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

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

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

Inheritance of XLH

Inheritance of XLH

Bone-Kidney Axis

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

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

Presentation of XLH

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)

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

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

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

Hypophosphataemic Rickets - Treatment Phosphate 50-70mg/kg/day (4 - 5 doses per day) Maintenance dose 20- 40mg/kg/day Phosphate Sandoz – 500mg tablet K Phos Neutral – 250 mg capsules Joules Solution 28mg/ml Calcitriol or Alfacalcidol 10-50 ng/kg/day Maintenance dose 20-30 ng/kg/day One Alpha drops 100 ng/drop. One Alpha Capsules 250 ng or 1.0 mcg Calcitriol capsules 250 & 500 ng

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

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

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

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

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

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;88:3591-3597 ©2003 by Endocrine Society

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

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

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