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Hypophosphataemic rickets - a case study presented by Dr Yassmin Musthaffa

Friday 27 May 2022

Hypophosphataemic rickets - a case study presented by Dr Yassmin Musthaffa

Case study presented by Mater Children's Private Brisbane's Dr Yassmin Mushaffa, General Paediatrician and Paediatric Endocrinologist with Paedicare.

Case

A 5-year-old girl of Cook Island/Caucasian descent presented with short stature, progressive bowing leg deformities and pain that were limiting mobility and precluding age-appropriate activities such as climbing on playground equipment (Figure 1).

There was no family history of bone disorders or short stature. She had appropriate dietary calcium intake. Her height (3rd to 5th centile) was disproportionate to her weight (75th to 90th centile) and mid-parental height (90th centile).

She had tender, widened lower limb metaphyses, moderate genu varus and bilateral tibial torsion  (Figure 1). No frontal bossing, rachitic rosary, dental findings or weakness were apparent. There was no history of frequent respiratory infections.

She had received high dose Vitamin D and calcium therapy from 3 years of age for a provisional diagnosis of Vitamin D and calcium deficiencies despite serum values within the age-corrected reference range (Table 1).

She had hypophosphataemia and a low tubular maximal reabsorption of phosphate (TmP) adjusted for glomerular filtration rate (TmP/GFR). The intact Fibroblast Growth Factor 23 (FGF23) concentration was 55.1pg/ml (<30pg/ml).

A massively parallel sequencing hereditary rickets panel revealed a heterozygous de novo pathogenic variant PHEX:c.349+1G>A, and a paternally inherited variant of unknown significance PHEX:c.922A>G p.Met308Val.With a clinically unaffected father, the latter variant was considered benign.

A diagnosis of X-linked hypophosphataemic (XLH) rickets was made. She commenced oral calcitriol and phosphate with improvement in clinical, radiological and biochemical parameters.

Figure 1.

Figure 1. (a) Lower limb images at diagnosis showing genus varus, widened metaphyses and torsion at the tibia bilaterally with an intercondylar femur distance of 5 cm. (b) Left leg and (c) arm X-ray showing extensive metaphyseal fraying, widening and cupping of the physis and bowing deformity of all long bones prior to treatment for X-linked Hypophosphataemic rickets. An improvement in bone pain, leg deformity and mobility matched the resolution of metaphyseal irregularities following phosphorus and calcitriol treatment for (d) 6 months (e) 12 months and (f) 24 months.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure 1. (a) Lower limb images at diagnosis showing genus varus, widened metaphyses and torsion at the tibia bilaterally with an intercondylar femur distance of 5 cm. (b) Left leg and (c) arm X-ray showing extensive metaphyseal fraying, widening and cupping of the physis and bowing deformity of all long bones prior to treatment for X-linked Hypophosphataemic rickets. An improvement in bone pain, leg deformity and mobility matched the resolution of metaphyseal irregularities following phosphorus and calcitriol treatment for (d) 6 months (e) 12 months and (f) 24 months.

Background

Rickets results from decreased serum calcium and/or phosphate, attributable to nutritional deficiencies or genetic/acquired defects in Vitamin D (25OHD) metabolism. Whether the initiating insult is abnormal calcium or phosphate levels, both mineral deficits will generate hypophosphataemia. This is due to either secondary hyperparathyroidism or mechanisms resulting in hypophosphataemia. It is primarily the clinical and genetic features that are relevant in ascertaining the aetiology of hypophosphataemic rickets (HR).  However, biochemical features can provide a clue for FGF23-mediated forms and Hereditary hypophosphataemic rickets with hypercalciuria (HHRH). Aside from tumour-induced osteomalacia or drug-induced toxicity, most types of HR are congenital, causing life-long renal phosphate wasting and may have multi-system manifestations.1,2

Serum phosphate concentration is largely determined by renal tubular phosphate handling. TmP is normally in the range of 90 percent and occurs via the proximal tubule.3 Renal phosphate wasting causes hypophosphataemia and multiple consequences including HR that is unresponsive to 25OHD therapy. Phosphate wasting may be secondary to altered FGF23 signalling, a circulating factor secreted from bone4 termed a “phosphatonin” because of its ability to reduce serum phosphorus levels.  In the renal proximal tubule, FGF23 inhibits phosphate reabsorption.4 FGF23 is a counter-regulatory hormone for 1,25OHD. In the bone-kidney feedback loop, 1,25OHD stimulates FGF23, which in turn suppresses 1,25OHD. This mechanism involves FGF23 inhibiting the activation of 25OHD via 1α-hydroxylase and promoting its degradation via 24-hydroxylase, thus opposing the effect of PTH.4 Consequently, FGF23 reduces both renal and intestinal phosphate absorption. A number of causes of HR are mediated by inappropriately elevated levels of FGF23,4 resulting in phosphaturia, hypophosphataemia and inappropriately low/normal 1,25-dihydroxyvitamin D (1,25OHD). Serum alkaline phosphatase (ALP) activity is elevated, but usually not to the degree observed in nutritional rickets. Serum calcium and 25OHD are normal in the absence of nutritional deficiencies. PTH may be mildly elevated at diagnosis and is secondary to the effects of FGF23 on 1,25OHD.

XLH  accounts for 80% of HR, with an estimated incidence of 3.9 per 100,000 live births.2XLH results from inactivating mutations in phosphate-regulating endopeptidase homologue X-linked (PHEX). Mutations are not always identifiable even with a clear family history. Sporadic cases are common. There is no genotype-phenotype correlation.2  Although females with XLH have one normal copy of the gene, disease severity is independent of gender.

Clinical presentation

Patients typically present in childhood with delayed walking, bone pain, progressive deformity and anteromedial rotational tibial torsion, resulting in bowing and a waddling gait.2Short stature is frequent. Delayed therapy leads to irrecoverable height loss.  Metaphyseal flaring, frontal bossing and rachitic rosary may be evident. Upper limb deformities are virtually absent in XLH, and characterise rickets arising from nutritional deficiencies. There is correlation of the dental and bone phenotype. Spontaneous dental abscesses may occur without any signs of trauma or decay and can lead to loss of primary and permanent teeth. Craniosynostosis may occur, with associated Arnold Chiari I malformation or syringomyelia.1Common complications in adults include enthesopathy, osteomalacia and hearing loss.1

Investigations

XLH is commonly misdiagnosed as nutritional rickets (calcium and/or 25OHD deficiency), metaphyseal dysplasia or physiological bowing. These differentials can be excluded on biochemical and radiological investigations. XLH should be suspected in the presence of low age-specific serum phosphate. Renal phosphate wasting is determined by TmP/GFR, derived from an age-specific calculation that includes a paired, fasting serum and urine collection.3,5  A low TmP/GFR in the presence of hypophosphataemia suggests inappropriate phosphaturia.

Abnormalities in serum and urine calcium should raise suspicion of alternative diagnoses. Hypocalcaemia with hypophosphataemia would suggest 25OHD deficiency rickets or rarely, a defect in 25OHD metabolism due to mutations in the 1α-hydroxylase or 25OHD receptor genes.6In contrast, primary hyperparathyroidism may cause hypophosphataemia with hypercalcaemia. Hypercalciuria during hypophosphatemia would suggest a proximal tubulopathy which is FGF23-independent.2,6Glucosuria, proteinuria or aminoaciduria may also be present. In response to hypophosphataemia, FGF23 secretion is appropriately suppressed, with increased 1,25OHD production, intestinal calcium absorption and hypercalciuria. Recognising renal tubulopathies cannot be over-emphasised as specific treatment of the underlying disease is crucial, in addition to cautious phosphate and active Vitamin D supplementation.

Discussion

Management of XLH is more complicated than that of the more common nutritional rickets. Involving  experienced clinicians may optimise outcomes and minimise therapy-related adverse effects. Optimising growth, minimising pain, skeletal deformity and dental complications are the main goals of treatment. In children without clinical signs, the goal is to prevent rickets. Earlier treatment improves outcomes.7Most children are treated beyond skeletal maturity to prevent osteomalacia and pseudofractures in adulthood.7Conventional treatment has been directed at counteracting the consequences of FGF23 excess: phosphate replacement for renal phosphate wasting and an activated Vitamin D analogue for 1,25OHD deficiency.2,6

Phosphorus has a short half-life and multiple daily doses are required. Thus, conventional therapy is burdensome and limited by gastrointestinal side-effects and poor palatability. These are key factors in non-compliance, ultimately leading to a failure of conventional therapy. Furthermore, conventional treatments do not address the underlying pathogenesis of increased FGF23 in XLH. Recently, a novel anti-FGF23 monoclonal antibody therapy (Burosumab) was shown to specifically neutralise the effects of FGF23 in XLH. In paediatric phase III trials, Burosumab significantly improved rickets severity, growth and biochemical parameters compared to conventional treatment, with limited adverse effects.8Burosumab therapy has been accessed for a number of patients in Australia through clinical trials and compassionate-use programs.  Regulatory approval for Burosumab with the Australian Therapeutic Goods Administration is awaited and it is yet to be listed on the pharmaceutical benefit scheme.

In summary, HR should be considered in cases of rickets presenting with hypophosphataemia, normal 25OHD levels or where Vitamin D treatment does not resolve the clinical, biochemical or radiological derangements. Conventional therapies are sub-optimal. Recently available novel therapies targeting the pathophysiology of the disease may improve outcomes.  

Learning points

  • Low levels of phosphate are found in almost all types of rickets and is likely to cause the mineralisation defect, irrespective of the underlying pathophysiology.
  • A family history is not always present. Genetic causes of rickets may arise de novo.
  • The tubular reabsorption rate of phosphorus (TRP), the maximal tubular reabsorption of phosphorus per glomerular filtration rate (TmP/GFR) and/or the urinary phosphate / creatinine are critical measurements to distinguish rickets due to insufficient intake (e.g. nutritional rickets), from all causes of rickets associated with renal phosphate wasting.
  • X-linked hypophosphataemic (XLH) rickets is the most common type of Hereditary Rickets. Identifying the underlying cause and prompt initiation of appropriate therapy will improve clinical symptoms (growth, pain, deformity) in XLH but resolution may not be complete.
  • Burosumab, a monoclonal antibody that targets FGF-23, is a novel therapy shown to be effective and superior to conventional therapy in children with  XLH.

Table 1 Biochemical Parameters

 

Age 3 years

Age 4 years

Age 5 years

Age 6 years

Age 7 years

Age 8 years

25, OHD

(50-150) nmol/l

66

89

122

 

 

 

1,25 OHD (48-190)

 

 

176

 

 

 

Corrected Ca (2.20 - 2.65) mmol/L

2.39

 

2.27

2.34

2.25

2.25

Ph mmol/L

0.77 (1.10 - 2.20)

0.80 (1.10 - 2.20)

0.77 (0.9 - 2.0)

1.07 (0.9 - 2.0)

0.91 (0.9 - 2.0)

0.82 (0.9 - 2.0)

ALP U/L

510 (120-370)

530 (120-370)

452 (120-370)

381 (120-440)

414 (120-440)

442 (120-440)

Magnesium (0.65 - 1.1) mmol/L

 

 

0.84

 

 

 

PTH (1.0 - 7.0) pmol/L

 

 

7.7

 

3.8

5.6

Creatnine umol/L

< 30

 

< 30

 

< 30

30

Urine ca: Cr ratio (<0.7mmol/L)

 

 

0.3

0.5

0.27

 

TmP/GFR (1.02-1.62)

 

 

0.776

 

 

 

Intervention

25OHD 2000IU

25OHD 5000IU

Calcium 500mg

Phosphorous (40mg//kg/day) five times daily

Calcitriol (50ng/kg/day) twice daily

Phosphorous (40mg//kg/day) four times daily

Calcitriol (43ng/kg/day) twice daily

Phosphorous (22mg//kg/day) four times daily

Calcitriol (37ng/kg/day) twice daily

Phosphorous (21mg//kg/day) four times daily

Calcitriol (26ng/kg/day) twice daily

25-hydroxy Vitamin D (25OHD, cholecalciferol); 1,25-dihydroxy Vitamin D (1,25OHD, calcitriol), Phosphate (Ph); Alkaline phosphatase (ALP); Parathyroid hormone (PTH); Urine calcium: Creatnine ratio (Ca:Cr). tubular maximum for phosphate reabsorption (TmP/GFR). ‘Intervention’ implies medical therapy that was commenced or optimised following the biochemical result.


References

1. Haffner D, Emma F, Eastwood DM, et al. Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia. Nat Rev Nephrol. 2019;15(7):435-455. doi:10.1038/s41581-019-0152-5

2. Holm IA, Econs MJ, Carpenter TO. Familial Hypophosphatemia and Related Disorders. In: Pediatric Bone. ; 2012:699-726. doi:10.1016/B978-0-12-382040-2.10026-7

3. Kruse K, Kracht U, Göpfert G. Renal threshold phosphate concentration (TmPO4/GFR). Arch Dis Child. 1982;57(3):217-223. http://www.ncbi.nlm.nih.gov/pubmed/6280622. Accessed May 28, 2017.

4. Endo I, Fukumoto S, Ozono K, et al. Clinical usefulness of measurement of fibroblast growth factor 23 (FGF23) in hypophosphatemic patients: Proposal of diagnostic criteria using FGF23 measurement. Bone. 2008;42(6):1235-1239. doi:10.1016/J.BONE.2008.02.014

5. Walton RJ, Bijvoet OLM. NOMOGRAM FOR DERIVATION OF RENAL THRESHOLD PHOSPHATE CONCENTRATION. Lancet. 1975;306(7929):309-310. doi:10.1016/S0140-6736(75)92736-1

6. Lambert AS, Linglart A. Hypocalcaemic and hypophosphatemic rickets. Best Pract Res Clin Endocrinol Metab. 2018;32(4):455-476. doi:10.1016/j.beem.2018.05.009

7. Quinlan C, Guegan K, Offiah A, et al. Growth in PHEX-associated X-linked hypophosphatemic rickets: the importance of early treatment. Pediatr Nephrol. 2012;27(4):581-588. doi:10.1007/s00467-011-2046-z

8. Imel EA, Glorieux FH, Whyte MP, et al. Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial. Lancet (London, England). 2019;393(10189):2416-2427. doi:10.1016/S0140-6736(19)30654-3

Author acknowledgement

Musthaffa Y1,2, Conwell LS1,2

1: Department of Endocrinology and Diabetes, Queensland Children’s Hospital, South Brisbane, QLD, Australia.

2: School of Clinical Medicine, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia

 

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