1. XLH in Children & Adolescents
Professor Nick Shaw
Dept of Endocrinology & Diabetes
Birmingham Children’s Hospital

2. What is XLH Rickets? X- linked – gene carried on an X-chromosome
Hypophosphatemic – low phosphate level in the blood
Rickets – softening of the bones due to low phosphate

3. X-linked Hypophosphataemic Rickets
4’11”
5’1”
5’2”

4. Inheritance of XLH

5. Inheritance of XLH

6. Bone-Kidney Axis

7. X-linked dominant Hypophosphataemic Rickets (XLH)
Due to genetic change ( mutation) in PHEX gene on X-chromosome
This causes high levels of FGF23 in blood
Occurs with a frequency of 1 in 20,000 people
Males usually more severely affected
Dental pulp abscesses due to defects in dentine
Calcification of tendons and ligaments ( enthesopathy) and osteoarthritis in adults

8. Presentation of XLH Known family history Bowed legs as a toddler
Knock knees in an older child
Waddling gait
Short stature
Recurrent dental abscesses

9. Presentation of XLH

10. XLH - Diagnosis
Blood tests: Low Phosphate level Raised Alkaline Phosphatase Normal Vitamin D
Ensure phosphate level is compared with normal range for children
Urine: Excess phosphate + normal calcium
X-rays: Irregular ends of long bones (metaphyses)

11. XLH Example 2.5 yr old South Asian girl
Developed bowed legs from age 1 year
Progressive bowing of legs over 3 months
Seen by an Orthopaedic Surgeon – “Rickets”
Referred to Paediatrician – thought to have rickets due to Vitamin D deficiency
Treatment with Vitamin D – no improvement

12. XLH - Example No family history Ht: 2-9% Wt: 25%
Bowed Legs – 10.5 cm distance between her knees
Blood: Low Phosphate
0.62 mmol/l
Raised Alkaline Phosphatase
Normal Vitamin D
Urine: excess Phosphate

13. Hypophosphataemic Rickets - treatment objectives
Prevention of bone deformity & need for orthopaedic surgery
Normal growth & activity
Avoidance of complications

14. Hypophosphataemic Rickets - Treatment
Phosphate 50-70mg/kg/day (4 - 5 doses per day)
Maintenance dose mg/kg/day
Phosphate Sandoz – 500mg tablet
K Phos Neutral – 250 mg capsules
Joules Solution 28mg/ml
Calcitriol or Alfacalcidol ng/kg/day
Maintenance dose ng/kg/day
One Alpha drops 100 ng/drop.
One Alpha Capsules 250 ng or 1.0 mcg
Calcitriol capsules 250 & 500 ng

15. Hypophosphataemic Rickets - Monitoring
Blood: Calcium, Phosphate, Alkaline Phosphatase
Creatinine Parathyroid Hormone,
Urine: Calcium/Creatinine ratio
Knee X-ray - every 1-2 years
Kidney Ultrasound scan - 2 yearly
Growth and skeletal deformity – every visit
See every 3 to 4 months during infancy & puberty

16. Hypophosphataemic Rickets – dose adjustment
Keep balance between phosphate & One Alpha doses
 Parathyroid Hormone (PTH) ( normal plasma calcium) -
 One Alpha or  Phosphate
 Plasma Calcium (normal PTH) - ↓ One Alpha
 Plasma Calcium &  PTH - ? Tertiary hyperPTH
Plasma phosphate levels not a good guide
Alkaline Phosphatase level useful but not very sensitive
Growth rate and shape of legs useful markers

17. Response to treatment Spectrum of severity
Some can be treated easily with a good response – others can be more difficult
Growth usually better if treated under the age of 2 years
Compliance with treatment will affect response
Lunchtime phosphate dose often a problem in teenagers

19. Hypophosphataemic Rickets - Potential Problems
Diarrhoea or abdominal pain with Phosphate
Persistent short stature
Persistent leg deformity
Need to take medicine 4 to 5 times daily
Autonomous Hyperparathyroidism
Nephrocalcinosis
High blood calcium

20. Hypophosphataemic Rickets -Complications
Review of 24 cases age 1.5 – 16 yrs
Craniosynostosis – 3 cases (Surgery in 1)
Tertiary hyperparathyroidism – 2 cases
Orthopaedic surgery – 5 cases
Nephrocalcinosis – 11 cases
Chiari Type 1 malformation – 1 case
Dental abscesses – 10 cases
Pai B, Hogler W, Shaw NJ, ESPE 2011, Glasgow

21. Growth in XLHR in relation to age of onset of treatment
Height z-scores in group 1 ( ) and group 2 (□) at treatment onset, at the end of first treatment year, at age 9.0 yr, and at final height (adult height or PAH). The bottom of each box indicates the first, the cross line indicates the second (median), and the top indicates the third quartile; the bottom and top lines indicate the minimum and maximum values. P values refer to the difference between groups 1 and 2. Rx, Treatment.
Mäkitie O et al. JCEM 2003;88:
©2003 by Endocrine Society

22. Orthopaedic Surgery Usually not performed under age 6 years
Used to require major surgery with corrective osteotomy
Now much easier with new technique of epiphysiodesis ( 8 plates) – only useful while growing

23. XLH - Milestones
1937: First description of “ Vitamin D resistant rickets”
1980: Use of Phosphate supplements & Calcitriol as treatment
1995: Identification of the PHEX gene
2001: Recognition of high FGF23 levels
2014: Clinical trials of FGF23 antibody in adults and children

24. Family Support Groups