Forty-eight patients included in the RenalTube database with the diagnosis of XLH confirmed by defect-of-function mutations found in the PHEX gene were analyzed. Demographic and genetic data from patients are shown in Table 1. Patients were from 39 families and were being followed in pediatric nephrology units of 17 Spanish hospitals (Fig. 1). Fifteen patients were males and 33 females. Median age at diagnosis was 2.00 (IQR 2.65) years, and the age ranged from 0 to 9 years.
Table 1
Demographic and genetic data of 48 patients belonging to 39 families (Roman number indicates family).
Patient | Relationship | Sex | Age at diagnosis | cDNA mutation | Protein mutation |
I.1 | Index | F | 3 m | c.758_759delTT | p.F26Cfs |
I.2 | Sister | F | 1 y | c.758_759delTT | p.F26Cfs |
II.1 | Index | F | 1 y 5 m | c.2223_2224delAC | p.A514Afs516X |
III.1 | Index | F | 1 y 6 m | c.1578_1579delAA | p.K299Nfs304X |
IV.1 | Index | M | 1 y 4 m | c.893A > T | p.N71I |
IV.2 | Brother | M | 4 y | c.893A > T | p.N71I |
V.1 | Index | F | 5 y | c.2633G > C | p.R651P |
VI.1 | Index | F | 2 y | c.1885C > T | p.Q402X |
VII.1 | Index | M | 8 y | c.?-2664dup2949-? | Splice region variant |
VII.2 | Brother | M | 2 y | c.?-2664dup2949-? | Splice region variant |
VII.3 | Daughter | F | 11 m | c.?-2664dup2949-? | Splice region variant |
VII.4 | Daughter | F | 1 y | c.?-2664dup2949-? | Splice region variant |
VIII.1 | Index | F | 4 y | c.886insT | p.K69X |
IX.1 | Index | F | 5 y | c.2048G > A | p.W456X |
X.1 | Index | F | 5 y | g.22099152G > T | Splice region variant |
XI.1 | Index | M | 2 y 3 m | c.2648_?del | p.A656_?del |
XII.1 | Index | F | 2 y | c.2327_?del | p.R549_?del |
XIII.1 | Index | F | 5 y | g.22168393_delA | Splice region variant |
XIV.1 | Index | F | 9 m | c.1552C > T | p.R291X |
XV.1 | Index | F | 1 y 1 m | g.22190503G > A | Splice region variant |
XVI.1 | Index | F | 4 y | c.889_893delGTAAA | p.V70Sfs77X |
XVII.1 | Index | F | 5 y | c.2086_?del | p.A469_?del |
XVIII.1 | Index | F | 2 y | c.1180T > C | p.W167R |
XIX.1 | Index | F | 7 m | c.2282C > T | p.P534L |
XX.1 | Index | F | 2 y 1 m | c.2416G > A | p.G579R |
XXI.1 | Index | F | 4 y 5 m | c.2920C > T | p.R747X |
XXII.1 | Index | F | 4 y | c.2920C > T | p.R747X |
XXIII.1 | Index | M | 2 y | c.1152delA | p.L157Lfs220X |
XXIV.1 | Index | F | 3 y | c.1572C > A, c.1580_1582delTGA | p.Y297X |
XXV.1 | Index | F | 1 y 6 | g.22076478A > T | Splice region variant |
XXVI.1 | Index | F | 4 y | g.22190507G > A | Splice region variant |
XXVII.1 | Index | F | 6 m | c.889_893delGTAAA | p.V70Sfs77X |
XXVII.2 | Father | M | 8 y | c.889_893delGTAAA | p.V70Sfs77X |
XXVIII.1 | Index | M | 1 y 6 m | c.2879G > T | p.C733F |
XXVIII.2 | Sister | F | 6 m | c.2879G > T | p.C733F |
XXIX.1 | Index | F | 1 y 9 m | c.2642T > C | p.F654S |
XXX.1 | Index | M | 1 y 1 m | c.2387T > G | p.L569R |
XXX.2 | Mother | F | 1 y 6 m | c.2387T > G | p.L569R |
XXXI.1 | Index | F | 8 y 2 m | c.2085G > C | p.K468N |
XXXII.1 | Index | M | 1 y 6 m | c.2282C > T | p.P534L |
XXXIII.1 | Index | M | 5 y | g.22033125T > G | Splice region variant |
XXXIV.1 | Index | M | 2 y 2 m | c.2380C > T | p.R567X |
XXXV.1 | Index | M | 7 m | c.2005G > T | p.V442P |
XXXV.2 | Mother | F | 2 y 6 m | c.2005G > T | p.V442P |
XXXVI.1 | Index | F | 6 m | c.2416G > A | G579R |
XXXVII.1 | Index | M | 1 y 9 m | g.22099152G > A | Splice region variant |
XXXVIII.1 | Index | F | 1 y 6 m | c.2617delG | p.D646Ifs |
XXXIX.1 | Index | M | 2 y 2 m | c.1363_1364delTC | p.S228Pfs236X |
F: female, M: male, m: month, y: year. |
Presenting manifestations are shown in Table 2 for each patient. Bone deformities and radiological signs of active rickets were the most frequent findings leading to diagnosis. Ten patients were diagnosed because of family screening. Age at diagnosis of these patients was no different from that of the rest of the series as it ranged from 0.5 to 8 years with a median age of 1.04 years.
Table 2
Clinical manifestations at diagnosis.
Patient | Bone Deformities | Active Rickets | Longitudinal Growth Retardation (≤ 2 SDS) | Dental Problems |
I.1 | No | - | No | - |
I.2 | Yes | - | Yes | - |
II.1 | Yes | Yes | Yes | No |
III.1 | - | Yes | Yes | Yes |
IV.1 | No | No | Yes | Yes |
IV.2 | No | No | No | No |
V.1 | Yes | Yes | Yes | No |
VI.1 | Yes | No | No | No |
VII.1 | - | - | - | - |
VII.2 | - | Yes | - | No |
VII.3 | - | Yes | Yes | No |
VII.4 | - | - | Yes | - |
VIII.1 | Yes | Yes | No | No |
IX.1 | Yes | Yes | No | No |
X.1 | Yes | Yes | Yes | No |
XI.1 | Yes | Yes | Yes | No |
XII.1 | Yes | Yes | - | - |
XIII.1 | - | Yes | - | - |
XIV.1 | Yes | Yes | No | No |
XV.1 | Yes | Yes | Yes | - |
XVI.1 | Yes | - | Yes | No |
XVII.1 | - | - | Yes | - |
XVIII.1 | Yes | Yes | Yes | No |
XIX.1 | Yes | Yes | - | No |
XX.1 | Yes | - | Yes | - |
XXI.1 | Yes | Yes | No | No |
XXII.1 | Yes | Yes | Yes | No |
XIII.1 | Yes | Yes | No | No |
XXIV.1 | Yes | - | No | - |
XXV.1 | Yes | Yes | No | No |
XXVI.1 | Yes | Yes | Yes | No |
XXVII.1 | Yes | Yes | No | No |
XXVII.2 | - | Yes | - | No |
XXVIII.1 | Yes | - | No | - |
XXVIII.2 | Yes | Yes | No | No |
XXIX.1 | Yes | Yes | Yes | No |
XXX.1 | Yes | Yes | Yes | - |
XXX.2 | - | Yes | - | No |
XXXI.1 | Yes | Yes | Yes | No |
XXXII.1 | Yes | Yes | No | No |
XXXIII.1 | - | - | Yes | - |
XXXIV.1 | Yes | Yes | No | No |
XXXV.1 | Yes | Yes | No | - |
XXXV.2 | Yes | Yes | Yes | - |
XXXVI.1 | Yes | Yes | No | No |
XXXVII.1 | Yes | Yes | Yes | Yes |
XXXVIII.1 | Yes | Yes | No | No |
XXXIX.1 | Yes | Yes | - | No |
Percentage of patients | P/A/U | P/A/U | P/A/U | P/A/U |
73/6/21 | 73/6/21 | 46/38/17 | 6/63/31 |
SDS: Standard deviation score. Dash: information in this field was missing from the database. |
P/A/U: Present/Absent/Unreported |
Twenty-two out of 40 patients (55%) in whom the height was registered presented growth retardation (height ≤ 2 SDS). Patients’ height (X ± SEM) was − 1.89 ± 0.19 SDS (n = 40) (Fig. 2). In 87% (35/40) the height was below the 50th percentile. Weight was − 0.88 ± 0.14 SDS (n = 41) and body mass index 0.2 ± 0.15 SDS (n = 40).
Biochemical findings at diagnosis are shown in Table 3. Mean values (± SEM) of available data were serum phosphate 2.7 ± 0.1 mg/dl; -2.81 ± 0.11 SDS, (n = 41), alkaline phosphatase (892 ± 84 mU/ml) (n = 39), 1,25(OH)2D62 ± 7 pg/ml (n = 34), parathyroid hormone (PTH)70 ± 7 pg/ml (n = 33), and tubular phosphate reabsorption (TPR) 69 ± 4%(n = 26).
Table 3
Biochemical manifestations at diagnosis.
Patient | Serum phosphate | Serum alkaline phosphatases (mU/ml) | Serum 1,25(OH)2D (pg/ml) | Serum intact PTH (pg/ml) | TPR (%) |
mg/dl | SDS |
I.1 | 3.4 | -2.21 | 1230 | 87 | - | - |
I.2 | 3.8 | -1.05 | 1916 | 76 | - | - |
II.1 | 2.6 | -2.68 | 695 | 57 | 81 | 79 |
III.1 | 2.1 | -3.36 | 1646 | 16 | 68 | 32 |
IV.1 | 2.8 | -2.41 | 378 | 73 | 29 | 78 |
IV.2 | 3.0 | -2.44 | 232 | 40 | 43 | 82 |
V.1 | 2.1 | -3.99 | 1513 | 147 | 78 | 85 |
VI.1 | 2.6 | -2.68 | 525 | 33 | 64 | 78 |
VII.1 | - | - | - | - | - | - |
VII.2 | 2.4 | -2.95 | 516 | - | - | - |
VII.3 | - | - | 991 | 28 | 30 | - |
VII.4 | - | - | - | - | - | - |
VIII.1 | 3.1 | -2.27 | 598 | 55 | 39 | 38 |
IX.1 | 3.0 | -2.44 | 1824 | 47 | 59 | 67 |
X.1 | 2.9 | -2.61 | 639 | 33 | 136 | 74 |
XI.1 | 2.3 | -3.09 | - | - | 58 | - |
XII.1 | 2.7 | -2.54 | - | - | 48 | - |
XIII.1 | - | - | - | - | - | - |
XIV.1 | 3.3 | -2.34 | 892 | 64 | 65 | 75 |
XV.1 | 2.0 | -3.49 | 704 | 20 | - | 39 |
XVI.1 | 2.4 | -3.47 | 571 | 108 | 71 | 26 |
XVII.1 | 2.5 | -3.30 | - | 28 | 30 | - |
XVIII.1 | 2.3 | -3.09 | 1864 | 31 | 64 | 73 |
XIX.1 | - | - | - | - | - | - |
XX.1 | 2.9 | -2.27 | 446 | 88 | 116 | 93 |
XXI.1 | 3.1 | -2.27 | 470 | 56 | 49 | 86 |
XXII.1 | 2.8 | -2.78 | 697 | 74 | 32 | 76 |
XXIII.1 | 2.1 | -3.36 | 733 | - | 68 | 82 |
XXIV.1 | 2.2 | -3.22 | 514 | 61 | 78 | 58 |
XXV.1 | 2.9 | -2.27 | 1940 | 40 | 57 | 58 |
XXVI.1 | 2.3 | -3.64 | 423 | - | - | 82 |
XXVII.1 | 2.9 | -2.86 | 432 | 31 | 23 | - |
XXVII.2 | - | - | - | - | - | - |
XXVIII.1 | 3.0 | -2.14 | 236 | 78 | 54 | - |
XXVIII.2 | 3.3 | -2.34 | 426 | 171 | 57 | 90 |
XXIX.1 | 1.8 | -3.77 | 1555 | - | - | - |
XXX.1 | 3.1 | -2.00 | 829 | 183 | 101 | 88 |
XXX.2 | 2.2 | -3.22 | 158 | 25 | - | - |
XXXI.1 | - | - | - | - | - | - |
XXXII.1 | 2.8 | -2.41 | 692 | 41 | 111 | - |
XXXIII.1 | 2.1 | -3.99 | - | - | 76 | 54 |
XXXIV.1 | 2.3 | -3.09 | 856 | 64 | 101 | 46 |
XXXV.1 | 3.5 | -2.08 | 916 | - | 227 | 82 |
XXXV.2 | 2.2 | -3.22 | 1620 | - | - | 70 |
XXXVI.1 | 2.8 | -2.41 | 1093 | 65 | 66 | - |
XXXVII.1 | 2.4 | -2.95 | 1527 | 46 | 94 | - |
XXXVIII.1 | 2.4 | -2.95 | 856 | 40 | 58 | - |
XXXIX.1 | 3.0 | -2.14 | 759 | 51 | 43 | - |
1,25(OH)2D: 1,25 dihydroxyvitamin D. PTH: Parathyroid hormone. TPR: Tubular phosphate reabsorption. Dash: information in this field was missing from the database. |
No differences were found between males and females for clinical manifestations, growth impairment or biochemical data at diagnosis. Likewise, no genotype-phenotype correlation was found. Actually, even patients within the same family presented different severity of clinical and biochemical manifestations.
Growth and biochemical variables of 26 patients after a median follow up time of 7.42 years (IQR = 11.26) are shown in Table 4, Fig. 3 and Fig. 4. Anthropometric data were − 1.94 ± 0.16 SDS for height (n = 24), -0.82 ± 0.10 SDS for weight (n = 22) and 0.14 ± 0.19 SDS for BMI (n = 22). Comparison of data from patients with information both at diagnosis and last follow-up showed mean variations of 0.13 ± 0.23 SDS for height (p > 0.05) (n = 20), 0.35 ± 0.14 SDS for weight (p = 0.02) (n = 20) and 0.13 ± 0.20 SDS for BMI (p > 0.05) (n = 20).
Table 4
Biochemical manifestations at last follow up.
Patient | Serum phosphate | Serum alkaline phosphatases (mU/ml) | Serum 1,25(OH)2D (pg/ml) | Serum intact PTH (pg/ml) | TPR (%) |
mg/dl | SD (Z score) |
I.1 | 2.9 | -2.07 | 787 | - | 30 | 72 |
I.2 | 2.7 | -2.90 | 1035 | - | 35 | 50 |
II.1 | 3.8 | -1.05 | - | - | 34 | 70 |
III.1 | - | - | - | - | - | - |
IV.1 | 3.0 | -1.91 | 231 | 78 | 32 | 60 |
IV.2 | 2.6 | -3.06 | 266 | 73 | 44 | 48 |
V.1 | - | - | - | - | - | - |
VI.1 | - | - | - | - | - | - |
VII.1 | - | - | - | - | - | - |
VII.2 | - | - | - | - | - | - |
VII.3 | 1.9 | -3.69 | - | - | 77 | 42 |
VII.4 | 1.8 | -3.85 | 665 | - | 108 | 73 |
VIII.1 | 2.4 | -3.47 | 868 | 15 | 84 | 81 |
IX.1 | - | - | - | - | - | - |
X.1 | 3.0 | -2.41 | 962 | 50 | 93 | 85 |
XI.1 | 2.8 | -2.78 | 632 | 45 | 49 | 42 |
XII.1 | 2.8 | -2.23 | 636 | - | 112 | 86 |
XIII.1 | 1.7 | -4.22 | - | 29 | 86 | 64 |
XIV.1 | 2.8 | -2.41 | - | 96 | 20 | 70 |
XV.1 | 2.0 | -3.55 | - | 20 | 75 | 45 |
XVI.1 | - | - | - | - | - | - |
XVII.1 | 1.7 | -4.22 | 120 | 32 | 99 | 42 |
XVIII.1 | - | - | - | - | - | - |
XIX.1 | 2.4 | -2.66 | - | - | 200 | - |
XX.1 | 3.3 | -1.73 | 312 | 72 | 53 | 45 |
XXI.1 | 2.6 | -2.56 | 348 | 43 | 26 | 53 |
XXII.1 | - | - | - | - | - | - |
XXIII.1 | 3.0 | -2.44 | - | 29 | 28 | - |
XXIV.1 | - | - | - | - | - | - |
XXV.1 | 1.9 | -3.77 | - | - | 37 | - |
XXVI.1 | 2.8 | -2.78 | 240 | 86 | 25 | 70 |
XXVII.1 | 2.8 | -2.41 | - | 58 | 49 | 76 |
XXVII.2 | 2.3 | -2.88 | - | - | 117 | 80 |
XXVIII.1 | - | - | - | - | - | - |
XXVIII.2 | - | - | - | - | - | - |
XXIX.1 | 4.8 | 0.31 | 244 | 68 | 73 | 89 |
XXX.1 | - | - | - | - | - | - |
XXX.2 | - | - | - | - | - | - |
XXXI.1 | - | - | - | - | - | - |
XXXII.1 | - | - | - | - | - | - |
XXXIII.1 | 2.1 | -3.36 | - | - | 114 | 76 |
XXXIV.1 | - | - | - | - | - | - |
XXXV.1 | - | - | - | - | - | - |
XXXV.2 | - | - | - | - | - | - |
XXXVI.1 | - | - | - | - | - | - |
XXXVII.1 | - | - | - | - | - | - |
XXXVIII.1 | - | - | - | - | - | - |
XXXIX.1 | - | - | - | - | - | - |
1,25(OH)2D: 1,25 dihydroxyvitamin D. PTH: Parathyroid hormone. TPR: Tubular phosphate reabsorption. Dash: information in this field was missing from the database. |
Mean SDS for serum phosphate was − 2.72 ± 0.20 (n = 25). Alkaline phosphatases, 1,25 (OH)2D and PTH levels were 525 ± 82 mU/ml (n = 14), 53 ± 7 pg/ml (n = 15) and 68 ± 8 pg/ml (n = 26) respectively. Mean tubular phosphate reabsorption was 65 ± 3% (n = 22).Comparison between diagnosis and last follow-up data revealed a variation of 0.20 ± 0.28 SDS for serum phosphate (p > 0.05) (n = 20), 5 ± 7 pg/ml for 1,25 (OH)2D (p > 0.05) (n = 10), 0 ± 11 pg/ml for PTH (p > 0.05) (n = 16) and − 7 ± 8% for tubular phosphate reabsorption (p > 0.05) (n = 11).
Eight out of 24 patients with renal ultrasounds at last follow-up presented nephrocalcinosis.