Differential diagnosis of nutritional rickets

A 2-and-a-half-year-old patient presents with delayed growth, bone pain and bowing of the lower extremities, and appears to suffer from pain in their legs. Which of these would be an appropriate diagnosis?

The correct answers are:

• Nutritional rickets
• Vitamin-D-dependent rickets type 1A
• X-linked hypophosphatemia (XLH)
• Hereditary hypophosphatemic rickets with hypercalciuria (HHRH)

Delayed growth, bone pain and bowing of the lower extremities are all signs of rickets, regardless of the underlying cause.² There are multiple inherited or acquired causes of rickets, including nutritional rickets, vitamin-D-dependent rickets type 1A, XLH and HHRH.⁸

References: 2. NHS. Accessed October 2020; 8. Haffner D et al. Nat Rev Nephrol 2019;15:435-455

Which of these might indicate that the patient does not have nutritional rickets?

The correct answers are:

• Short stature
• History of spontaneous tooth abscesses
• Failure to respond to treatment with vitamin D supplements
• Muscle weakness

Different causes of rickets can be split into three forms - nutritional, vitamin D-dependent and vitamin D-independent (also called inherited non-vitamin D-dependent).^6,8 Nutritional rickets is most commonly caused by a dietary deficiency of vitamin D or, in rarer cases, of calcium or phosphorus. Vitamin D supplements, administered with calcium, are the mainstay in nutritional rickets treatment, typically resulting in resolution of symptoms.⁴ Therefore, an alternative diagnosis should be suspected for patients who do not rapidly respond to vitamin D treatment.

Oral manifestations of rickets vary between the different forms:⁶

• Vitamin D-dependent rickets is associated with enamel hypoplasia and impaired tooth mineralisation
• Patients with nutritional rickets often have delayed tooth eruption but are unlikely to experience spontaneous abscesses
• Patients with hypophosphosphataemic rickets may present with impaired tooth calcification, and hypomineralisation of the interglobular dentin. Interglobular dentin formation can impair the calcification of the primary and permanent dentition creating microscopic enamel cracks and dentinal microleakage within the tooth. This results in hypomineralised dentin and enamel, which can trap bacteria and microorganisms and lead to dental abscesses

A history of spontaneous tooth abscesses therefore suggests a patient has a hypophosphataemic form of rickets.

References: 4. Chibuzor M T et al. Cochrane Database Syst Rev 2020;4:CD012581; 6. Patel-Bhakta H G and Campbell P R. Accessed October 2020; 8. Haffner D et al. Nat Rev Nephrol 2019;15:435-455

Based on these findings, which of these would be an appropriate differential diagnosis?

The correct answer is:

• Vitamin-D-dependent rickets type 1A
• X-linked hypophosphataemia (XLH)
• Hereditary hypophosphataemic rickets with hypercalciuria (HHRH)
• Nutritional rickets

These results are most indicative of XLH. Characteristic results for each disease are listed below:⁸

Reference: 8. Haffner D et al. Nat Rev Nephrol 2019;15:435-455

PTH: parathyroid hormone; TmP/ GFR: tubular maximum reabsorption of phosphate per glomerular filtration rate.

Which investigations would you initiate to confirm a diagnosis of X-linked hypophosphataemia (XLH)?

The correct answers are:

• Biochemical tests
• Radiographs
• 6-minute walk test
• Clinical examination

In the case of suspected XLH, evidence-based guidelines recommend the following initial diagnostic work up:⁸

• A detailed clinical evaluation, including evidence of rickets, growth failure, dental abnormalities and signs of craniosynostosis and/or intracranial hypertension
• A radiological evaluation to diagnose and grade rickets and osteomalacic lesions
• Biochemical tests, including serum levels of phosphate, calcium, alkaline phosphatase, parathyroid hormone, 25(OH) vitamin D, 1,25(OH)2 vitamin D and creatinine, and urinary levels of calcium, phosphate and creatinine by use of a spot urine test for calculation of the tubular maximum reabsorption of phosphate per glomerular filtration rate and urinary calcium:creatinine ratio

Reference: 8. Haffner D et al. Nat Rev Nephrol 2019;15:435-455

Which of these clinical features might indicate a diagnosis of X-linked hypophosphataemia (XLH)?

The correct answers are:

• Upper limb deformities
• Lower limb deformities presenting when the child begins to walk
• Hearing loss
• Craniosynostosis

The presence and severity of symptoms can vary between patients with XLH. In many cases they begin within the first 18 months of life, when a child begins to bear weight on their legs. These symptoms can include:⁹

• bowing or twisting of the lower legs (upper limbs are usually not affected)
• short stature/ slow growth
• bone pain
• muscle pain and weakness
• a waddling gait
• joint pain
• abnormal tooth development
• tooth abscesses and dental pain
• rickets that does not improve with traditional vitamin D therapy
• craniosynostosis
• hearing loss

Reference: 9. Genetic and Rare Diseases Information Centre. Accessed October 2020

Which two blood tests would be most useful for confirming a diagnosis of X-linked hypophosphataemia (XLH)?

The correct answers are:

• FGF23
• Calcium
• Parathyroid hormone
• Tubular maximum reabsorption of phosphate per glomerular filtration rate (TmP/ GFR)

Hypophosphataemia, caused by renal phosphate wasting (measured by TmP/ GFR) and elevated FGF23 levels, is a biochemical hallmark of XLH.⁷

Reference: 7. Carpenter T O et al. J Bone Miner Res 2011;26:1381-1388

7. The X-rays above show the legs of a healthy 3-year-old child and the legs of a 3-year-old with X-linked hypophosphataemia. Which child has XLH?

The correct answers is:

• A
• B

What are the signs on X-ray B that indicate a diagnosis of X-linked hypophosphataemia (XLH)?

The correct answers are:

• Marked bowing of legs
• Lucency of the metaphyses
• Fractures
• Masses

Radiographic changes of rickets are evident at the growth plate (physis) of rapidly growing long bones. The lucent gap between the metaphysis and epiphysis expands longitudinally and the metaphysis may appear indistinct, frayed and irregular. The metaphyseal margin may appear concave (or cupped), and fractures and bowing of the bones may occur.¹⁰

References: 10. Thacher T D et al. J Trop Pediatr 2000;46:132-139

Patients with X-linked hypophosphataemia (XLH) may see many specialists before a diagnosis is made. Which of the following healthcare professionals could make a diagnosis of XLH?

The correct answers are:

• Dentist
• Paediatrician
• Rheumatologist
• Neurologist

In children, the main clinical symptoms of XLH are abnormal gait, lower limb deformity and decreased growth velocity, which may be recognised by a paediatrician or a rheumatologist. A high prevalence of dental abscesses in patients aged >3 years⁸ means that a dentist may often be consulted. Patients might present with an abnormal skull shape as the consequence of premature fusion of the parietal and frontal bones⁸ which could lead to a diagnosis of XLH by a neurologist.

References: 8. Haffner D et al. Nat Rev Nephrol 2019;15:435-455

Is it necessary to carry out molecular genetic testing to confirm the diagnosis?

The correct answer is:

• Yes
• No

In patients with a negative family history (approximately one-third of reported patients), mutational analysis of the PHEX gene is recommended. This can provide negative or positive confirmation in ~70–90% of cases (the analysis is inconclusive in the remaining cases). Identification of a causative mutation for X-linked hypophosphataemia (XLH) can allow for genetic counselling and screening of at-risk relatives. The testing may also yield a negative result for XLH, at which point other hereditary causes of hypophosphataemia can be considered.⁸

References: 8. Haffner D et al. Nat Rev Nephrol 2019;15:435-455

Watch a short video to hear the diagnostic journey of Emile, discussed by his parents and a paediatric endocrinologist, Prof Agnès Linglart, Hôpital Bicêtre, Paris, France