Genetic background of infantile hypophosphatemia: a narrative review

Abstract

Background and Objective

Infantile hypophosphatemia (defined as a serum phosphate level below 1.6 millimoles per liter before 6 months of age and below 1.48 millimoles per liter between 6 months and 1 year of age) is one of the most common electrolyte disorders in clinical practice, which may be caused by acquired or genetic factors. Currently, the summary of the characteristics of infantile hereditary hypophosphatemia remains incomplete, which poses challenges to early identification and clinical treatments. This paper aims to review the genetic background of infantile hypophosphatemia, with the expectation of supporting clinical decision-making.

Methods

We conducted a comprehensive literature search using PubMed and the China National Knowledge Infrastructure (CNKI), with a specific focus on the genetic mechanisms and infant phenotypes of hereditary hypophosphatemia. This review primarily encompasses English-language literature published between 2015 and 2025; however, where appropriate, earlier published literature and Chinese-language literature have also been included.

Key Content and Findings

The genetic background of infantile hypophosphatemia can be summarized from two aspects: (I) increased secretion of fibroblast growth factor 23 (FGF23) caused by genetic factors; (II) etiologies not mediated by FGF23, such as pathogenic variants associated with genes encoding channel proteins, as well as genes encoding enzymes or receptors in the 1,25-dihydroxyvitamin D3 [1,25(OH)₂D₃] metabolic pathway. These factors lead to a reduction in intestinal phosphate absorption and bone resorption, as well as an increase in renal phosphate excretion, ultimately resulting in a decrease in serum phosphate levels.

Conclusions

In cases of infants with hypophosphatemia of unknown etiology, the possibility of genetic factors should be taken into consideration. We have enumerated more than ten genetic disorders associated with infantile hypophosphatemia. These disorders involve pathogenic variants in over a dozen genes and affect multiple target organs, primarily including the kidneys, intestines, and bones. These diseases can be classified according to whether they are mediated by FGF23. We believe that this review would offer valuable insights into the clinical diagnosis and treatment of infantile hypophosphatemia related to genetic etiologies.

Introduction

Background

Phosphorus is one of the most crucial elements in the human body. Approximately 85% of the phosphorus in the organism combines with calcium to form hydroxyapatite, which is deposited in the bones. The remaining phosphorus is distributed in the intracellular and extracellular fluids and participates in a variety of physiological processes (1). Firstly, phosphate groups are involved in the production of adenosine triphosphate (ATP) to store energy for cellular activities (2,3). Intracellular phosphate groups also participate in the synthesis of nucleotides and phospholipids, as well as the transmission of various cellular signals (2). In addition, they are also involved in the expression of the osteopontin gene, the apoptosis of chondrocytes, and the differentiation of vascular smooth muscle. While the phosphates outside the cells maintain a certain concentration in the serum (1). Hypophosphatemia is one of the commonly encountered electrolyte disorders in clinical practice. The incidence of hypophosphatemia among hospitalized patients is approximately 5% (3). The incidence of hypophosphatemia in neonates in the neonatal intensive care unit is about 30% (4). Infants’ growth and development require more phosphate consumption, which often leads to phosphate deficiency, making infants more prone to hypophosphatemia. Infantile hypophosphatemia refers to a condition where the extracellular phosphate concentration is below 1.6 millimoles per liter before 6 months of age, and below 1.48 millimoles per liter between 6 months and 1 year of age (5).

The primary organs involved in regulating serum phosphate levels are the bones, intestines, kidneys, and parathyroid glands. The hormones involved include 1,25-dihydroxyvitamin D₃, also named 1,25(OH)₂D₃, parathyroid hormone (PTH) and phosphatonins, such as fibroblast growth factor 23 (FGF23), phosphate-regulating neutral endopeptidase (PHEX), dentin matrix acidic phosphoprotein 1 (DMP1). These organs and hormones maintain phosphate homeostasis by preserving a dynamic equilibrium among intestinal phosphate absorption, renal phosphate loss, and skeletal phosphate resorption. 1,25(OH)₂D₃ can promote intestinal absorption of phosphate, renal reabsorption of phosphate, and osteoclast-mediated bone resorption, thereby increasing the serum phosphate level. FGF23 is an important phosphatonins in the human body, which is primarily synthesized and secreted by osteocytes, osteoblasts, and odontoblasts (2). FGF23 can inhibit the activity of 1-α-hydroxylase in the kidneys by down-regulating the expression of the CYP27B1 gene, and enhance the activity of 24-hydroxylase in the kidneys by up-regulating the expression of the CYP24A1 gene, thereby reducing the synthesis and increase the degradation of 1,25(OH)₂D₃ (2,6). Sodium-dependent phosphate cotransporter 2a (NPT2a) and sodium-dependent phosphate cotransporter 2c (NPT2c) are expressed on the brush edge of proximal tubular cells. FGF23 acts in concert with PTH to induce the internalization of NPT2a and NPT2c, thereby reducing the density of distribution of NPT2a and NPT2c along the brush border of proximal tubular epithelial cells, and subsequently decreasing the tubular reabsorption of phosphate (TRP). Therefore, when the serum level of FGF23 rises, the intestinal absorption of phosphate and the osteoclastic resorption of bone are attenuated, while the renal excretion of phosphate is increased, ultimately leading to a decrease in the serum phosphate level (7). PTH can enhance the activity of 1-α-hydroxylase and inhibit the activity of 24-hydroxylase, thereby promoting the synthesis of 1,25(OH)₂D₃. However, the net effect of PTH on serum phosphate is to reduce the serum phosphate level (2). Other phosphatonins, including PHEX, DMP1, mainly regulate the serum phosphate level by influencing the serum FGF23 level. Serum phosphate can regulate the production of 1,25(OH)₂D₃, PTH, and FGF23 through multiple endocrine negative feedback loops (1,7).

The primary approach for regulating serum phosphate concentration is to adjust renal tubular phosphate transport (2). Evidence of renal phosphate loss can be evaluated by calculating the transport maximum of phosphate adjusted for glomerular filtration rate (TmP/GFR) or the TRP. Both calculation methods require the simultaneous measurement of phosphate and creatinine levels in both urine and serum. To calculate TmP/GFR, fasting serum phosphate and creatinine need to be collected, and a second morning urine sample is required to measure phosphate and creatinine level. The formula for calculating TmP/GFR in children is as follows: serum phosphate − [(urine phosphate × serum creatinine)/urine creatinine]. The normal range of TmP/GFR in children is generally similar in value to the normal range of serum phosphate at each age. However, TRP can be calculated from randomly collected data and is more convenient for infants (1). The formula for calculating the percentage of TRP is as follows: 1 − [(urine phosphate × serum creatinine)/(serum phosphate × urine creatinine)] ×100 (3). However, vitamin D deficiency must be corrected before using TmP/GFR or TRP for causal diagnosis, as secondary hyperparathyroidism caused by vitamin D deficiency can affect the results of TRP and TmP/GFR. Additionally, patients must have discontinued all phosphate supplementation. Hypophosphatemia can be classified into two categories: high TmP/GFR or the percentage of TRP greater than 85–95%, and low TmP/GFR or the percentage of TRP less than 85–95%. High TmP/GFR or the percentage of TRP greater than 85–95% indicates that the kidneys retain phosphate, while low TmP/GFR or the percentage of TRP less than 85–95% indicates renal phosphate loss (2).

Generally, hypophosphatemia in infancy can be classified into two categories: one is caused by acquired factors, and the other is caused by genetic factors. Hypophosphatemia in infancy can also be divided into acute and chronic types according to its onset (8). Acquired factors can lead to either acute or chronic hypophosphatemia, while genetic factors typically result in chronic hypophosphatemia (2).

Infantile acute hypophosphatemia results from the redistribution of phosphate, specifically its transfer from the extracellular fluid to the intracellular space, rather than from systemic phosphate depletion (1). This condition is commonly associated with respiratory or metabolic alkalosis, refeeding after starvation, insulin infusion, or hyperinsulinemia (8). Although mild acute hypophosphatemia is typically transient, severe acute hypophosphatemia can lead to a series of life-threatening symptoms, such as respiratory failure, heart failure, hemolysis, seizures, encephalopathy, and coma (1,2).

Chronic hypophosphatemia in infants is commonly associated with systemic phosphate depletion. Its acquired etiologies include insufficient phosphate reserves due to prematurity, and nutritional deficiencies of phosphate resulting from inadequate intake or absorption disorders, which typically manifest as high TmP/GFR or TRP higher than 85–95%. In contrast, reduced renal phosphate reabsorption caused by immature renal tubules or acquired Fanconi syndrome due to direct damage to renal tubules by drugs presents as low TmP/GFR or TRP less than 85–95%. Infantile hypophosphatemia caused by genetic factors presents as low TmP/GFR or TRP less than 85–95% and can be distinguished based on whether it is mediated by FGF23. Children with chronic hypophosphatemia may gradually exhibit a series of rickets-like skeletal manifestations due to impaired bone mineralization (3). Chronic hypophosphatemia can also affect the development of muscles, joints, and teeth (8). Therefore, if not addressed promptly, it will significantly impact the growth, development, mobility and quality of life of infants, causing lifelong damage to the affected children. It has been reported that the prevalence of hereditary hypophosphatemia is 2.2 to 4.8 in 100,000 children (9). With advanced gene sequencing technologies and improved understanding of genetic diseases, more and more genetic hypophosphatemic disorders have been discovered.

Objective

We have described over ten genetic disorders associated with infantile hypophosphatemia. These disorders involve pathogenic variants in more than a dozen genes and affect multiple target organs, primarily including the kidneys, intestines, and bones. Therefore, this article elaborates on the characteristics of infantile hypophosphatemia from a genetic perspective, aiming to provide some valuable insights for clinical diagnosis and treatment. We present this article in accordance with the Narrative Review reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-aw-699/rc).

Methods

Search strategy

The search strategy was designed to identify relevant literature on hereditary hypophosphatemia, with a particular attention to its genetic mechanisms and phenotypic manifestations in infancy. The focus is on articles written in English and published between 2015 and 2025; however, earlier publications or those written in Chinese were also included when necessary. Table 1 summarizes our search strategy.

Table 1. The search strategy summary.

Items	Specification
Date of search	Initial search was conducted on August 10th, 2025. A secondary search was conducted on September 16th, 2025. A third search was conducted on January 4th, 2026
Databases searched	PubMed and China National Knowledge Infrastructure
Search terms used	Genetic, congenital, hypophosphatemia, infant, rickets, fibroblast growth factor 23, FGF23
Timeframe	Focused on articles 2015–2025
Inclusion and exclusion criteria	Included clinical trials, animal experiment, clinical practice guideline, reviews, case reports, and National Health Standards of the People’s Republic of China; excluded articles not available in English or Chinese
Selection process	X.Z. and L.H. jointly selected the papers for the literature review. X.Z. conducted the analysis of the selected papers, while L.H. provided supervision throughout the process

FGF23, fibroblast growth factor 23.

Databases and keywords

The primary database utilized for the search was PubMed and China National Knowledge Infrastructure (CNKI). Published material was found using combinations of the keywords: genetic, congenital, hypophosphatemia, infant, rickets, FGF23.

General clinical features of infantile hereditary hypophosphatemia

The clinical manifestations of diseases associated with infantile hereditary hypophosphatemia are diverse, yet there are commonalities among different diseases. Rickets is caused by impaired bone matrix formation or incomplete osteoid mineralization, which leads to excessive cartilage growth and hinders the formation of new trabecular bone and cortical bone. The typical manifestations of rickets in infancy include cranial bone softening, frontal bossing, dolichocephaly, widened wrists or ankles, scoliosis, short stature, and delayed motor development. During the growth process of pediatric patients, it is possible that the degree of growth restriction in the lower limbs is significantly higher than that in the trunk or upper limbs (1,2).

Classification of infantile hereditary hypophosphatemia

Infantile hereditary hypophosphatemia can be classified according to whether it is mediated by FGF23. FGF23-mediated hereditary hypophosphatemia that can occur in infancy includes autosomal dominant hypophosphatemic rickets (ADHR), generalized arterial calcification of infancy (GACI), McCune-Albright syndrome (MAS), osteoglophonic dysplasia (OGD), X-linked hypophosphatemic rickets (XLH), autosomal recessive hypophosphatemic rickets type 1 (ARHR1), and autosomal recessive hypophosphatemic rickets type 3 (ARHR3). Non-FGF23-mediated diseases of hypophosphatemia that can occur in infancy include hereditary hypophosphatemic rickets with hypercalciuria (HHRH), infantile hypercalcemia type 2 (HCINF2), dent disease 1 (DENT1), vitamin D-dependent rickets type 1A (VDDR1A), vitamin D-dependent rickets type 1B (VDDR1B), vitamin D-dependent rickets type 2 (VDDR2), and vitamin D-dependent rickets type 3 (VDDR3).

Hypophosphatemia mediated by FGF23 shares common biochemical characteristics, including decreased serum phosphate, increased urinary phosphate excretion, normal serum calcium and urinary calcium, normal 25-hydroxyvitamin D₃, also named 25 (OH)-D₃, decreased or normal 1,25(OH)₂-D₃, elevated alkaline phosphatase (ALP) and normal or elevated PTH. In non-FGF23-mediated hypophosphatemia, 1,25(OH)-2D₃ may be elevated, leading to increased serum calcium or urinary calcium (1,2). Table 2 summarizes the genetic and clinical features of genetic diseases associated with infantile hypophosphatemia. Table 3 summarizes the characteristics of laboratory test results for genetic diseases associated with infantile hypophosphatemia. Figure 1 summarizes the relevant genes and pathogenic mechanisms of hereditary infantile hypophosphatemia.

Table 2. The genetic and clinical characteristics of infantile hypophosphatemia-related genetic diseases.

Disease	Gene	Protein	Inheritance	Incidence	Clinical feature							Specific treatment	Prognosis
					Growth retardation	Rickets	Facial dysmorphism	Nephrocalcinosis	Arterial calcifications	Skin lesions	Alopecia
XLH	PHEX	PHEX	XLD	1/20,000	√	√						Burosumab	Short stature, lower limb malformation, gait abnormalities, periodontal abscesses, false fracture, enthesopathy, osteoarthritis, sensorineural deafness
ADHR	FGF23	FGF23	AD	NA	√	√						Iron supplementation	Short stature, muscle weakness, limited mobility, osteomalacia, fractures
GACI	ENPP1	ENPP1	AR	1/200,000	√				√	Skin calcium deposits			Hypertension, myocardial or cerebral infarction, heart failure, short stature, deafness, death
MAS	GNAS	GNAS		1/1,000,000–1/100,000	√	Sometimes	Sometimes			Cafe au-lait macules		Adrenalectomy, metyrapone, ketoconazole, trilostane	Impaired neurodevelopment, adrenal cortical insufficiency, fractures, bone deformity, short stature
OGD	FGFR1	FGFR1	AD	NA	√	√	√						Delayed tooth eruption, cystic change in metaphysis of long bone, asymmetrical dwarf
ARHR1	DMP1	DMP1	AR	NA	√	√							Short stature, long bone deformation, osteosclerosis of the skull, enthesopathy, dental abscesses, enlarged pulp chambers
ARHR3	FAM20C	FAM20C	AR	NA	√	√	√						Long-bone sclerosis, cerebral ectopic calcification, abnormal tooth development, facial or extremal deformities
HHRH	SLC34A3	NPT2c	AR	NA	√	√		√				Avoiding calcium and vitamin D	Short stature, long bone deformity, nephrolithiasis
HCINF2	SLC34A1	NPT2a	AR	NA	√			√				Limiting calcium and vitamin D	Short stature, nephrolithiasis, osteoporosis
Dent disease 1	CLCN5	CLCN5	XLH	NA	√	√		√				Thiazide diuretics, kidney transplantation	Osteomalacia, renal failure
VDDR1A	CYP27B1	1-α-hydroxylase	AR	NA	√	√						Do not require phosphate	Short stature, long bone deformity
VDDR1B	CYP2R1	25-hydroxylase	AR	NA	√	√						Do not require phosphate	Short stature, long bone deformity
VDDR2	VDR	VDR	AR	NA	√	√					√	Superphysiological doses of calcium and active vitamin D, do not require phosphate	Alopecia, short stature, long bone deformity
VDDR3	CYP3A4	CYP3A4	AD	NA	√	√						Superphysiological doses of active vitamin D, do not require phosphate	Short stature, long bone deformity

ADHR, autosomal dominant hypophosphatemic rickets; ARHR1, autosomal recessive hypophosphatemic rickets type 1; ARHR3, autosomal recessive hypophosphatemic rickets type 3; CLCN5, chloride channel 5; CYP27B1, 1-α hydroxylase/cytochrome P450 27B1; CYP2R1, 25-hydroxylase/cytochrome P450 2R1; CYP3A4, Cytochrome P450 3A4; DMP1, dentin matrix acidic phosphoprotein 1; ENPP1, ectonucleotide pyrophosphatase/phosphodiesterase 1; FAM20C, family with sequence similarity 20 member C; FGF23, fibroblast growth factor 23; FGFR1, fibroblast growth factor receptor 1; GACI, generalized arterial calcification of infancy; GNAS, α subunit of the stimulatory guanine nucleotide-binding protein; HCINF2, infantile hypercalcemia-2; HHRH, hereditary hypophosphatemic rickets with hypercalciuria; MAS, McCune-Albright syndrome; NA, not available; NPT2a, sodium-dependent phosphate cotransporter 2a; NPT2c, sodium-dependent phosphate cotransporter 2c; OGD, osteoglophonic dysplasia; PHEX, phosphate regulating neutral endopeptidase on chromosome X; SLC34A1, solute carrier family 34, member 1; SLC34A3, solute carrier family 34, member 3; VDR, vitamin D receptor; VDDR1A, vitamin D-dependent rickets type 1A; VDDR1B, vitamin D-dependent rickets type 1B; VDDR2, vitamin D-dependent rickets type 2; VDDR3, vitamin D-dependent rickets type 3; XLH, X-linked hypophosphatemic rickets.

Table 3. The characteristics of the laboratory test results of infantile hypophosphatemia-related genetic diseases.

Diseases	Laboratory
	Phosphate	TmP/GFR	Calcium	Urine calcium excretion	25-hydroxy-vitamin D	1,25-dihydroxy-vitamin D	Alkaline phosphatase	Intact FGF23	PTH	Urine amino acids/protein, glucose, and/or electrolytes
ADHR	Low	Low	Normal	Normal	Normal	Low to normal	High	High	Normal to high	–
GACI	Low	Low	Normal	Normal	Normal	Low to normal	High	High	Normal to high	–
MAS	Sometimes low	Sometimes low	Normal	Normal	Normal	Low to normal	High	High	Normal	–
OGD	Low	Low	Normal	Normal	Normal	Low to normal	High	High	Normal	–
XLH	Low	Low	Normal	Normal	Normal	Low to normal	High	High	Normal to high	–
ARHR1	Low	Low	Normal	Normal	Normal	Low to normal	High	High	Normal to high	–
ARHR3	Low	Low	Normal	Normal	Normal	Low to normal	High	High	Normal	–
HHRH	Low	Low	Normal	High	Normal	Normal to high	High	Low	Normal to high	–
HCINF2	Low	Low	High	High	Normal	Normal to high	High	Low	Normal to high	–
Dent disease 1	Low	Low	Normal	High	Normal	Normal to high	High	Low	Normal to high	All high
VDDR1A	Low	Low	Low	Low	Normal	Low	High	Unclear	High	High urine amino acids
VDDR1B	Low	Low	Low	Low	Low	Low to normal	High	Unclear	High	–
VDDR2	Low	Low	Low	Low	Normal	High	High	Unclear	High	–
VDDR3	Low	Low	Low	Low	Low	Low	High	Unclear	High	–

ADHR, autosomal dominant hypophosphatemic rickets; ARHR1, autosomal recessive hypophosphatemic rickets type 1; ARHR3, autosomal recessive hypophosphatemic rickets type 3; FGF23, fibroblast growth factor 23; GACI, generalized arterial calcification of infancy; HCINF2, infantile hypercalcemia-2; HHRH, hereditary hypophosphatemic rickets with hypercalciuria; MAS, McCune-Albright syndrome; OGD, osteoglophonic dysplasia; PTH, parathyroid hormone; TmP/GFR, the transport maximum of phosphate adjusted for glomerular filtration rate; VDDR1A, vitamin D-dependent rickets type 1A; VDDR1B, vitamin D-dependent rickets type 1B; VDDR2, vitamin D-dependent rickets type 2; VDDR3, vitamin D-dependent rickets type 3; XLH, X-linked hypophosphatemic rickets.

Figure 1.

Genes and pathogenic mechanisms of hereditary infantile hypophosphatemia. Factors leading to increased synthesis of FGF23 in bones include: (I) pathogenic variants in the PHEX gene and FGF23 gene render FGF23 insensitive to cleavage; (II) inactivating variants in the ENPP1 gene result in decreased serum ENPP1 levels; (III) somatic gain-of-function variants in the GNAS gene; (IV) inactivating variants in the DMP1 gene lead to reduced serum DMP1 levels. Factors related to vitamin D that cause decreased intestinal phosphate absorption are: (I) inactivating variants in the VDR gene lead to 1,25(OH)₂D₃ resistance; (II) inactivating mutations in the CYP27B1 gene reduce the activity of 1-α-hydroxylase, and inactivating mutations in the CYP2R1 gene decrease the activity of 25-hydroxylase, thereby leading to reduced synthesis of 1,25(OH)₂D₃; (III) gain-of-function variants in the CYP3A4 gene accelerate the inactivation of 1,25(OH)₂D₃. Factors causing reduced renal reabsorption of phosphate include: (I) inactivating variants in the SLC34A1 gene leading to the decrease of NPT2a distribution in the proximal renal tubules; (II) inactivating variants in the SLC34A3 gene result in the decrease of NPT2c distribution in the proximal renal tubules; (III) inactivating variants in the CLCN5 gene cause the dysfunction of CLCN5 distributed in proximal convoluted renal tubules; (IV) missense variants in the FGFR1 gene lead to continuous FGFR1 activation, thereby promoting the production of FGF23 in the kidneys. “↑”, increase; “↓”, decrease. CYP27B1, 1-α-hydroxylase/cytochrome P450 27B1; CYP2R1, 25-hydroxylase/cytochrome P450 2R1; CYP3A4, 24-hydroxylase/cytochrome P450 3A4; CLCN5, chloride voltage-gated channel 5; DMP1, dentin matrix acidic phosphoprotein 1; ENPP1, ectonucleotide pyrophosphatase/phosphodiesterase 1; FGF23, fibroblast growth factor 23; FGFR1, fibroblast growth factor receptor 1; GNAS, α subunit of the stimulatory guanine nucleotide-binding protein; PHEX, phosphate regulating neutral endo-peptidase on chromosome X; SLC34A1, solute carrier family 34, member 1; SLC34A3, solute carrier family 34, member 3; VDR, vitamin D receptor; 1,25(OH)₂D₃, 1,25-dihydroxyvitamin D₃.

Infantile hereditary hypophosphatemia mediated by FGF23

Variants in the gene encoding phosphate regulating neutral endo-peptidase on chromosome X (PHEX)

XLH (MIM#307800) is the most prevalent genetic hypophosphatemia disorder. Its estimated annual incidence ranges from 3.9 to 5.0 cases per 100,000 individuals, and the estimated prevalence is 1.3 to 4.8 cases per 100,000 individuals (6,10). XLH is caused by inactivating variants in the gene encoding PHEX gene. The PHEX gene is expressed in osteocytes and odontoblasts, similar to the FGF23 gene (10). Previous studies have indicated that the preprotein convertase complex 7B2-PC2 mediates the degradation of FGF23. The absence of PHEX protein prevents the cleavage of the precursor PC2, thereby reducing the activity of 7B2-PC2 and impeding the degradation of FGF23 (11). Experiments conducted on PHEX knockout mouse models have demonstrated that the inactivating variants in the PHEX gene leads to an increase in the level of intact FGF23 (active FGF23) in the serum, which in turn causes hypophosphatemia (12).

The typical clinical symptoms of XLH can manifest in infancy, including rickets, short stature, and craniosynostosis (6,10). Affected newborns do not exhibit any specific symptoms of X-linked hypophosphatemia because they were developed in an environment of normal phosphate levels, even those born from affected mothers (10). The increase in osteopontin caused by PHEX gene mutations can not only lead to impaired bone mineralization but also result in the formation of periodontal abscesses, which are commonly observed in children over 3 years old (6). Pseudofractures are a common clinical manifestation of XLH in adults but are uncommon in children. Compared with adult patients, clinical manifestations that are relatively rare in child patients also include enthesopathy, osteoarthritis, and sensorineural deafness (2,10). The general biochemical characteristics of infants with XLH have been described previously. However, during the first 3 to 6 months after birth, infants with X-linked hypophosphatemia may exhibit fluctuating phosphate concentrations, and hypophosphatemia may occur only intermittently (10).

The foundational treatment for XLH encompass the supplementation of phosphate, active vitamin D and its analogues (calcitriol or alfa calcitriol). The possible side effects of phosphate supplementation include diarrhea and secondary hyperparathyroidism, while those of active vitamin D supplementation include nephrocalcinosis and hypercalcemia. Therefore, the dose needs to be adjusted according to body size, growth rate and bone mineralization rate (6). Orthopedic surgery is only employed for patients whose deformities cannot be corrected through conventional treatment. Burosumab is a fully human monoclonal antibody targeting FGF23, which has been approved by the United States Food and Drug Administration (FDA) for the treatment of XLH patients aged 6 months and above (13). Burosumab neutralizes the effect of FGF23 by binding to it, thereby increasing the renal reabsorption of phosphate and promoting the production of 1,25(OH)₂D₃, which in turn elevates the serum phosphate level (10,13). Studies have demonstrated that Burosumab is more effective than conventional treatments in improving the rickets and bowing in children with XLH (6).

Variants in the gene encoding FGF23

The gene encoding FGF23 was discovered during research aimed at identifying the genetic etiology of ADHR (MIM#193100). Normally, overexpressed FGF23 is cleaved by proteases, remaining inactive amino-terminal and carboxy-terminal fragments. The missense mutation of FGF23 gene causes the replacement of either of the two arginine residues (R) within subtilisin-like proprotein convertase (SPC) cleavage site 176RHTR179 (RXXR motif) of the FGF23: R176Q, R179W or R179Q, rendering the expressed FGF23 insensitive to protease cleavage. Since the FGF23 expressed in children with ADHR cannot be completely cleaved, the level of FGF23, which is the active form of FGF23, increases in the serum, leading to a decrease in serum phosphate levels (14,15).

The uniqueness of ADHR in hereditary hypophosphatemia lies in the fact that the acquired factor of iron deficiency can interact with genetic factors to lead to the phenotype of ADHR (16,17). When the body is iron-deficient, hypoxia inducible factor-1 (HIF-1ɑ) accumulates within cells, resulting in an increase in the expression of the FGF23 gene. Iron deficiency can cause anemia, leading to tissue hypoxia. Hypoxia has been proven to be a stimulator of FGF23. Under normal iron content conditions in the body, hypoxia can independently promote the expression of the FGF23 gene. Therefore, disorders of iron and oxygen metabolism in infancy can lead to hypophosphatemia by promoting the production of FGF23 (18).

ADHR can manifest in childhood or present with a delayed onset in adulthood. Existing experimental evidence has demonstrated that neonatal iron deficiency can lead to abnormal phosphate metabolism by increasing FGF23 levels in both normal mice and ADHR mice (18). Currently, ADHR cases with onset before the age of 1 have been identified, presenting clinically as rickets (15). This indicates that ADHR in children can have an early onset, which warrants the attention of pediatricians. ADHR and XLH are clinically indistinguishable and can only be differentiated through the genetic pattern, specifically by confirming the presence of male-to-male genetic transmission. In terms of treatment, in addition to phosphate and calcitriol supplementation, oral iron can supplements can synergistically improve bone mineralization by reducing serum FGF23 levels (17,19). Once the patient’s iron level is optimized, the supplementation of calcitriol and phosphate can be discontinued. Therefore, burosumab is not recommended for the treatment of ADHR (17). The content of iron plays a crucial role in the diagnosis, treatment, monitoring, and prognosis of ADHR. Research has demonstrated that low-dose iron supplements and calcitriol may prevent the recurrence of the disease (15).

Variants in the gene encoding ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1)

ENPP1 catalyzes the hydrolysis of ATP/Guanosine triphosphate into adenosine monophosphate/guanosine monophosphate, thereby generating pyrophosphate (PPi). PPi can inhibit the deposition of hydroxyapatite and is a potent inhibitor of bone mineralization and vascular calcification (20). However, inactivating variants in the ENPP1 gene not only lead to a decrease in serum ENPP1 levels but also cause an increase in serum FGF23 levels, ultimately resulting in hypophosphatemia (21).

Inactivating variants in the ENPP1 gene can lead to GACI (MIM#208000), which is characterized by ectopic mineralization, particularly in the internal elastic lamina of medium- and large-sized arteries (21-23). The incidence of GACI is approximately 1 in 200,000 (21). Prenatally, infants with GACI can present with fetal distress, excessive amniotic fluid and pericardial effusion, even premature delivery or stillbirth (22). After birth, the main manifestations of infants with GACI are various cardiovascular symptoms caused by calcification and stenosis of the large and middle arteries, such as hypertension, myocardial infarction, heart failure, and cerebral infarction (21,24). The probability of death within 6 months after birth is up to 55% (21). Extravascular calcification, such as periarticular calcification, may also occur (21). Infants with GACI may have decreased serum phosphate levels and increased urinary phosphate levels (23). Currently, the common treatment for hypophosphatemia in infants with GACI is the supplementation of phosphate and active vitamin D, but it is unclear whether this treatment will exacerbate arterial calcification (21,23). ENPP1 variants can also lead to autosomal recessive hypophosphatemic rickets type 2 (ARHR2), manifested as rachitic bone deformities, periarticular calcification, and deafness, which often occur in early childhood or adulthood (22,23). There are some children who present with both GACI and ARHR2 phenotypes (23).

Variants in the gene encoding the α subunit of the stimulatory guanine nucleotide-binding protein (GNAS)

G protein receptors are widely distributed in various kinds of tissues throughout the body. The somatic gain-of-function variants in the gene encoding the GNAS can lead to hyperfunction of multiple endocrine glands and lesions in multiple tissues, namely MAS (MIM#174800) (25,26). MAS is a rare clinical syndrome with an incidence rate of 1/1,000,000–1/100,000 (25). It presents with diverse clinical manifestations, including fibrous dysplasia (FD) of bone, cafe-au-lait skin macules, precocious puberty, and other endocrine disorders such as hyperthyroidism and hypersecretion of growth hormone (26,27).

FD of bone can appear independently or as part of MAS, accounting for approximately 7% of all benign bone tumors (25). FD typically emerges during early childhood (3–5 years old) and is rare in infants (26). It results from abnormal differentiation of bone progenitor cells and is classified into monostotic and polyostotic types (2). Lesions are commonly found in the proximal femur and the craniofacial bones, which can lead to skeletal deformities and pathological fractures. In infancy, FD typically presents as striated lesions on X-ray images. In patients with FD, serum FGF23 is secreted by osteocytes and osteoblasts in normal and FD-affected bone tissues. The mechanism underlying the elevated serum FGF23 levels remains unclear and cannot be solely explained by activating mutations in the GNAS gene. Hypophosphatemia may fluctuate over time and is more prevalent during periods of high phosphate demand, such as infancy. The clinical sequelae of FD accompanied by hypophosphatemia are relatively severe, including earlier and more frequent fractures, bone pain, suboptimal surgical outcomes, and a higher risk of deformity (26).

Cafe-au-lait skin macules are one of the characteristic clinical manifestations of MAS, typically occur at birth or shortly after birth (25). Adrenocorticotropic hormone-independent hypercortisolism is one of the rare yet serious clinical manifestation in MAS and can be the initial symptom in MAS patients with onset during the neonatal period (28). Patients are usually small for gestational age at birth, may present with a Cushingoid face, and can experience feeding difficulties, growth and development retardation, hypertension, or hyperglycemia. Cafe-au-lait skin macules and Adrenocorticotropic hormone-independent hypercortisolism facilitate the early identification of MAS patients.

In terms of treatment, currently, there are no drugs available to improve the bone quality of FD and reduce the occurrence of complications. Surgical operations are the primary approach for repairing fractures and bone deformities, supplemented by physical therapy and pain management. For patients with hypophosphatemia, even without bone pain symptoms, intervention measures should be taken as early as possible. The treatment method is oral administration of high-dose phosphate and high-dose calcitriol (25,27). Molecular targeted therapy, gene therapy, and cell therapy for FD are all under research (26). MAS lies in the whole life cycle. Regarding the hyperfunction state of endocrine glands caused by MAS, different age groups require different focuses. Long-term follow-up is required, and targeted treatment should be adopted (25).

Variants in the gene encoding fibroblast growth factor receptor 1 (FGFR1)

FGFR1 is a receptor that plays a crucial role in the osteogenesis of axial and craniofacial bones (29). Activating variants in the FGFR1 gene is the genetic cause of OGD (MIM#166250) (30). OGD is a rare autosomal dominant genetic disease. In infancy, it can manifest as premature closure of cranial suture, protruding eyes, low nose bridge, midface dysplasia, and even feeding difficulties and overall growth retardation. Subsequently, delayed tooth eruption, cystic changes in the metaphysis of long bone, and asymmetrical short stature may occur (29,30). Previous studies have suggested that the hypophosphatemia observed in OGD patients may be caused by the increased production of FGF23 within OGD lesions (30). The treatment for hypophosphatemia in OGD patients is the supplement of phosphate and active vitamin D supplementation (30). However, surgical intervention may be required for persistent bone deformities in some patients (29).

Variants in the gene encoding DMP1 and the family with sequence similarity 20 member C (FAM20C)

Similar to FGF23, DMP1 is also expressed in osteoblasts and odontoblasts and plays a crucial role in bone matrix mineralization (31). Inactivating variants in the DMP1 gene can lead to elevated serum FGF23 levels (32). The phosphorylation of DMP1 depends on Golgi-associated secretory pathway kinase, also known as FAM20C. Inactivating variants in the FAM20C gene result in impaired DMP1 phosphorylation, indirectly leading to increased serum FGF23 levels (33).

Inactivating variants in DMP1 can lead to ARHR1 (MIM#241520). ARHR1 and XLH are clinically indistinguishable in infancy and can therefore only be differentiated based on their distinct genetic patterns (34). Inactivating variants in the FAM20C gene can lead to ARHR3 (MIM#259775). Clinically, it is difficult to distinguish ARHR3 patients from those with XLH during infancy. However, as ARHR3 children grow older, they may also develop long-bone sclerosis and cerebral ectopic calcification. In the case of FAM20C gene mutations, the dental phenotype appears to be more severe, manifesting as defects in the formation and mineralization of dentin, cementum, and enamel, or amelogenesis hypoplasia (33). Currently, the treatment for ARHR1 and ARHR3 involves the supplementation of phosphate and calcitriol (33,34). There have also been attempts to use burosumab in adult ARHR1 patients (35).

Infantile hereditary hypophosphatemia not mediated by FGF23: pathogenic variants in genes encoding channel proteins

Variants in the gene encoding NPT2c and NPT2a

The gene solute carrier family 34, member 3 (SLC34A3) encodes the renal NPT2c. Inactivating mutations in SLC34A3 gene lead to a reduction in the expression and distribution of NPT2c in the proximal renal tubules (36). The gene solute carrier family 34, member 1 (SLC34A1) encodes the renal NPT2a. After inactivation mutations in the SLC34A1 gene, the mutant NPT2a proteins completely lose the original functions because the incorrect localization within the cells prevents them from being transported to the cell membrane (37). All the above-mentioned variations result in a decrease in the renal reabsorption of urinary phosphate, leading to hypophosphatemia (37,38).

Inactivating variants in SLC34A3 gene can lead to HHRH (MIM#241530). HHRH is a rare autosomal recessive genetic disorder. In addition to hypophosphatemia in infancy, patients with HHRH may also have hypercalciuria (36,38). Different from FGF23-mediated hypophosphatemia, in HHRH patients, the compensatory increase in the blood level of 1,25(OH)₂D₃ leads to increased intestinal calcium absorption, resulting in increased urinary calcium, while the serum calcium level is usually normal. Therefore, patients with HHRH should be treated with phosphate alone without the use of active vitamin D and calcium. Otherwise, it will exacerbate hypercalcinuria and may even lead to an increase in nephrocalcinosis and kidney stones (7,38).

Inactivating mutation in SLC34A1 gene can cause an autosomal recessive genetic disorder, namely HCINF2 (MIM#616963) (37,39). Different from infants with HHRH, in addition to hypophosphatemia caused by renal phosphate loss, infants with HCINF2 can also experience severe hypercalcemia due to the compensatory increase in the blood level of 1,25(OH)₂D₃, as well as polyuria, vomiting, and dehydration. Renal ultrasound may indicate the presence of nephrocalcinosis. In terms of treatment, infants with HHRH need to limit the intake of calcium and vitamin D while supplementing phosphate (39). Inactivating mutations in SLC34A1 gene can also lead to Fanconi renotubular syndrome-2 (FRTS2, MIM#613388) in children, as well as hypophosphatemic nephrolithiasis/osteoporosis-1 (NPHLOP1, MIM#612286) in adults (7,39).

Variants in the gene encoding electrogenic chloride/proton exchanger-5

The chloride channel 5 (CLCN5) gene is located on the X chromosome and encodes a voltage-gated chloride/proton exchanger, namely electrogenic chloride/proton exchanger-5 (3). The primary function of electrogenic chloride/proton exchanger-5 is to participate in the reabsorption of low-molecular-weight proteins and a series of electrolytes by renal proximal convoluted tubular cells. Inactivating variants in CLCN5 gene can lead to the dysfunction of electrogenic chloride/proton exchanger-5, resulting in low-molecular-weight proteinuria and the loss of a range of electrolytes (40).

Inactivating variants in CLCN5 gene can lead to DENT1 (MIM#300009). DENT1 is an X-linked recessive genetic disorder, which is one of the causes of hereditary Fanconi syndrome. The main clinical manifestations in infants with DENT1 include low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, and kidney stones. In addition, infants with DENT1 usually present with incomplete Fanconi syndrome, manifesting varying degrees of hypophosphatemia, hypokalemia, acidosis, hypouricemia, glucosuria, and aminoaciduria (40). These features are typically observed in males, while female carriers may exhibit a milder phenotype (41). The treatment focuses on alleviating hypercalciuria and preventing kidney stones, mainly through high fluid intake, a low-salt diet, and the administration of thiazide diuretics. However, caution must be exercised regarding hypovolemia and hypokalemia when initiating or adjusting thiazide medications. Treatment of rickets with vitamin D must be carried out with caution as it may exacerbate hypercalcemia. Kidney transplantation can fundamentally cure the disease without the risk of recurrence (40). The prognosis is favorable for most patients. Nevertheless, 30–80% of affected male patients progress to end-stage renal failure between the ages of 30 and 50 (40,41).

Infantile hereditary hypophosphatemia not mediated by FGF23: pathogenic variants related to vitamin D

Vitamin D₃ must undergo two hydroxylation processes to be converted into a form with hormonal activity. First, vitamin D₃ is hydroxylated by 25-hydroxylase in the liver to produce 25-hydroxyvitamin D₃, also namely 25(OH)D₃. Then, 25(OH)D₃ is transported to the kidneys, where it is hydroxylated by 1-α-hydroxylase to generate 1,25(OH)₂D₃ which has hormonal effects. Subsequently, 1,25(OH)₂D₃ is metabolized and inactivated through hydroxylation at the 24th position by 24-hydroxylase. 25-hydroxylase (cytochrome P450 2R1, CYP2R1), 1-α hydroxylase (cytochrome P450 27B1, CYP27B1) and 24-hydroxylase (cytochrome P450 24A1, CYP24A1) are all cytochrome P450 enzymes. 1,25(OH)₂D₃ can promote the intestinal absorption of phosphate, the renal reabsorption of phosphate, and the release of bone phosphate into the blood (42).

Variants in the gene encoding 1-α-hydroxylase in the kidneys

The CYP27B1 gene encodes renal 1-α-hydroxylase. Inactivating mutations in CYP27B1 gene prevent the hydroxylation of 25(OH)D₃ to 1,25(OH)₂D₃ (42). These variants can lead to VDDR1A (MIM#264700) (43).

VDDR1A is a rare autosomal recessive genetic disorder. As an early-onset hereditary rickets, affected children may exhibit growth and development delays in early infancy, and rickets symptoms typically manifest within 1 to 2 years after birth (44). The biochemical manifestations of infants with VDDR1A include low serum 1,25(OH)₂D₃ levels, hypocalcemia, secondary hyperparathyroidism, elevated ALP, hypophosphatemia, and hyperphosphaturia, while the levels of 25(OH)D₃ remains normal. Treatment involves the supplementation of active vitamin D and calcium, and usually does not require additional supplementation of phosphate (43,44).

Variants in the gene encoding 25-hydroxylase in the livers

The CYP2R1 gene encodes hepatic 25-hydroxylase. Inactivating variants in CYP2R1 result in the inability of vitamin D to be hydroxylated to 25(OH)D₃. These variants can lead to VDDR1B (MIM#600081) (42). Since the clinical phenotypes of VDDR1B are similar to those of VDDR1A, genetic testing is required for differentiation. Compared with children with VDDR1A, the differences in blood biochemistry are manifested as low serum 25(OH)D₃ levels, while the 1,25(OH)₂D₃ levels can be normal or decreased. The treatment also involves administering active vitamin D and calcium (45).

Variants in the gene encoding the vitamin D receptors

Inactivating mutations in the gene encoding the vitamin D receptor (VDR) can lead to impaired signal transduction of the vitamin D receptor, resulting in resistance of various organs to 1,25(OH)₂D₃ in (42). These mutations can lead to VDDR2 (MIM#277440), also known as hereditary vitamin D-resistant rickets (HVDRR) (46).

VDDR2 is a rare autosomal recessive genetic disorder. The distinct clinical manifestation of infants withVDDR2 compared to those with VDDR1A and VDDR1B is that alopecia can appear after birth, and the degree of alopecia is positively correlated with the severity of the disease (46). Similar to children with VDDR1A, children with VDDR2 have significantly elevated serum 1,25(OH)₂D₃ levels, while their serum 25(OH)D₃ levels are often normal (42). In terms of treatment, infants with VDDR2 initially requires supraphysiological doses of calcium and active vitamin D (46).

Variants in the gene encoding the cytochrome P450 3A4 enzyme

Cytochrome P450 3A4 enzyme (CYP3A4) is primarily located in the livers and small intestines and can metabolize many exogenous substances. Gain-of-function variants in CYP3A4 gene can lead to vitamin D deficiency by accelerating the inactivation of 25(OH)D₃ and 1,25(OH)₂D₃ (42). These variants can lead to VDDR3 (MIM#619073) (47).

VDDR3 is a rare autosomal dominant genetic disorder. Different from the aforementioned vitamin D-dependent rickets, the blood biochemical manifestations of infants with VDDR3 are low levels of 25(OH)D₃ and 1,25(OH)₂D₃. Therapeutically, supraphysiological doses of active vitamin D are also required (47).

Limitation

Although this review is comprehensive, it still shares the common limitations of such studies. Firstly, the selection of papers included in this review was based on the authors’ judgment and expertise, which introduces a certain degree of subjectivity. Although we endeavored to cover a wide range of relevant literature, the lack of a systematic search strategy may result in the omission of some relevant studies.

Conclusions

Infantile hypophosphatemia is one of the most common electrolyte disorders in clinical practice. Apart from various acquired causes such as premature birth, with the continuous development of genetic testing technology, an increasing number of infantile hereditary hypophosphatemia related diseases have been discovered. We have summarized the genetic background of infantile hypophosphatemia from two aspects: firstly, pathogenic variants leading to increased secretion of FGF23; secondly, factors not mediated by FGF23, such as pathogenic variants of genes encoding channel proteins and pathogenic variants of genes encoding enzymes or receptors in the metabolic pathway of 1,25(OH)₂D₃.

The primary target organs affected by infantile hereditary hypophosphatemia include the bones, kidneys and intestines. The skeletal manifestations associated with hereditary hypophosphatemia in infants encompass growth retardation, craniomalacia, forehead protruding, large fontanel, facial dysmorphism such as low nose bridge and midface dysplasia, dolichocephaly, widening of the wrists or ankles, curvature of the spine and lower limbs deformity. The renal phenotypes of infantile hereditary hypophosphatemia include hyperphosphaturia, decreased serum vitamin D levels, hypercalcemia, nephrocalcinosis, kidney stones, low-molecular-weight proteinuria, polyuria, and dehydration. The intestinal phenotype of infantile hereditary hypophosphatemia includes feeding difficulties, poor weight gain, and repeated vomiting. In addition, the phenotypes of infantile hereditary hypophosphatemia also include hypertension, myocardial infarction, heart failure, skin calcium deposits, cafe au-lait macules and alopecia.

In summary, it may indicate that the infant’s hypophosphatemia is hereditary hypophosphatemia when the following manifestations occur: clinical abnormal manifestations include growth retardation, feeding difficulties, poor weight gain, repeated vomiting, polyuria, dehydration; Abnormal physical signs include cranialmalacia, forehead bossing, enlarged fontanelles, cranial deformities, facial dysmorphism such as low nose bridge and midfacial dysplasia, hypertension, skin calcium deposits, Cushing’s face, milky coffee spots, and alopecia. Abnormal laboratory test results included hypophosphatemia, hyperphosphaturia, decreased TmP/GFR or the percentage of TRP less than 85–95%, hypercalcemia, hypercalciuria, decreased serum vitamin D levels, hyperparathyroidism, elevated serum ALP, low-molecular-weight proteinuria, increased cortisol, hyperthyroidism, and sex hormone abnormalities. Imaging examinations may reveal rickets, FD, nephrocalcinosis or kidney stones.

Due to the current insufficient general understanding of infantile hereditary hypophosphatemia, pediatricians may not be able to diagnose potential cases of these disorders. Nevertheless, these diseases can cause severe damage to the child’s development and quality of life. Based on this review, when infantile hypophosphatemia is associated by the aforementioned symptoms and abnormal examination results, pediatricians should carefully search for potential genetic causes. Accurate genetic diagnosis can facilitate the formulation of personalized treatment plans, thereby improve the patients’ quality of life and prognosis. Overall, this article outlines the genetic background of infantile hypophosphatemia, providing valuable information for clinical diagnosis and treatment.

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