (2016) [50] | Conference abstract | 20 | 14 (70%) | Mean (range), 50 (23–69) | NR | KRN23 (last dose ≥ 12 months at enrolment) | Enthesopathy (100%), joint stiffness (100%), impaired mobility (100%), short stature (95%), bowing of tibia/fibula (95%), dental abnormalities (85%), gait disturbance (85%), fracture/pseudofracture (~ 50%), pain (45%), hyperparathyroidism (30%) | Osteotomy (65%) | NR |
| Salcion-Picaud et al. (2018) [51] | Conference abstract | 81 | 55 (68%) | Mean (SD), 42 (14) | Phosphate and/or vitamin D during childhood, 63 (78%); phosphate and/or vitamin D analogues at time of study, 41 (51%) | Skeletal abnormalities (88%), pain (80%), joint pain (71%), hip osteoarthritis (65%), spinal stenosis (63%), bone pain (22%) | NR | Analgesics (40%) | |
| Salcion-Picaud et al. (2018) [52] | Conference abstract | 31 | 22 (71%) | Mean, 27.3 | NR | NR | Limb abnormalities (55%) | NR | NR |
| Shanbhogue et al. (2018) [18] | Journal article | 27 | 19 (70%) | NR; range 18–73 | Median height (IQ range), non-treated [n = 16] 163 (157–167), treated [n = 11] 158 (156–166); median weight (IQ range), non-treated 72 (66–89), treated 70 (67–79); median BMI (IQ range), non-treated 27 (25–34), treated 28 (26–31) | Phosphate and vitamin D analogues, 11 (41%) | Fracture (18%) | NR | NR |
| Skrinar et al. (2015) [13] | Conference abstractf | 195 | NR | Mean (range), 46 (18–74) | NR | NR |
Joint pain (89%), gait disturbance (86%), bone pain (73%), fracture/ pseudofracture (44%) |
NR | Regular pain medication use (69%), opiates (20%) |
| Skrinar et al. (2015) [14] | Conference abstractf | 150 | NR | Median (range), 46 (18–73) | NR | Phosphate/vitamin D therapy, 93 (62%) | Joint and bone pain (97%), restricted range of motion (93%), short stature (87%), gait disturbance (83%), bowing of the tibia/fibula (78%), osteoarthritis (60%), bowing of the femur (67%), fracture/pseudofracture (47%), hyperparathyroidism (33%), nephrocalcinosis (25%) | Any orthopaedic surgery (65%), osteotomy (63%), knee replacement (12%), hip replacement (8%) | Any pain medication (70%), opioids (18%) |
| Song et al. (2007) [37] | Journal article | 11a | 10 (91%) | Mean (range), 33 (18–60) | NR | Phosphate and vitamin D, 6 (55%); phosphate only, 1 (9%); vitamin D only, 1 (9%) | Bowing of the legs (100%), dental abnormalities (82%) | Osteotomy (82%) | NR |
| Stickler and Morgenstern (1989) [29] | Journal article | 52g | 31 (63%)h | NR | NR | Vitamin D only, 17 (33%); vitamin D and phosphate, 32 (62%); vitamin D analogues and phosphate, 11 (21%) | Leg pain (50%), knee pain (35%), renal failure (6%), hip and back pain (2%), shoulder pain (2%) | Kidney transplant (4%) | NR |
| Sullivan et al. (1992) [38] | Journal article | 17a | 8 (47%) | Mean (range), 38 (20–65) | NR | Phosphate and active vitamin D, 14 (82%); active vitamin D only, 1 (6%) | Bone or joint pain (100%) | Osteotomy (53%) | NR |
| Theodore-Oklota et al. (2018) [41] | Journal article | 18 | 15 (83%) | Mean (range), 42 (20–60) | NR | Phosphate, 11 (61%); vitamin D, 10 (55%) | Joint pain (100%), stiffness/difficulty bending limbs/joints (100%), fatigue (83%), dental abscesses (78%), weakness (50%), short stature (56%), bone pain (67%), bone bowing (67%), bone weakness (44%), muscle pain (44%), loss of balance/vertigo (39%), loss of hearing (28%), tinnitus (28%) | NR | NR |
Data are presented as available in the publications. Research studies with relevant information were included in this analysis. Research studies were identified from both journal articles and congress abstracts that were included in this systematic review. Publications reporting the same study have been grouped; where both a congress abstract and a journal article were published on a specific study, data from the article are presented
aThese studies also included children; only data for adults (aged ≥ 18 years) are presented here
bNecrosed or endodontically treated teeth (100% of patients); ≥ 2 missing permanent teeth (56% of patients)
cThese studies included individuals aged 17 years
dSevere pain was defined as a worst pain score of > 6.0 on the Brief Pain Inventory
eData on XLH-specific treatment were not available for one patient; data on height were not available for one male and one female patient
fThese abstracts present different data from the same study; this study has been published as a journal article since the systematic review was performed [6]
gData on manifestations were not available for two patients
hData on sex were not available for three patients
BMI, body mass index; IQ, interquartile; NR, not reported; NSAID, nonsteroidal anti-inflammatory drug; SD, standard deviation; XLH, X-linked hypophosphataemia