Introduction
Phosphate homeostasis and pathophysiology of hypophosphatemia
Phosphate is a crucial component of the body, with the majority of phosphate in
the human body present in the bone (85%), most of the rest (14%)
is present intracellularly, and only<1% is present in the
extracellular space [1]. Although it is
not as tightly regulated as serum calcium, it has many beneficial effects on the
body. Its chronic deficiency is associated with a significant diminish in bone
mineralization. Many factors that control calcium levels are also involved in
controlling serum phosphate. Although its abnormal serum level does not cause an
immediate effect on the body, its chronic deficiency is associated with a
significant diminish in bone mineralization [1]. Hypophosphatemia occurs when the serum phosphate level
is<2.5 mg/dl [2]
[3] (normal value in the
adult is 3–4.5 mg/dl) [4]. In infants and children, a higher phosphate level is necessary to
prevent rickets; the normal adult value could be insufficient [4]
[5], and the normal value in children is 4–7 mg/dl
[4].
Hypophosphatemia develops mainly via decreased reabsorption and increased loss of
phosphate through urine, which might be resulted from hyperparathyroidism [2] during chronic kidney disease or vitamin
D deficiency [6]. Additionally, the
urinary loss of phosphate could be caused by genetic disorders of renal
sodium/phosphate co-transporters. More rarely is due to the
gastrointestinal cause; malnutrition, inadequate phosphate intake, or tumor
[2].
The phosphate level is controlled by the 1,25-dihydroxyvitamin D, parathyroid
hormone, fibroblast growth factor-23 (FGF23), and phosphate regulating gene with
homologies to endopeptidase on X-chromosome (PHEX). The sodium/phosphate
co-transporter function to reabsorb phosphate from kidney tubules by phosphate
transport from the kidney’s proximal tubule to the blood, which is under
the control of PHEX and FGF23, a substrate of this endopeptidase. These
transporters are regulated by parathyroid hormone (PTH), 1,25 dihydroxyvitamin
D, and dietary phosphate [4]. Both PTH and
FGF23 affect the upregulation of these transporters [5]. Furthermore, FGF23 is released from
osteoblasts and osteocytes and inhibits PHEX and phosphate reabsorption. Thus,
any factor that raises FGF23 eventually leads to phosphate urea and
hypophosphatemia [7]. Hereditary
hypophosphatemia could be XLH [8],
autosomal dominant [9], or autosomal
recessive hypophosphatemic rickets (ARH) [10].
Epidemiology of X-linked hypophosphatemia
This rare condition is reported to have an incidence of 1 in 20 000 births.
Presently,>460 mutations related to XLH have been stated in the
literature [11].
Generally, this disease is genetic and transmitted from parents to offspring;
thus, it appears mostly during childhood. However, XLH with no family history of
this ailment is also described in adolescents/adults [12], and many sporadic cases – 10
out of 30 cases – were also found in a comparative study by Whyte et al.
[13]. XLH affects both females and
males; however, in some families, it has been detected that males may have more
severe sorts of disease than females [13].
There is no confirmed data in the literature to approve that XLH is related to
the region/area of living/staying.
Clinical presentation
The symptoms and signs of chronic hypophosphatemia could appear from early
childhood, by growth retardation, bone/joint pain, widening of the
common spaces, rachitic lesion, bowing of the leg, muscle weakness, and
difficulty in walking, delayed dentition/dental problems [14]
[15], vitamin D resistance rickets, and frequent
fractures/stress fractures. The main clinical feature of XLH in
childhood is rickets, most probably falsely diagnosed as nutritional or vitamin
D deficient rickets and treated accordingly [16], which could lead to lower limb deformities and short stature in
the future [17]
[18]. In addition, decreased bone
mineralization will affect the growth plate [19] and, at the same time, increase FGF23 receptor expression in the
bones, resulting in ossification in the skull [20].
The development of clinical features of this disease vary according to the
severity of the mutation; some cases will not have sign and symptoms till
adulthood and present with bone pain, muscle ache, stress fractures, dental
problems and, affecting their quality of life [15]
[21], others were even
without symptoms in the adulthood [22].
Cases associated with clinical features, early diagnosis, and treatments are
allied with improved consequences [23].
Clinical presentation in childhood
Most of the patients reported having short stature and bowing of legs (tibia,
fibula, or both), followed by turning of the femur and genu valgum [17]. Short length in XLH appears initially
in the course of the disease, and the –1.4 z-sore for height was
recorded in early age in a study on children with≤4 years [24], and a z-score range of –
(6.5–1) was recorded in children with wider age group≤18 years
[25]. The discrepancy in the bone
length of the legs and their defects lead to abnormality in the gait of these
patients; orthopedic surgery is often needed [17]
[19]
[26].
Dental problems were detected in a significant number of children. For example,
decreased bone mineralization and pulp enlargement due to hypophosphatemia will
lead to thinning of the enamel, with more risks of dental caries, fractures,
abscesses, and infection of the oral cavity [17]
[19]. In addition, a
craniofacial abnormality that might result in headache, vertigo, elevated
intracranial pressure, or rarely papilledema [27] could be among the manifestations of XLH during childhood [19]
[28].
Clinical presentation in adulthood
In adulthood, due to disease progression, the patients most probably presented
with bone pain, difficulty walking, and pseudo-fractures; these manifestations
are combined with short stature and other sequelae of the disease from childhood
rickets [17]
[29]. There is also a risk of development of
enthesopathy; studies showed a more significant percentage of enthesopathy after
adulthood, especially after the age of thirty; almost all of the patients have
this problem which results in joint stiffness and pain, in addition to
degenerative osteoarthritis and other common abnormality could develop [17]
[30]. Phosphate depletion in muscles with decreased muscle activity
and motion, could be responsible for the weaknesses that present in muscles of
XLH patients [31]
[32].
Diagnosis of X-linked hypophosphatemia
Early diagnosis/treatment initiation, satisfying management, and
consistent follow-up of patients with XLH regulate their long-term consequences
and upcoming quality of life (QoL), including improved general growth and
height, bone mass accrual, fewer bone deformations, and healthier dental growth
[33]. Thus, medical/family
history, auxology, musculoskeletal test, and proper investigation (radiology,
biochemistry, and genetic studies) benefit starting the correct XLH diagnosis
[12].
Diagnosis of XLH is made by low serum phosphate and phosphate urea [34], which are associated with slightly
lower serum 25-hydroxyvitamin D and probably normal serum calcium. In
comparison, other findings of XLH on diagnosis are somewhat elevated alkaline
phosphatase (ALP) and PTH. For genetic causes, family history and pedigree help
diagnose, while genetic study fully confirms the exact diagnosis.
Medical history
A thorough medical history, including family history, for starting the mode of
inheritance is considered an essential task in diagnosis. Suppose one of the
parents has XLH with clinical signs of XLH, such as short stature, misshapen
legs, frequent scars from orthopedic surgical operations, anomalies of the skull
shape with frontal bossing, and loss of permanent teeth due to persistent dental
sores and periodontal infection [12]. On
the other hand, the diagnosis in most cases was delayed when there was no family
history of the XLH, which is described in 30% of de novo PHEX mutations.
Some adults with XLH who have milder manifestation cannot visit health care or
follow up on their visit to reach the diagnosis, and sometimes the diagnosis of
these adult patients are difficult; their abnormality could be failed to relate
to childhood disease [35].
Physical screening
A detailed physical examination should be conducted, such as intensive auxology
(head circumference, standing height/length, sitting height, and body
weight) [12]. The typical and
characteristic appearance in familial XLH is rickets, which displays long bone
deformities, including limb bowing, late walking, waddling gait, and
bone/joint aches rising gradually once toddlers start
standing/walking [36].
Additionally, osteomalacia, degenerative joint disease, enthesopathy, and
repeated dental sore can be observed [37].
Also, 60% of XLH patients own dental infections of deciduous and
permanent teeth due to diminished mineralization of dentine/enamel that
permits bacteria to attack the pulp and results in tooth abscesses even when
there is no trauma/tooth decay [38].
Radiological screening
At an early age with XLH, a radiograph of a wrist/knee shows classical
radiological alterations of rickets-widening, cupping, and fraying of the
metaphysis. Generally, radiological screening shows deformities principally in
the lower limbs, metaphyseal widening, poor definition of bone contours,
rachitic rosary, and frontal bossing [11].
Malformations in flexion of the distal diaphysis, radii, ulnas, and tibias with
dorsal column worsening were also observed. Teeth radiograph of patients
presents dentin with various mineralization appearance, large pulp chambers,
with grey areas between anterior and posterior teeth [39].
Biochemical screening
Biochemical screening should be achieved as soon as possible after the seven days
of life, including serum phosphate (low), creatinine and alkaline phosphatase
(ALP, higher), urinary phosphate (wasting), and creatinine. In adult patients,
the ALP could be normal or elevated [17]
[40]. Additionally,
screening for parathyroid hormone (PTH) (normal or upper normal range), serum
calcium (normal), and urinary calcium excretion (normal) also should be done
[41]. Measurements of plasma levels of
both intact FGF23 and C-terminal FGF23 are also recommended when necessary to
exclude some other diseases. Serum phosphate shows different ranges according to
age; unfortunately, most laboratories do not show age-specific phosphate ranges,
one of the factors that could result in delayed diagnosis of the disease [40].
Gene mutation
This disease is profoundly associated with inheritance and genetic causes;
however, cases with no family history of XLH are also reported [12]. Therefore, to exclude other
differential diagnoses associated with identical biochemical and/or
clinical abnormalities, genetic testing could be necessary to aid diagnosis,
although a history of the same problem in one of the family member make
diagnosis more accessible, as stated in the review by Dahir et al. 2020 [17]. Approximately 90% of XLH
rickets are associated with PHEX gene mutations. The PHEX gene encodes a
metalloprotease, a member of the M13 family of zinc-dependent proteases of the
cell membrane type II, and is expressed in the bone, teeth, lung, ovary, testes,
and parathyroid gland [11]. XLH, due to
PHEX mutations, follows an X-linked dominant inheritance pattern. Thus, the
affected fathers transmit the disease to their daughters and none of their sons,
while affected mothers have a 50% risk having an affected
daughter/son.
Consequently, PHEX gene mutation assessment and exome sequencing are helpful and
gold parameters for diagnosing this syndrome [36]. This form of hypophosphatemic rickets is the most predominant
type (80%) of familial XLH. In contrast, the rarer types are autosomal
dominant, autosomal recessive, and hereditary hypophosphatemic rickets with
raised urinary calcium levels [15].
Management and treatment
Conventional therapy
XLH is a life-long illness; none of the medications among conventional
treatments can correct the original abnormality and cure the patient; the
medications are used to improve phosphate and 1,25-hydroxyvitamin D levels
and prevent further progression of skeletal and other clinical
abnormalities, and better life quality [42].
The conventional treatment of this condition is the active form of vitamin
D3; calcitriol or vitamin D analogues (alfacacidol) and phosphate
supplements to correct or improve the hypophosphatemia, bowing legs,
rickets, and rate of growth in children and improve hypophosphatemia,
decrease bone pain, bone deformity and decrease the risk of pseudo-fractures
and non-union [16]
[42] and periodontitis [43] in adults. Phosphate correction
should go in line with vitamin D correction; otherwise, there is the
possibility of developing hyperparathyroidism and renal complications [42]
[44]. Continuous phosphate supplementation is accompanied by
decreased patient compliance due to the requirement of frequent daily doses
of phosphate tablets because its intake is associated with a rapid rise and
rapid drop of phosphate in the serum. Another factor that makes the patient
not adhere to the treatment is its complication and side effects [44].
Conventional phosphate and active vitamin D3 therapies are associated with
improvement in bone deformity, rickets and osteomalacia, growth rate [42], and dental abscesses [44]. Still, the improvement in the
growth rate is insufficient; on the other hand, growth hormone therapy would
increase the growth rate but could be associated with further bone
complications and increased risk of deformities [45]. Early start of conventional
treatment as early as one year of age is correlated to better outcomes than
after one year of age [46]. However,
even in those with an early start of treatment, there is short stature
compared to normal children [47].
Little data exist on using these medications in adult patients, but
improvement of enthesopathy, osteomalacia, osteoarthritis, and prevention of
pseudo-fracture were reported [42].
Advanced therapy
The primary pathophysiology of this disease is an increase in FGF23, which
can recently be targeted by using human monoclonal antibodies to treat
hypophosphatemia and its associated complications. It was approved and used
in 2018 by the FDA for children and adults [42]. This treatment is superior to a mixture of phosphate and
alfacalcidol treatment. In addition, it can decrease the FGF23 that is
increased in these patients and will result in an improvement in phosphate
level and its associated complications [42].
According to the recommendations and guidelines of 2019 on the management of
XLH, the use of monoclonal antibodies is required in any patient with XLH
who did not benefit from conventional therapy radiologically; bone diseases
do not improve, and complications developed with the use of phosphate and
active vitamin D medications as conventional therapy, and for non-compliance
patient with these medications [44].
In addition, the use of monoclonal antibodies, such as burosumab, is
associated with improvement in the growth rate and decreases the risk of
development of reduced height. Furthermore, studies investigating the impact
of burosumab on pain, fracture healing and overall life quality show
promising results [48]. However,
despite its effectiveness, its treatment is safe in a double-blind study
with six months continuation period treatment in adulthood with XLH [49] and other studies in adults and
children. Still, long-term burosumab use needs to be studied, which is
required [48].
As hypophosphatemia is associated with bone, dental, and hearing problems,
several specialists must manage this condition. The team should include
pediatricians specialized in endocrine diseases (if diagnosed from
childhood), adult endocrinologists, orthopedics, rheumatologists and even
odonatologists, otologists, physical therapists, and psychologists [42]. A large number of patients
required operations to correct the abnormality in the legs or other bones,
especially in severe limb deformities; the corrective osteotomy is needed,
although these operations better to be done in adulthood because before
adulthood, it is associated with the risk of reoccurring of the same
abnormalities that are why better to be done only in a patient with severe
limitation of movement and misalignment, and after epiphyseal closure [50] and according to the
recommendation/guideline of 2019, these orthopedic surgeries
shouldn’t be started if the children on the treatment of less than a
year [44].
Dental problems that present from childhood continue to adulthood, and most
of the patients lose many teeth when reaching adulthood and could require a
denture at an early age [42]. The role
of psychologists is also essential, especially in some cases of depression
due to the effect of the disease burden and abnormal shape of the legs,
abnormal gait, and short stature on self-esteem and social interaction. Even
the loss of teeth and bad oral hygiene are among the factor that affects the
patient psychologically [42]. Thus,
the management should not compromise on medication only, but patient care
and follow-up are critical, with psychological support. Most of these
patients couldn’t socially interact with people and go out or get
jobs and continue to work as usual people due to the pain and disability
that they have, and due to short stature and other disease complication that
affect their psychological health [51]
[52]. Thus, an early
diagnosis from the beginning of the disease is crucial to decrease the
physical, social, economic, and psychological risk and other disease burdens
of XLH on the patient [42]
[51]
[52].
PTH (to avoid secondary hyperparathyroidism) and ALP (to ensure bone healing)
should be investigated during follow-up [16]. In addition, radiological monitoring for skeletal
deformity/osteopenia and ultrasound (US) to investigate urinary
stone formation are also necessary [53].
Therefore, this report aimed to present a case of hypophosphatemia, XLH, with
clinical features of the disease from childhood, without seeking medical
care for his condition with his mother and his two brothers, who have short
statures, bone pain and frequent fractures.
Case presentation
A 27-year old male with disproportionate short stature complained of
bilateral lower limb pain and difficulty walking around for a month. An
orthopedic physician referred him to the Endocrine Unit of the Internal
Medicine in early 2021. A thorough history was taken related to his
condition, sociodemographic status, family history, medical history (during
childhood and adulthood), surgical history, and drug/medication
history.
Baseline biochemical profiles of the studied patient are given in the
Supplementary Table.
His condition started with paresthesia in both lower limbs in the last six
months, progressing gradually with pain in both thighs and shins. The pain
was mild, and then the pain and paranesthesia became severe over time. After
one month, he started to have nodular swelling and pain in both thighs and
shins. The pain was more on the left lower limb affecting his daily
activity. Progressively over a month, he became disabled and could not move
around without help.
Ethical approval
All procedures in this study were performed following the ethical standards of the
national research committee and the 1964 Helsinki declaration and its later
amendments or comparable ethical standards. On the other hand, written informed
consent was taken from the patient to publish his data and images. The research was
approved by the scientific and ethical committee of the College of Medicine, the
University of X, meeting No. 4 on October 05, 2021.
Childhood and past medical histories
In the narration of the patient’s mother and brother, he was born
generally at full term. During his childhood, he was unlike his peers as his
walking was slower, and his height was shorter even after puberty. In addition,
he had a history of recurrent falls, and he could not do exercise; despite the
problems mentioned above, they did not seek medical help previously, only one
time because of the detection of bowing of his leg; they brought him to a
surgeon who recommended and asked for operation, but they could not agree to do
the process, because of the high cost and their financial situations, and did
not visit hospital or clinic for follow up visits later on. He did not assess
for rickets and did not receive active vitamin D3. His dentition was delayed to
2–3 years of age. He also complained of paresthesia, inability to walk
efficiently, and the development of muscle pain after a long walk that prevents
him from sleeping at night. He did not have known hematological problems, anemia
or treatment for these conditions.
He did not have a hearing problem; however, he had a history of otitis media at
age 21 years and received treatment and improved. Also, he had tooth and gum
problems, with toothache throughout his life, which made him extract several
teeth because of loosening his teeth due to gum inflammation, and he could not
eat hard food; his dentist stated that he could not do an implant because of his
weak gum. He did not have a history of cardiovascular, respiratory,
gastrointestinal, or genitourinary systems problems with no history of renal
stone or dysuria.
Family history and family member
He had two brothers and one sister; his father was healthy and died in an
accident without any health problems. On the other hand, his mother and brothers
(older than him) had short stature from childhood and skeletal abnormalities.
Still, they did not visit the hospital; only his brother visited the hospital
after acute pain in the left thigh with the inability to walk, which was
diagnosed with a stress fracture fixation of his fracture was made with a
surgical operation. Still, the cause of his stress fracture did not find as he
refused to be investigated and examined for his condition. At the same time, his
married sister had minor thalassemia; otherwise, she was healthy and had two
healthy children with average heights. His uncles and aunts were healthy; three
of his uncles died as elderly due to chronic diseases without apparent skeletal
abnormalities. His cousins were healthy without short stature, but none of his
uncles, aunts, or cousins’ height exceeded 160 cm.
Socioeconomic state
The patient was from a low-income family that lived in a rural area. His father
died a long time ago. Nevertheless, he studied and passed school successfully
and graduated from the College of Agriculture, in 2016. After his graduation and
because of unemployment, he started working and standing for about nine hours
each day, selling popcorn and French fries on carts outdoors with his brother
till his situation became worse and he developed severe pain in his lower limbs
and disability.
Medication and drug history
He did not use a known drug, and there was no history of chronic medication use;
he was not a drug user, smoker, or alcohol drinker.
General clinical examination and workup for the patient
The patient’s vital signs were typical, with a pulse rate of 81
beats/minute (bpm) and arterial blood pressure of
105/70 mm Hg. Anthropometric parameters were measured, including
height (145 cm), weight (52 kg), and BMI
(24.73 kg/m2). On systemic examination, there was
no pallor, jaundice, cyanosis, or leg oedema. Cardiovascular and pulmonary tests
were routine. Musculoskeletal investigation revealed; short stature with a short
forearm and bowing of the legs. He had bilateral thigh nodular mass and
tenderness in which the nodular swelling of the thigh was more on the left side.
His grade of POWER was G4. Hematological and biochemical analyses for serum and
urine were done.
Orthopedic examination
He had a waddling gate, deformity with signs of stress fracture and union of both
upper and lower extremities on radiograph and physical examination with coronal
deformity. There was no hypotonia with normal reflexes and range of motion of
all joints in the upper and lower extremities. Bilateral bowing of both femurs
with a normal range of motion in both hips and knee joints was also observed.
The left knee was valgus about 20° while the right knee was varus about
12° ([Fig. 1]). Also, he had a
windswept deformity, which supports the metabolic cause of dwarfism. There was
no pain/tenderness in the chest with no signs of fracture or united
fractures. Examination of the oral cavity, showing poor oral hygiene, dental
carries, missing of several teeth, gingivitis, and de-papillated tongue ([Fig. 2])
Fig. 1 Plain radiograph (scanogram) of pelvis, both hips, both
knees, and both ankle joints in AP standing. The AP and lateral view of
the right leg are shown at the bottom right of the figure. This plain
radiograph shows generalized diffuse osteopenia, with thinning of the
cortex and loss of bone marrow trabeculation, looser zone and stress
fracture in both mid shaft femur and tibia, Bilateral femora vara, genu
varum of the right knee, and genu valgus of the left knee.
Radiological assessment
After history and clinical examinations, a radiological investigation and DEXA
scan were performed. The patient was sent for the AP and lateral view plain
radiographs of both upper and lower limbs, wrist/hands, PA view chest radiograph
and lateral view plain radiograph of the lumbosacral region. There was
generalized diffuse osteopenia of the skeleton, with thinning of the cortex and
loss of bone marrow trabeculation, varus deformity of right femur about
25°, looser zone of both mid-shaft femur and mid-shaft tibia, which
indicates stress fracture of compression part of a long bone ([Fig. 1]). Chest radiograph was normal,
with no signs of stress fracture or the looser zone in the ribs, with regular
thoracic cage and lumbosacral spines, and average wrist and hand plain
radiograph, no more open area in the upper limbs, but there was bowing of both
humerus with signs of previous fractures in both humerus and right radius ([Fig. 3]). DEXA scan showed severe
osteoporosis with an average trabecular bone score (TBS). Bone mineral density
(BMD) at the left femur neck was 0.636 g/cm2 with a
markedly low T-score (–3.0) and a Z-core of –2.5.
Fig. 2 Picture of the oral cavity with X-ray imaging showing poor
oral hygiene, dental caries, missing several teeth, gingivitis, and
de-papillated tongue.
Biochemical investigations
At baseline, his renal/liver function tests, serum electrolytes, and lipid
profile were average except for low high-density lipoprotein (HDL). Complete
blood count (CBC) showed raised red blood cells (RBC) count with low hemoglobin
(Hb) and packed cell volume (PCV). Blood film showed microcytic hypochromic
anemia with completely normal iron status. Hb electrophoresis was recommended to
exclude thalassemia minor for his hematological abnormality. Tissue
transglutaminase antibodies IgG and IgA were also normal.
On the other hand, his assessment of bone status showed decreased serum phosphate
with low 25-vitamin D3 and slightly elevated PTH and considerably raised ALP
with normal serum calcium ([Table 1]).
Renal tubular acidosis was excluded, with an average serum bicarbonate level and
no glucosuria. The 24-hour urine collection was investigated but gave false
results due to inadequate urine collection because of his pain, deformity, and
inability to collect urine appropriately. Urine phosphate, calcium, and
creatinine were assessed from a single sample of urine (R: Medscape) and showed
elevated urine phosphate levels. At the same time, with the assessment of serum
phosphate and creatinine, the fractional excretion rate of phosphate
(FEPPi) and renal tubular reabsorption of phosphate (TRP) was
calculated. FPE was 0.803, while TRP was lowered to 19.7%.
Thus, the computed maximum tubular reabsorption of phosphate per glomerular
filtration rate (MTP/GFR) was 1.69.
Table 1 Bone profile assessment at baseline and follow-up
visits of the studied patient.
|
Parameter
|
Normal Range
|
Baseline
|
1st follow-up
|
2nd follow-up
|
3rd follow-up
|
last follow up
|
|
Total serum Ca+2 (mg/dl)
|
8.3–10.8
|
9.39
|
8.64
|
9.81
|
–
|
8.58
|
|
Free serum Ca+2 (mg/dl)
|
4.61–5.33
|
–
|
–
|
–
|
4.49
|
–
|
|
Serum phosphate (mg/dl)
|
2.7–4.5
|
1.0
|
2.07
|
1.6
|
1.4
|
2.1
|
|
PTH (pg/ml)
|
15–65
|
81
|
–
|
–
|
61.55
|
82.32
|
|
25-Hydroxyvitamin D (ng/ml)
|
30–100
|
13
|
–
|
29.1
|
12.82
|
22.13
|
|
ALP (IU/l)
|
46–126
|
193
|
–
|
–
|
205
|
278
|
Ca+2: Calcium; PTH: Parathyroid hormone; ALP: Alkaline
phosphatase.; Note: Total serum Ca+2 was corrected
for albumin.
Therefore, based on these investigations, a diagnosis of hypophosphatemia was
made, and the treatment was started with phosphate (1.0 g/day)
and alfacalcidol (1.0 μg/day). In addition, his whole
blood sample was sent for PHEX and FGF23 gene sequencing.
Follow-up
All follow-up examinations were recorded, and the improvement/any change
in his investigation or clinical condition was recorded. Two months later, he
visited the hospital to follow up, and his clinical status was greatly improved;
he walked without any walking aid, slightly limping, with no pain in the bone of
the lower limbs. The biochemical investigation for the bone status and CBC have
performed again; there was an improvement of his serum phosphate level toward
normal, with an increase in his PCV and Hb, while there was an increase in his
RBC farther from normal.
In the whole sequencing for PHEX and FGF23 genes, a pathogenic variant was
detected for the PHEX gene with X-linked dominant inheritance. At the same time,
no pathogenic variant was detected for the FGF23 gene. Genetic testing for his
mother and brothers were recommended, but they were living in a rural area and
had not agreed to visit the hospital at city center to conduct the test. Based
on these investigations, the diagnosis of XLH was confirmed. One month later,
the phosphate level was slightly decreased again. Thus, the phosphate dose was
increased to 2.5 g/day for better improvement.
On patient follow up another month later, although the patient was clinically
felt well but the phosphate level began to decrease again to
1.6 mg/dl, with normal serum calcium and increased
25-hydroxyvitamin D3 from 13 to 29.1 ng/ml. Thus, the patient
was recommended to continue on the prescribed medications. He addressed that he
took his medication regularly upon questioning, and he suggested to be
maintained on the same high phosphate dose (2.5 g/day) because
of his low serum phosphate level.
The patient could not attend his follow up visits to medical and endocrine
follow-up in next month as he underwent a surgical operation in preceding month,
to fix left femur shaft fractures with corrective osteotomy. Consequently, his
left femur was fixed with locked intramedullary nail which provide prophylactic
fixation for the stress fracture, also ([Fig.
4]).
Fig. 3 Plain radiograph of (a) chest (PA view) and
lumbosacral spine (lateral view) reveals normal Thoracic cage, no signs
of union or looser zone in the ribs, (b) Upper extremities shows
osteopenia and bowing of both humerus and signs of previous fracture in
both humerus, and right radius, with no looser zone.
On next follow up visit, the patient came to follow up, then plain radiograph AP
and lateral view of both thigh and legs were performed, and there were no signs
of the union at the fracture site that could be the result of the failure of
intramedullary nail to place correctly due to the deformity. On his plain
radiograph, signs of osteopenia and osteoporosis were still existed with
thinning of the cortex and loss of bone trabeculation. He complained of right
hip and knee pain due to leg length discrepancy, and next operation was
recommended. Examination of the gait revealed limping Trendelenburg type due to
leg length discrepancy, with a 2.0 cm discrepancy in the length of the
lower limbs upon standing. There was no hypotonia with normal reflex/range of
motion of all joints in the upper and lower extremities ([Fig. 4]).
Biochemical investigations showed a greater decrease in phosphate level; although
the patient denied that he decreased intake of the phosphate tab, and he did not
address any complain about receiving his treatment. While during his next visit
and upon further questioning and doubting a further decrease in his phosphate
level, he claimed that he got diarrhea when he received an increased dose of
phosphate. Thus, he did not take medicine daily rather, he received it
irregularly for the last seven months. Therefore, the dose of the phosphate tab
was decreased to 1.0 g/day, to reduce the side effects and
failure of phosphate reabsorption. Hence, the patient was advised to consult his
doctor for any complaint about his medications rather than receiving it
haphazardly. The result of Hb electrophoresis revealed beta thalassemia minor
(HbA2 of 5.6% while its normal range is 1.5–3.5%).
On last follow up, after a month from receiving the phosphate tab, typically with
a 1.0 g/day dose, his biochemical situation was better; the
phosphate began to elevate toward normal, with increasing 25-hydroxyvitamin D3
and even improvement in the CBC values toward normal with the following
improvements: baseline versus final value of 35.5 vs 41.1% for PCV, 11.7
vs 13.4 g/dl for Hb, with serum phosphate value of 1 vs
2.1 mg/dl ([Table 2]). A
week later, the next operation was performed.
Fig. 4 These images show post-operative examination and imaging,
in the top left image, the patient standing with 2 cm
discrepancy in the length of the lower limbs. Corrective osteotomy for
the left femur with locked intramedullary nails, which provided
prophylactic fixation for the stress fracture also. Plain radiographs
show non-union four months after the operation.
Table 2 Hematological, CBC, and iron status investigations
of the studied patient.
|
Parameter
|
Normal Range
|
Baseline
|
1st follow-up
|
3rd follow-up
|
last follow up
|
|
WBC
|
4.0–11×109/l
|
5.6×109
|
7.3×109
|
7.6×109
|
7.3×109
|
|
RBC
|
4.5–5.5×1012/l
|
5.7×1012
|
6.37×1012
|
6.18×1012
|
6.45×1012
|
|
PCV (%)
|
35–55
|
35.5
|
40.9
|
38.8
|
41.6
|
|
Hb (g/dl)
|
11.5–16.5
|
11.7
|
–
|
12.3
|
13.4
|
|
MCV (fl)
|
75–100
|
62.3
|
–
|
62.8
|
64.5
|
|
MCH (pg)
|
25–35
|
20.6
|
–
|
20
|
20.8
|
|
MCHC (g/dl)
|
31–38
|
33
|
–
|
31.8
|
32.2
|
|
RDW (%)
|
10–14
|
14.4
|
–
|
15.5
|
15.3
|
|
Platelet
|
150–450×109/l
|
319×109
|
335×109
|
336×109
|
309×109
|
|
Ferritin (ng/ml)
|
30–400
|
282.2
|
–
|
201.2
|
–
|
|
Transferrin (mg/dl)
|
200–360
|
–
|
–
|
251
|
–
|
|
Total Iron (μg/dl)
|
65–175
|
–
|
–
|
119
|
–
|
|
TIBC (μg/dl)
|
250–410
|
–
|
–
|
291
|
–
|
CBC: Complete blood count; WBC: White blood cell; RBC: Red blood cell;
PCV: Packed cell volume; MCV: Mean corpuscular volume; MCH: Mean
corpuscular hemoglobin; MCHC: Mean corpuscular hemoglobin concentration;
RDW: Red cell distribution width; TIBC: Total iron binding capacity.
Discussion
In this study, we comprehensively studied hereditary hypophosphatemia in a male
patient aged 27 years old using various clinical, laboratory, and imaging
assessments. However, his family members, including his mother and his brothers
supposed to have the same disease but did not agree to visit the hospital to confirm
their case using advanced molecular investigation and receive treatment to improve
their condition.
The PHEX gene is expressed in bone, teeth, and parathyroid glands that negatively
regulates FGF23 expression through an unknown mechanism. The FGF23 has a
phosphaturic effect to maintain circulating phosphate levels within a normal range.
Osteocytes and osteoblasts excrete it as the physiological response to
hyperphosphatemia. The same effect on the expression of the FGF-23 has elevated
25-hydroxyvitamin D levels in the blood and probably PTH [54]. Thus, FGF-23 is essential in regulating
the homeostasis of phosphorus and partially of calcium. Numerous hereditary and
acquired diseases occur due to increased or decreased activity of the FGF-23, such
as those caused by inactivating mutations in the PHEX gene [55]. Thus, in this study, we confirmed that the
patient’s hypophosphatemia occurred due to PHEX gene mutation and removal
inhibitory effect of the PHEX gene on FGF23 and thus increased loss of phosphate in
the urine. The same outcome was found in other case reports studies such as
Bacchetta and Salusky, 2012 [2],
Radlović et al., 2014 [54], and
Rafaelsen et al., 2015 [25].
We have realized that the patient’s bone and joint irregularities and
deformities that made him use a walking aid resulted from prolonged hypophosphatemia
that was not diagnosed during his childhood and not receiving a specific treatment
to correct his case to some degree or prevent further sequelae. Furthermore, since
it is known that the maintenance of the levels of intra and extracellular phosphate
inside a narrow band is essential for several biological processes, including energy
metabolism, skeletal development and bone integrity besides, phosphorus deficiency
can compromise chondrocyte maintenance, causing the block of bone formation,
resulting in delayed growth and rickets, therefore justifying the short stature and
other skeletal deformities in the reported patient [56].
The whole follow-up period for this patient was one year. Although some skeletal
abnormalities were already developed and could not be corrected, using phosphate
tablets in this patient improved his pain and physical activity significantly from
a
disabled patient to a patient that could walk on his own with a walking aid (stick)
only. Most clinical signs related to hypophosphatemia were significantly improved,
including painful bones and joints, especially on the lower extremities, inability
to walk correctly, and improvement of his serum biochemical parameters and
hematological tests, especially phosphate level, were found. The same findings were
seen in other case studies such as Maia et al. 2018 [57]; Sarat et al. 2016 [58]; and
Radlović et al., 2014 [54]. The
medications (phosphate and active vitamin D supplementations) also improved his PCV
and Hb. Better phosphate control was associated with better PCV and Hb level in this
patient, as revealed through 12 months of follow up. This improvement in PCV and Hb
could be explained by lowering of FGF23 toward normal level after phosphate
supplementation. To our knowledge, no previous studies linked the improvement of
PCV/Hb with phosphate level correction, phosphate, or active vitamin D
supplementation in familial hypophosphatemia, or in thalassemia patients, this
requires thorough study especially in thalassemia patients. Recent study in The
Netherlands, demonstrated an evidence of erythropoietin-FGF23 signaling pathway in
bone marrow progenitor cells and its relation to hereditary anemia [59]. Collectively, the medication improved his
laboratory results to approach normal levels and cleared profound clinical signs
that deteriorated his health condition for an extended period. Some of his skeletal
deformity was also corrected with an operation and corrective osteotomy for bowing
the femur. However, his osteopenia and osteoporosis could need longer periods of
phosphate use to be revealed, and the other bone deformities could require more than
one surgical operation.
