DEPARTMENT
Rickets: Not Just a Disease
Caused by Vitamin D
Deficiency
Lauren Head Zauche, BSN, RN
KEY WORDS
Case study, hypophosphatemia, rickets
CASE PRESENTATION
A 2-year, 10-month-old White girl presented to a pedi-
atric clinic with an abnormal wide gait and genu varum.
She had been an established patient at the clinic since
her 4-month well-child visit. Concerns regarding her
motor development were noted at her 6-month well-
child visit, when she presented with generalized muscle
hypotonia, was unable to roll supine to prone or prone
to supine, and was unable to sit unassisted. Addition-
ally, the patient had dropped to the 5th to 10th percen-
tile for weight at 6 months from the 25th percentile at
her 4-month visit. At her 6-month visit, the patient
was referred to a statewide program for infants and tod-
dlers with developmental delays for nutritional support
and physical therapy. After 1 month in this program, the
patients development significantly improved, and she
was able to roll over in each direction and was able to
sit unsupported at 12 months. Although she was mak-
Lauren Head Zauche, Doctoral Student and Pediatric Nurse
Practitioner Student, Emory University Nell Hodgson Woodruff
School of Nursing, Atlanta, GA.
Conflicts of interest: None to report.
Correspondence: Lauren Head Zauche, BSN, RN, Emory
University Nell Hodgson Woodruff School of Nursing, 1520 Clifton
Rd NE, Atlanta, GA 30329; e-mail: lmhead@emory.edu.
J Pediatr Health Care. (2016) -, ---.
0891-5245/$36.00
Copyright Q 2016 by the National Association of Pediatric
Nurse Practitioners. Published by Elsevier Inc. All rights
reserved.
http://dx.doi.org/10.1016/j.pedhc.2016.11.005
www.jpedhc.org
Case StudyPrimary Care
ing progress, she had not begun to crawl or pull to a
stand by 12 months, and both weight and length drop-
ped to the 5th percentile.
The patient was referred to a neurology specialist at
her 12-month visit to rule out a neurologic cause for
her symptoms. A complete neurologic examination,
including magnetic resonance imaging of the brain
and spine failed to support a neurologic cause. There
was a considerable gap in care between the ages of
12 months and 24 months. At the patients 24-month
visit, she was unable to walk, and her weight had
both fallen below the 5th percentile and her length
below the 10th percentile. Although the patient was
referred to an orthopedic specialist during her 24-
month well-child visit, the visit did not take place
because of the familys loss of medical insurance. The
patient was lost to follow-up between her 24-month
visit and her visit at 2 years 10 months.
Medical History
The patient was born via a spontaneous vaginal deliv-
ery at 37 gestational weeks with no prenatal or postnatal
complications. Her birth weight was 3.2 kg. The stan-
dard 48-hour hospitalization after birth was uneventful,
and her newborn screening result was normal.
Family Medical History
The family history was negative for any childhood dis-
eases, including genetic, endocrine, and metabolic ab-
normalities. However, the patients mother reported
that as a child, she was also delayed in meeting mile-
stones in the gross motor developmental domain, and
she had short stature, at a height of 4 feet 10 inches.
No other pertinent family history was noted.
Social History
The patient lived at home in a one-bedroom apartment
with her mother and two older siblings in a rural area.
The patient and her siblings had recently returned
-/- 2016 1
from a 2-month stay in foster care because of domestic
violence, for which her mother obtained a restraining
order against the father. At the time of the visit, the
mother had no support or help from any other relatives.
The patient attended daycare 3 days a week and stayed
at home with her mother the remaining time.
Review of Systems
According to the mother, the patient was not in any pain
while standing, walking, or moving her lower extrem-
ities, and she had not experienced muscle spasms or
tremors. The patient was fatigued often, sleeping 8 to
10 hours at night with a 2-hour nap during the day.
The patient ate a well-balanced diet, including fruits
and vegetables and sources of iron and calcium. All
other developmental domains except gross motor
were normal, and the remainder of the review of sys-
tems results were negative.
Physical Examination
The patient, who was 2 years and 10 months old,
weighed 10.0 kg (<3rd percentile), with a height of
81 cm (<3rd percentile) according to a standardized
CASE STUDY QUESTIONS
1. What is the etiology and pathophysiology of X-linked hypophosphatemic (XLH) rickets, and how does its pa-
thology differ from other forms of rickets?
2. What are differential diagnoses for XLH rickets, and what is the clinical presentation of XLH rickets?
3. How is XLH rickets diagnosed and treated?
4. What are challenges associated with caring for a patient with XLH rickets in a rural setting?
CASE STUDY ANSWERS
1. What is the etiology and pathophysiology of XLH
rickets, and how does its pathology differ from other
forms of rickets?
Rickets refers to a disease in children in which
growing bones fail to mineralize or ossify as a result
of a deficiency in calcium, phosphorus, or vitamin D
(Greenbaum, 2011). In normal bone metabolism,
bone is formed through the mineralization of calcium
and phosphate as hydroxyapatite crystals and is influ-
enced by vitamin D and the parathyroid hormone
(PTH; Penido & Alon, 2012). Rickets can be caused by
a variety of different factors that affect the levels of cal-
cium, phosphate, and vitamin D, including nutritional
causes, kidney disorders, and genetic abnormalities
(Greenbaum, 2011; Holm, 2008).
The most commonly recognized form of rickets is
referred to as nutritional rickets, or vitamin D-deficient
rickets. Although prevalent in the United States in the
early 20th century, public health measures to ensure
that children receive an adequate vitamin D intake
have drastically reduced the prevalence of vitamin-D
deficient rickets, although breastfed infants who do
2 Volume -  Number -
growth chart. Her vital signs were normal. The patients
gait was wide and showed waddling. Decreased
strength and range of motion were noted bilaterally in
the lower extremities, but normal strength and full
range of motion were observed in the upper extrem-
ities. Significant genu varum was noted. No scoliosis
or widening of the ribs was present. The remainder of
the physical examination findings were normal.
Diagnostic Tests
A pediatric nurse practitioner ordered a comprehen-
sive metabolic panel, along with serum phosphate
and 1,25-dihydroxyvitamin D tests. Serum 1,25-
dihydroxyvitamin D level was 45 pmol/L (reference
range = 36108 pmol/L), and serum phosphate level
was 1.7 mg/dl (reference range = 2.54.6 mg/dl). All
results from the comprehensive metabolic panel
were normal, including serum calcium level. Full-
length leg, hip, and tibia/fibula radiologic films were
also ordered. The patients bones appeared osteo-
penic, with cupping of metaphyses at the tibia, fibula,
and knees and with evidence of subperiosteal bone
resorption.
not receive vitamin D supplementation are at risk
(Holm, 2008). In vitamin D-deficient rickets, decreased
vitamin D intake impairs calcium and phosphate ab-
sorption from the intestines (Penido & Alon, 2012). As
hypocalcemia develops, compensatory mechanisms
occur, including elevation in PTH and mobilization of
calcium from the bone, resulting in decreased bone
density (Holm, 2008; Penido & Alon, 2012).
Furthermore, kidney disorders that can result in
hypophosphatemia and rickets include Fanconi
syndrome, which involves defects in the proximal
renal tubule, and renal tubular acidosis, both of which
lead to increased phosphate excretion (Holm, 2008).
Rickets may also result from genetic abnormalities
that control the response of the body to 25-hydroxy
vitamin D (25[OH]D), 1,25-dihydroxyvitamin D (1,25
[OH]2D), and phosphate. Vitamin D 1a-hydroxylase
deficiency is a genetic form of rickets in which a loss-
of-function mutation occurs in the gene that encodes
1a-hydroxylase enzyme, preventing 25(OH)D from
being converted into the active form, 1,25(OH)2D
(Holm, 2008). Another genetic form of rickets is
Journal of Pediatric Health Care
hereditary 1,25(OH)2D-resistant rickets, which is
caused by a mutation in the vitamin D receptor
(Holm, 2008). As a result, tissues in the body are resis-
tant to vitamin D.
Rickets may also result from an autosomal trait or an
X-linked dominant trait that leads to hypophosphate-
mia (Razali, Hwu, & Thilakavathy, 2015). Autosomal
hypophosphatemic rickets can be caused by a gain-
or loss-of-function mutation in a gene that regulates
serum phosphate levels and accounts for 20% of all fa-
milial hypophosphatemic rickets (Razali et al., 2015).
XLH rickets accounts for the remaining 80% of familial
hypophosphatemic rickets cases and affects nearly 1
in every 20,000 children (Pavone et al., 2014). Because
it is an X-linked dominant disorder, this disease can
affect both boys and girls. If the father has the disease,
all daughters, but no sons, will be affected. On the con-
trary, if the mother has the disease, each child has a 50%
chance of being affected. In this particular case, the
mother was unaware that she had the disease, and
her two older children, one boy and one girl, were
not affected. Some individuals with XLH rickets can
have hypophosphatemia, delayed motor skills in early
childhood, and short stature, without bone disease,
which was the case for the mother of the patient
(Greenbaum, 2011). The Figure shows the genetic
pedigree of the patients family for XLH rickets. Family
history of XLH rickets from previous generations was
unknown.
XLH rickets results from a mutation of the
phosphate-regulating gene (PHEX) on the X chromo-
some (Goldsweig & Carpenter, 2015; Pavone et al.,
2014). In addition to calcitriol and PTH, phosphorus
is regulated by fibroblast growth factor-23 (FGF-23;
Goldsweig & Carpenter, 2015; Greenbaum, 2011;
Holm, 2008; Pavone et al., 2014). FGF-23 is released
by osteocytes and acts on the proximal tubule of
the kidney to decrease the expression of sodium-
FIGURE. Genetic pedigree of patient for X-linked hypophosphatemic (XLH) rickets.
www.jpedhc.org
phosphate cotransporters (Goldsweig & Carpenter,
2015; Pavone et al., 2014). As a result, less
phosphate is reabsorbed from the kidney. Normally,
PHEX controls the breakdown of FGF-23 and thus
regulates the renal excretion of phosphate (Penido
& Alon, 2012). However, in XLH rickets, the defect
in PHEX leads to a reduced breakdown of FGF-23,
which results in renal phosphate wasting
(Goldsweig & Carpenter, 2015; Pavone et al., 2014).
With low serum phosphate level, there is a lack of
phosphate available for bone mineralization. The
result of this pathology is rickets, in which growing
bones fail to mineralize and ossify (Greenbaum,
2011; Holm, 2008). As a result, the bones do not
obtain adequate density, which leads to bending of
the bones when they are subjected to weight
bearing or muscle pulling.
2. What are differential diagnoses for XLH rickets,
and what is the clinical presentation of XLH rickets?
Differential diagnoses of XLH rickets include failure
to thrive and motor developmental delays in infancy
(Greenbaum, 2011; Holm, 2008). Other differential
diagnoses include nutritional rickets, renal tubular
acidosis, Fanconi syndrome, tyrosinemia, cystinosis,
pseudohypoparathryoidism, and other genetic
abnormalities (Greenbaum, 2011; Holm, 2008).
Clinical manifestations of rickets result from the un-
derlying deficiency in vitamin D, calcium, or phos-
phorus. Although the presentation of all forms of
rickets includes decreased growth rate, hypotonia, de-
layed acquisition of motor skills, and skeletal abnormal-
ities, the clinical symptoms differ depending on the
specific cause and the age of each child (Greenbaum,
2011; Holm, 2008). For instance, children with rickets
caused by vitamin D 1a-hydroxylase deficiency
usually present with alopecia (Holm, 2008). Individuals
with vitamin D-deficient rickets may exhibit cranio-
tabes and chest deformities, including widening and
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swelling of the ribs at the costochondral junction
(rachitic rosary) and a horizontal depression along the
lower anterior chest due to the diaphragm pulling on
the ribs during inspira-
tion (Harrison groove) Clinical
(Holm, 2008). Howev- manifestations of
er, skeletal abnormal-
rickets result from
ities in XLH rickets are
usually limited to the the underlying
lower extremities, deficiency in
which may include
vitamin D, calcium,
genu varum (bow-
legs), tibial or femoral or phosphorus.
torsion, and coxa vara
of the femoral neck, resulting in a waddling gait
(Chan, 2016; Cremonesi et al., 2014; LaRosa, 2016;
Pavone et al., 2014).
In this case, the child presented with a history of de-
layed motor milestones, short stature, and genu varum.
Only the lower extremities appeared affected, because
strength and tone in the upper extremities were within
normal limits. Additionally, there was no widening or
swelling of the ribs. These pertinent positive and nega-
tive signs are suggestive of XLH rickets.
Unfortunately, the effects of XHL rickets can
become severe before any signs and symptoms
(Pavone et al., 2014). Most children are not diagnosed
until after the child begins to stand and walk, because
the bowing of legs does not occur until a child bears
weight (Pavone et al., 2014). This was the case for this
patient.
3. How is XLH rickets diagnosed and treated?
XLH rickets is diagnosed primarily on the basis of
radiographic abnormalities (Greenbaum, 2011; Holm,
2008). On x-ray images, the bones may appear
osteopenic, and the edges of the metaphyses may
lose the appearance of a sharp border as a result of
thickening of the growth plate due to decreased
calcification (Greenbaum, 2011). Additionally, the
edge of the metaphyses, which are normally convex
or flat, appear concave, a phenomenon known as
cupping (Greenbaum, 2011). The diagnosis is sup-
ported by clinical examination and laboratory test re-
sults, which can help distinguish the cause of rickets
(Greenbaum, 2011). Furthermore, a family history of
rickets or short stature would support this diagnosis.
Laboratory tests useful for the diagnosis of XLH rickets
include urinary phosphate and serum calcium, PTH,
phosphate, and calcitriol levels (LaRosa, 2016;
Sharkey, Grunseich, & Carpenter, 2015). As shown in
the Table, XLH rickets differs from other forms of rickets
in that serum 25(OH)D level is generally normal despite
low serum phosphate level (Holm, 2008). All other
pertinent laboratory test results are normal except for
urine phosphate level (Holm, 2008).
Patients who are diagnosed with XLH rickets should
be referred to a pediatric orthopedist for management
and also for possible surgical evaluation, depending
on the severity of skeletal abnormalities (LaRosa,
2016). Referrals may also be made to an endocrinology
specialist (Holm, 2008).
Guidelines for treating hypophosphatemic rickets
include a prescription for oral phosphate and calcitriol
at least throughout puberty (Greenbaum, 2011). Rec-
ommendations for dosages vary widely, from 20 to
80 ng/kg/day of calcitriol to 20 to 180 mg/kg/day of
elemental phosphorus, which reflects uncertainty
about the optimal dosage to effectively treat yet prevent
adverse reactions (Carpenter, Imel, Holm, Jan de Beur,
& Insogna, 2011). Some guidelines suggest that it is best
to start the elemental phosphorous dosage at 20 to
40 mg/kg/day divided into three to five doses per day
to help prevent diarrhea, a common adverse reaction
(Greenbaum, 2011; Pavone et al., 2014; Sharkey et al.,
2015). However, frequent dosing of phosphate may
affect adherence, so less frequent dosing is acceptable
if tolerated (Greenbaum, 2011). In addition to phos-
phate supplementation, calcitriol should initially be
prescribed at 20 to 30 ng/kg/day divided into two doses
and can be titrated up to minimize gastrointestinal ef-
fects (Carpenter et al., 2011; Greenbaum, 2011).
Although calcitriol levels are generally normal in
patients with XLH rickets, phosphate needs calcitriol
for bone mineralization.
The patient in this case study was initially started on
the lowest recommended dose of both calcitriol and
elemental phosphorus by the pediatric nurse practi-
tioner, who consulted with a pediatric endocrinologist

TABLE. Laboratory test results for rickets

Serum
Serum Serum parathyroid Serum Urine
calcium phosphate hormone 25(OH)D phosphate
Test level level level level level
Vitamin D deficient Normal Normal High Low Normal
Vitamin D 1a-hydroxylase deficiency Low Low High Low Normal
Vitamin D resistant Low Low Normal Normal/slightly low High
Familial hypophosphatemic rickets Normal Low Normal Normal/slightly low High
Renal disease Low High High Low Low
Note. Sources: Greenbaum (2011) and Holm (2008).

4 Volume -  Number - Journal of Pediatric Health Care

over the telephone. The patient was prescribed 1 mg of
calcitriol twice a day (20 ng/kg/day) and 150 mg of
elemental phosphorus twice a day (30 mg/kg/day) until
she could be seen by the pediatric endocrinologist, who
then assumed the responsibility of managing the pa-
tients medication.
The goal of treatment is to increase bone mineraliza-
tion and prevent leg deformities. Although modest ele-
vations in serum phosphate levels as result of
supplementation are desired, the goal is not to
normalize phosphate levels, because this may cause
adverse effects, including diarrhea, hyperparathyroid-
ism, and nephrocalcinosis (Sharkey et al., 2015). To
avoid these complications, laboratory monitoring every
3 months is recommended (Carpenter et al., 2011). Lab-
oratory tests should include serum phosphate, calcium,
and urinary calcium levels to assess the adequacy of the
dosage; serum and urinary creatinine levels to monitor
renal function; alkaline phosphatase level to assess
skeletal response; PTH level to monitor for secondary
hyperparathyroidism; and a random spot urine collec-
tion (Carpenter et al., 2011). Alkaline phosphatase
should decrease over time, which indicates bone heal-
ing, and a urine spot calcium/creatinine ratio should
remain less than 0.3 mg/mg (Carpenter et al., 2011). If
PTH is elevated, the phosphate dosage can be reduced
or calcitriol may be
increased (Carpenter The goal of
et al., 2011). If the pa- treatment is to
tient has hypercalce-
mia or hypercalciuria, increase bone
the calcitriol dosage mineralization and
should be decreased prevent leg
(Carpenter et al.,
2011). Renal ultraso- deformities.
nography should be
performed every 2 to 5 years to check for neprhocalci-
nosis (Carpenter et al., 2011).
Patients and their families should be educated
about the importance of adhering to the treatment
regimen to prevent further bone abnormalities and
risk of surgical correction and about the need for reg-
ular follow-up to prevent complications associated
with pharmacologic treatment. Families should be
told to return for follow-up sooner if the patient expe-
riences gastrointestinal adverse effects, because this
may be a sign that the dosage may need to be
adjusted. Families should be instructed that dental hy-
giene is extremely important, because children with
XLH rickets are at high risk for dental abscesses; chil-
dren should brush their teeth two to three times daily
and have routine dental visits (Carpenter et al., 2011).
Additionally, genetic counseling for family members
who may consider having a biological child or an
additional biological child may be warranted to
discuss their future childs or childrens genetic risk
for inheriting XLH.
www.jpedhc.org
Effects of hypophosphatemia begin in infancy before
any leg deformities; significant loss of height will occur
if treatment is not started before the age of 2 years
(Carpenter et al., 2011). Therefore, monitoring growth,
specifically height, is essential for early diagnosis,
which strongly influences outcomes.
4. What are challenges associated with caring for a
patient with XLH rickets in a rural setting?
Caring for pediatric patients in a rural setting presents
multiple challenges surrounding access to care. When
presented with a rare or complicated case in which
referral is necessary, pediatric providers may have diffi-
culty ensuring that their patients are seen by a specialist
(Basco & Rimsza, 2013). In general, there is a shortage
of pediatric subspecialists in the United States, with
the provider-to-children ratio for most specialties at
1:100,000 to 1:200,000 (Basco & Rimsza, 2013; Mayer,
2006). In fact, the American Academy of Pediatrics
(AAP, 2013) Committee on Pediatric Workforce issued
a policy statement indicating that the current workforce
of pediatric subspecialists is inadequate to meet the
needs of children, in particular for children living in ru-
ral and other underserved areas.
A huge disparity exists in the geographic distribution
of specialty providers, because most specialists are
found within academic centers in urban settings
(Mayer & Skinner, 2009). Children from rural areas,
therefore, have a long distance to travel to receive
care. One third of children in the United States have
to travel over 40 miles to see a specialist, and a quarter
of children live over 2 hours away from a pediatric
specialist (Mayer, 2006). The distance and time required
to travel to see a specialist places a large burden on fam-
ilies, especially if families are working or do not have
access to transportation. Because of the short supply
of pediatric specialists, pediatric patients often are
forced to wait weeks or months to see a specialist
(Childrens Hospital Association, 2012). Sixty-eight
percent of rural pediatricians reported dissatisfaction
with waiting times for their patients, and 65% rated
the number of pediatric specialists available as poor
(Pletcher, Rimsza, & Cull, 2010).
Furthermore, the number of pediatric specialists who
accept pediatric Medicaid patients has dropped signifi-
cantly (AAP, 2012). From 2006 to 2012, the number of
pediatric orthopedic surgeons who accepted Medicaid
declined 39% (AAP, 2012). Given that Medicaid is the
primary health insurance for a large proportion of rural
populations, failure to accept Medicaid poses another
significant barrier to health care access.
In the case presented here, the closest pediatric or-
thopedic specialist was 55 miles away, but the closest
pediatric orthopedic specialist who accepted Medicaid
was 93 miles away, and the wait time was 11 weeks.
Transportation challenges, loss of health insurance,
and lack of family support resulted in a delay in care
-/- 2016 5
of over a year from the time when the first referral was
made.
Advocating for the patients health is part of the re-
sponsibility of pediatric health care providers. Pediatric
providers can help children access care by assessing the
feasibility of the family seeing a specialist, helping to
arrange transportation with Medicaid if necessary, and
finding a specialist who accepts the familys health in-
surance. Providers should follow up with patients
who are referred to a specialist to monitor any disease
progression during the wait time and to ensure that
the patient is still able to keep the scheduled appoint-
ment with the specialist.
CONCLUSION
The child in this case was diagnosed with XLH rickets
and was followed up by an orthopedic surgeon. She
was prescribed both oral phosphate and calcitriol and
continued to receive physical therapy. Given the signif-
icant skeletal abnormalities by the time she received
pharmacologic treatment, surgical correction will be
needed. As illustrated by this case, it is important to
identify causes of developmental delays and intervene
as early as possible; early diagnosis is essential to
reduce morbidity. Given the challenges of seeing a
specialist, particularly for patients who live in rural
areas, it is important to follow up with patients to pro-
mote continuity of care.
Rickets should be included in the differential diag-
nosis of children presenting with failure to thrive, de-
lays in motor development, and orthopedic or motor
abnormalities. Laboratory tests, especially for serum
phosphate and vitamin D levels, can be ordered to
screen for rickets when included as a differential before
obtaining radiologic films. A thorough family history
should always be taken, and to ensure early treatment,
infants of affected parents should be screened for hypo-
phosphatemia.
The author would like to acknowledge Dr. Sharron
Close, PhD, MS, CPNP-BC for her edits and guidance
on this manuscript and Juanita Norris Howard,
CPNP-BC for her help with this case.
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