Pediatric Summary Report Secondary Findings in Pediatric Subjects Non-diagnostic, excludes newborn screening & prenatal testing/screening P Current Version Rule-Out Dashboard Release History Status (Pediatric): Passed (Consensus scoring is Complete) Curation Status (Pediatric): Released

Condition: Hypophosphatemic rickets, X-linked dominant
Mode(s) of Inheritance: X-linked
Actionability Assertion
Gene Condition Pairs(s)
Final Assertion
PHEX0010619 (x-linked dominant hypophosphatemic rickets)
Assertion Pending
Actionability Rationale
This topic was initially scored prior to development of the process for making actionability assertions. The Pediatric AWG decided to defer making an assertion until after the topic could be reviewed through the update process.
Final Consensus Scoresa
Outcome / Intervention Pair
Nature of the
Gene Condition Pairs: PHEX 0010619 (OMIM:307800)
Morbidity of XLHR (rickets, growth, bone/joint pain) / Oral phosphate plus vitamin D analog supplements
Rickets / Borusumab

Narrative Description of Evidence
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Condition
The population prevalence of X-linked hypophosphatemic rickets (XLHR) is approximately 1 in 20,000 with an incidence of 3.9–5 per 100,000 live births.
1 2
Clinical Features
(Signs / symptoms)
Pediatric manifestations in XLHR range from isolated hypophosphatemia to progressive, severe lower-extremity bowing with a decrease in height velocity after the child starts ambulating and the characteristic clinical signs of rickets. Joint pain and impaired mobility associated with enthesopathy (calcification of the tendons, ligaments, and joint capsules), osteophyte formation, or other radiologic findings can occur as well as stress fractures. Adults with XLHR have a significantly reduced final height and may develop osteoarthritis of the lower limbs. Cranial abnormalities include frontal bossing, craniosynostosis, and Chiari malformations (which may cause headache and vertigo). XLHR can also lead to spontaneous dental abnormalities including abscesses, cavities and abnormal enamel. In rare cases, sensorineural hearing loss has been reported.
1 2 3
Natural History
(Important subgroups & survival / recovery)
XLHR frequently manifests in the first two years of life when lower-extremity bowing becomes evident with the onset of weight bearing. However, it sometimes does not manifest until adulthood as previously unevaluated short stature. The features of XLHR are the same in males and females. With consistent treatment, prognosis is good and skeletal deformities can be normalized, but growth rates usually remain subnormal. Despite pharmacologic therapy, some individuals have persistent lower-limb bowing and torsion, which may be due in part to poor compliance with pharmacologic therapy during childhood and the teen years.
1 2
2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
To establish the extent of disease and needs of an individual diagnosed with XLHR, the following evaluations are recommended:
• A lower-extremity x-ray (teleoroentgenogram), and x-ray of the wrists to assess the extent of skeletal disease
• Bone age measurement to evaluate growth potential
• Craniofacial examination for signs of craniosynostosis
• Dental examination
• Hearing evaluation
• X-ray of skeletal sites with reported pain to assess for possible enthesopathy or stress fractures
• Dental examination
• Hearing evaluation
Individuals of any age:
• Evaluation of those with headache and vertigo for Chiari malformation
• Consultation with a clinical geneticist and/or genetic counselor. (Tier 4)
Pharmacologic treatment for XLHR focuses on improving pain and correcting bone deformities. Typically, children are treated from the time of diagnosis until growth is complete. Pediatric treatment consists of oral phosphate administered three to five times daily and high-dose calcitriol. Treatment during growth partially corrects leg deformities, decreases the number of necessary surgeries, and improves adult height. However even with this treatment, many patients can still have suboptimal growth and bone healing. One retrospective study evaluated 19 XLHR patients grouped by age at treatment onset (8 patients in group 1: <1.0 years old; median age 0.35 years and 11 patients in group 2: >1.0 years old, median age 2.1 years). The median height z-score was higher in group 1 than in group 2 at treatment onset (SD scores of -0.4 vs. -1.7; p=0.001) and at the end of the first treatment year (SD scores of -0.7 vs. -1.8; p=0.009). The degree of hypophosphatemia was similar in both groups, but serum alkaline phosphatase remained higher in group 2 throughout childhood. Radiographic signs of rickets were more marked in group 2, but even patients with early treatment developed significant skeletal changes of rickets, suggesting that treatment begun in early infancy results in improved outcome but does not completely normalize skeletal development. (Tier 3)
2 3 4
Burosumab, a human monoclonal antibody against FGF23, has been approved by the FDA, though to date it has not been incorporated into practice guidelines. An open-label study in 52 children aged 5 to 12 with XLHR showed improved renal tubular phosphate reabsorption, serum phosphorus levels, standing height, and physical function and reduced pain and severity of rickets at week 64 of treatment. An open-label study in 13 children aged 1 to 4 years with XLHR showed improved serum phosphorus and rickets and prevented early declines in growth at week 64 of treatment. (Tier 5)
5 6 7
Surgical treatment is frequently pursued to correct skeletal deformities if pharmacological treatment is ineffective or patients are non-compliant. No controlled trials of the different surgical techniques have been undertaken; the literature consists of case series. A retrospective case series of 10 patients (8 females and 2 males; average age of 7 years, 7 months; average follow-up of 7 years, 8 months) most of whom underwent hemiepiphysiodesis for correction of angular limb deformity demonstrated that the surgery was completely successful in patients under age 10 with restoration of neutral mechanical axis and normal ranges while requiring no change in medical management, no cast, and no delay in weight bearing. A recent multicenter case series reported on 10 patients with craniosynostosis, 8 (6 males and 2 females) of whom had familial HR and underwent cranial vault remodeling surgery (CVR) in addition to phosphate plus vitamin D analog therapy. These patients all had improved symptoms or stabilization of the condition, leading to the recommendation of prompt referral to a craniofacial specialist when head shape abnormalities are observed. (Tier 3)
Because individuals with XLHR are susceptible to recurrent dental abscesses which may result in premature loss of decidual and permanent teeth, good oral hygiene with flossing and regular dental care and fluoride treatments are the cornerstones of prevention. (Tier 3)
A systematic review assessed whether growth hormone supplementation in combination with conventional treatment improves growth velocity, phosphate retention, and bone mineral density in pediatric XLHR patients. A single study was included, a small cross-over trial of five (two male and three female) children across a 24-month period with mean age (SE) 5.6 (1.4) years. RhGH therapy improved the height standard deviation score, with mean (SE) of -1.90 (0.40) during 12 months of placebo administration and 4.04 (1.50) during 12 months of rhGH therapy and transiently increased serum phosphate and tubular maximum for phosphate reabsorption. No evidence indicated that the use of rhGH therapy is associated with changes in longitudinal growth, mineral metabolism, endocrine, renal function, bone mineral density, and body proportions. (Tier 1)
No surveillance recommendations have been provided for the Pediatric context.
Circumstances to Avoid
No circumstances-to-avoid recommendations have been provided for the Pediatric context.
3. What is the chance that this threat will materialize?
Mode of Inheritance
X-linked dominant
1 2 3
Prevalence of Genetic Variants
No genetic variant prevalence information has been provided for the Pediatric context.
(Include any high risk racial or ethnic subgroups)
Despite a wide degree of clinical variability in XLHR, penetrance is often said to be 100% by age one year. There is no known difference between penetrance in males and females. (Tier 3)
2 3
Relative Risk
(Include any high risk racial or ethnic subgroups)
Information on relative risk was not available for the Pediatric context.
Individuals with XLHR have variable expressivity. (Tier 3)
The severity can differ among members of the same family. (Tier 4)
4. What is the Nature of the Intervention?
Nature of Intervention
Oral phosphate plus vitamin D analog supplements must be taken 3 to 5 times per day from the time of diagnosis until long bone growth is complete, which has led to problems with compliance in children and adolescents. This treatment has gastrointestinal side effects of diarrhea and gastrointestinal upset. Complications of treatment include hyperparathyroidism, hypercalciuria, and nephrocalcinosis. Periodic clinical evaluation is needed to assess for these therapeutic complications, including blood evaluations and renal ultrasound. The risk of surgical intervention to correct bone deformities in children before age 10 years is prematurely stopping growth. Burosumab is delivered via subcutaneous injection every 2 to 4 weeks and has shown a favorable safely profile, with mild to moderate treatment-related adverse events such injection site reactions.
2 5 6 7
5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
Earlier treatment leads to better outcomes. The disease manifests frequently in the first two years of life when lower-extremity bowing becomes evident with the onset of weight bearing. The extremely variable presentation may lead to the diagnosis not being made until adulthood, which may manifest as previously unevaluated short stature or having a child with XLHR. (Tier 3)
2 3
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.

Gene Condition Associations
Condition Associations
OMIM Identifier
Primary MONDO Identifier
Additional MONDO Identifiers
Reference List
1. X-linked hypophosphatemia. Orphanet encyclopedia,
2. MD Ruppe. X-Linked Hypophosphatemia. 2012 Feb 09 [Updated 2017 Apr 13]. In: MP Adam, HH Ardinger, RA Pagon, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from:
3. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. HYPOPHOSPHATEMIC RICKETS, X-LINKED DOMINANT; XLHR. MIM: 307800: 2017 Mar 03. World Wide Web URL:
4. Carpenter TO, Imel EA, Holm IA, Jan de Beur SM, Insogna KL. A clinician's guide to X-linked hypophosphatemia. J Bone Miner Res. (2011) 26(7):1381-8.
5. Carpenter TO, Whyte MP, Imel EA, Boot AM, Hogler W, Linglart A, Padidela R, Van't Hoff W, Mao M, Chen CY, Skrinar A, Kakkis E, San Martin J, Portale AA. Burosumab Therapy in Children with X-Linked Hypophosphatemia. N Engl J Med. (2018) 378(21):1987-1998.
6. Whyte MP, Carpenter TO, Gottesman GS, Mao M, Skrinar A, San Martin J, Imel EA. Efficacy and safety of burosumab in children aged 1-4 years with X-linked hypophosphataemia: a multicentre, open-label, phase 2 trial. Lancet Diabetes Endocrinol. (2019)
7. Food and Drug Administration. CRYSVITA (burosumab-twza). Publisher: Novato, CA. (2008) Accessed: 2019-02-06. Website:
8. Huiming Y, Chaomin W. Recombinant growth hormone therapy for X-linked hypophosphatemia in children. Cochrane Database Syst Rev. (2005)
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