X-Linked Hypophosphatemia

Baby Detect > Nephrology > X-Linked Hypophosphatemia

Hypophosphatemic rickets, X-linked – OMIM#307800

https://omim.org/entry/307800 – PHEX gene

Also known as: vitamin D resistant rickets; hypophosphatemic vitamin D resistant rickets

1. The Disease:

The phenotypic spectrum of X-linked hypophosphatemia (XLH) ranges from isolated hypophosphatemia to severe lower-extremity bowing.

2. The Symptoms:

XLH frequently manifests in the first two years of life when lower-extremity bowing becomes evident with the onset of weight bearing; however, it sometimes cannot manifest until adulthood, as previously unevaluated short stature. In adults, enthesopathy (calcification of the tendons, ligaments, and joint capsules) associated with joint pain and impaired mobility may be the initial presenting complaint. Individuals with XLH are prone to spontaneous dental abscesses; sensorineural hearing loss has also been reported. Lack of early signs or symptoms does not exclude the diagnosis.

  • In children, the corresponding clinical features may include delayed growth and short stature, craniosynostosis and raised intracranial pressure, deformities of weight-bearing limbs, muscle weakness, gait abnormalities, tooth abscesses and excessive dental caries;
  • Following growth plate closure, a part of adolescent and young adult patients continue to experience debilitating symptoms while others may experience a “honeymoon” phase (similar to other metabolic bone diseases) with fewer musculoskeletal problems (except dental manifestations). During this phase, conventional therapy with phosphate supplements and active vitamin D analogues is often stopped, because subjective and skeletal benefits are thought to be lacking (13). During adolescence, the psychological burden increases (14), which may contribute to poor adherence and lack of follow-up.

3. Actions to take in case of early diagnosis

Babies with a positive genetic test (males with 1 hemizygous mutation or females with an heterozygous mutation in the PHEX gene) should continue breastfeeding

  • Laboratory findings: low serum phosphate concentration and reduced tubular resorption of phosphate corrected for glomerular filtration rate (TmP/GFR) are characteristic. Additionally, the normal physiologic response to hypophosphatemia of an elevation of 1,25 (OH)2 vitamin D is absent. Serum calcium and 25-hydroxy vitamin D are within the normal range; parathyroid hormone is normal to slightly elevated. Alkaline phosphatase is characteristically elevated in children, especially during periods of rapid growth, and usually returns to normal in adulthood with or without treatment.
  • The diagnosis is based on X-rays, genetic and laboratorial results, familial history and clinical signs when available.
  • XLH is a lifelong condition that requires lifetime management and regular follow-up with a nephrology specialist and a multidisciplinary approach to care, including paediatrics, physiotherapy, nutrition and genetics.
  • Pain and lower-extremity bowing improve with frequent oral administration of phosphate and high-dose calcitriol. Children are generally treated from the time of diagnosis until long bone growth is complete. The role of pharmacologic treatment in adults is less clear; such treatment is generally reserved for individuals with symptoms such as skeletal pain, upcoming orthopedic surgery, and biochemical evidence of osteomalacia with an elevated alkaline phosphatase, or recurrent pseudofractures or stress fractures. Persistent lower-limb bowing and/or torsion resulting in misalignment of the lower extremity may require surgery.
  • In 2018, the European Medicines Agency (EMA) granted conditional market authorization to the fully humanized monoclonal anti-FGF23 antibody burosumab for the treatment of XLH in children ≥ 1 year.
  • The prognosis is good with consistent treatment.
  • Agents/circumstances to avoid: Treatment with phosphate without calcitriol because of the increased risk for hyperparathyroidism.
  • Genetic counselling is highly recommended for family planning and evaluation of at-risk family members. X-linked hypophosphatemia is inherited in an X-linked manner. An affected male passes the pathogenic variant to all his daughters and none of his sons; an affected female passes the pathogenic variant to 50% of her offspring. Offspring who inherit the pathogenic variant will be affected, but because of the great intrafamilial variation, severity cannot be predicted.

4. For more information:

Orphanet: https://www.filiereorkid.com/rachitisme-hypophosphatemique/

Biblio:

  • https://www.ncbi.nlm.nih.gov/books/NBK83985/
  • Laurent MR, De Schepper J, Trouet D, et al. Consensus Recommendations for the Diagnosis and Management of X-Linked Hypophosphatemia in Belgium [published correction appears in Front Endocrinol (Lausanne). 2021 May 25; 12. PMID: 33815294.