Diagnosis

XLH is a genetic disorder of bone metabolism, expressed in varying degrees in terms of bone involvement. It always manifests in abnormally low serum inorganic phosphorus levels, as first documented by Winters et al in 1958 based on extensive family studies in the Carolinas.  The XLH Network keeps in contact with leaders in research and treatment of XLH.  Physicians who don't have experience in diagnosing or managing XLH can contact us for help in finding an expert to consult. 

In principle, diagnosing an infant or toddler when there is a known family history of XLH should be straightforward, but even then the diagnosis has often been misconstrued, even by experts.  In too many cases, it appears the diagnostician mistakes general population normal values for serum inorganic phosphorus for actual age-matched normal values.  If the lab report states the reference range to be 2.5-4.5 mg/dl, that range is normal only for adults.  It is also important to consider normal variations in serum phosphorus throughout the day, as well as what foods have been eaten prior to testing.

If the diagnosis isn't as straight forward, then testing may show the following results:

  • X-ray evidence of rickets (not seen in all children)
  • Low serum phosphorus, as compared with age-matched normals
  • Normal serum calcium
  • Elevated alkaline phosphatase levels in children (perhaps not in adults)
  • Phosphorus wasting in the urine (low TMP/GFR)
  • Normal vitamin D (25-OHD) level
  • Inappropriately normal bioactivatsed vitamin D (1,25(OH)2D3) level 
  • Parathyroid hormone may be normal or moderately elevated.

Sample reference ranges for phosphorus by age:

Source:  PEDIATRIC REFERENCE RANGES, 3rd edition, by Steven J. Soldin, published by AACC Press, Washington, DC, 1999 pages 145-146

PHOSPHORUS
    Male Female
Test Age n mg/dL mmol/L n mg/dL mmol/L
1. 1-30d 62 3.9-6.9 1.25-2.25 66 4.3-7.7 1.40-2.50
  31-365d 83 3.5-6.6 1.15-2.15 66 3.7-6.5 1.20-2.10
  1-3y 126 3.1-6.0 1.00-1.95 119 3.4-6.0 1.10-1.95
  4-6y 112 3.3-5.6 1.05-1.80 107 3.1-5.5 1.00-1.80
  7-9y 117 3.0-5.4 0.95-1.65 107 3.1-5.5 1.00-1.80
  10-12y 135 3.2-5.7 1.05-1.85 115 3.3-5.3 1.05-1.70
  13-15y 109 2.9-5.1 0.95-1.65 110 2.8-4.8 0.90-1.55
  16-18y 95 2.7-4.9 0.85-1.60 122 2.5-4.8 0.80-1.55
 
2. 0-5d (<2.5 kg) 50 4.6-8.0 1.50-2.60 50 4.6-8.0 1.50-2.60
  1-3y 50 3.9-6.5 1.25-2.10 50 3.9-6.5 1.25-2.10
  4-6y 38 4.0-5.4 1.30-1.75 38 4.0-5.4 1.30-1.75
  7-9y 72 3.7-5.6 1.20-1.80 72 3.7-5.6 1.20-1.80
  10-11y 62 3.7-5.6 1.20-1.80 62 3.7-5.6 1.20-1.80
  12-13y 73 3.3-5.4 1.05-1.75 73 3.3-5.4 1.05-1.75
  14-15y 91 2.9-5.4 0.95-1.75 91 2.9-5.4 0.95-1.75
  16-19y 107 2.8-4.6 0.90-1.50 107 2.8-4.6 0.90-1.50
 
3. 0-30d 181 2.7-7.2 0.87-2.33 140 3.8-8.0 0.97-2.58
  31-90d 87 3.0-6.8 0.97-2.20 84 3.0-7.5 0.97-2.42
  3-12mo 109 3.0-6.9 0.97-2.23 119 2.5-7.0 0.81-2.26
  13-24mo 69 2.5-6.4 0.81-2.07 78 3.0-6.5 0.97-1.81
  2-<13y 148 3.0-6.0 0.97-1.94 254 2.5-6.0 0.81-1.94
  13-<16y 175 3.0-5.4 0.97-1.94 72 3.0-5.6 0.97-1.81
  16-<18y 72 3.0-5.2 0.97-1.68 196 3.0-4.8 0.97-1.55
 
Specimen: 1., 2., 3., Serum or Plasma
 
Reference:
 
1. Soldin SJ, Hicks JM, Bailey J, et al. Pediatric reference ranges for phosphate on the Hitachi 747 analyzer. Clin. Chem. 1997; 43:S198. (Abstract)
  2. Lockitch G, Halstead AC, Albersheim S, et al. Age and sex specific pediatric reference intervals for biochemistry analytes as measured with the Ektachem 700 analyzer. Clin. Chem 1988;34:1622-5.
  3. Soldin SJ, Hunt C, Hicks JM. Pediatric reference ranges for Phosphorus on the Vitros 500 Analyzer. Clin Chem 1999;45:A22 (Abstract)
 
Method:
 
1. Hitachi 747 using ammonium molybdate method (Boehringer-Mannheim, Diagnostics, Indianapolis, IN).
  2., 3. Ektachem 700 (2) and 500 (3) using ammonium molybdate method (Johnson & Johnson, Rochester, NY).
 
Comments:
 
1., 3. Study used hospitalized patients and a computerized approach to removing outliers. Values are 2.5 - 97.5th percentiles.
  2. Study used normal healthy children. Values are 2.5 - 97.5th percentiles.

(In this table, n is the number of subjects assessed in each age category.)

In comparing phosphorus levels to the charts below, it may be necessary to make a conversion.  To convert mg/dL to/from mmol/L, SIGMA provides an inorganic phosphorus reference standard: 
     20mcg per ml equivalent to 645 nanomoles per ml
     Since a deciLitre is 100 ml, this is the same as saying:
     2000mcg/dL or 2mg/dL or 645 mcmoles/L or 0.645mmol/L
Therefore, 1mg/dL is the same as 0.322 mmol/L

Source:  XLH Network mailing list, February, 2000, reference ranges from a laboratory in the USA.

Patient AgeInorganic Phosphorus Normals
Less than 6 days 4.0-9.0 mg/dL
6 days-2 years 4.0-8.0 mg/dL
2 years-12 years 3.0-6.0 mg/dL
12 years-64 years 2.0-5.9 mg/dL
Over 64 years 2.1-4.3 mg/dL

Source:  Medical School, University of Iowa, Pathology Handbook 

Patient AgePhosphorus Normals
Newborn 4.2-9.0 mg/dL
1 year 3.8-6.2 mg/dL
2-5 years 3.5-6.8 mg/dL

References

X-linked hypophosphatemic rickets: a disease often unknown to affected patients.
1994. Michael J. Econs, Gregory P. Samsa, Michael Monger, Marc K. Drezner, John R. Feussner. Bone and Mineral 24:17-24.

PubMed ID: 8186731 

New perspectives on the biology and treatment of X-Linked Hypophosphatemic rickets.
Carpenter, Thomas O.; Pediatric Clinics of North America 44(2): 443-466 (1997)
PubMed ID: 9130929 

Diagnosis of X-linked hypophosphatemic vitamin D resistant rickets.
Yamamoto T.; Acta Paediatr Jpn. 1997 Aug;39(4):499-502.
PubMed ID: 9316300

Hypophosphatemic rickets: still misdiagnosed and inadequately treated.
Greene WB, Kahler SG.; South Med J. 1985 Oct;78(10):1179-84.
PubMed ID: 2996152

© 2011, The XLH Network Inc.
The authors of this web site are not medical professionals, and this information does not substitute for medical care. Information on these pages is based on biomedical research, published in peer-reviewed journals, and international research conferences. Additionally, in some cases anecdotal information is provided by subscribers of the F-HYPDRR group, a mailing list for The XLH Network Inc. A listing of XLH research is available. Please read our full disclaimer

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Last modified May 4, 2011


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