Table 4.

Summary of clinical, biochemical, and genetic characteristics of various forms of rickets

Type of rickets and subtypes	Gene involved	OMIM	Pathophysiology	Inheritance	Classical clinical presentation and pathognomic features of different subtypes	Pi	Ca	25 (OH)D	1,25 (OH)2D	PTH	FGF23	TP/GFR	Urine Pi	Urine Ca	Characteristic radiographic findings
1. Calciopenic rickets					Classical features of rickets involving both upper and lower limbs including bone deformities, bone pain, frontal bossing, rachitic rosar y, muscle weakness, frequent respiratory infections	N/↓	↓/N	↓/N	Depends on sub-type	↑	Test not necessary, usually N	Test not necessary, expected:↓	Test not necessary, variable	↓	Classical features of rickets like diffuse osteopenia, fraying, cupping at metaphysis, pathological fractures, Looser's zones
					Short stature
					Hypocalcemic tetany, seizures
					Enamel hypoplasia
					Family history not common
(a) Nutritional rickets	NA	NA	Vitamin D and/or calcium deficiency	NA	History of poor sunlight exposure, high latitude, malnutrition, malabsorption	N/↓	N/↓	↓/N	Variable	↑	N	↓	Variable	↓
(b) Vitamin D-dependant rickets type 1A (VDDR 1A)	CYP27B1:12q14., 12q13.1, 12q13.3	264700	Impaired synthesis of 1,25 (OH)2D	AR	Can have early presentation at 2–24 months with hypotonia, irritability, tetany, seizures.	N/↓	↓	N	↓	↑	N/↓	↓	Variable	↓
					Later onset disease presents like nutritional rickets
(c) Vitamin D-dependant rickets type 1B (VDDR 1B)	CYP2R1:11p15.2	600081	Impaired synthesis of 25(OH)D	AR	Heterozygous patients can have less severe bone deformity. Disease severity may improve spontaneously with age.	N/↓	↓	↓	Variable	↑	N	↓	Variable	↓
(d) Vitamin D-dependant rickets type 2A (VDDR 2A)/ HVDRR	VDR:12q13.11, 12q12-q14	277440	Impaired signaling of VDR-mutations in VDR	AR	Two-thirds may have universal alopecia with failure to grow eye lashes and eye brows.	N/↓	↓	N	↑	↑	N/↓	↓	Variable	↓
					Can present very early at 2–8 months of age.
(e) Vitamin D-dependant rickets type 2B (VDDR 2B)	HNRNPC	264700	Impaired signaling of VDR-alteration of VDR-DNA interaction	AR		N/↓	↓	N	↑	↑	N	↓	Variable	↓
(f) Vitamin D-dependant rickets type 3 (VDDR 3)	CYP3A4	Pending	↑inactivation of 1,25(OH)D	AR		↓	↓	↓	↓	↑	?N	↓	Variable	↓
2. Phosphopenic rickets: FGF23 mediated causes					Lower limb predominantly involved	↓	Variable N		↓	N/mildly ↑	↑	↓	↑	Usually N	Classical radiographic features of rickets, Distinctive flaring of distal femoral and proximal tibial metaphyses
					More severe short stature
					Dental abscesses common
					Craniotabes, tetany not seen
					Family h/o may be positive
(a) X-linked dominant hypophosphatemic rickets (XLHR)	PHEX: Inactivating mutation	307800	↑Expression of FGF23	XD	Early onset – within 1–2 years of life. Enthesopathy	↓	N	N	↓	N/mildly↑	↑	↓	↑	N	Enthesal calcification
			↑MEPE and ASARM protein mediated inhibition of hydroxyapatite formation and renal tubular reabsorption of phosphate		Dental decay or abscess
					Craniosynostosis
					Hearing impairment
					Arnold Chiari malformation
(b) Autosomal dominant hypophosphatemic rickets (ADHR)	FGF 23: Activating mutation	193100	GOF muta tion of FGF23 gene→	AD	Relapsing remitting	↓	N/↓	N	↓	N/mildly↑	↑	↓	↑	N
			↓proteolytic degradation		↑severity with concomitant iron deficiency
					Lower limb preponderance less common
(c) Hypophosphatemic rickets with hyperparathyroidism	α-Klotho: Excessive production	612089	↑Bioactivity of FGF23, hyperplasia of parathyroid glands	AD	Arnold Chiari malformation	↓	↑	N	↓	↑	↑	↓	↑	N
					Parathyroid gland hyperplasia
(d) Autosomal recessive hypophosphatemic rickets type 1 (ARHR1)	DMP1: inactivating mutation	241520	↑Expression of FGF23, direct effect on osteocytes leading to defective bone mineralization	AR	Hearing loss	↓	N	N	↓	N	↑	↓	↑	N/↑	Osteosclerosis at the base of the skull and in calvarial bones
					Craniosynostosis
					Enthesopathy, kyphosis, spinal ankylosis
(e) Autosomal recessive hypophosphatemic rickets type 2 (ARHR2)	ENPP1: inactivating mutation	613312	↑Expression of FGF23, inhibition of bone mineralization due to increased pyrophosphate	AR	Arterial calcification (in severe infantile form)	↓	N	N	↓	N	↑	↓	↑	N	Arterial calcification
					Ectopic calcification
(f) Autosomal recessive hypophosphatemic rickets type 3 (ARHR3) or Raine syndrome	FAM20C: Inactivating mutation	259775	↑Expression and ↓ degradation of FGF23	AR	Craniofacial anomalies (hypoplasia of the nose/midface)	↓	N	N	↓	N	↑	↓	↑	N	Osteosclerotic long bones
					Osteosclerosis of bones										Periosteal bone formation
					Seizures, delayed motor milestones										Cerebral calcification
					Abnormal dental enamel
(g) Fibrous dysplasia/ McCune-Albright syndrome	GNAS: Activating mutation	174800	↑Expression of FGF 23 in bone lesions	Post zygotic somatic mutation	Fibrous Dysplasia of bone, Café-au-lait spots, precocious puberty	↓	N	N	↓	N	↑	↓	↑	N	Monostotic or polyostotic fibrous dysplasia.
															Advanced bone age if accompanied by precocious puberty
(h) Osteoglophonic dysplasia (OGD)	FGFR1: activating mutation	166250	↑Expression of FGF 23 in bone	AD	Rhizomelic short stature	↓	N	N	↓	N	↑	↓	↑	N	Nonossifying bone lesion (hollowed out appearance of the bones)
					Craniofacial bone dysplasia causing facial dysmorphism
					Craniosynostosis										Craniosynostosis
(i) Cutaneous skeletal hypophosphatemia syndrome/Epidermal nevus syndrome	NRAS, KRAS, HRAS: activating mutation	163200	↑Expression of FGF 23 in bone	Somatic Mosaic mutations	Cutaneous lesions (Linear nevus sebaceous)	↓	N	N	↓	↑/N	↑	↓	↑	N	Segmental skeletal lesions
					Alopecia
					High Serum IgE
					Seizures & developmental defects
(j) Opismodysplasia	INPPL1: inactivating mutation	258480	↑Expression of FGF 23 in bone	AR	Severe short stature	↓	N	N	↓	N	↑	↓	↑	N	Delayed epiphyseal ossification in long bones
					Micromelia										Platyspondyly
															Abnormalities of metacarpals and phalanges
(k) Tumor-induced osteomalacia (TIO)	Acquired disorder/FN1-FGFR1 transcriptional fusion	NA	↑Production of FGF23 from mesenchymal tumor	NA	Almost always in adults	↓	N	N	↓	N	↑	↓	↑	N	Osteomalacia
					Clinical manifestation due to the causative tumor like a lump, bony swelling, epistaxis or nasal blockade										SSTR imaging with PET-CT for tumor localization
(l) Iron Infusion–induced Hypophosphatemia	Acquired disorder	NA	? Impaired cleavage of intact FGF23 leading to increased biological activity	NA	Mostly in adults	↓	N	N	↓	N	↑	↓	↑	N	Osteomalacia
					Relevant history of repeated intravenous iron (carboxymaltose or polymaltose) infusions
3. Phosphopenic rickets: non-FGF23 mediated causes					Similar to FGF23 mediated phosphopenic rickets along with nephrocalcinosis, nephrolithiasis, occasionally renal failure	↓	N/↑	N	↑	Variable variable		↓	↑	↑	Classical radiographic features of phosphopenic rickets
															Nephrocalcinosis seen on USG kidneys
(i) X-linked recessive hypophosphatemic rickets	CLCN5: inactivating mutation	300554	Renal loss of phosphate as well as calcium and protein due to loss of function mutation of voltage gated hydrogen-chloride transmembrane exchange transporter	XR	Proteinuria	↓	N/↑	N	↑	Variable variable		↓	↑	↑
					Nephrocalcinosis, urolithiasis
					Hematuria
					Renal failure
(ii) Hereditary hypophosphatemic rickets with hypercalciuria (HHRH)	SLC34A3: inactivating mutation	241530	Increased renal excretion of phosphate due to loss of function mutation of sodium-phosphate cotransporter type 2c in proximal renal tubule	AR	Nephrocalcinosis, urolithiasis	↓	N/↑	N	↑	N/↓	N/↓	↓	↑	↑
(iii) ADHR with nephrolithiasis type 1	SLC34A1: inactivating mutation (monoallelic)	612286	Increased renal excretion of phosphate due to loss of function mutation of sodium-phosphate cotransporter type 2a in proximal renal tubule	AD	Infantile hypercalcemia	↓	N/↑	N	↑	N/↓	N	↓	↑	↑
(iv) ADHR with nephrolithiasis type 2	SLC9A3R1: inactivating mutation	612287	Increased renal excretion of phosphate due to loss of function mutation of NHERF1 which in turns leads to endocytosis of sodium-phosphate cotransporter type 2a in proximal renal tubule	AD	Proteinuria, Renal failure	↓	N/↑	N	↑	N/↓	N	↓	↑	↑
(v)Renal tubulopathies (Fanconi syndrome, Dent disease and related disorders)	Inactivating mutation of CLCN5 (Dent disease1), OCRL (Dent Disease 2), GATM (FRTS 1), SLC34A1(FRTS 2), CTNS (cystinosis)	300009, 300555, 134600, 613388, 219800	Increased renal loss of phosphate due to proximal tubulopathies along with aminoaciduria, glucosuria	AR	Polyuria, Aminoaciduria, Normoglycemic glycosuria, non-anion gap metabolic acidosis	↓	N	N	↑	Variable (depending upon CKD stage)	Variable (depending upon CKD stage)	↓	↑	↑	Disease specific findings like Basal ganglia hyperintensities in Wilson’s disease or hepatomegaly in galactosemia
					Short stature
					Features s/o particular etiology like: photophobia and corneal erosions (cystine crystals on slit lamp) in cystinosis
					Cataract in Lo we syndrome, galactosemiaLiver disease in galactosemia, Wilson’s
					Intellectual disability in Lowe syndrome
					Neuropsychiatric manifestations & KF ring in Wilson’s disease
(vi) Iatrogenic proximal tubulopathy	Drug Induced, Autoimmune diseases like multiple myeloma, amyloidosis	Acquired disorder	Drug induced proximal renal tubular damage	Acquired disorder	Specific drug history like cisplatin, carboplatin, ifosfamide, amikacin, tenofovir	↓	N	N	↑	Variable	↓	↓	↑	Variable

AD, autosomal dominant; AR, autosomal recessive; ASARM, acidic serine aspartate-rich MEPE-associated motif; Ca, serum calcium; CKD, chronic kidney disease; DNA, deoxyribonucleic acid; FGF23,fibroblast growth factor 23; FRTS, Fanconi renotubular syndrome; GOF, gain of function; IgE, immunoglobulin E; KF, Kayser-Fleischer; MEPE, matrix extracellular phosphoglycoprotein; N, normal; NA, not applicable; NHERF1, sodium/hydrogen exchange regulatory factor 1; OMIM, online Mendelian inheritance in man; P, serum phosphorus; PETCT, positron emission tomography-computed tomography; PTH, parathormone; SSTR, somatostatin receptor; TP/GFR, ratio of tubular reabsorption of phosphate to glomerular filtration rate; Urine Ca, urinary levels of calcium; Urine P, urinary levels of phosphorus; USG, ultrasonography; VDR, vitamin D receptor; XD, X-linked dominant; XR, X-linked recessive; 1,25,OHD, serum 1,25 dihydroxy vitamin D; 25OHD, serum 25-hydroxy vitamin D.