Non-nutritional rickets: Approach to diagnosis and management

Case 1

A 5-year-old boy presented with progressive genu varum from the age of 1 year, poor linear growth from 1.5 years, and delayed motor milestones. He was the first child of nonconsanguineous parents, with a family history of short stature and lower limb deformities in multiple maternal relatives (mother, maternal aunts, and grandparents), and a maternal history of femoral fracture. He was born late preterm with a birthweight of 2 kg and had neonatal hypoglycemia and jaundice. Motor milestones were delayed, with independent standing achieved at 1.5 years and walking at 2 years; at presentation, he was unable to run or hop.

Anthropometry revealed a weight of 12.4 kg (−3.5 SDS) and a height of 87.5 cm (−4.9 SDS), with an upper segment: lower segment ratio of 1.5:1. The intercondylar distance was 6.2 cm. Examination showed frontal bossing, occipital prominence, rachitic rosary, genu varum, lumbar lordosis, and wrist and ankle joint widening. Bone age was 2.5 years, with a corrected height SDS of −2.13.

Investigations showed serum calcium (Ca²⁺) 9.5 mg/dL (8.8–10.8 mg/dL), phosphate 1.8 mg/dL (4.5–6.5 mg/dL), magnesium 1.9 mg/dL (1.7–2.2 mg/dL), and alkaline phosphatase (ALP) 1051 U/L (100–420). Maternal evaluation showed vitamin D at 24.8 ng/mL (20–60 ng/mL), parathyroid hormone (PTH) at 65 pg/mL (15–65 pg/mL), and phosphate at 1.3 mg/dL (2.5–4.5 mg/dL). A 24-h urine study showed urinary phosphorus 86.6 mg/day, tubular maximum phosphate reabsorption per glomerular filtration rate (TmP/GFR) 1.4 mg/dL (3–5.5), and tubular reabsorption of phosphate (TRP) 0.69 (>0.85), with no hypercalciuria. X-rays showed features of active rickets with a Thacher score of 7/10, and maternal X-rays showed diffuse osteopenia.

Clinical features of short stature and genu varum, radiographic rickets, hypophosphatemia with renal phosphate wasting, and a positive maternal history were consistent with familial hypophosphatemic rickets. The index patient and his mother were started on calcitriol and oral phosphate supplementation. Genetic testing identified a hemizygous pathogenic variant in the PHEX gene, exon 20, c.1979G>A, consistent with XLHR, classified as pathogenic.

Case 2

A 2-year and 8-month-old boy presented with inward bowing of the legs and widening of the wrists and ankles for 6 months. Parents also noted the absence of scalp hair regrowth after ceremonial head shaving at 4 months of age and loss of eyebrows for the past 1 year. He was the third child of non-consanguineous parents, with similar complaints in an elder sibling. He was born at term with a birthweight of 1.9 kg by normal vaginal delivery. Gross motor delay was present, with neck holding at 6 months, sitting without support at 1 year, and inability to stand without support at presentation.

Anthropometry revealed a weight of 8.25 kg (−4.13 SDS) and height of 76.5 cm (−4.8 SDS), with a US: LS ratio of 1.3:1 and head circumference 48 cm (−0.8 SDS). Clinical examination showed pallor and alopecia, along with frontal and parietal bossing, rachitic rosary, Harrison’s sulcus, wrist widening, genu varum, kyphosis, and generalized hypotonia. He was treated with multiple courses of vitamin D for the above complaints for the past 1 year.

Further workup showed serum Ca²⁺ 7.7 mg/dL, ionized calcium (iCa) 0.73 mmol/L, phosphate 1.8 mg/dL, ALP 6033 U/L, intact PTH (iPTH) 392 pg/mL, and 25(OH)D₃ 82.5 ng/mL. X-rays were suggestive of active rickets, with cupping, fraying, and splaying of the metaphyses, along with osteopenia and delayed ossification.

Clinical features of severe rickets with alopecia, hypocalcemia, hypophosphatemia, vitamin D sufficiency, and markedly elevated ALP and iPTH, and radiographic evidence of active rickets were consistent with vitamin D-dependent rickets (VDDR). He was treated with calcium, calcitriol, and maintenance vitamin D supplementation. Genetic testing showed VDR (NM_000376.3) exon 3 c.88C>T p.Arg30* homozygous, autosomal recessive (AR) VDDR2A (OMIM#277440), pathogenic.

Case 3

A 4-month-old girl presented with failure to thrive, recurrent seizures, and global developmental delay. She had a history of recurrent hospital admissions for pneumonia. Two siblings died as neonates from similar symptoms along with early-onset seizures.

She weighed 3.4 kg (−5.14 SDS) with length 55 cm (−3.28 SDS), weight for length −3.34 SDS, and occipitofrontal circumference 37 cm (−2.83 SDS). Examination showed coronal suture overriding, frontal bossing, rachitic rosary, Harrison sulcus, and central hypotonia. Blood investigations showed persistent hypercalcemia (13.6 mg/dL, iCa 4.1 mmol/L), phosphorus 5.8 mg/dL, and ALP 15 U/L.

Early-onset rickets with seizures, failure to thrive, hypercalcemia, and low ALP suggested HPP. Seizures were managed with pyridoxine, and she was discharged on a low-calcium diet pending asfotase alfa therapy. Genetic testing confirmed compound heterozygous ALPL variants: c.422G>T p.Arg141Leu (exon 5) and c.1090C>T p.Arg364* (exon 9), AR inheritance, pathogenic for HPP.

The above three cases show that NNR initially presents with features similar to nutritional rickets, leading to delayed diagnosis and multiple courses of vitamin D and calcium. Understanding the physiology of calcium, phosphate, vitamin D, and bone mineralization is essential to effective management of NNR.

Phosphopenic rickets

This originates from primary hypophosphatemia due to FGF23 excess (XLHR and ADHR) or renal tubular defects, bypassing the calcium-PTH axis. FGF23 directly inhibits renal phosphate reabsorption (NaPi-IIa/c internalization) and suppresses calcitriol, maintaining normal/low-normal calcium with inappropriately low 1,25(OH)₂D despite hypophosphatemia. Unlike calcitropic forms, PTH remains low/normal, preventing hypocalcemia but failing to correct phosphate.

XLHR

It is the most common cause of hypophosphatemic rickets. The incidence of XLHR is 3.9/100,000 livebirths and accounts for 80% cases of familial hypophosphatemic rickets.^[12,13] It occurs due to inactivating mutations in the phosphate-regulating gene with homologies to endopeptidase on the X chromosome (PHEX), leading to downregulation of FGF23 degradation and increased FGF23 levels.^[14] PHEX regulates serum FGF23 via proprotein convertases such as subtilisin/kexin-type 2. Its dysfunction elevates osteopontin and the acid-serine-aspartate-rich matrix extracellular phosphoglycoprotein-associated peptide, impairing mineralization in XLHR.^[15] Thus, XLHR arises from osteoblast/odontoblast defects, accounting for its distinct features.^[13] Skeletal abnormalities, mainly affecting the lower limbs, occur after weight-bearing in late infancy. It is associated with disproportionate short stature, tooth abscess, dolichocephaly, and hearing loss. Enthesopathies, periodontitis, osteoarthritis, and pseudo-fractures in adults cause significant morbidity.^[6] Family history of rickets supports early diagnosis. X-linked dominant transmission affects 50% of offspring from carrier mothers and all daughters (but no sons) of affected fathers. Notably, approximately 30% of XLHR cases are caused by de novo mutations.^[16] In a recent study, patients with PHEX deleterious mutations (premature stop codons, such as nonsense, deletions, and splice-site mutations) had lower tubular phosphate reabsorption and 1,25(OH)₂D levels than those with plausible mutations (such as missense mutations). The XLHR phenotype might be predicted by the type of PHEX mutation.^[17]

ADHR

ADHR, a rare disorder from activating FGF23 gene variants, produces cleavage-resistant FGF23 protein.^[18] This elevates serum FGF23, mimicking other FGF23 excess states. Incomplete penetrance causes variable phenotypes, with symptoms often emerging post-childhood. Adults develop osteomalacia-related weakness, fatigue, bone pain, and pseudo-fractures. Iron deficiency triggers symptoms by boosting FGF23 expression.^[19]

AR hypophosphatemic rickets (ARHR)

ARHR1 results from mutations in dentin matrix acidic phosphoprotein 1 (DMP1), which promote FGF23 expression in osteocytes/osteoblasts.^[2,20] ARHR2 stems from homozygous mutations in the ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) gene, disrupting phosphate/pyrophosphate balance, bone mineralization, and causing tissue calcification. Both mimic XLHR clinically, with unclear FGF23 elevation mechanisms. Unlike ENPP1-related generalized arterial calcification of infancy, ARHR2 shows profound hypophosphatemia, likely protecting against arterial calcification and variable phenotypes, including enthesopathy and hyperparathyroidism.^[21]

McCune–Albright syndrome

It is a classical triad of café-au-lait spots, precocious puberty, and fibrous dysplasia. The bony deformity may be confused with rickets at times. The renal phosphate wasting can, at times, present with features of rickets.

Tumor-induced osteomalacia (TIO)

It is a rare, acquired paraneoplastic syndrome characterized by FGF23-mediated renal phosphate wasting, hypophosphatemia, and inappropriately low or normal 1,25(OH)₂D levels. Impaired mineralization results in osteomalacia in adults and rickets when it occurs in children, presenting with bone pain, muscle weakness, fractures, growth failure, and lower limb deformities. Tumors are typically small mesenchymal neoplasms, often in bone or soft tissue, and may be difficult to localize.^[22]

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH)

It is an AR renal phosphate-wasting disorder caused by loss-of-function mutations in SLC34A3, encoding the proximal tubular sodium-phosphate cotransporter NaPi-IIc. Reduced phosphate reabsorption leads to hypophosphatemia, increased 1,25(OH)₂D synthesis, increased intestinal calcium absorption, and consequent hypercalciuria, with a risk of nephrocalcinosis. Children present with rickets, growth retardation, bone pain, and deformities, while serum calcium is normal and PTH is typically suppressed or low normal. FGF23 levels are normal or low, distinguishing HHRH from FGF23-mediated hypophosphatemic rickets such as XLHR and TIO.

Renal tubular acidosis (RTA)

Fanconi syndrome denotes generalized proximal tubular dysfunction resulting in excessive urinary losses of phosphate, glucose, amino acids, uric acid, potassium, and bicarbonate. Causes include Wilson disease, cystinosis, tyrosinemia type 1, galactosemia, Lowe (oculocerebrorenal) syndrome, mitochondrial disorders, ifosfamide nephrotoxicity, and rarely idiopathic forms. Metabolic acidosis from bicarbonate wasting exacerbates phosphaturia and impairs bone mineralization by intracellular acidosis-driven calcium release. Proximal RTA (type II), without full Fanconi syndrome, may also cause rickets through mechanisms similar to those of acidosis-mediated mechanisms. In an Indian cohort of rickets at a tertiary care center, RTA (53.2%) was the most common cause, followed by phosphopenic (22%) and calcipenic rickets (17.7%).^[23]

VDDR

It stems from reduced calcium availability, either nutritional vitamin D deficiency or genetic defects in 1,25(OH)₂D metabolism/action (VDDR), triggering secondary hyperparathyroidism. Low serum Ca²⁺ stimulates PTH, which enhances renal calcitriol synthesis and intestinal Ca²⁺ absorption while causing phosphate wasting through downregulation of NaPi-IIa/c, resulting in hypocalcemia. This leads to secondary hyperparathyroidism, hypophosphatemia, and rickets. Clinical hallmarks include early hypocalcemic seizures/tetany, craniotabes, and cardiomyopathy in infants.

HPP: A Mineralization enzyme defect

HPP is caused by biallelic (severe forms) or monoallelic (milder forms) loss-of-function mutations in ALPL, encoding TNSALP. TNSALP hydrolyses inorganic pyrophosphate (PPi), a potent inhibitor of hydroxyapatite crystal formation. TNSALP deficiency leads to extracellular PPi accumulation, blocking bone mineralization despite adequate serum calcium and phosphate.^[29] Six clinical subtypes (perinatal, infantile, childhood, odontohypophosphatasia, adult, and prenatal benign) span a spectrum from lethal neonatal disease to isolated early premature tooth loss.^[30] Critically, serum ALP is the single most important screening test; it is dramatically low in all forms. The paradox of rickets with low ALP is pathognomonic of HPP and should never be overlooked.

Clinical presentation

The clinical presentation of NNR varies by the age of onset, underlying mechanism, and severity. In contrast to nutritional rickets, which typically presents in infancy with hypocalcemic tetany or skeletal changes, NNR manifests in toddlerhood (e.g., XLHR) or is detected incidentally on biochemical screening (milder phosphonic forms).

Common musculoskeletal features include:

• Limb deformities: Genu varum (bow-legs) in toddlers; genu valgum (knock-knees) in older children; torsional deformities; tibial/femoral bowing [Figure 1]

• Short stature: Disproportionately short lower segment; decreased growth velocity below 25^th percentile

• Rachitic features: Rachitic rosary, widened wrists, frontal bossing; more common in calcitriol-deficient forms

• Bone pain and tenderness: Lower limbs; worsens with weight-bearing

• Waddling gait and muscle weakness: Proximal myopathy, particularly in VDDR and Fanconi syndrome

• Delayed walking milestones

• Condition-specific features are mentioned in Table 2.

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Figure 1:

Clinical and radiological features of non-nutritional rickets. (a) Genu valgum deformity, (b) genu varum, (c) wrist deformity, (d) rachitic rosary (expanded costochondral junctions) (black arrows), (e) alopecia in vitamin D-resistant rickets type 2A (black arrow), (f) wrist widening (black arrows), (g) dolichocephaly in X-linked hypophosphatemic rickets, (h) X-rays of the wrists and knees (anteroposterior views) showing metaphyseal splaying (white arrow), fraying (black arrow), and cupping (blue arrows), at the wrist and knee.

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Biochemical evaluation

The clinical clues should direct the investigations in NNR, as the list of investigations is exhaustive. The biochemical evaluation of suspected NNR includes serum calcium, phosphate, ALP, PTH, 25(OH)D₃, 1,25(OH)₂D, creatinine (Cr), urea, blood pH, bicarbonate, magnesium, urinary calcium and phosphate, spot Ca/Cr ratio, TRP or TmP/GFR. Table 3 summarizes the characteristic biochemical profiles across major conditions. ALP is always elevated in active rickets—a normal or low ALP with clinical rickets should immediately raise suspicion for HPP.

Phosphate assessment

Serum Pi is low in most forms of rickets, more profoundly in hypophosphatemic than calcipenic. In early calcipenic rickets, Pi may remain low-normal until PTH-driven renal wasting depletes bone mineral stores.^[16] Hypophosphatemic rickets shows low serum phosphate, raised ALP, and reduced TmP/GFR. PTH remains normal/slightly elevated as FGF23 suppresses 1,25(OH)₂D production, indirectly driving secondary PTH rise.^[8] Phosphate and ALP levels peak in infancy/childhood and normalize post-puberty, requiring age-specific reference ranges.^[30] ALP tracks rickets activity and treatment response effectively.^[31]

TmP/GFR (renal phosphate wasting)

TmP/GFR is a measurement of phosphate reabsorption in relation to filtered phosphate load. TmP/GFR assessment requires simultaneous second morning fasting serum and spot urine using the formula: TmP/GFR = serum Pi − [(urine Pi × serum creatinine)/(urine creatinine)]. Brodehl’s formula is the pediatric gold standard with age-specific norms, while Walton–Bijvoet nomogram (adults only) overestimates in children, and Payne nomogram provides an alternative.^[32] Dietary phosphate deficiency falsely reduces TmP/GFR since it reflects maximum tubular capacity relative to serum levels. It can be confirmed with low urine Pi/Cr; phosphate loading may be required before a valid TmP/GFR assessment.^[17] Reduced TmP/GFR confirms wasting but cannot distinguish VDDR (PTH-driven) from hypophosphatemic (FGF23/renal transporter).

Vitamin D in VDDR

Serum 25(OH)D₃ >20 ng/mL reflects sufficient vitamin D status, and <12 ng/mL suggests deficiency. Levels are reduced in VDDR 1B/3 due to 25-hydroxylase deficiency. In calcipenic rickets with hyperparathyroidism, low 25(OH)D₃ indicates nutritional etiology when correlated with dietary calcium intake; treatment failure suggests VDDR 1B/3. 1,25(OH)₂D levels distinguish subtypes as low in types 1A/1B/3 and elevated in types 2A/2B,^[24] HHRH, and NaPi-IIa/c defects. Levels are inappropriately low/normal in FGF23-mediated rickets.^[8]

In the evaluation of NNR, serum pH and bicarbonate should be assessed first to identify hyperchloremic metabolic acidosis suggestive of distal or proximal RTA. If acidosis is present, a fasting urine sample should then be obtained to measure urinary pH, Ca/Cr ratio, TmP/GFR, glycosuria, aminoaciduria, and low-molecular-weight proteinuria, thereby helping to distinguish isolated hypophosphatemic rickets from RTA-related Fanconi-type disorders, Dent disease, and cystinosis.^[33] An ultrasound (USG) of kidney, ureters, and bladder will be useful in distal RTA, HHRH, and Dent disease to screen for nephrocalcinosis and nephrolithiasis.^[9]

FGF23

Measurement of FGF23 helps to distinguish FGF23-mediated rickets from other causes of hypophosphatemic rickets.^[16] Plasma EDTA sample with prompt centrifugation is essential to avoid falsely low levels. FGF23 concentrations are strongly influenced by Pi intake and vitamin D therapy, and are typically 2–3-fold higher in conventionally treated XLHR than in untreated patients.^[34] The levels are uninterpretable during burosumab treatment, as the drug-FGF23 complex elevates measured levels.^[35] In individuals on oral phosphate and active vitamin D, fasting Pi, and FGF23 should ideally be measured 1–2 weeks after treatment withdrawal,^[6] while high-normal FGF23 in the context of hypophosphatemia should be regarded as inappropriately normal and thus consistent with FGF23-driven disease. Using an assay-specific cutoff for FGF23 testing can reliably identify FGF23-mediated hypophosphatemia but cannot differentiate between its genetic subtypes, which often require subsequent genetic analysis.^[36]

Radiographs

X-rays of fast-growing sites (distal ulna and knee/ankle metaphysis) reveal features of rickets, including widened physes and loss of the provisional calcification zone. Later cupping, fraying, splaying, cortical spurs, and delayed ossification centers [Figure 1].^[16] XLHR shows metaphyseal changes with thicker cortices, coarse trabeculations without resorption/radiolucency.^[6,8]

Rickets severity score (RSS)

Plain X-rays of the wrists and knees (anteroposterior views) remain the cornerstone of rickets diagnosis and monitoring. The RSS, also known as Thacher score, a validated 10-point semi-quantitative radiographic scoring system, should be applied at diagnosis and after 12 months of therapy to objectively assess treatment response.^[37] The use is limited due to dual-site radiation.

Dual-energy X-ray absorptiometry (DXA) provides bone mineral density (BMD) assessments of the lumbar spine and the total body. In XLHR, DXA often shows normal or even elevated BMD despite clinical rickets, reflecting periosteocytic mineralization defects not captured by areal BMD.^[38] In HPP, DXA may underestimate skeletal severity. Renal ultrasonography is mandatory at baseline and annually during treatment to screen for nephrocalcinosis, particularly in patients receiving calcitriol plus phosphate supplementation.

Genetic testing

Next-generation sequencing (NGS) panels encompassing all genes known to cause NNR (e.g., PHEX, FGF23, DMP1, ENPP1, SLC34A3, CYP27B1, CYP2R1, VDR, ALPL, CLCN5, OCRL1, ATP7B, FAH, and SLC3A1) could be used as the primary genetic investigation in all children presenting with features of NNR.^[39] Gene panel testing achieves a molecular diagnosis in >80% of cases with a classic phenotype. Whole-exome sequencing is reserved for cases that are panel-negative.

Tumor localization

TIO requires identification of the causative mesenchymal tumor, which is typically small (<2 cm), slow-growing, and located in bone or soft tissue. The investigation of choice is 68Ga-DOTATATE positron emission tomography/computed tomography (PET/CT), which exploits somatostatin receptor overexpression by these tumors and has sensitivity exceeding 90%.^[22] Functional imaging should be followed by magnetic resonance imaging for precise anatomical localization before surgical planning

Diagnostic algorithm

The following step-by-step diagnostic algorithm guides the clinician from initial suspicion to definitive diagnosis of NNR [Figure 2]. It should be applied after nutritional rickets (vitamin D and calcium deficiency) has been excluded.

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Figure 2:

Diagnostic approach to suspected non-nutritional rickets. CKD: Chronic kidney disease, ALP: Alkaline phosphatase, iPTH: Intact parathyroid hormone, PO4: Phosphate; TRP: Tubular reabsorption of phosphate, 25(OH)D3: 25-hydroxyvitamin D, 1,25(OH)2D: 1,25-dihydroxyvitamin D, FGF23: Fibroblast growth factor 23, HHRH: Hereditary hypophosphatemic rickets with hypercalciuria, XLHR: X-linked hypophosphatemic rickets, TIO: Tumor-induced osteomalacia, VDDR1B: Vitamin D-dependent rickets type 1B, VDDR2: Vitamin D-dependent rickets type 2, VDDR3: Vitamin D-dependent rickets type 3.

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General principles

Management of NNR requires a multidisciplinary team comprising pediatric endocrinology, nephrology (for renal tubular disorders), genetics, orthopedics, dentistry, and dietetics. Goals of therapy include normalization of bone mineral homeostasis; resolution of radiographic rickets (RSS improvement); improvement of growth velocity and adult height prediction; correction of limb deformities; reduction of bone pain; and prevention of nephrocalcinosis, hyperparathyroidism, and craniosynostosis. Regular monitoring (clinical, biochemical, and radiological) at 3–6 months’ interval is essential. In Table 4 summarizes the treatment for major NNR disorders.

XLHR

Recent consensus guidelines recommend initiating phosphate supplementation with elemental phosphorus at approximately 20–60 mg/kg/day (0.7–2.0 mmol/kg/day), usually in 4–5 divided doses. Since phosphorus is rapidly absorbed and excreted, doses above 80 mg/kg/day are rarely required. Dose titration should be guided primarily by serum ALP, which serves as a key biomarker of rickets healing.^[6] Oral phosphate lowers ionised calcium and stimulates PTH secretion, increasing the risk of secondary (and rarely tertiary) hyperparathyroidism unless counterbalanced.^[8] Active vitamin-D analogs are therefore used to suppress PTH and raise 1,25(OH)₂D, which is typically low or inappropriately normal; initial doses are usually calcitriol 20–30 ng/kg/day in 1–2 divided doses or alfacalcidol 30–50 ng/kg/day once daily, adjusted according to PTH, and urinary calcium to avoid hypercalciuria and nephrocalcinosis.^[6]

Burosumab (Crysvita^®) is a fully human IgG1 monoclonal antibody that binds FGF23, preventing its interaction with FGFR1c/Klotho renal receptor complexes.^[4] By neutralizing excess FGF23, burosumab restores proximal tubular phosphate reabsorption and upregulates calcitriol synthesis, correcting the dual defect of hypophosphatemia and insufficient calcitriol. The Phase 3 pivotal trial demonstrated superior radiographic healing (RSS reduction), improved growth velocity, normalization of serum phosphate, and significant functional gains in children ≥1 year compared to conventional phosphate/calcitriol therapy.^[40] Based on this evidence, Western Clinical Practice Guidelines recommend burosumab as first-line therapy for XLHR in children and adolescents.

VDDR

VDDR1A is treated with pharmacological doses of calcitriol (0.01–0.05 µg/kg/day), which corrects the calcitriol deficiency caused by CYP27B1 deficiency. Oral calcium supplementation may be required initially. Therapy is lifelong and does not require escalation over time, as the enzyme defect is irreversible. VDDR1B (CYP2R1 mutations) responds to calcitriol (0.3–2 µg/day) or high-dose conventional vitamin D3, depending on residual 25-hydroxylase activity. VDDR2A hereditary vitamin D resistant rickets, HVDRR) presents the greatest therapeutic challenge due to end-organ resistance to calcitriol. High-dose calcitriol (5–60 µg/day) and calcium supplementation are required.^[41] In cases with severe alopecia indicating complete VDR abolition, oral therapy is invariably ineffective, and prolonged intravenous calcium infusions (7–9 h/day) may be the only recourse. Remarkably, skeletal lesions may heal with IV calcium alone, bypassing the need for VDR signaling entirely.^[23,41]

TIO

Complete surgical resection of the FGF23-secreting tumor is curative, with normalization of phosphate typically occurring within days of resection. When the tumor is unresectable (unlocalized or metastatic), burosumab has demonstrated efficacy in adults and is increasingly accepted as an option. Percutaneous ablation (radiofrequency or cryoablation) is an alternative for small, accessible lesions.^[22] Recurrence mandates surveillance imaging with 68Ga-DOTATATE PET/CT at 12-monthly intervals.

HPP

Asfotase alfa is a human recombinant TNSALP fusion protein that provides enzyme replacement therapy for the perinatal, infantile, and juvenile-onset forms of HPP. It is administered by subcutaneous injection (2 mg/kg 3 times/week or 1 mg/kg 6 times/week). Recent studies have demonstrated remarkable survival benefits in the perinatal and infantile forms (historical mortality >50%), rapid radiographic healing, and improvement in motor function.^[5] Key monitoring parameters include serum ALP (target: approaching the low end of the normal range), plasma pyridoxal-5’-phosphate, spine and long-bone X-rays, and chest radiography to detect respiratory improvement.^[6] The adult form of odontohypophosphatasia may not require enzyme replacement unless symptomatic fractures or functional impairment are present.^[29]

Fanconi syndrome and RTA

Management is directed at the underlying cause (e.g., copper chelation in Wilson disease; cysteamine in cystinosis; and dietary restriction in galactosemia and tyrosinemia). Symptomatic treatment includes oral potassium bicarbonate or sodium bicarbonate for acidosis (2–4 meq/kg target serum bicarbonate 22–24 mmol/L), oral phosphate supplementation, and calcitriol where 1α-hydroxylation is impaired due to tubular dysfunction.^[41] Alkali therapy alone may partially correct phosphaturia by improving intracellular pH-dependent transport.

Orthopedic considerations

Guided growth surgery (hemi-epiphysiodesis using tension-band plates) is the preferred orthopedic intervention for angular deformities in NNR children who have significant genu varum (>10°) or genu valgum (>15°) that fails to correct after 12–18 months of optimal medical therapy.^[42] Osteotomy is reserved for severe or fixed deformities, ideally performed once biochemical control is achieved preoperatively to optimize healing. In patients with XLHR receiving burosumab, surgical outcomes are substantially improved due to better underlying bone quality. All patients with XLHR should have an annual dental review from age 2 years.

Monitoring and long-term follow-up

In children of XLHR on conventional therapy (oral phosphate and active vitamin D), regular assessment includes growth, intercondylar and intermalleolar distances, rickets signs, bone pain, gait, and dental and hearing status, with visits every 1–3 months initially and then 3–6 months once stable. Biochemical monitoring typically includes serum ALP, calcium, phosphate, PTH, creatinine (eGFR), 25(OH)D₃, and 1,25(OH)₂D, with 24h urine calcium and TmP/GFR measured every 3–6 months; annual renal ultrasonography and periodic limb radiographs are recommended to detect nephrocalcinosis, hypercalciuria-related complications, and to assess radiological healing or deformity progression.^[41]

For FGF23-mediated rickets treated with burosumab, monitoring of fasting serum phosphate is checked more frequently during titration (e.g., every 2–4 weeks initially, then 3–6 months once stable) and should be kept in the lower age-related normal range. Urinary calcium and renal USG are monitored every 3–6 months to detect hypercalciuria or nephrocalcinosis.^[6] In VDDR and other non-FGF23 disorders, phosphate is not the primary target; instead, calcitriol/alfacalcidol and calcium supplementation are titrated to maintain 25(OH)D₃ and 1,25(OH)₂D in the upper-normal range. Serum calcium and urine calcium are closely watched to avoid hypercalciuria-related complications, generally monitored every 3–6 months in active treatment and yearly once stable.^[41]

For XLHR, neurological examination is recommended annually, or more frequently if there are headaches or an abnormal skull shape. Orthopedic examination should be performed at least once a year. A dental examination is advised twice yearly after tooth eruption. Hearing tests should be carried out from 8 years onward at least annually, and more frequently in the presence of hearing difficulties. Renal USG for nephrocalcinosis should be performed annually.^[6] Wrist and knee X-rays with RSS scoring are performed every 6 months until growth plate closure. RSS <1.5 indicates adequate radiological response. Ophthalmological review (slit-lamp examination for band keratopathy) is recommended for children on prolonged calcitriol therapy.

Transition to adult endocrine services should be planned from age 15–16 years and is a critical period, as symptoms often worsen in adulthood (enthesopathy, hearing loss, dental deterioration, fatigue, and chronic pain). Adult patients with XLHR require multidisciplinary care encompassing endocrinology, rheumatology, audiology, and dental surgery. Burosumab is approved for adults with XLHR.^[43]