ORIGINAL ARTICLE

FGF23 analysis of a Chinese family with autosomal dominanthypophosphatemic rickets

Yue Sun • Ou Wang • Weibo Xia • Yan Jiang •

Mei Li • Xiaoping Xing • Yingying Hu •

Huaicheng Liu • Xunwu Meng • Xueying Zhou

Received: 22 January 2011 / Accepted: 16 May 2011 / Published online: 28 June 2011

� The Japanese Society for Bone and Mineral Research and Springer 2011

Abstract Autosomal dominant hypophosphatemic rickets

(ADHR; MIM 193100) is a hereditary disorder character-

ized by isolated renal phosphate wasting, hypophosphate-

mia, and inappropriately normal 1,25-dihydroxyvitamin D3

levels. Recent studies have shown that the fibroblast

growth factor 23 (FGF23) gene is responsible for this

disease. FGF23 protein is a phosphaturic factor that is

elevated in several diseases associated with hypophospha-

temia and rickets but varies with disease status in ADHR.

In the present study we observed a Chinese family of Han

ethnic origin diagnosed with ADHR. The proband is a

30-year-old woman with no history of rickets but with

multiple tooth abscesses as a young adult. She presented

with progressive painful swelling of the left ankle after a

blunt trauma at 26 years of age. She developed back pain,

generalized weakness, and fatigue, and she could barely

walk at age 27. She was found to have severe hypophos-

phatemia, low ratio of phosphorus tubule maximum (TmP)

to glomerular filtration rate (GFR) (TmP/GFR), and ele-

vated alkaline phosphatase at age 28. Her brother, 26 years

old, presented with fatigue at 24 years of age and is nor-

mophosphatemic. The parents of this family had no history

of rickets or hypophosphatemia. Direct sequence analysis

of genomic DNA demonstrated a single heterozygous

c.527G[A (p.R176Q) mutation in the FGF23 gene in three

family members, including the proband, her brother, and

their mother. Intact FGF23 assay of seven time points

during the oral phosphate loading test showed no signifi-

cant relationship between intact FGF23 and serum phos-

phorus levels of the subject with ADHR and a control. It is

probably the first report of a Chinese family with ADHR.

Keywords Autosomal dominant hypophosphatemic

rickets � Chinese � FGF23 � Mutation � Phosphatonins

Introduction

Autosomal dominant hypophosphatemic rickets (ADHR;

MIM 193100) is a hereditary disorder characterized by

isolated renal phosphate wasting, hypophosphatemia, and

inappropriately normal 1,25-dihydroxyvitamin D levels.

Patients with ADHR show incomplete penetrance of bone

pain, rickets, osteomalacia, lower extremity deformities,

short stature, and tooth absences. The age at onset is var-

iable, and rare cases show spontaneous resolution of the

phosphate-wasting defect [1, 2]. According to previous

studies, delayed onset of clinically evident disease has only

been observed in women [3], and different forms of clinical

presentation were observed in one family with ADHR [4].

In 2000, the ADHR Consortium used positional cloning

to identify the gene responsible for the disease, and

detected three different missense mutations in the FGF23

gene (R176Q, R179Q, and R179W) in four unrelated

families. These four pedigrees are of British, German, and

American origin [5]. The mutations locate at a protease

cleavage site (RXXR), leading to impaired proteolytic

Y. Sun and O. Wang contributed equally to this work.

Y. Sun � O. Wang � W. Xia (&) � Y. Jiang � M. Li � X. Xing �Y. Hu � H. Liu � X. Meng � X. Zhou

Department of Endocrinology, Key Laboratory

of Endocrinology, Ministry of Health,

Peking Union Medical College Hospital,

Chinese Academy of Medical Sciences, Shuaifuyuan No. 1,

Wangfujing Dongcheng District, Beijing 100730, China

e-mail: xiaweibo@medmail.com.cn

Y. Sun

Department of Endocrinology, Beijing Shijitan Hospital,

Capital Medical University, Beijing, China

123

J Bone Miner Metab (2012) 30:78–84

DOI 10.1007/s00774-011-0285-5

cleavage and thereby enhancing the biological activity of

circulating FGF23 [6, 7]. The FGF23 protein is a novel

secreted protein that consists of 251 amino acids directly or

indirectly involved in the pathogenesis of many disorders

associated with hypophosphatemia such as tumor-induced

osteomalacia (TIO), X-linked hypophosphatemic rickets

(XLH), autosomal recessive hypophosphatemic rickets

(ARHR), and McCune–Albright syndrome [5, 8, 9]. Serum

FGF23 concentrations are frequently elevated in subjects

with TIO and XLH [10, 11]. However, the FGF23 con-

centrations are not universally elevated in subjects with

ADHR, suggesting that the variable phenotype in ADHR

may result from the FGF23 fluctuations [3].

In this study, we observed a core family of Chinese ethnic

origin with ADHR. Penetrance of the disease was notably

different among three affected family members. Direct

sequence analysis of genomic DNA demonstrated the pres-

ence of a single heterozygous c.527G[A (p.R176Q) muta-

tion in the FGF23 gene in three of the family members. We

measured the intact FGF23 levels in four family members as

well as eight normal controls. We also sought to define

whether the fluctuation of serum phosphorus could influence

the FGF23 levels in subjects with ADHR.

Materials and methods

Subjects

The study has been approved by the Department of Sci-

entific Research of Peking Union Medical College Hospi-

tal. All participants were given informed consent before

study participation.

In the present study we observed a Chinese family of the

Han ethnic group consisting of four family members. All

family members were evaluated both clinically and bio-

chemically. The pedigree of this family is shown in Fig. 1a.

The proband was a 30-year-old woman who was diagnosed

as afflicted with hypophosphatemic osteomalacia in our

clinic on the basis of clinical and laboratory investigations.

Her brother, 4 years younger, did not have the presentation

of bone deformities and his serum phosphorus concentra-

tion was in the normal range. The parents of this family

were phenotypically normal.

Biochemical parameters

All laboratory data were collected before treatment with

phosphorus and 1,25-dihydroxyvitamin D3. Blood samples

of family members were collected after an overnight fast.

Second spot urine and 24-h urine were collected. Serum

calcium and phosphate levels were measured spectropho-

tometrically using routine assays available at the central

laboratory of our hospital. Renal tubular maximum of

phosphate/glomerular filtration rate was calculated from a

nomogram by Bijvoet et al. [12]. Serum intact parathyroid

hormone level was measured with a solid-phase two-site

chemiluminescent immunoassay [Diagnostic Products

Corporation (DPC)].

Measurement of serum FGF23

Serum FGF23 was measured by two-site enzyme-linked

immunosorbent assay (ELISA) using an FGF23 ELISA Kit

(Kainos, Japan). The kit was developed to detect only the

uncleaved peptide using the combination of two mono-

clonal antibodies that recognize the N-terminal and the

C-terminal portions of biologically active FGF23 with a

detection limit of 3 pg/ml [13, 14].

Oral phosphate loading tests

In the oral phosphate loading tests, 192 ml neutral phos-

phate (containing 1.5 g Pi) was orally administrated to the

Fig. 1 Pedigree of the Chinese family with autosomal dominant

hypophosphatemic rickets (ADHR) and fibroblast growth factor

(FGF)23 gene sequencing results. a In the pedigree of this Chinese

family, the arrow denotes the proband. Subjects with FGF23 mutation

are marked with solid black symbols. b DNA sequencing results of the

FGF23 gene demonstrate a heterozygous mutation (c.527G[A,

p.R176Q) in four affected family members (II-7, III-1, and III-2).

Red arrow denotes the mutation c.527G[A

J Bone Miner Metab (2012) 30:78–84 79

123

proband and eight healthy volunteers at 7 a.m. During the

tests, the subjects were not allowed to do heavy exercise or

eat. Their serum samples were taken at seven time points

including 0, 30, 60, 90, 120, 150, and 210 min after taking

phosphate. Serum phosphorus and intact FGF23 concen-

trations at those different time points were measured.

Molecular genetic analysis

Blood samples were taken from the four family members

(II-6, II-7, III-1, and III-2 (see Fig. 1a). Genomic DNA was

extracted from 0.2 ml whole blood using a commercial

DNA extraction kit (QIAamp DNA; Qiagen, Germany)

according to the manufacturer’s protocol. All 22 exons of

the PHEX gene and 3 exons of the FGF23 gene and their

corresponding intron–exon boundaries were amplified by

polymerase chain reaction (PCR) with primers according to

previous publications [15]. All these primers were located

approximately 20–100 bases away from the intron–exon

boundaries. PCR superMix (Transgen, China) was used in

all reactions. In each 5-ll reaction system, we added 25 ll

PCR superMix, 1 ll DNA, 22 ll ddH2O, and 1 ll primers.

The amplification products were purified and sequenced by

an automated sequencer (ABI 3700) according to the

manufacturer’s protocol.

Statistical analyses

Statistical analyses were performed by the SPSS 13.0

software package. Values are expressed as mean ± SD.

Differences between groups were calculated using Stu-

dent’s independent t test. Correlations were calculated

between the serum FGF23 and the phosphorus levels for

the subject with ADHR and the controls. A probability of

P \ 0.05 was considered to be statistically significant.

Results

Clinical features

The proband (III-1) is a woman who is 30 years old and

157 cm tall. She presented with progressive painful

swelling of the left ankle after a blunt trauma at 26 years of

age. The ankle pain became worse when she tried to

exercise. X-rays of her ankles and feet showed osteoporosis

and old fractures of the second metatarsal bone of both feet

(Fig. 2a). Magnetic resonance imaging (MRI) showed

localized swelling of the soft tissues of both feet and dis-

rupted signaling of the second metatarsal bone in the left

foot (data not shown). She was treated with a traditional

antipyretic analgesic but continued to experience extremity

breaks for about 2 months. The swelling was relieved but

the pain continued. About 4 months later, she developed

back pain, generalized weakness, and fatigue, and she

could barely walk. When she came to our clinic, she was

found to have severe hypophosphatemia with serum

phosphorus concentration of 1.61 mg/dl, parathyroid hor-

mone (PTH) of 119.5 pg/ml, low TmP/GFR (1.11 mg/dl),

and elevated alkaline phosphatase (ALP) (157 IU/l). Bone

mineral density (BMD) measured by dual-energy X-ray

absorptiometry densitometers of her femoral neck and

lumbar vertebrae (L2–L4) were notably low, with Z scores

of -2.17 and -2.8, respectively. Bone scan revealed

multiple areas (cervical rib, vertebrae, articular genua, and

ankle joints) of increased tracer uptake (Fig. 2b). The

ultrasound study of her parathyroid glands was normal. She

did not have a history of rickets but had multiple tooth

abscesses as a young adult. According to the clinical

manifestations and laboratory findings, we diagnosed

hypophosphatemic osteomalacia. After treatment with

high-dose neutral phosphate and calcitriol, the pain was

relieved, the biochemical parameters normalized, and she

could walk with crutches.

The brother of the proband (III-2) is 26 years old,

172 cm tall. He presented with occasional fatigue at

24 years of age. He had no history of rickets, fractures, or

tooth absences. His serum phosphorus concentration, total

calcium, and 24-h urinary phosphorus were in the normal

range (see Table 1). BMD of his femoral neck and lumbar

vertebrae (L2–L4) showed Z scores of 0.7 and 0.4,

respectively.

The parents of the proband, both 55 years old, had no

history of rickets, fractures, or presence of hypophospha-

temia. The mother reported two teeth abscesses when she

was around 50. According to the mother’s statement, none

of her brothers and sisters, or her parents, showed hypo-

phosphatemia and rickets/osteomalacia. All the laboratory

findings of the four family members are shown in Table 1.

Changes of serum FGF23 and phosphorus during oral

phosphate loading tests

At the time of the proband’s initial presentation, FGF23

had not been measured. After 2 years of neutral phosphate

treatment, with normophosphatemia and relief of symptoms,

her serum intact FGF23 concentration was 33.9 pg/ml.

Serum intact FGF23 concentrations were not significantly

increased in the brother and the parents of this family as well

(see Table 1).The normal range in healthy controls is

29.2 ± 6.5 pg/ml (n = 8) in our laboratory.

During the oral phosphate loading tests, the serum

phosphorus concentration of the proband was below the

normal range at 0 min; it increased from 30 to 210 min

after loading. The highest serum phosphorus concentra-

tions occurred in the 60 min after taking neutral phosphate,

80 J Bone Miner Metab (2012) 30:78–84

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both in the proband and in the control (3.78 and 6.04 mg/dl,

respectively). The tendency of phosphorous fluctuation

was similar between the subject with ADHR and controls.

The serum intact FGF23 concentrations of the proband

were higher than controls at all seven time points in the

tests. Conversely to the fluctuation of phosphorus, when the

Fig. 2 Imaging data of proband with ADHR. a X-ray of ankles and feet shows osteoporosis and two fractures of the second metatarsal bone of

both feet (red arrows). b Bone scan shows multiple areas (cervical rib, vertebrae, articular genua, and ankle joints) of increased tracer uptake

Table 1 Laboratory findings for the Chinese family with autosomal dominant hypophosphatemic rickets (ADHR)

II-6 II-7 III-1 III-2

Serum phosphorus 4.19 4.40 1.61 3.26

Serum total calcium 9.32 9.76 9.08 9.04

Serum ALP 77 75 157 48

Serum Cr 106 79 77 90

i-PTH NA NA 119 NA

25(OH)D NA NA 10.8 NA

1,25(OH)2D NA NA 18.9 NA

TmP/GFR 4.93 5.01 1.11 3.08

Serum intact FGF23 27.3 31.2 33.9a 32.3

Values of the biochemical parameters shown in this table were obtained before treatment

Reference values: serum phosphate, 2.3–4.3 mg/dl in adults; serum total Ca, 8.5–10.8 mg/dl; serum alkaline phosphatase (ALP), 27–107 IU/l;

serum creatinine (Cr), 53–132 lmol/l; serum 25(OH) D, 8–50 ng/ml; serum 1,25(OH)2D, 18–45 pg/ml; serum i-PTH, 7–53 pg/ml. Serum intact

fibroblast growth factor (FGF)23, 29.2 ± 6.5 pg/ml (n = 8) in our laboratory

NA, not available; i-PTH, intact parathyroid hormone; TmP/GFR, ratio of phosphorus tubule maximum (TmP) to glomerular filtration rate (GFR)a Serum intact FGF23 was measured after 2 years of neutral phosphate and active vitamin D treatment when the serum phosphorus concentration

was 2.67 mg/dl

J Bone Miner Metab (2012) 30:78–84 81

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serum phosphorus came to the highest point (60 min), the

FGF23 was decreased. On the other hand, the intact FGF23

concentration of the controls fluctuated within a narrow

range (98% ± 4.0% of baseline). The results for serum

phosphorus and intact FGF23 are shown in Fig. 3. There

was no significant correlation between intact FGF23 and

serum phosphorus levels of the subject with ADHR

(r = 0.007, P = 0.989) and the controls (r = -0.182,

P = 0.696).

Molecular genetic analysis

We analyzed the PHEX gene of the proband and found no

mutation in all its 22 exons and the exon–intron bound-

aries. Sequence analysis of the FGF23 gene demonstrated a

heterozygous missense mutation in exon 3 (c.527G[A,

p.R176Q) in three of the family members including the

proband (III-1), her brother (III-2), and their mother (II-7)

(see Fig. 1b). This mutation was a recurrent mutation in

ADHR patients. The family was catalogued as having

autosomal dominant hypophosphatemic rickets/osteomala-

cia, and it probably was the seventh family with ADHR

that has been reported [4, 5, 16].

Discussion

Autosomal dominant hypophosphatemic rickets, a rare

form of hypophosphatemic rickets, was observed more

than 40 years ago [17, 18]. There are other inherited forms

of hypophosphatemic rickets, including an X-linked dom-

inant form (XLH; MIM 307800) caused by mutation in the

PHEX gene, an autosomal recessive form (ARHR; MIM

241520) caused by mutation in the DMP1 gene, and a form

of hypophosphatemic rickets with hypercalciuria (HHRH;

MIM 241530) caused by mutation in the SLC34A3 gene

[19]. In 2000, the disease-causing gene of ADHR was

identified as FGF23, which encodes a secreted protein

involved in phosphate homeostasis [5]. Up to the present,

six unrelated families of British, German, American,

Spanish, and Tunisian origins with ADHR have been

reported [4, 5, 16]. The present study of a Chinese family

with ADHR is the first report of a family of Asian origin

affected with this disease.

The clinical presentation of ADHR is similar to XLH,

such as hypophosphatemia, decreased or inappropriately

normal serum levels of 1,25-dihydroxyvitamin D3, as well

as rickets and osteomalacia [1]. Adult patients of these two

conditions are difficult to differentiate clinically. In the

Chinese family we observed, the age of onset of the pro-

band was 26, and she presented with hypophosphatemia

and osteomalacia. Based on the clinical and laboratory

findings, we diagnosed her with hypophosphatemic osteo-

malacia. With regard to her family history, the brother of

the proband and the parents of this family were pheno-

typically normal. To give the patient an effective therapy,

mutation screening of the PHEX and FGF23 genes was

performed. Actually, the diagnosis of ADHR cannot be

confirmed without genetic analysis in this family. Thus,

although a patient with ADHR shows additional unique

features of incomplete penetrance, delayed onset, and

spontaneous resolution of the phosphate-wasting defect [1,

20], molecular genetic analysis should be considered.

The FGF23 gene, responsible for ADHR, is composed

of three exons, spanning 10 kb of genomic sequence [5]. It

encodes a 32-kDa secreted protein that has N-terminal

fibroblast growth factor (FGF) homology to other FGFs

and a unique 72-amino-acid C-terminal domain [21]. The

FGF23 protein is predominantly produced by osteocytes in

bone [22]. As a member of ‘‘phosphatonins,’’ the intact

FGF23 could inhibit sodium-dependent phosphate reab-

sorption and 1a-hydroxylase activity in the proximal tubule

of the kidney, leading to phosphaturia and suppression of

circulating 1,25(OH)2D3 levels [23]. In patients with TIO

and XLH, the serum intact FGF23 concentrations are fre-

quently elevated [10, 11, 24], indicating that the excess

FGF23 meditates renal phosphate wasting in these hypo-

phosphatemic diseases.

Fig. 3 Serum concentrations of phosphorus and intact FGF23 of the

proband with ADHR (blue diamonds) and normal controls (pinksquares) over time during oral phosphate loading. a Dashed hori-zontal line indicates the lower limit of serum phosphorus concentra-

tion (2.3 mg/dl) in the normal population. Phosphorus concentration

of the proband was 2.05 mg/dl at test baseline (time = 0 min). After

the proband took 192 ml neutral phosphate (Pi, 1.5 g), her serum

phosphorus concentration was subsequently normalized. The highest

serum phosphorus concentrations occurred in 60 min in both proband

and controls. b Dashed horizontal line indicates value of normal

control for FGF23 assays. Intact FGF23 concentrations in the proband

were higher than in the controls at all seven time points in the tests.

The concentration rose initially after treatment in the proband but

slightly decreased in the controls (time = 30 min)

82 J Bone Miner Metab (2012) 30:78–84

123

In this Chinese family, three of the family members

were found to carry a heterozygous p.R176Q mutation in

the FGF23 gene, which may lead to resistance of the

proteolytic processing that converts the intact FGF23 into

inactive fragments [6, 7] and increase in the level of serum

intact FGF23. In contrast to our expectation, serum con-

centrations of intact FGF23 of the three mutation carriers

were all in the normal range. The result of our investigation

is consistent with one study of FGF23 concentrations in 42

subjects from three kindreds with ADHR that showed that

only 9% of subjects with FGF23 gene mutations had ele-

vated plasma intact FGF23, and the level seemed to be

elevated only in the presence of active disease [3]. Another

study also mentioned that FGF23 was normal in adult

patients with idiopathic phosphate diabetes [25]. One of the

explanations is that FGF23 level was decreased in the

patients with vitamin D deficiency [24]. When the patients

were normophosphatemic and had normal serum levels of

1,25-dihydroxyvitamin D, as in our study, serum intact

FGF23 may not significantly increase. All these findings

indicate that in normophosphatemic or asymptomatic

patients with FGF23 mutations, remission of the phos-

phate-wasting defect may be partially the result of modu-

lating the intact FGF23 concentrations to normal.

To find a correlation between phosphorus and FGF23 in

patients with ADHR, we analyzed the fluctuations of serum

phosphorus and FGF23 concentrations in a short period

with phosphate loading. In a previous study, intact FGF23

was found to correlate negatively with serum phosphate in

ADHR patients with low phosphate, and the concentration

increased after treatment with phosphate and calcitriol [3].

According to our observation, there were no significant

correlations between intact FGF23 and serum phosphorus

levels of the subject with ADHR or the control during a

short period. One study of acute change of intact FGF23 in

male healthy volunteers showed that FGF23 did not change

consistently with phosphate concentrations in the phos-

phate infusion test [26]. Because of its small sample size,

our study may not have sufficient power to detect even

moderately large associations at the usual significance level

of P \ 0.05. Although lacking of large sample investiga-

tions, we presume that comparing with normal controls, the

stable modulation of FGF23 concentration may be impac-

ted in subjects with ADHR when serum phosphorus

changes. The mechanism is unclear. Some other phos-

phatonins such as matrix extracellular phosphoglycoprotein

(MEPE) and dentin matrix protein1 (DMP1) may be

involved.

Consequently, we present the first report of a family of

Chinese ethnic with ADHR. The diagnosis was confirmed

based on clinical and molecular genetic analysis. A single

heterozygous c.527G[A (p.R176Q) mutation in the

FGF23 gene was detected in three of the family members,

including the proband, her brother, and their mother.

Although the serum intact FGF23 concentrations of the

subjects with the FGF23 mutation were in the normal

range, the stable modulation of FGF23 concentration may

be impacted compared to the control, according to the oral

phosphate loading test results. More investigations should

be performed to elucidate the precise mechanism of the

involvement of FGF23 in the pathology of those phos-

phate-wasting diseases.

Acknowledgments Research funding was provided by the National

Natural Science Foundation of China (NSFC) under grant No.

81070687 and the Doctoral Fund of Ministry of Education of China

under grant No. 20040023055.

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