Non-nutritional rickets: Approach, precision medicine, and outcomes

Abstract

Rickets are chronic bone disorders marked by impaired mineralization of the growing skeleton. While most cases arise from nutritional deficiencies, non-nutritional forms are frequently underrecognized. Subtle signs such as alopecia in vitamin D dependent rickets type 2A, cataract in Lowe syndrome, dental abscesses or sensorineural hearing loss in X-linked hypophosphatemia can prompt timely diagnosis and referral. A structured approach combining growth and skeletal assessment, targeted biochemistry (calcium, phosphate, alkaline phosphatase, parathyroid hormone, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D), radiography, and early genetic testing once nutritional deficiency or renal failure are excluded improves diagnostic accuracy. Molecular confirmation enables precise subclassification into hypophosphatemic and calciopenic rickets, supporting genotype-directed therapy, including burosumab for X-linked hypophosphatemia. Early, tailored treatment enhances radiographic healing, growth, and function. Emerging genotype-phenotype correlations further inform genetic counselling and prognosis, strengthening the multidisciplinary management of these complex disorders.

Key Words: Calcium; Vitamin D; Calciopenic rickets; Hypophosphatemic rickets; Algorithm; Fibroblast growth factor 23

Core Tip: Non-nutritional rickets represent a heterogeneous group of disorders. Presentation before 6 months or after 2 years of age, stigmata of specific systemic illnesses, and lack of response to oral calcium and vitamin D should raise clinical suspicion. A systematic diagnostic algorithm can guide evaluation. Parathyroid hormone may serve as a useful initial biochemical discriminator between calciopenic and hypophosphatemic rickets. Fibroblast growth factor 23 assays help distinguish fibroblast growth factor 23-dependent and independent hypophosphatemic rickets subtypes. Levels of 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D help sub-classify heritable forms of calciopenic rickets. Several entities require molecular techniques for diagnostic confirmation, enabling precision medicine and genetic counselling.

INTRODUCTION

Rickets are skeletal disorders of childhood occurring due to hampered mineralization at the growth plate. Failure of hypertrophied chondrocyte apoptosis (for which elemental phosphorus is indispensable) and excessive immature osteoid deposition causes widening at the sub-epiphyseal growth plate[1,2]. The earliest descriptions of the signs can be traced back to 120 Anno Domini in texts by Soranus, a physician from Rome, followed by Daniel Whistler in 1645[3,4]. The prevalence is variable, lying between 10%-70% in Middle East, Africa and Asia[5]. Most cases occur due to nutritional deficiencies of vitamin D and calcium (Ca), explaining the higher incidence in the developing world[2,5,6].

In infants and young children, rickets may present with cranial features such as craniotabes, frontal bossing, parietal flattening, widened cranial sutures, and a persistently large fontanelle. In crawling infants, the upper limbs are often more affected due to weight bearing on rapidly growing bones, whereas walking toddlers commonly develop lower limb deformities, including genu varum or genu valgum. Other characteristic signs are double malleoli, rachitic rosary, and a horizontal groove along the lower chest wall known as Harrison sulcus[7]. However, these signs are not specific to the underlying pathology.

Biochemical investigations like serum Ca, phosphorus (PO₄), alkaline phosphatase (ALP), and 25-hydroxyvitamin D [25(OH)D] may aid the diagnosis of rickets per se and confirm nutritional deficiencies. Early radiographic features of rickets include loss of the sharply defined zone of provisional calcification at the growth plate, producing an indistinct metaphyseal margin[8]. With disease progression, the metaphysis show widening with characteristic fraying, cupping, and splaying, and the growth plate appears widened due to impaired mineralization; epiphyseal ossification may be delayed, with small and osteopenic epiphyses[8]. Rickets may also coexist with osteomalacia, in which defective mineralization of osteoid can produce Looser zones (pseudofractures) on imaging[9].

However, these clinical, biochemical, and radiological features do not suffice for etiological delineation, which is a pre-requisite for optimal management given that children with rickets secondary to non-nutritional rickets (NNRs) show absent or sub-optimal response to therapy with Ca and vitamin D[10]. Biochemical investigations like 1,25-dihydroxyvitamin D [1,25(OH)₂D], urine Ca, urine creatinine, fibroblast growth factor (FGF)-23, next generation sequencing (NGS) panels, etc., are often required to establish the diagnosis in these cases to proceed with therapy directed to the underlying pathology. These, however, may not be available at most centers accessible to the community in low and middle-income countries (LMIC). An insight into settings where NNR should be suspected and a well-structured approach towards etiological diagnosis empower the pediatricians and physicians for early diagnosis and referral when required. The various etiologies, known genes and mutations, available therapies, and their respective outcomes are also reviewed here.

LITERATURE REVIEW

A systematic literature search was conducted across PubMed and EMBASE databases, covering publications from January 2000 through February 2026. Additional searches were performed in Orphanet, Online Mendelian Inheritance in Man, and ClinVar to capture genotype-phenotype data and variant-level information for individual disease entities.

The search employed Boolean combinations of the following terms: “Non-nutritional rickets”, “hypophosphatemic rickets”, “FGF-23”, “fibroblast growth factor 23”, “genetic rickets”, “hereditary rickets”, “phosphate wasting”, “renal tubular disorders”, “precision medicine”, “targeted therapy”, and “Burosumab”. For individual clinical entities, gene-specific strings were incorporated - for example, “hereditary hypophosphatemic rickets with hypercalciuria AND SLC34A3” - to ensure comprehensive disease-level coverage.

Eligibility criteria

Eligible publications included original research articles, randomized and non-randomized clinical trials, case series, and relevant narrative or systematic reviews, restricted to English language publications. Case reports were included when they described novel mutations, rare phenotypes, or atypical treatment responses. Conference abstracts and grey literature were excluded.

Study selection and quality assessment

Titles and abstracts were screened independently by two authors, with discrepancies resolved by consensus. Full texts of potentially eligible articles were retrieved and assessed against the inclusion criteria. To minimize publication bias and ensure completeness, the reference lists of all selected articles were manually reviewed to identify additional pertinent studies not captured by the primary search.

APPROACH

An understanding of the etiological classification and pathophysiological perspectives of rickets (Figures 1 and 2) is a pre-requisite to accurate diagnosis. Clinical assessment must include detailed history of onset of rachitic features, associated symptoms, previous hospitalizations, surgeries, known systemic illnesses, family history, anthropometry, general and systemic examination. An exhaustive list of clinical signs pointing towards the diagnosis of rickets per se has been summarized in existing literature[2].

Figure 1 Etiological classification of rickets. ¹Multiple known causative genes. FGF-23: Fibroblast growth factor 23; XLH: X-linked hypophosphatemic ricket; PHEX: Phosphate regulating endopeptidase homolog X-linked; ADHR: Autosomal dominant hypophosphatemic rickets; ARHR1: Autosomal recessive hypophosphatemic rickets type 1; DMP1: Dentin matrix protein 1; ARHR2: Autosomal recessive hypophosphatemic rickets type 2; ENPP1: Ectonucleotide pyrophosphatase/phosphodiesterase 1; FAM20C: Family with sequence similarity 20-member C; PFD: Polyostotic fibrous dysplasia; GNAS: Guanine nucleotide-binding protein alpha-stimulating; FGFR1: Fibroblast growth factor receptor 1; INPPL1: Inositol polyphosphate phosphatase-like 1; PTH1R: Parathyroid hormone 1 receptor; Ca: Calcium; PO₄: Phosphorus; HHRH: Hypophosphatemic rickets with hypercalciuria; SLC34A3: Solute carrier family 34 member 3; NPHLOP1: Nephrolithiasis and osteoporosis type 1; SLC34A1: Solute carrier family 34 member 1; NPHLOP2: Nephrolithiasis and osteoporosis type 2; NHERF1: Na⁺/H⁺ exchanger regulatory factor 1; SLC9A3R1: Solute carrier family 9 member A3 regulator 1; FS: Fanconi syndrome; dRTA: Distal renal tubular acidosis; VDDR1A: Vitamin D dependent rickets type 1A; CYP27B1: Cytochrome P450 family 27 subfamily B member 1; VDDR1B: Vitamin D dependent rickets type 1B; CYP2R1: Cytochrome P450 family 2 subfamily R member 1; VDDR2A: Vitamin D dependent rickets type 2A; VDDR2B: Vitamin D dependent rickets type 2B; VDR: Vitamin D receptor; VDDR3: Vitamin D dependent rickets type 3; NNR: Non-nutritional ricket; IBD: Inflammatory bowel disease.

Figure 2 Regulation of calcium and phosphate homeostasis and disorders associated with rickets. Schematic representation of calcium (Ca) and phosphate homeostasis regulated by parathyroid hormone (PTH), 1,25-dihydroxyvitamin D [1,25(OH)₂D], and fibroblast growth factor 23 (FGF-23). In Ca regulation (upper panel), PTH increases bone resorption, renal Ca²⁺ reabsorption via transient receptor potential vanilloid 5, and 1,25(OH)₂D synthesis, while 1,25(OH)₂D enhances intestinal absorption via transient receptor potential vanilloid 6. In phosphate regulation (lower panel), FGF-23 and PTH reduce renal phosphate reabsorption by downregulating sodium-phosphate cotransporters NaPi-IIa (solute carrier family 34 member 1) and NaPi-IIc (solute carrier family 34 member 3), while 1,25(OH)₂D increases intestinal phosphate absorption. Disorders shown include vitamin D-dependent rickets (vitamin D dependent rickets type 1A: Cytochrome P450 family 27 subfamily B member 1; vitamin D dependent rickets type 1B: Cytochrome P450 family 2 subfamily R member 1; vitamin D dependent rickets type 2: Vitamin D receptor), X-linked hypophosphatemia (X-linked hypophosphatemic rickets; phosphate regulating endopeptidase homolog X-linked), autosomal dominant hypophosphatemic rickets (autosomal dominant hypophosphatemic rickets; FGF-23), autosomal recessive hypophosphatemic rickets (autosomal recessive hypophosphatemic rickets; dentin matrix protein 1, ectonucleotide pyrophosphatase/phosphodiesterase 1), fibrous dysplasia/McCune-Albright syndrome (fibrous dysplasia/McCune-Albright syndrome), and hereditary hypophosphatemic rickets with hypercalciuria (hereditary hypophosphatemic rickets with hypercalciuria; solute carrier family 34 member 3). PTH: Parathyroid hormone; Ca: Calcium; 1,25(OH)₂D: 1,25-dihydroxyvitamin D; TRPV5: Transient receptor potential vanilloid 5; CaSR: Calcium-sensing receptor; FGF-23: Fibroblast growth factor 23; VDDR: Vitamin D dependent rickets; VDDR2: Vitamin D dependent rickets type 2; TRPV6: Transient receptor potential vanilloid 6; 1,25(OH)₂D₃:1,25-dihydroxyvitamin D₃; VDDR1A: Vitamin D dependent rickets type 1A; VDDR1B: Vitamin D dependent rickets type 1B; VDDR3: Vitamin D dependent rickets type 3; Pi: Phosphate; XLH: X-linked hypophosphatemic ricket; ARHR: Autosomal recessive hypophosphatemic ricket; FD: Fibrous dysplasia; MAS: McCune-Albright syndrome; IIH: Idiopathic hypercalciuria; ADHR: Autosomal dominant hypophosphatemic ricket.

An informed approach should proceed from clinical suspicion of rickets to radiological and biochemical confirmation, with adequate consideration of rickets mimickers as a differential (Figure 3). Following this, dietary habits, approximate estimation of macronutrient and dairy intake (using recall-based methods), along with features of other micronutrient deficiency can aid in establishing or ruling out nutritional deficiency [nutritional rickets (NRs)].

Figure 3 Algorithm for etiological diagnosis of rickets using biochemical tests. ¹Exception: Raised alkaline phosphatase in mucolipidosis. ²In the clinical context of established nutritional deficiency or risk factors for vitamin D deficiency. ³Differentiation between fibroblast growth factor 23 (FGF-23) mediated hypophosphatemic ricket and non FGF-23 mediated hypophosphatemic ricket may be made using FGF-23 assays or urinary Ca creatinine ratio or 1,25-dihydroxyvitamin D. ⁴Requires polymerase chain reaction for diagnosis. ⁵Rule out hypothyroidism and growth hormone deficiency. Ca: Calcium; PO₄: Phosphorus; ALP: Alkaline phosphatase; 25(OH)D: 25-hydroxyvitamin D; PTH: Parathyroid hormone; CR: Calciopenic ricket; NR: Nutritional ricket; VDDR1B: Vitamin D dependent rickets type 1B; VDDR3: Vitamin D dependent rickets type 3; FGF-23: Fibroblast growth factor 23; HR: Hypophosphatemic rickets; JMC: Jansen metaphyseal chondrodysplasia; KL: Klotho; ARHR2: Autosomal recessive hypophosphatemic rickets 2; 1,25(OH)₂D: 1,25-dihydroxyvitamin D; HP: Hypophosphatasia; PHP: Pseudo hypophosphatasia; RM: Rickets mimicker; CKD: Chronic kidney disease; dRTA: Distal renal tubular acidosis; pRTA: Proximal renal tubular acidosis; FS: Fanconi syndrome; LMW: Low-molecular-weight; NGS: Next-generation sequencing; VDDR1A: Vitamin D dependent rickets type 1A; VDDR3: Vitamin D dependent rickets type 3; VDDR2A: Vitamin D dependent rickets type 2A; VDDR2B: Vitamin D dependent rickets type 2B; TMD: Tibia metaphyseal-diaphyseal; MPS: Mucopolysaccharidosis; GAG: Glycosaminoglycans; ED: Epiphyseal dysplasia; SED: Spondyloepiphyseal dysplasia; SMD: Spondylometaphyseal dysplasia; CAKUT: Congenital anomalies of the kidney and urinary tract; DM: Diabetes mellitus; SNHL: Sensorineural hearing loss; DIP: Distal interphalangeal joint; PIP: Proximal interphalangeal joint; SGA: Small for gestational age.

Clinical considerations

Dietary and drug history: Preterm infants are likely to be PO₄ deficient if on exclusive breast feeds or on soy-based preparations[11,12]. Given that breast milk is deficient in vitamin D (concentration of 25-50 IU/L), all infants are invariably dependent on prescribed supplements for vitamin D intake[11]. Identification of medications frequently used in preterm infants, such as furosemide, corticosteroids, and methylxanthines, may contribute to osteopenia by increasing bone resorption, reducing osteoblastic activity, impairing intestinal Ca absorption, and promoting renal Ca loss, ultimately leading to decreased bone mineralization[13].

Phenytoin, phenobarbitone, oxcarbamazepine and rifampicin cause increased hepatic 25(OH)D metabolism. Clinical evaluation is incomplete without ruling out Ca and vitamin D deficiency in the mother, especially in LMIC where clustering of nutritional deficiencies may occur within families secondary to maternal nutritional deficiency superimposed over socio-economic factors[14]. In high income countries, vitamin D deficiency tends to occur in immigrants, non-Caucasian racial groups and even native citizens owing to extreme winter, low sunlight and use of sun-screens[15,16].

Clinical signs with age: Physiological genu varum (bowed legs) is present at birth and gradually corrects as the child grows, with the lower limbs becoming aligned by approximately 1.5-2 years of age. This is followed by the development of mild genu valgum (about 5° to 6°), which typically persists throughout childhood. To this regard an intermalleolar distance ≤ 8 cm, intercondylar distance < 3 cm and genu-valgum under 12° are essentially normal between 2-11 years of age. In rickets, the pattern of limb deformity often reflects the age at onset. Genu varum is more commonly observed when rickets develops before 2 years of age, whereas genu valgum or a wind-swept deformity is more frequent when the disease presents after 2-3 years. When rickets occurs during the pubertal growth spurt, rapid progression of knock-knee deformity may be seen due to accelerated skeletal growth[17].

When to suspect NNR and clues to specific etiologies: Presentation within the first 6 months or after 2 years of age should prompt consideration of etiologies other than nutritional deficiency. Associated systemic symptoms such as jaundice, recurrent vomiting, or chronic diarrhea may indicate underlying hepatic or gastrointestinal disease[10]. Acidotic breathing, hypertension, anemia, and edema may point toward a renal disorder. The presence of cataracts may suggest metabolic conditions such as Wilson disease, Lowe syndrome or cystinosis[10,18,19]. Failure to thrive, polyuria, nocturia, hematuria, graveluria, or renal stones may suggest renal tubular disorders such as distal renal tubular acidosis (dRTA), hereditary hypophosphatemic rickets (HHR) with hypercalciuria (HHRH), Dent disease, or hypophosphatemic rickets (HRs) associated with nephrolithiasis, and may also occur in primary hyperparathyroidism (PHPT)[20].

Neuromuscular irritability in the form of paresthesia, Chvostek or Trousseau signs, seizures and tetany suggest calciopenic rickets (CRs), while partial or generalized alopecia is characteristic of vitamin D dependent rickets type 2A (VDDR2A). Café-au-lait macules with irregular borders may indicate McCune-Albright syndrome, whereas a linear nevus may point toward linear nevus sebaceous syndrome, both associated with HRs[17]. Predominant deformity of the lower limbs is seen in HHR including X-linked HR (XLH), autosomal dominant HR (ADHR), autosomal recessive HR (ARHR; ARHR1 and ARHR2), amongst others. In contrast, more prominent involvement of the upper limbs may be observed in CR, including NR or vitamin D related hereditary forms[10].

Conductive hearing loss may occur in XLH and ARHR1. Craniosynostosis and sensorineural hearing loss (SNHL) are features shared by XLH, dRTA and hypophosphatasia (HP). A positive family history in the setting of LMIC is usually indicative of NR. However, the various forms of HHR (including XLH, ADHR, ARHR), vitamin D related hereditary forms, renal tubular acidosis (RTA) including Fanconi syndrome (FS) may elicit their respective patterns of inheritance, noted over a three-generation pedigree chart.

CR is commonly associated with thin hypoplastic enamel, dental caries, and delayed eruption of primary and permanent teeth. In XLH and ARHR1, characteristic findings include periradicular dental abscesses without caries, increased caries susceptibility, taurodontism with enlarged pulp chambers, delayed dentition, and early loss of permanent teeth. Raine syndrome may present with hypoplastic amelogenesis imperfecta and delayed tooth eruption, while HP is characterized by premature loss of primary teeth, early loss of permanent teeth, periodontitis, and posterior tooth ankylosis. dRTA due to WD repeat domain 72 mutations can also present with hypomaturation-type amelogenesis imperfecta[17].

Biochemical considerations

First line investigations - beyond values: These include Ca, PO₄, 25(OH)D, creatinine, ALP and parathyroid hormone (PTH). Children normally have higher PO₄ and lower creatinine values compared to adults, necessitating interpretation with age-adjusted values, rather than laboratory reference ranges. Likewise, variability in ALP values in children implicates the use of published locally available or international reference ranges. Raised ALP is diagnostic of rickets and helps rule out rickets mimickers and HP (Figure 3). ALP usually lies between 400-800 IU/L in HR, but above 2000 IU/L in CR. It may be falsely normal in nutritional deficiencies (protein, zinc, vitamin C, vitamin B12, magnesium). HP occurs due to loss of function mutations in ALPL gene leading to impaired tissue-nonspecific ALP (TNSAP) activity leading to impaired matrix mineralization and thereby increased phosphate (and often Ca) levels. Pseudo HP is a condition clinically and biochemically identical to HP, occurring due to post-translational defects[21]. The enzyme activity is intact against artificial substrates (e.g., 4-methylumbelliferyl phosphate) but absent against natural substrates like phosphoethanolamine, and pyridoxal 5’-phosphate[22]. ALP may be normal even in RTA cases where acidosis inhibits osteoblast activity, given that a higher pH is required by TNSAP for conversion of pyrophosphate to inorganic phosphate (required for hydroxyapatite crystal formation)[17].

Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is the other essential enzyme for phosphate generation, while sodium-phosphate cotransporter 2c [solute carrier family 34 member 3 (SLC34A3)] is essential for its entry into hypertrophic chondrocytes. Defects in these are known to cause ARHR2 and HHRH respectively. For serum PO₄, the circadian rhythm (highest levels at 3:00 and nadir at 11:00) and assay interference with monoclonal immunoglobulins, bilirubin, drugs (amphotericin B, niacin and phosphate binders) can also alter its measurement[23]. Thus, a fasting sample is recommended for PO₄ measurement.

No hypophosphatemia - essential considerations: Low PO₄ is seen in all forms of rickets, however, exceptions are known. Serum PO₄ levels may be normal initially even in HR[24]. Normal to high PO₄ values are seen in chronic kidney disease. Chronic PTH exposure may render the proximal renal tubules resistant to its phosphaturic action in CR as intracellular Ca is required for the Gq/11-linked phospholipase C-protein kinase C pathway[25,26]. dRTA shows normal PO₄ levels as the proximal renal tubules responsible for PO₄ reabsorption are intact. HP and pseudo HP also have normal PO₄ levels.

Hypophosphatemia: In cases of hypophosphatemia, renal phosphate wasting should be confirmed by calculating tubular reabsorption of PO₄ (TRP), using tubular maximum for PO₄ adjusted for glomerular filtration rate (GFR) using the algorithm by Kenny and Glen[27] or the nomogram by Walton and Bijvoet. As these have several limitations, Brodehl formula which is more applicable to the higher serum PO₄ levels in children, may be used to calculate tubular absorption of PO₄ adjusted for GFR (Figure 4). Of note, serum sample for these should be taken in the fasting state, while the urine sample should be the second-void. These indices are likely to yield falsely low values in the presence of severe hypophosphatemia. Thus, their interpretation upon repeating after 6 weeks of oral PO₄ therapy is prudent[17]. The etiology for renal phosphate wasting may be ascertained by FGF-23 assays. Multiple assays detecting intact FGF-23 or C-terminal FGF-23 are known[23]. However, these are limited by their low availability and high cost. Where indicated, urinary Ca creatinine ratio (UCaCrR) and 1,25(OH)₂D may be used as proxy markers for FGF-23[28]. In the absence of FGF-23, cytochrome P450 family 27 subfamily A member 1 remains stimulated leading to increased intestinal Ca absorption, hypercalciuria and thereby raised UCaCrR. Age-specific normal values are available for tubular absorption of PO₄ adjusted for GFR, urinary PO₄ to creatinine ratio and UCaCrR[29,30].

Figure 4 Indices to ascertain renal phosphorus wasting in hypophosphatemia. ¹Falsely low values in severe hypophosphatemia. ²May be used across all ranges of TRP and falsely low values in severe hypophosphatemia. ³Limitations: (1) Ideally requires oral phosphorus Loading; (2) Nomogram established for adults - children have physiologically higher serum phosphorus levels; (3) Overestimates tubular maximum reabsorption of phosphate/glomerular filtration rate if TRP > 0.8; and (4) Falsely low values in severe hypophosphatemia. U_Phosphate: Urinary phosphate; U_Creatinine: Urinary creatinine; P_Phosphate: Plasma phosphate, P_Creatinine: Plasma creatinine; TP: Tubular phosphate; GFR: Glomerular filtration rate; TRP: Tubular reabsorption of phosphate; PO₄: Phosphorus; TmP: Tubular maximum reabsorption of phosphate.

Ca and PTH levels - essential considerations: Correction of serum Ca for the albumin with Payne’s formula may lead to overestimation in patients with hypoalbuminemia or renal insufficiency[31]. Moreover, measurement of ionized Ca should be preferred when available as it represents the biologically active fraction and is unaffected by posture and venous stasis[32]. Ca levels may be low or low-normal in all forms of CR (NNR, NR and malabsorption) due to secondary hyperparathyroidism (SHPT) in CR. PTH should be estimated using a second-generation or third generation assay. Its role primarily lies in differentiation between CR and HR, with higher values in CR. A PTH cut-off of 100 pg/mL was suggested by a study from Eastern India[33]. Hypercalcemia with rickets may indicate PHPT, which is accompanied by low PO₄ levels. A similar picture, but with suppressed PTH may be seen in Jansen metaphyseal chondrodysplasia occurring due to PTH receptor mutations. Treatment related (due to activated vitamin D) hypercalcemia and that due to SHPT may occur in HR. Hypercalcemia may also occur in Klotho or ENPP1 mutations due to stabilization of epithelial Ca channel transient receptor potential vanilloid-5[34]. The etiology of CR may be established by 25(OH)D and 1,25(OH)₂D levels.

Radiological considerations

Early radiographic changes include widening of the zone of provisional calcification and loss of the sharp metaphyseal line at the growth plate, resulting in an ill-defined metaphyseal border. As the disease progresses, the metaphysis shows fraying, cupping, and splaying, along with widening of the growth plate due to impaired mineralization. Epiphyseal ossification centers may appear delayed, small, and osteopenic with irregular margins. Rickets are frequently associated with osteomalacia, reflecting defective mineralization of osteoid, and may occasionally demonstrate Looser zones or pseudofractures[7,35]. Lines of healing that usually appear after 1-3 weeks of oral Ca and vitamin D in NR may appear even in NNR with vitamin D therapy. Quantitative scores like Thacher rickets severity score and Radiographic Global Impression of Change may be employed for severity assessment and monitoring with therapy[36,37].

Additional radiologic findings can help identify the underlying etiology. Features such as thin cortices, subperiosteal bone resorption, distal clavicular resorption, and bone cysts (osteitis fibrosa cystica) suggest excess PTH, typically seen in CRs with SHPT, and rarely in PHPT[38]. In contrast, cortical thickening may be observed in XLH. Patients with XLH or ARHR may also develop enthesopathy due to calcification at tendon and ligament insertions. Other skeletal features include increased axial skeletal density in XLH, calvarial and skull base sclerosis in ARHR1, ectopic calcifications in ARHR2, and periosteal bone formation with osteosclerosis in ARHR3[34].

In a systematic review, axial and sagittal deformities - especially torsional malalignment and procurvatum - were most commonly seen in HR, with a predominance among patients with XLH[39]. Under-reporting of sagittal deformities in CR and the need for more consistency in imaging standards and diagnostic criteria were also identified by the authors.

BRIEF OVERVIEW OF VARIOUS FORMS

HHR-pathophysiology

FGF-23, produced mainly by osteocytes and osteoblasts, is a key regulator of phosphate and vitamin D homeostasis. In the kidney, it binds to FGF receptor 1 isoform C with the co-receptor αKlotho and suppresses cytochrome P450 family 27 subfamily B member 1 (CYP27B1), reducing active vitamin D levels, while increasing phosphate excretion[40]. It also promotes degradation of the sodium-phosphate cotransporters sodium-phosphate cotransporter 2a (NaPi-2a) and SLC34A3, leading to renal phosphate wasting and hypophosphatemia, the biochemical hallmark of the disease (Figure 5)[41,42].

Figure 5 Actions of fibroblast growth factor 23 in phosphate homeostasis. Schematic showing regulation of phosphate and calcitriol (1,25-dihydroxyvitamin D) by fibroblast growth factor 23 (FGF-23). Increased serum phosphate and calcitriol stimulate FGF-23 secretion. FGF-23 acts on the renal proximal tubule to inhibit sodium-phosphate cotransporters NaPi-IIa (solute carrier family 34 member 1) and NaPi-IIc (solute carrier family 34 member 3), reducing phosphate reabsorption and lowering serum phosphate. It also suppresses renal 1α-hydroxylase (cytochrome P450 family 27 subfamily B member 1) and stimulates 24-hydroxylase (cytochrome P450 family 24 subfamily A member 1), decreasing calcitriol levels and intestinal phosphate absorption. Parathyroid hormone shows bidirectional interaction with FGF-23 in a negative feedback loop to maintain phosphate and calcitriol homeostasis.

In the distal tubule, FGF-23 increases Ca and sodium reabsorption through effects on transient receptor potential vanilloid-5 and NCC transporters[43]. These actions partly overlap with those of PTH[44,45]. It also acts directly on bone by suppressing TNSAP, impairing hydroxyapatite formation and skeletal mineralization[46]. Together with chronic hypophosphatemia, this leads to the rachitic manifestations of the disease.

FGF-23 mediated HR: XLH

Epidemiology: XLH is the most common form of hereditary rickets, with a prevalence of 1:(20000-60000), likely an underestimate given underdiagnosis in the periphery[47,48]. Affected individuals face substantially elevated morbidity and reduced life expectancy[49]. Patients with chronic idiopathic hypophosphatemia (comprising XLH and tumor induced osteomalacia) were found to be at higher risk of composite cardiovascular complications, heart failure, CKD, periodontitis, depression and death[50]. It occurs due to mutations in the phosphate regulating endopeptidase homolog X-linked (PHEX) gene, coding for a protein responsible for FGF-23 regulation. PHEX is mainly expressed in osteoblasts and dentine. The encoded enzyme acts on small integrin-binding ligand N-linked glycoproteins proteins, particularly osteopontin, while also regulating FGF-23 levels by influencing its expression[51].

Specific clinical features: The birth length is essentially preserved, reflecting a normophosphatemic prenatal milieu. Lower limb deformities - genu varum or valgum - develop within the first six months and are evident by age two in approximately 80% of children, affecting over 90% overall. Accompanying features include delayed motor milestones, abnormal gait, and metaphyseal widening. Craniosynostosis occurs in roughly 60% of cases; recurrent periradicular dental abscesses (without caries) are reported in approximately 70%, and Chiari type I malformation may occur in a subset. In adulthood, the disease transitions to a predominantly musculoskeletal phenotype - osteoarticular pain, enthesopathies, spinal stenosis, pseudofractures, and sensorineural hearing loss - reflecting lifelong phosphate wasting[52]. Obesity (30% in childhood), SHPT (35% of adults), cardiometabolic complications and left ventricular hypertrophy are amongst the known co-morbidities[53,54].

Genotype-phenotype correlation: Over 500 pathogenic PHEX variants have been identified, encompassing missense, nonsense, splice-site, insertion, and deletion types (e.g., C142W, K359X, L450P, N620TfsX13, EX2del, Q682X). Missense variants were found to be the most common in a recent study. Residual PHEX enzymatic activity correlated positively with serum phosphate and inversely with rickets severity in functional studies[55]. In a previous study from Mexico, height percentile or rickets severity score did not differ between exonic and intronic variants indicating no clear genotype-phenotype correlation in this cohort[56]. The majority of earlier studies also showed no genotype-phenotype correlation[48,57-60].

Treatment: Oral PO₄ and calcitriol constituted the mainstay of treatment until 2018 when burosumab was approved. The available PO₄ preparations, dispensable as syrup, for children are acid phosphate (Joulie’s solution - concentration of 30 mg elemental PO₄ per ml solution) and neutral phosphate (concentration of 1 g elemental PO₄ per 60 mL solution). For adults, tablets at strengths of 250 mg and 500 mg are available. Activated vitamin D augments PO₄ absorption and has been found to further improve outcomes (details of modalities and doses in Table 1)[52,61]. Doses in children are weight based and require modification based on changes in weight, height velocity, deformity correction, ALP, PTH and gastric tolerance (detailed monitoring summarized in Table 2). Calcitriol leads to increased intestinal Ca absorption and thereby hypercalciuria, which in children occurs later after treatment initiation owing to a hungry-bone like state. Once hypercalciuria sets in, monitoring for nephrocalcinosis and calculi (found in up to 50% patients) is necessary, even though it may not necessarily hamper the renal function. Owing to the unpleasant taste and gastric intolerance, adolescents and young adults tend to discontinue the conventional therapy. Re-initiation is warranted in symptomatic adults[52]. Burosumab is a humanized IgG1 anti-FGF-23 antibody with an efficacy proven to be higher than conventional treatment[62]. In the countries where it is available, it has already replaced conventional treatment after 6 months or 1 year of age. With a half-life of 16-19 days, it has a peak and trough effect and thus can cause severe hyperphosphatemia. Thus, oral PO₄ should be stopped 1 week prior to burosumab initiation and PO₄ levels should be checked just prior to the ensuing dose. Recombinant growth hormone has been used with conventional therapy for its role in improved PO₄ retention and height velocity. It is currently endorsed as adjunctive therapy with both burosumab and conventional therapy[63]. However, a meta-analysis showed no difference in final height with or without recombinant growth hormone[64]. Other attempted therapies include cinacalcet, calcitonin and mitogen-activated protein kinase inhibitors (no human studies)[65]. These are however, not recommended. Recommended therapeutic modalities are further reviewed in Table 1[66-70]. A comprehensive monitoring strategy inclusive of growth, pain, quality of life, oral health, renal calcification screen, neuroimaging and spine imaging (for syringomyelia) should be employed while monitoring these patients (Table 2).

Table 1 Therapies available for X-linked hypophosphatemic rickets and their outcomes.

Treatment modalities	Dose	Improvement	No improvement	Caution
Oral phosphorus	Children: 20-60 mg/kg/day in 3-5 divided doses. Adolescents: 3 divided doses. Adults: 800-1600 mg/day in 2 divided doses	Children: (1) Height velocity; and (2) Lower limb deformities. Adults: (1) Osteomalacia related pain[68]; and (2) Periodontitis, dental function[69]. Clinical improvement has been seen in 1-2 years[72]. Corrective surgery for deformities is required in about half the adolescents. Over half may have short stature as adults	Children: Hearing loss. Adults: (1) Osteo-arthritis related pain; and (2) Enthesiopathies	(1) Acidic taste; (2) Gastric discomfort and diarrhoea (doses > 80 mg/kg/day); and (3) SHPT and sub-optimal radiological response, if given without activated forms of vitamin D
Calcitriol	Children: 20-30 ng/kg/day (0.5-1.5 μg/day) in 2-3 divided doses. Adults: 0.50-0.75 μg/day in 2-3 divided doses			(1) To be given only along with oral phosphorus in children; (2) Hypercalciuria; and (3) Nephrocalcinosis[69]
Alphacalcidiol	Children: 40-60 ng/kg/day (1-3 μg/day) in a single daily dose. Adults: 0.75-1.5 μg/day in a single daily dose
Burosumab[62,70]	Children: [Above 6months (as per United States-FDA) or 1 year (as per EMA)] start at 0.8 mg/kg body weight sub-cutaneously every 14 days. In children with weight < 10 kg, start at 1 mg/kg. Maximum dose 2 mg/kg or 90 mg every 14 days. Adults: Initiate at 1 mg/kg sub-cutaneously every 14 days. Increase to maximum dose of 1.8 mg/kg or 90 mg sub-cutaneously every 14 days	Children: (1) Height velocity (normalizes by 2 years); (2) Decreased periodontal abscess; (3) Physical function; and (4) Pain (12 months). Clinically deformities improve in 2-3 years[62]. Biochemically: TmP-GFR increases within 1 week, ALP normalises by 1 year[70]. Adults: (1) Musculoskeletal pain (6-12 months); (2) Decreased renal PO4 wasting and rise in serum PO4 levels (6 months); (3) Stiffness (12 months); (4) ALP (12 months); (5) Radiological signs (12 months); and (6) Fewer endo-dontic infections	Children: Catch-up growth may be slow. Adults: Physical function stiffness	(1) Stop oral phosphorus 1 week prior to initiation of burosumab; (2) Ensure adequate oral calcium intake; (3) Stop in adolescent and adult females who are sexually active unless using contraception; and (4) Contraindicated in pregnancy but not in lactation
Recombinant growth hormone	Children: 0.6-1 U/kg/week	Children: (1) Height velocity; and (2) PO4 retention	Children: No difference in final height compared to none	Adjunct to conventional therapy or burosumab. Pre-requisite: Adequately controlled bony deformities, ALP and PTH

FDA: Food and Drug Administration; EMA: European Medicines Agency; TmP: Tubular maximum reabsorption of phosphate; GFR: Glomerular filtration rate; ALP: Alkaline phosphatase; PO₄: Phosphorus; SHPT: Secondary hyperparathyroidism; PTH: Parathyroid hormone.

Table 2 Monitoring in X-linked hypophosphatemic rickets.

Domain	Assessment	Suggested frequency	Key considerations
Clinical evaluation	Growth (height, weight, BMI)	At every visit in children; 6-12 monthly in adults	Monitor growth velocity and disproportion
	Limb deformities, gait, bone pain	Every visit	Assess progression and need for orthopedic referral
	Head shape, craniosynostosis signs	Regular in early childhood	Neuro symptoms warrant imaging
	Dental evaluation	Every 6 months after tooth eruption	High risk of abscesses and periodontal disease
	Hearing assessment	From approximately 8 years or if symptomatic	Sensorineural hearing loss may occur
	Functional status (mobility, fatigue)	Annually or as indicated	Include 6-minute walk test where feasible
Biochemical monitoring	Serum calcium, phosphate, ALP, PTH, creatinine	Every 3-6 months (more frequent in active treatment)	ALP is a key marker of disease activity
	25-hydroxyvitamin D	Yearly	Maintain sufficiency
	1,25-dihydroxyvitamin D	Annually (especially on targeted therapy)	Avoid excess contributing to hypercalciuria
	Urinary calcium (spot Ca/Cr or 24 hours)	Every 3-6 months	Monitor for hypercalciuria
	TmP/GFR and serum phosphate	Frequent during treatment initiation (2-4 weekly), then spaced	Especially important with burosumab
Imaging	Radiographs (wrists/knees/long bones)	Every 1-2 years or if clinically indicated	Assess rickets healing and deformity
	Renal ultrasonography	Every 1-2 years	Detect nephrocalcinosis
	Dental imaging (OPG/CBCT)	From approximately 6 years, based on need	Detect occult dental pathology
	Brain MRI	If neurological symptoms or craniosynostosis suspected	Not routine
	Spine MRI	If symptoms of stenosis or back pain	Targeted imaging only
Cardiovascular	Blood pressure	At least annually	Hypertension may occur
	Echocardiography	If persistent hypertension	Not routine screening
Treatment monitoring	Clinical + biochemical response	Every 3-6 months initially	Adjust therapy based on trends, not single values
	Adverse effects (nephrocalcinosis, hyperparathyroidism)	Ongoing	Especially with phosphate + active vitamin D
Quality of life	Quality of life assessment tools	Every 1-2 years	Particularly in older children and adults

BMI: Body mass index; ALP: Alkaline phosphatase; PTH: Parathyroid hormone; Ca: Calcium; Cr: Creatinine; TmP: Tubular maximum reabsorption of phosphate; GFR: Glomerular filtration rate; OPG: Orthopantomogram; CBCT: Cone beam computed tomography; MRI: Magnetic resonance imaging.

ADHR

Gain of function mutations in FGF23 making the protein resistant to cleavage by endopeptidases are responsible for this variant of HR. Mutational hotspots like R176Q/R176W and R179Q/R179W are known with phenotypic mutations arising due to varying FGF-23 levels[71,72]. R179 mutations in a study were found to be causative of earlier age at onset of symptoms and severe phenotype[73]. Interestingly, iron deficiency anemia has been found to be an environmental trigger[74].

ARHR1

This entity is known to occur due to inactivating mutations in dentin matrix protein 1 (DMP1), which is amongst the small integrin-binding ligand N-linked glycoproteins group of proteins with a role in bone and dentine formation[75]. Elevated sclerostin levels may be found in ARHR1 and XLH due to higher bone mineral density. Variants involving the C-terminal of the protein had higher rates of short stature than those involving the N-terminal. Most cases are inherited and seen in communities with consanguineous marriages. c.1A>G (p.Met1Val) represents a plausible mutational hotspot[76]. Heterozygous carriers of DMP1 (IVS5-1G) may present without rickets with just focal osteomalacia[77]. Co-occurrence of SPP-1 mutations has been found to be causative of a severe phenotype[77]. Osteosclerosis at skull base may be noted[78].

ARHR2

Variants in ENPP1 leading to loss of enzyme activity causes ARHR2, which is now believed to be clinical continuum to generalized arterial calcification of infancy (GACI). In a review, 76% affected patients had GACI, while 64% of those with isolated ARHR2 had cardiovascular complications. Signs of GACI may be identifiable even prenatally in the form of polyhydramnios, non-immune hydrops and fetal effusion[79]. These may enable early detection and antenatal counselling especially in cases with affected elder siblings or first-degree relatives. Early onset hearing loss, ossification of posterior longitudinal ligament and pseudoxanthoma elasticum, thrombocytopenia, enthesopathy, PHPT, hypoglycemia and hepatopathy are other reported manifestations due to pathogenic ENPP1 variants[80-82]. These patients require periodic surveillance with ultrasound and echocardiography to detect vascular and cardiac calcifications[83].

Biochemically, patients with FGF-23 mediated HHR have low PO₄, normal Ca, normal PTH, raised ALP, decreased TRP, low 1,25(OH)₂D and no hypercalciuria. Treatment of ADHR and ARHR1 is on similar lines as XLH. The objectives, like XLH are improved height velocity, deformity correction and ALP (not PO₄) normalization. In ARHR2, vascular calcification is a contraindication for activated vitamin D. Further, doses of PO₄ (40 mg/kg/day) and calcitriol (15 ng/kg/day) are lower[84]. Enzyme replacement therapy has proven effective in animal studies but human studies verifying efficacy and safety are lacking[85]. Patients developing PHPT may require partial parathyroidectomy or cinacalcet[34,86]. Data on long-term outcomes and natural history are lacking for these entities. The other rarer forms of FGF-23 mediated HHR have been summarized in Table 3[74].

Table 3 Rare forms of fibroblast growth factor 23 mediated Hereditary HR[113].

No.	Entity	Gene (chromosome)	Inheritance	Physiological role	Phenotype	Comments
1	Raine syndrome (ARHR3)	FAM20C (7p22.3)	AR	Kinase for FGF-23 and calcium binding phosphoprotein family of proteins (including SIBLING group)[34]	Ocular proptosis, mid-facial hypoplasia, depressed nasal bridge, cerebral calcifications (in parietal and occipital periventricular white matter), micrognathia, cleft palate, choanal atresia, corpus callosum and hypophysis dysgenesis, osteosclerosis and periosteal reaction. In lethal forms, mortality within the 1st month of life. Non-lethal forms have developmental delay, seizures and hypoacusis, amongst others	No genotype-phenotype correlation. Differentials include congenital cytomegalovirus infection, Crouzon syndrome, osteopetrosis dysplasia and desmosterolosis. Cerebral calcifications, osteopetrosis and rickets may also be seen in RTA due to carbonic anhydrase type 2 deficiency, but the calcification is predominantly in basal ganglia and the cortex
2	HR with hyperparathyroidism	Translocation between chromosomes 13 and 9, and the breakpoint on chromosome 13 is located adjacent to the Klotho gene	AD	Implicated in regulation of FGF signaling, aging and calcium homeostasis	Hypercalcemia. Raised PTH (similar to values in CR)	Very rare entity - only 2 reported cases
3	Fibrous dysplasia	GNAS	Post-zygotic mutation, unlikely to be hereditary	Encodes alpha subunit of stimulatory G-protein required for receptor binding of various hormones	Precocious puberty, hyperthyroidism, thyroid nodular disease, café-au-lait macules. Up to half the patients may have hypophosphatemia	Anecdotal evidence exists in favor of use of burosumab. Bisphosphonates and denosumab have been found to reduce the risk of fractures but increased risk of hypophosphatemia
4	Opsismodysplasia	INPPL1 (11q13.4)	AR	Encodes Src homology 2 domain-containing inositol phosphatases. It functions as a 5-phosphatase that modulates intracellular signaling and metabolic pathway	Relative macrocephaly with frontal prominence, midfacial hypoplasia, a low nasal bridge, short nose with anteverted nostrils, and an elongated philtrum; a constricted thoracic cage; small hands and feet; delayed epiphyseal ossification, metaphyseal cupping, and platyspondyly	Raised FGF-23 not seen in all patients
5	Osteoglophonic dysplasia	FGFR1 (heterozygous gain of function mutations)	AD	Tyrosine kinase family of receptors required for modulation of bone development	Tower-shaped skull, craniosynostosis, prominent supraorbital ridge, maxillary hypoplasia, depressed nasal bridge, mandibular prognathism, dental anomalies, vertebral anomalies, rhizomelic short stature, non-ossifying fibromasbone mineralization defects	Comprises of craniosynostosis (classical of FGFR1 AND FGFR2 mutations) and dwarfism (as in FGFR3 mutations) related manifestations
6	Jansen metaphyseal chondrodysplasia	PTHR1	AD (most cases de novo)	G-protein coupled receptor on kidney, bone and chondrocytes for PTH and PTHrP	Shortened limbs starting infancy. Radiographs reveal rachitic changes, bone erosions and cortical thinning. Patients biochemically have increased serum calcium, reduced phosphate levels, and raised alkaline phosphatase-are present, despite normal concentrations of PTH and PTHrP	H223R mutation has more severe hypercalcemia compared to the I458K and T410R mutations
7	Schimmel penning-Feuerstein-Mims syndrome/cutaneous skeletal hypophosphatemia syndrome	Somatic gain-of-function mosaicisms in RAS genes (HRAS, NRAS, and KRAS)		Encodes small GTPase proteins that act as molecular switches regulating fundamental cellular processes, including growth, proliferation, differentiation, survival, and motility		Burosumab was found to be effective in some cases

ARHR3: Autosomal recessive hypophosphatemic ricket 3; HR: Hypophosphatemic rickets; FAM20C: Family with sequence similarity 20-member C; GNAS: Guanine nucleotide-binding protein alpha-stimulating; INPPL1: Inositol polyphosphate phosphatase-like 1; FGFR1: Fibroblast growth factor receptor 1; PTHR1: Parathyroid hormone receptor 1; RAS: Rat sarcoma viral oncogene homolog; HRAS: Harvey rat sarcoma viral oncogene homolog; NRAS: Neuroblastoma rat sarcoma viral oncogene homolog; KRAS: Kirsten rat sarcoma viral oncogene homolog; AR: Autosomal recessive; AD: Autosomal dominant; FGF-23: Fibroblast growth factor 23; SIBLING: Small integrin-binding ligand, N-linked glycoproteins; PTH: Parathyroid hormone; PTHrP: Parathyroid hormone-related protein; CR: Calcipenic rickets; RTA: Renal tubular acidosis; FGFR2: Fibroblast growth factor receptor 2; FGFR3: Fibroblast growth factor receptor 3; H223R: Histidine 223 to arginine; I458K: Isoleucine 458 to lysine; T410R: Threonine 410 to arginine.

Non FGF-23 mediated HHR

HHRH: With an estimated incidence of 1:25000, HHRH is an autosomal recessive disorder caused by loss-of-function variants in SLC34A3, which encodes the renal cotransporter SLC34A3[87,88]. Reduced serum phosphate stimulates renal CYP27B1, resulting in increased synthesis of 1,25(OH)₂D, which enhances intestinal Ca absorption. The consequent increase in Ca absorption suppresses PTH and promotes hypercalciuria[89]. Consequently, nearly 70% individuals with bi-allelic mutations have renal calcifications[90]. Even heterozygosity for a mutated allele may predispose to a three-fold higher risk of nephrocalcinosis[89]. In one of the largest systematic reviews, no difference was found in skeletal manifestations and renal calculi in between truncating and non-truncating variants[90]. However, 72.2% individuals with bi-allelic mutations had early onset HHRH, while 19% surprisingly had no skeletal manifestations of whom 53% harbored the variant p.Ser192 Leu. Over two-thirds had nephrocalcinosis and/or renal calculi. Amongst the relatives with mono-allelic mutations, 30% had renal calcification and 50% had low bone mass[90]. HHRH typically presents with childhood rickets or early-onset osteoporosis accompanied by nephrolithiasis, often in the context of an autosomal recessive family history. Dental abscesses, Chiari malformation and craniosynostosis are typically absent[89]. Nephrocalcinosis predisposes patients to CKD unlike XLH. In fact, bi-allelic carriers of variants had a six-fold increased risk compared to the general population[91]. Hyperparathyroidism and vitamin D deficiency should be corrected before further evaluation. HHRH should be suspected in the absence of features suggestive of PHPT or MEN syndromes. Assessment of bone turnover markers, dual energy X-ray absorptiometry, and renal ultrasonography is recommended to detect subclinical bone disease and asymptomatic nephrolithiasis or nephrocalcinosis[89]. Biochemically, patients with non FGF-23 mediated HHR have low PO₄, raised Ca, low PTH, raised ALP, decreased TRP, raised 1,25(OH)₂D and hypercalciuria. Management with oral phosphate supplementation alone is usually sufficient, as it corrects hypophosphatemia and reduces 1,25(OH)₂D production. The use of active vitamin D analogues such as calcitriol is generally avoided because they may worsen hypercalciuria. Dietary sodium and protein restriction, adequate hydration and thiazides are also recommended to reduce the risk of nephrolithiasis. Treatment outcomes are typically favorable[83].

HRs with nephrolithiasis and osteoporosis type 1: Mutations in solute carrier family 34 member 1 (SLC34A1), which encodes the renal sodium-phosphate cotransporter NaPi-2a, can lead to several disorders affecting phosphate homeostasis, including nephrolithiasis and osteoporosis type 1 (NPHLOP1), Fanconi renotubular syndrome type 2, and infantile hypercalcemia type 2[7]. Interestingly, 3% of the population may have putative variants causing loss of SLC34A1 function. Whether these increase the risk of nephrolithiasis remains controversial[92,93]. NPHLOP1, initially described as an autosomal dominant condition, represents the severe end of phenotypic spectrum, whereas heterozygous mutations causing hypercalciuria, nephrolithiasis, and reduced bone mineral density in adulthood represent milder forms. Severe forms present in infancy unlike HHRH, where presentation occurs in childhood or adulthood. Biochemical profile is identical to HHRH[74]. Variants in SLC34A1 can also cause Fanconi renotubular syndrome type 2, a disorder characterized by generalized proximal tubular dysfunction with increased urinary losses of phosphate and other solutes. Affected individuals may present with rickets in childhood or osteomalacia in adulthood, along with hypercalciuria, glycosuria, aminoaciduria, and tubular proteinuria, but typically without RTA. Infantile hypercalcemia type 2 represents another clinical presentation, characterized by severe hypercalcemia, failure to thrive, vomiting, dehydration, and nephrocalcinosis. Despite their phenotypic variability, these conditions share a common underlying mechanism-impaired NaPi-2a-mediated phosphate transport in the proximal tubule. Treatment strategies are similar to those used in HHRH. Oral phosphate replacement can alleviate bone pain, improve muscle strength, and promote healing of rickets, while reducing urinary Ca excretion and circulating 1,25(OH)₂D levels. However, other features of proximal tubular dysfunction, such as glycosuria or aminoaciduria, uric acid levels and renal dysfunction generally persist. In a study involving carriers of SLC34A1 and SLC34A3, bi-allelic carriers on oral PO₄ had decrease but not normalization of ALP after a treatment duration of 2 years[91].

HRs with nephrolithiasis and osteoporosis type 2: Nephrolithiasis and osteoporosis type 2 is an autosomal dominant disorder caused by variants in solute carrier family 9 member A3 regulator 1, which encodes the adaptor protein Na⁺/H⁺ exchanger regulatory factor 1. This protein regulates several membrane transporters and receptors in the proximal tubule, including the sodium-phosphate cotransporter NaPi-2a and the PTH receptor. Na⁺/H⁺ exchanger regulatory factor 1 helps maintain proper expression of NaPi-2a at the apical membrane and modulates PTH-mediated signaling pathways. Known variants have been localized to PDZ1(E68A) and PDZ2 (L110V, R153Q, E225K) domains of the protein, with the first variant being unique in leading to proteins that don’t interact with PTH receptor[93-95]. The frequency of variants in patients with such phenotypes was not higher than the European population. Solute carrier family 9 member A3 regulator 1 (and SLC34A1) variants thus have disputed association with the reported phenotypes[87]. Distinction from HHRH and NPHLOP1 requires molecular testing by NGS. Treatment is on similar lines as HHRH.

RTA: These entities arise due to renal tubular defects of varied congenital and acquired etiologies. Operating mechanisms include phosphaturia, acidosis leading to inhibited osteoblastic activity and decreased 1-alpha hydroxylase[10]. Severity of rickets is higher in dRTA due to persistent acidosis and hypercalciuria. Differentiation between the two requires blood and urine biochemistry (approach and treatment described in Figure 6)[96,97]. A review of all the possible etiologies for both is beyond the scope of this review. Several excellent reviews exist[98,99]. FS are combined defects characterized by proximal tubular dysfunction causing glycosuria, aminoaciduria, low molecular weight proteinuria, urinary Na loss and phosphaturia. Multiple entities causing FS have specific treatment - nitisinone for tyrosinemia type 1, cysteamine for cystinosis and copper chelation for Wilson’s disease are great examples. While literature on outcomes specific to rickets in these entities is scarce, they have been reviewed in Table 4[19,100,101]. For primary dRTA solute carrier family 4 member 1 (SLC4A1), ATPase H⁺ transporting V0 subunit a4 (ATP6V0A4), ATPase H⁺ transporting V1 subunit b1 (ATP6V1B1), forkhead box I1, and WD repeat domain 72 are known loci. Hemolytic anemia in SLC4A1, late onset SNHL in ATP6V0A4 and early onset SNHL in ATP6V1B1 genes may be clinical clues. ATP6V1B1 and ATP6V0A4 were found to require higher alkali doses than SLC4A1[102]. However, variants may not be detected in over one-fourth of the patients and genotype-phenotype correlation is not the rule[103]. Optimal treatment in primary dRTA was found to resolve rickets in 17 out of 18 children in an Indian study[104]. Outcomes are generally good, up to 30% may develop CKD by puberty[102].

Figure 6 Approach to rickets due to renal tubular acidosis. ¹Preparations: Syrups - potrate (bicarbonate and potassium 2 mEq/mL), nodosis (0.8 mEq/mL). Tablets: Sodamint (3.6 mEq/300 mg, 6 mEq/500 mg, 7.8/650 mg), acidose 500 mg. NAGMA: Normal anion gap metabolic acidosis; UAG: Urine anion gap; UOG: Urine osmolar gap; PCO₂: Partial pressure of carbon dioxide; RTA: Renal tubular acidosis; FS: Fanconi syndrome; LMW: Low molecular weight.

Table 4 Inherited forms of Fanconi syndrome - treatment and outcomes.

Disease	Gene	Inheritance	Paraphrased salient features	Genotype-phenotype correlation	Precision medicine/targeted management	Outcomes
Cystinosis	CTNS	AR	Infantile nephropathic form usually presents in infancy with Fanconi syndrome, failure to thrive, polyuria, polydipsia, photophobia, and hypophosphatemic rickets; juvenile forms present later and are milder	Severe biallelic CTNS loss-of-function variants usually cause infantile nephropathic cystinosis; residual-function variants are associated with juvenile or ocular-predominant disease	Cysteamine to deplete lysosomal cystine, cysteamine eye drops for corneal crystals, kidney-supportive Fanconi replacement, and early kidney-transplant planning	Early cysteamine improves growth and delays CKD/ESKD; without treatment, progressive renal failure, bone disease, and extra-renal complications are typical
Galactosemia	GALT	AR	Neonatal cholestasis, hepatomegaly, sepsis risk, cataract, hypoglycemia, and occasionally Fanconi syndrome with rickets	Classic GALT deficiency produces severe neonatal disease; genotype influences residual enzyme activity and long-term neurodevelopmental risk	Immediate lifelong galactose/lactose restriction, treatment of liver failure/sepsis, and correction of tubular losses when Fanconi syndrome is present	Renal tubular dysfunction may improve with metabolic control; neurologic, reproductive, and developmental sequelae can persist despite diet
Tyrosinemia type 1	FAH	AR	Failure to thrive, liver dysfunction, renal tubular Fanconi syndrome, hypophosphatemic rickets, and markedly elevated succinylacetone/alpha-fetoprotein	FAH deficiency causes fumarylacetoacetate toxicity; phenotype ranges from acute liver failure in infancy to later renal/rickets-predominant presentation	Nitisinone plus low-tyrosine/phenylalanine diet; liver transplantation for refractory disease or suspected malignancy; phosphate/alkali replacement for Fanconi syndrome	Early nitisinone improves survival and often heals rickets and tubular dysfunction; delayed diagnosis increases risk of hepatocellular carcinoma, CKD, and residual bone deformity
Hereditary fructose intolerance	ALDOB	AR	Vomiting, hypoglycemia, hepatomegaly, jaundice/cholestasis, and sometimes proximal tubular dysfunction after fructose exposure	Biallelic ALDOB variants impair fructose-1-phosphate aldolase activity; severity reflects exposure and residual activity more than a strict mutation-specific pattern	Strict avoidance of fructose, sucrose, and sorbitol; rapid correction of metabolic derangements and tubular losses when present	Excellent prognosis with avoidance; ongoing exposure can lead to liver injury, growth failure, renal tubular dysfunction, and rickets
Wilson disease	ATP7B	AR	Hepatic disease, neuropsychiatric manifestations, Kayser-Fleischer rings, and occasionally Fanconi syndrome with rickets/osteomalacia	ATP7B variants cause variable hepatic-predominant or neurologic-predominant phenotypes; genotype-phenotype correlation is incomplete	Copper chelation or zinc therapy, dietary copper reduction, and treatment of Fanconi-associated phosphate/alkali losses	Tubular dysfunction may improve with copper control; untreated disease progresses to cirrhosis, neurologic disability, and skeletal complications
Lowe syndrome	OCRL	XLR	Congenital cataract, hypotonia, developmental delay/intellectual disability, seizures, proximal tubulopathy/Fanconi syndrome, nephrocalcinosis, and rickets	OCRL defects cause oculocerebrorenal disease; truncating or severe loss-of-function variants are generally associated with classic multisystem disease	Multidisciplinary care, tubular replacement therapy, cataract/glaucoma management, seizure/developmental support, and CKD surveillance	Lifelong morbidity is common, with persistent neurodevelopmental impairment, rickets/short stature, and progressive CKD in many patients
Dent disease type 1	CLCN5	XLR	Low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis/nephrolithiasis, phosphaturia, and hypophosphatemic rickets; acidosis may be absent	CLCN5 variants account for most Dent disease; truncating variants may be associated with more severe tubular dysfunction, though correlation is variable	Supportive care with high fluid intake, cautious thiazide use, citrate, phosphate/calcitriol when needed for rickets, and CKD prevention	Progression to CKD in adulthood is common; recurrent stones/nephrocalcinosis and persistent bone disease can occur
Dent disease type 2	OCRL	XLR	Dent phenotype plus variable extra-renal findings such as mild cataract or neurodevelopmental features; LMW proteinuria, hypercalciuria, nephrocalcinosis, and rickets	OCRL variants in Dent type 2 often produce a milder renal-predominant phenotype than classic Lowe syndrome, illustrating allelic heterogeneity	As for Dent disease, with additional ophthalmologic/neurodevelopmental assessment when indicated	Renal decline, stones, and bone disease remain major outcomes; extra-renal complications are milder than in Lowe syndrome but may accumulate
Glycogen storage disease type 1A	G6PC	AR	Hepatomegaly, fasting hypoglycemia, hyperlactatemia, hyperuricemia, hyperlipidemia, growth failure, and occasionally Fanconi-like tubular dysfunction with rickets	G6PC deficiency impairs hepatic glucose release; metabolic control, rather than a tight genotype pattern, strongly influences renal and bone phenotype	Frequent complex-carbohydrate feeding/cornstarch, management of metabolic abnormalities, and renal-bone monitoring	Improved metabolic control reduces systemic complications, but chronic kidney disease, hepatic adenomas, and poor growth may still develop
Fanconi-Bickel syndrome	SLC2A2 (GLUT2)	AR	Hepatomegaly, fasting hypoglycemia, postprandial hyperglycemia/galactosemia, proximal tubulopathy, rickets, and growth failure	Biallelic SLC2A2 variants disrupt GLUT2; genotype-phenotype correlation is limited, but complete loss usually causes classic hepatorenal disease	Dietary management with frequent feeds/cornstarch, phosphate and alkali replacement, vitamin D, and supportive renal care	Many children survive into adulthood, but short stature, rickets, and chronic renal/hepatic complications may persist
Fanconi renotubular syndrome type 1	GATM	AD	Isolated inherited Fanconi syndrome with rickets, metabolic acidosis, glycosuria, aminoaciduria, and low-molecular-weight proteinuria	Dominant GATM variants alter mitochondrial protein behavior in proximal tubules and can produce progressive tubulopathy with variable CKD risk	Supportive tubular replacement, CKD surveillance, and emerging interest in mutation-specific mitochondrial stress pathways as future targets	Persistent Fanconi syndrome is typical; progressive renal impairment can occur in some families
Fanconi renotubular syndrome type 2	SLC34A1	AR	Infant or childhood Fanconi syndrome with phosphaturia, glycosuria, aminoaciduria, metabolic acidosis, and rickets	Loss of NaPi-IIa impairs proximal phosphate transport; biallelic variants tend to cause early phosphate-wasting phenotypes	Phosphate and alkali replacement, rickets treatment, and kidney monitoring; genotype confirmation helps avoid misclassification with other phosphate-wasting disorders	Growth and rickets improve with treatment, but nephrocalcinosis/CKD risk depends on severity and long-term metabolic control
Fanconi renotubular syndrome type 3	EHHADH	AD	Fanconi syndrome with rickets, hypokalemia, polyuria, glycosuria, phosphaturia, and aminoaciduria	A dominant mistargeting mechanism causes mitochondrial dysfunction in proximal tubular cells; currently reported in very few families	Supportive therapy only at present; precision medicine is mainly genetic diagnosis and family counseling	Long-term data are sparse, but chronic tubular losses and growth/bone complications can persist
Fanconi renotubular syndrome type 4	HNF4A	AD	Proximal tubulopathy/Fanconi syndrome with rickets plus neonatal hyperinsulinism, macrosomia, glycosuria, and later diabetes in some patients	The recurrent p.Arg76Trp variant is strongly associated with this syndromic renal-metabolic phenotype	Personalized care includes management of hyperinsulinism or later diabetes in addition to tubular replacement and bone treatment	Variable long-term course; renal tubular dysfunction may persist, while endocrine manifestations evolve over time
Fanconi renotubular syndrome type 5	NDUFAF6	AR	Fanconi syndrome with rickets and mitochondrial disease features; reported cases may show pulmonary hypertension, polyuria, glycosuria, aminoaciduria, and phosphate wasting	NDUFAF6-related disease reflects mitochondrial complex I assembly defects; phenotype is multisystem and severity varies	Supportive renal care, management of mitochondrial complications, and precision diagnosis for counseling; no established disease-specific therapy	Outcomes depend on extra-renal mitochondrial involvement; renal tubular dysfunction and growth failure may be persistent

CTNS: Cystinosin, lysosomal cystine transporter; GALT: Galactose-1-phosphate uridylyltransferase; FAH: Fumarylacetoacetate hydrolase; ALDOB: Aldolase, fructose-bisphosphate B; ATP7B: ATPase copper transporting beta; CLCN5: Chloride voltage-gated channel 5; OCRL: Oculocerebrorenal syndrome of Lowe; G6PC: Glucose-6-phosphatase catalytic subunit; SLC2A2: Solute carrier family 2 member 2; GLUT2: Glucose transporter type 2; GATM: Glycine amidinotransferase; SLC34A1: Solute carrier family 34 member 1; EHHADH: Enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase; HNF4A: Hepatocyte nuclear factor 4 alpha; NDUFAF6: NADH dehydrogenase (ubiquinone) complex I assembly factor 6; AR: Autosomal recessive; AD: Autosomal dominant; XLR: X-linked recessive inheritance; LMW: Low molecular weight; CKD: Chronic kidney disease; ESKD: End-stage kidney disease.

Acquired HR

Tumor induced osteomalacia: Although rare in children, slow growing phosphaturic mesenchymal tumors (PMT) with fibronectin 1-FGF receptor 1/FGF-1 gene fusion have been known to secrete FGF-23 resulting in HR by various established mechanisms[105]. PMTs are commonly found in non-weight bearing areas like the radius, lateral scapula, iliac wings, ischiopubic area, tibia and fibula. Presentation in children is with growth failure and rachitic features. Adults in whom PMTs are commoner, may present with bone pain, pathological fractures, muscle weakness or rarely tumor-related symptoms like obstruction or bleeding. Given the vagueness of symptoms, diagnosis may be delayed by as long as 3 years[106]. Biochemical profile is similar to XLH, except that FGF-23 levels (365 RU/mL vs 95 RU/mL, P < 0.001) and ALP levels (282.8 IU/L vs 118.5 IU/L, P < 0.01) are much higher in tumor induced osteomalacia, while PO₄ levels are much lower (1.4 mg/dL vs 2.2 mg/dL, P < 0.05)[107]. Expression of somatostatin receptors 2A within these PMTs is frequently made use of for identification and localization using positron emission tomography computed tomography (CT) or single photon emission CT. Examples include: ^99mTc-hydrazinonicotinamide-octreotide (sensitivity: 86.3%, specificity: 99.1%) and ⁶⁸Ga-DOTATATE positron emission tomography-CT (sensitivity: 100%, specificity: 91%)[108,109]. Definitive treatment with PMT excision has been found to be effective as early as 9 months. Oral PO₄ at 15-60 mg/kg/day and activated vitamin D (calcitriol at 15-60 ng/kg in 2 divided doses or alfacalcidiol at 15-60 ng/kg/day as a single dose) may be used as bridge therapy or in cases where tumors are not localized or excision is not feasible[110]. Higher doses of activated vitamin D compared to XLH corroborate with the highlighted biochemical differences between the 2 pathologies. Intralesional triamcinolone and radiofrequency ablation are amongst other attempted measures in cases where tumors are not amenable to complete excision[111].

Intravenous iron preparation administration: Intravenous iron preparations like ferric carboxymaltose, ferric polymaltose and saccharated ferric oxide, when administered to patients without end-stage renal disease have been found to cause FGF-23 mediated HR[112]. The mechanisms are not completely understood but have been proposed to cause FGF-23 O-glycosylation[113]. Risk is higher with formulations such as iron polymaltose and ferric carboxymaltose, as well as in patients receiving repeated infusions. Lower baseline phosphate levels were strongly associated with increased risk, while higher baseline creatinine, greater body weight, and older age appeared to be protective[114]. Recognition of these risk factors may help identify patients at greater risk for clinically significant hypophosphatemia and guide closer biochemical monitoring. Cessation of these agents and substitution with iron dextran, ferumoxytol, or ferric derisomaltose constitutes the management.

Hereditary CR

Vitamin D dependent rickets 1A: Bi-allelic mutations in CYP27B1 gene, causing 1-alpha hydroxylase enzyme deficiency are responsible for this entity. Most cases present in infancy and are diagnosed by 2-3 years of age[115,116]. Biochemically, the expected low PO₄ levels due to SHPT are seen in only in 75% cases. Unexpectedly, instances of patients with normal 1,25(OH)₂D levels have also been noted. Cases may be falsely identified as NR, pseudohypoparathyroidism and RTA, short of molecular diagnosis[115]. Commonly identified mutations include c.195+2T>G, p.V88Wfs71, p.K192E and p.F443Pfs24. The last-mentioned mutation was found to be recurring in a large study from India[115]. From Turkey, p.K192E and c.195+2T>G were noted to be prevalent with c.195+2T>G and other truncating variants requiring higher doses of calcitriol[117]. The mainstay of treatment is activated forms of vitamin D, calcitriol or alfacalcidol targeting serum Ca levels of 8.5-9 mg/dL, normalization of ALP and PTH (which may remain high in some cases; Tables 4 and 5)[118,119].

Table 5 Hereditary forms of calciopenic rickets[2,125].

Condition	Gene (chromosome)	Mode of inheritance	Ca dose	Activated vitamin D (calcitriol/alfacalcidol) dose	Calcifediol dose	Vitamin D (cholecalciferol) dose	Biochemical response
VDDR1A	CYP27B1 (12q13)	AR	30-75 mg/kg/day; (0.5-3 g/day) elemental Ca	Calcitriol: 10-100 ng/kg/day; 0.3-2 μg/day. Alfacalcidol: 10-100 ng/kg/day; 0.5-3 μg/day	Not useful	Not useful	ALP: 3-12 months; Ca: 5 months; PTH: 6 months (may not normalize)
VDDR1B	CYP2R1 (11p15)	AR/AD	30-75 mg/kg/day; (0.5-2 g/day) elemental Ca)	Calcitriol: 10-100 ng/kg/day; 0.3-2 μg/day. Alfacalcidol: 10-100 ng/kg/day; 0.5-3 μg/day	15-50 μg/day	Heterozygous: 5000-10000 IU/day. Homozygous: 600000 every 3 months	3 months
VDDR2A	VDR (12q13)	AR	3-5 g/day; 400-1400 mg/m2/day	10-400 ng/kg/day; 5-60 μg/day (for both)	20-200 μg/day	Not helpful	6-12 months, may not occur in all children
VDDR2B	Unknown (post-receptor defect)	NK (isolated cases)
VDDR3	CYP3A4 (7q22)	AD (usually de novo mutations)	May be required (30-75 mg/kg/day)	Calcitriol: Low limit: 1 μg/day, upper limit: Not defined. Alfacalcidiol: Low limit: 2 μg/day, upper limit: Not defined	Low limit: 50 μg/day, upper limit: Not defined (metabolized rapidly)	10000-50000IU per day	3 months

VDDR1A: Vitamin D dependent rickets type 1A; VDDR1B: Vitamin D dependent rickets type 1B; VDDR2A: Vitamin D dependent rickets type 2A; VDDR2B: Vitamin D dependent rickets type 2B; VDDR3: Vitamin D dependent rickets type 3; CYP27B1: Cytochrome P450 family 27 subfamily B member 1; CYP2R1: Cytochrome P450 family 2 subfamily R member 1; VDR: Vitamin D receptor; CYP3A4: Cytochrome P450 family 3 subfamily A member 4; AR: Autosomal recessive; AD: Autosomal dominant; Ca: Calcium; ALP: Alkaline phosphatase; PTH: Parathyroid hormone.

Vitamin D dependent rickets 1B: This is a semi-autosomal dominant condition caused by inactivating mutations in cytochrome P450 family 2 subfamily R member 1 gene leading to decreased 25-alpha hydroxylase levels in the liver[118]. It is underdiagnosed owing to its resemblance to NR. Distinction is made by non-normalization of 25(OH)D after oral vitamin D therapy. Phenotype is essentially identical to vitamin D dependent rickets 1A. Differences in severity may occur due to gene-dosage effect causing milder phenotypes in patients with a single mutated allele[120]. p.L99P, p.G42_L46delinsR and p.K242N are amongst the commonly reported variants[121,122]. Therapeutic options include physiological doses of calcitriol or pharmacological doses of ergocalciferol or cholecalciferol, along with Ca supplementation. In regions where available, calcifediol (or calcidiol) offers a more effective option for vitamin D dependent rickets 1B, as it bypasses the defect in 25-hydroxylation (Tables 5 and 6)[120]. Improvement may be noted post pubertally due to upregulation of intestinal Ca transporter protein 1[123].

Table 6 Comparative pharmacology of vitamin D preparations.

Parameter	Cholecalciferol (Vitamin D3)	Calcidiol (25-hydroxyvitamin D3)	Alfacalcidol (1α-hydroxyvitamin D3)	Calcitriol (1,25-dihydroxyvitamin D3)
Biochemical form	Native vitamin D3	25-hydroxylated form	Synthetic 1α-hydroxylated analogue	Fully active hormonal form
Activation required	Hepatic + renal hydroxylation	Renal hydroxylation only	Hepatic hydroxylation only	None
Dependence on organ function	Liver and kidney dependent	Kidney dependent	Liver dependent	Independent of liver and kidney activation
Onset of action	Slow	Intermediate	Rapid	Rapid
Half-life	Long (weeks)	Intermediate (2-3 weeks)	Short (hours to days)	Very short (4-6 hours)
Mechanism of action	Prohormone	Circulating precursor	Converted to calcitriol in liver	Direct activation of vitamin D receptor
Clinical indications	Nutritional vitamin D deficiency	Malabsorption, obesity, liver disease	Chronic kidney disease, hypoparathyroidism	Severe hypocalcemia, CKD, hypoparathyroidism, VDDR
Risk of hypercalcemia	Low	Moderate	High	Highest
Monitoring requirements	Minimal	Intermittent	Frequent monitoring required	Close monitoring required

CKD: Chronic kidney disease; VDDR: Vitamin D dependent rickets.

VDDR2A: This entity represents end organ resistance to vitamin D forms due to bi-allelic mutations in the vitamin D receptor (VDR) gene[124]. The encoded protein belongs to steroid group of receptors and has 2 domains - the ligand binding domain (LBD) and DNA binding domain (DBD). Truncating and non-truncating variants have been found in both the domains. Presentation occurs by 19 months of age with enamel hypoplasia, alopecia (80%), recurrent pneumonia (10%-15%), growth failure (50%), rachitic features and hypocalcemic seizures. Alopecia occurs due to the role of VDR in hair follicle formation (calcitriol independent effect) and is usually absent at birth but may present prior to the skeletal manifestations[125,126]. Truncating-LBD and all DBD variants caused universal alopecia, while over half of those with non-truncating-LBD variants had alopecia. The biochemical profile highlights low Ca and PO₄, raised ALP, highly elevated PTH and 1,25(OH)₂D between 100-1000 pg/mL[120]. Hypophosphatemia was absent in over 40% patients, with similar levels in patients with or without alopecia and across the molecular spectrum. Alopecia is no longer believed to be a marker of poor response to Ca therapy[125,127]. Treatment is usually with high doses of oral Ca and calcitriol. Intravenous therapy may be required acutely in cases with hypocalcemic seizures, and chronically in patients with poor response to oral Ca. Further, children requiring IV Ca may develop adaptive mechanisms to sustain normal Ca levels with oral therapy even though 1,25(OH)₂D may remain elevated implying persistent end-organ resistance[128]. Patients with non-truncating-LBD variants have been found to have higher response rate to oral Ca, compared to those with truncating-LBD and non-truncating-DBD variants. The rate of biochemical response to oral Ca was just 30%[125]. PTH and not PO₄ levels, may be a marker of compliance[129].

Vitamin D dependent rickets type 2B: Phenotypically identical to VDDR2A, patients suffering from this condition have intact VDR but over-expression of a heterogeneous nuclear ribonucleoprotein leading to impaired down-stream signaling[130]. Interestingly, in the largest series of patients with rachitic changes, hypocalcemia, raised ALP and PTH and elevated 1,25(OH)₂D, patients had predominant lower limb deformities without alopecia. Serum PO₄ levels were higher, while urine PO₄ were lower than healthy controls[131]. Treatment is the same as that for VDDR2A.

Vitamin D dependent rickets 3: Gain of function mutations in cytochrome P450 family 3 subfamily A member 4 gene, coding for a cytochrome P450 enzyme responsible for multiple substrates cause this rare entity. Interestingly, the metabolism of substrates other than 25(OH)D remains unaffected. The only variant reported to occur in all 3 reported cases was Ile301Thr[132,133]. This variant was recently found to yield a novel vitamin D metabolite 11α,25(OH)₂D₃[134]. Biochemically, levels of 25(OH)D and 1,25(OH)₂D are very low and decline after a transient rise if the cholecalciferol or calcitriol therapy is discontinued (Tables 5 and 6)[135].

CONCLUSION

NNRs represent heterogeneous disorders with distinct etiologies, treatment requirements and outcomes. Distinction from NR may be challenging in resource-limited settings. Hydrocephalus in XLH, GACI in ARHR2, family history of renal calculi in HHRH, cataract in Lowe syndrome and Wilson disease, and alopecia in VDDR2A are just some of the abundant clinical pearls that can come to the rescue. Biochemical profile when interpreted promptly can not only guide prompt precision medicine but may also refine the database required for NGS (Figure 7). Reduced severity after adolescence in XLH and vitamin D dependent rickets type 1B allow less stringent regimens, early diagnosis employing organized algorithms holds the key. Molecular diagnosis may have to be resorted to for distinction of close mimics like HHRH and NPHLOP1, but its utility extends to appropriate prognostication and genetic counselling.

Figure 7 Diagnostic algorithm including hereditary and non-hereditary etiologies of rickets[17]. Pi: Phosphate; PTH: Parathyroid hormone; 25(OH)D: 25-hydroxyvitamin D; CKD: Chronic kidney disease; RTA: Renal tubular acidosis; RM: Rickets mimicker; PHPT: Primary hyperparathyroidism; NR: Nutritional rickets; VDD: Vitamin D deficiency; VDDR: Vitamin D dependent rickets; VDDR1B: Vitamin D dependent rickets type 1B; VDDR3: Vitamin D dependent rickets type 3; 1,25(OH)₂D: 1,25-dihydroxyvitamin D; CR: Calcipenic rickets; PTH: Parathyroid hormone; PR: Phosphopenic rickets; FGF-23: Fibroblast growth factor 23.

However, limited availability and high cost of advanced biochemical assays, genetic testing, and targeted therapies remain major barriers in LMIC. Development of simplified diagnostic algorithms, improved clinician awareness, and wider access to affordable molecular diagnostics are therefore essential to bridge this gap. Future research should focus on long-term outcome studies, genotype-phenotype correlations, biomarkers predicting therapeutic response, and emerging modalities such as enzyme replacement and gene-based therapies. Together, these advances hold promise for improving individualized care and lifelong outcomes in children with NNR. Further, exciting avenues in the form of enzyme replacement therapy for ARHR2 and potential for gene therapy directed towards specific loci may be the way ahead.