X linked hypophosphathemia

General Medical Guideline
Last modified
20 March 2021
  • Reduced phosphate reabsorption by the kidneys 
  • Low blood phosphate
  • Bone deformities

X-linked hypophosphatemia manifests in children with weak and soft bones as a result, bone deformities, especially leg bowing; delayed walking; waddling gait; bone/joint pain developing progressively once toddlers start standing and walking; reduced growth velocity as well as disproportionate growth; dental abscesses in ages over 3 years. Craniosynostosis, premature closure of cranial sutures, has been reported in patients with XLH as the first symptom even before other features as a low serum phosphate reveal. 

Adults may present with persistent bone pain, short stature: impaired limb growth with relatively preserved trunk growth results in disproportionate short stature, early osteoarthritis, hairline fractures and Looser zones, enthesopathy, and/or periodontitis, osteomalacia, pseudofractures, stiffness, enthesopathy and poor dental condition including periodontitis (inflammation of the gums). Patients might present with an abnormal skull shape — that is, dolichocephaly, characterized by parietal flattening, frontal bossing and widened sutures as the consequence of the premature fusion of the parietal and frontal bones. Osteomalacia-related bone pain needs to be distinguished from osteoarthritis-related bone pain. 

The most common oral findings are recurrent abscesses and/or fistulas in caries-free teeth in both the primary and permanent dentition phases. Other symptoms include late secondary dentition and radiographically visible, severely enlarged pulp chambers (in the context of XLH), especially hard tooth tissue mineralization disorders.

Regardless of whether the patient is an infant, child, adolescent or adult, early diagnosis followed by optimal treatment is crucial to control the clinical manifestations, prevent complications, and improve quality of life. 

Laboratory Individual affected by XLH typically have low serum phosphorus and inappropriately high urine phosphorus due to renal phosphorus wasting. Alkaline phosphatase is normal or elevated, and vitamin D, serum calcium, and parathyroid hormone (PTH) levels are usually normal.

Radiology Skeletal deformities are widening of the distal metaphyses at the wrist and ankle level. In contrast to rickets, secondary to vitamin D or calcium deficiency, in XLH, cortical bone often appears thickened and features of bone resorption are lacking. These abnormalities preferentially occur at sites of rapid growth (in particular the distal femora, distal tibiae, and distal radii) and typically affect costochondral junctions, which leads to the development of the rachitic rosary and Harrison’s groove. Radiography limited to the knees and/or wrists and/or the ankles is usually sufficient to diagnose rickets. Bone deformities primarily involve lower limbs. Adults might present with different radiographic features from children, including pseudo-fractures, early osteoarthritis of the spine, hip and knees (osteophytes on joint margins or narrowing of joint cartilage) and/or enthesopathy (such as bone proliferation at the site of ligament attachments or calcification of ligaments). Osteomalacia-related fractures are rarely observed in adults, whereas pseudo-fractures are frequently observed in adults. 

Surveillance Recommendations include height and weight, head circumference and skull shape abnormalities by a careful physical examination in all children at the time of diagnosis of XLH or other forms of rickets and repeated over time. Surveillance of rickets: bone abnormalities, bone pain, and fatigue; dental examination. Neurological examination on consequences of craniosynostosis and spinal stenosis.  Hearing screening. Kidney involvement: blood pressure and renal ultrasound. Laboratory: blood: Alkaline phosphatase, Calcium, Phosphate, Creatinine, Parathyroid hormone, 25(OH) vitamin D; urine calcium and creatinine

Treatment At present, there are two alternative therapies: - subcutaneous burosumab or -conventional therapy, consisting of oral phosphate and active vitamin D to correct the 1.25(OH)2vitamin D deficiency and to compensate for the renal phosphate wasting, respectively.

X-linked hypophosphatemia: Management and treatment prospects. Lambert AS, Zhukouskaya V, Rothenbuhler A, Linglart A. Joint Bone Spine. 2019 Jan 31. pii: S1297-319X(19)30010-7. doi: 10.1016/j.jbspin.2019.01.012.

Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia. Haffner D, Emma F, Eastwood DM, Duplan MB, Bacchetta J, Schnabel D, Wicart P, Bockenhauer D, Santos F, Levtchenko E, Harvengt P, Kirchhoff M, Di Rocco F, Chaussain C, Brandi ML, Savendahl L, Briot K, Kamenicky P, Rejnmark L, Linglart A. Nat Rev Nephrol. 2019 Jul;15(7):435-455. doi: 10.1038/s41581-019-0152-5. Review.

X-linked hypophosphatemic rickets: an Italian experts' opinion survey. Emma F, Cappa M, Antoniazzi F, Bianchi ML, Chiodini I, Eller Vainicher C, Di Iorgi N, Maghnie M, Cassio A, Balsamo A, Baronio F, de Sanctis L, Tessaris D, Baroncelli GI, Mora S, Brandi ML, Weber G, D'Ausilio A, Lanati EP. Ital J Pediatr. 2019 May 31;45(1):67. doi: 10.1186/s13052-019-0654-6.

Vakharia JD, Matlock K, Taylor HO, et al. Craniosynostosis as the Presenting Feature of X-linked Hypophosphatemic Rickets. Pediatrics. 2018;141(s5):e20172522 

Oral symptoms and oral health-related quality of life of individuals with x-linked hypophosphatemia Marcel Hanisch, Lauren Bohner, Martin M. I. Sabandal, Johannes Kleinheinz, and Susanne Jung. Head Face Med. 2019; 15: 8.

Burosumab versus conventional therapy in children with X-linked hypophosphatemia: a randomized, active-controlled, open-label, phase 3 trial. Imel EA, Glorieux FH, Whyte MP, Munns CF, Ward LM, Nilsson O, Simmons JH, Padidela R, Namba N, Cheong HI, Pitukcheewanont P, Sochett E, Högler W, Muroya K, Tanaka H, Gottesman GS, Biggin A, Perwad F, Mao M, Chen CY, Skrinar A, San Martin J, Portale AA. Lancet. 2019 Jun 15;393(10189):2416-2427. doi: 10.1016/S0140-6736(19)30654-3. Epub 2019 May 16. Erratum in: Lancet. 2019 Jul 13;394(10193):120. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)3065…


Rare Condition

X Linked Hypophosphatemia

X-linked hypophosphatemia (XLH) is known as the most common hereditary metabolic rickets with a prevalence of 1:20,000- 60,000. Manifestations are bone deformities (particularly bowing of...