Hypophosphatemic rickets, X-linked dominant

Actionability Pediatric Summary Report

Gene: PHEX (HGNC:8918)
Mode(s) of Inheritance:X-linked
Literature Search: 11/05/2018
Curation Status: Released - Under Revision (1.2.3)
Release History

Secondary Findings in Pediatric Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

Actionability Assertions

Gene Condition (MONDO ID) OMIM ID Final Assertion
PHEX X-linked dominant hypophosphatemic rickets (0010619) 307800 Assertion Pending

Actionability Assertion 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.

Actionability Scores

Outcome / Intervention Pair Severity Likelihood Effectiveness Nature of Intervention Total Score
Morbidity of XLHR (rickets, growth, bone/joint pain) / Oral phosphate plus vitamin D analog supplements 2 3C 2C 2 9CC
Rickets / Borusumab 2 3C 2N 2 9CN
View scoring key
Domain of Actionability Scoring Metric State of the Knowledgebase
Severity: What is the nature of the threat to health to an individual? 3 = Sudden death as a reasonably possible outcome
2 = Reasonable possibility of death or major morbidity
1 = Modest morbidity
0 = Minimal or no morbidity 		N/A
Likelihood: What is the chance that the outcome will occur? 3 = >40% chance
2 = 5%-39% chance
1 = 1%-4% chance
0 = <1% chance 		A = Substantial evidence or evidence from a high tier (tier 1)
B = Moderate evidence or evidence from a moderate tier (tier 2)
C = Minimal evidence or evidence from a lower tier (tier 3 or 4)
D = Poor evidence or evidence not provided in the report
N = Evidence based on expert contributions (tier 5)
Effectiveness: What is the effectiveness of a specific intervention in preventing or diminishing the risk of harm? 3 = Highly effective
2 = Moderately effective
1 = Minimally effective
0 = Controversial or unknown effectiveness
IN = Ineffective/No interventiona 		A = Substantial evidence or evidence from a high tier (tier 1)
B = Moderate evidence or evidence from a moderate tier (tier 2)
C = Minimal evidence or evidence from a lower tier (tier 3 or 4)
D = Poor evidence or evidence not provided in the report
N = Evidence based on expert contributions (tier 5)
Nature of intervention: How risky, medically burdensome, or intensive is the intervention? 3 = Low risk, or medically acceptable and low intensity
2 = Moderate risk, moderately acceptable or intensive
1 = Greater risk, less acceptable and substantial intensity
0 = High risk, poorly acceptable or intensive 		N/A
a Do not score the remaining categories

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.
View Citations

X-linked hypophosphatemia. Orphanet encyclopedia, ORPHA: 89936., MD Ruppe, et al. (2012) NCBI: NBK83985

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.
View Citations

X-linked hypophosphatemia. Orphanet encyclopedia, ORPHA: 89936., MD Ruppe, et al. (2012) NCBI: NBK83985, Online Medelian Inheritance in Man. (2017) OMIM: 307800

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.
View Citations

X-linked hypophosphatemia. Orphanet encyclopedia, ORPHA: 89936., MD Ruppe, et al. (2012) NCBI: NBK83985

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.

Mode of Inheritance

X-linked

X-linked dominant

View Citations

X-linked hypophosphatemia. Orphanet encyclopedia, ORPHA: 89936., MD Ruppe, et al. (2012) NCBI: NBK83985, Online Medelian Inheritance in Man. (2017) OMIM: 307800

Penetrance (Includes any high-risk racial or ethnic subgroups)

>= 40 %
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 View Citations

MD Ruppe, et al. (2012) NCBI: NBK83985, Online Medelian Inheritance in Man. (2017) OMIM: 307800

Expressivity

Individuals with XLHR have variable expressivity.
Tier 3 View Citations

Online Medelian Inheritance in Man. (2017) OMIM: 307800

The severity can differ among members of the same family.
Tier 4 View Citations

MD Ruppe, et al. (2012) NCBI: NBK83985

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.

Patient Management

To establish the extent of disease and needs of an individual diagnosed with XLHR, the following evaluations are recommended:

Children:

• 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

Adults:

• 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 View Citations

MD Ruppe, et al. (2012) NCBI: NBK83985

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 View Citations

MD Ruppe, et al. (2012) NCBI: NBK83985, Online Medelian Inheritance in Man. (2017) OMIM: 307800, Carpenter TO, et al. (2011) PMID: 21538511

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 View Citations

Carpenter TO, et al. (2018) PMID: 29791829, Whyte MP, et al. (2019) PMID: 30638856, Food and Drug Administration. (2008) URL: www.accessdata.fda.gov.

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 View Citations

MD Ruppe, et al. (2012) NCBI: NBK83985

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 View Citations

MD Ruppe, et al. (2012) NCBI: NBK83985

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 View Citations

Huiming Y, et al. (2005) PMID: 15674949

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.

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.
Context: Pediatric
View Citations

MD Ruppe, et al. (2012) NCBI: NBK83985, Carpenter TO, et al. (2018) PMID: 29791829, Whyte MP, et al. (2019) PMID: 30638856, Food and Drug Administration. (2008) URL: www.accessdata.fda.gov.

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.
Context: Pediatric
Tier 3 View Citations

MD Ruppe, et al. (2012) NCBI: NBK83985, Online Medelian Inheritance in Man. (2017) OMIM: 307800

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
OMIM Identifier Primary MONDO Identifier Additional MONDO Identifiers
PHEX 307800 0010619 0020720

References List

Carpenter TO, Imel EA, Holm IA, Jan de Beur SM, Insogna KL. (2011) A clinician's guide to X-linked hypophosphatemia. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 26(7):1381-8.

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. (2018) Burosumab Therapy in Children with X-Linked Hypophosphatemia. The New England journal of medicine. 378(21):1987-1998.

Food and Drug Administration. CRYSVITA (burosumab-twza). Publisher: Novato, CA (2008) Accessed: 2019-02-06. URL: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761068s000lbl.pdf

Huiming Y, Chaomin W. (2005) Recombinant growth hormone therapy for X-linked hypophosphatemia in children. The Cochrane database of systematic reviews. CD004447.

HYPOPHOSPHATEMIC RICKETS, X-LINKED DOMINANT; XLHR. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 307800, (2017) World Wide Web URL: http://omim.org/

MD Ruppe. X-Linked Hypophosphatemia. (2012) [Updated Apr 13 2017]. In: MP Adam, HH Ardinger, RA Pagon, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK83985/

Whyte MP, Carpenter TO, Gottesman GS, Mao M, Skrinar A, San Martin J, Imel EA. (2019) Efficacy and safety of burosumab in children aged 1-4 years with X-linked hypophosphataemia: a multicentre, open-label, phase 2 trial. The lancet. Diabetes & endocrinology. 7(2213-8595):189-199.

X-linked hypophosphatemia. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=89936

Early Rule-Out Summary

This topic passed the early rule out stage

Findings of Early Rule-Out Assessment

  1. Is there a qualifying resource, such as a practice guideline or systematic review, for the genetic condition?
  2. Does the practice guideline or systematic review indicate that the result is actionable in one or more of the following ways?

    3. a. Patient Management

    b. Surveillance or Screening

    c. Circumstances to Avoid

  3. Is there an intervention that is initiated during childhood (<18 years of age) in an undiagnosed child with the genetic condition?
  4. Does the disease present outside of the neonatal period?
  5. Is this condition an important health problem?
  6. Is there at least on known pathogenic variant with at least moderate penetrance (≥40%) or moderate relative risk (≥2) in any population?