Introduction
X-linked hypophosphatemia (XLH) is an inherited disorder characterized by low levels
of phosphate in the blood because of abnormal renal causing uncontrolled loss of phosphate
in the urine (phosphate wasting) and leads to soft, weak bones (rickets). XLH is usually
diagnosed in childhood. Features include bowed or bent legs, short stature, bone pain,
and severe dental pain. XLH is caused by mutations in the PHEX gene on the X chromosome,
and inheritance is X-linked dominant. Treatment generally involves supplements of
phosphate and high-dose calcitriol (the active form of Vitamin D) and may also include
growth hormones, corrective surgery, and dental treatment. The long-term outlook varies
depending on severity and whether complications arise. While some adults with XLH
may have minimal medical problems, others may experience persistent discomfort or
complications.
“Assistance Publique-Hôpitaux de Paris” is the largest university hospitals' network
in Europe, which includes 12 hospital groups located in the Paris region. Paris-Sud
University Hospitals are composed of three hospitals: Antoine-Béclère in Hauts-de-Seine,
Bicêtre, and Paul-Brousse in Val-de-Marne. The hospital group offers a complete health
care, characterized by strong complementarities in terms of pediatric–adult care,
within the framework of hospital–university excellence. France is the first country
in the European Union which set up and implemented national plans for rare diseases
including XLH.
The Rare Diseases Unit of the Bicetre Paris Sud Hospital hosted a dedicated preceptorship
for 2½ days (July 4–6, 2019). The event unconditionally sponsored with Kyowa Kirin
Pharma FZ-LLC. Unfortunately, it was not accredited for any continuous medical education
credits. The aim was to increase awareness of the physicians of the disease burden,
improve early recognition and optimize the clinical management of XLH in the Gulf
region. The educational objectives of the preceptorship are set out in [[Table 1]] and the highlights of the individual days are shown in [[Table 2]]. Most physicians (both adult and pediatric endocrinologists) came from several
Gulf countries together with some from Eastern Europe. Speakers were mostly from the
hosting center, clinical cases were presented by selected delegates, and some of the
sessions were jointly moderated by Gulf and French physicians.
Table 1: The declared educational objectives٭ of the GULF X-linked hypophosphatemia preceptorship
Table 2: Highlights of the plenary sessions on X-linked hypophosphatemia
Conference Highlights
Session 1: Rickets, pathophysiology and diagnosis
Physiology of phosphate homeostasis
Very appropriately, Professor Justine Bacchetta started with an overview of the physiology
of phosphate metabolism [[Figure 1]]. It was highlighted that exogenous regulators of phosphate may include; diet, season,
time of the day as those can affect 1, 25 vitamin D level. In diet, it is noteworthy
recognizing that 1 yogurt cup contains about 150 mg of calcium; so, during puberty
when there is a rapid growth, the child may need up to 10 yogurt cups to meet the
requirement. Obviously, fizzy drinks have much more of phosphate comes from the phosphoric
acid, which gives soft drinks a tangy flavor and prevents the growth of mold and bacteria,
which can multiply easily in a sugary solution. The normal range of serum phosphate
level is variable according to the age group; so, clinicians have to pay attention
to that before interpreting the results. Justine then referred to Dominique Prié's
article where he wrote about phosphate homeostasis, shedding the light on mutations
affecting the genes encoding the renal phosphate transporters or proteins regulating
phosphate transport activity; nevertheless, the role of fibroblast growth factor (FGF)-23-Klotho
axis in regulating phosphate levels and its involvement in phosphate disturbance in
chronic kidney disease was described. It was important to know that hyperphosphatemia
can induce cardiovascular pathology therefore reduces the longevity. Growth hormone
therapy increases phosphate absorption via the insulin growth factor 1, subsequently,
leading to increasing FGF-23. On the contrary, dopamine, steroids, Klotho and FGF-23
inhibit phosphate reabsorption. Infants with cow-milk protein intolerance who are
treated by special milk formula eg. Neocate, are at higher risk of developing hypophosphatemia
due to the very low phosphate content in such formulas[LE1] [ah2]. Patients on antacids
or proton pump inhibitors could have less intestinal phosphate absorption. For further
readings, please go through references.[[1]],[[2]],[[3]],[[4]],[[5]]
Figure 1: Illustration of phosphate homeostasis and its regulation
Hypophosphatemic rickets: Pathophysiology and clinical presentation
Professor Jean-Pierre Salles described the XLH and how it happens. Interestingly,
FGF-23 levels were observed to be higher in cases of McCune Albright patients compared
to XLH and that is possibly related to GNAS mutation. High phosphate intake leads
to secondary hyperparathyroidism to facilitate phosphate excretion in the urine. When
assessing hypophosphatemia, circadian variation should be taken into consideration
as low phosphate can be just pseudohypophosphatemia. Calcitriol and active Vitamin
D increases FGF-23 in XLH patients. In a response to a delegate, Professor Justine
Bacchetta (France) thought it would be a bad idea to reduce or counteract KLOTHO as
the cardiovascular risk would increase.[[6]]
Genetics of rickets
Professor Outi Mäkitie (Finland) described the genetics of different types of rickets.
FGF-23 can interact with various receptors; so, it binds in a KLOTHO-dependent fashion
to FGF receptors (FGFRs) 1, 2, and 3 and it binds to FGFR-4 independently of KLOTHO.
Therefore, we gather from that there is a close relationship between FGF-23 and KLOTHO,
hence KLOTHO deficiency can give similar phenotype of FGF-23 deficiency. It is one
hormone but several receptors, one co-receptor and various effects. Rickets can be
classified into calcipenic and phosphopenic; calcipenic is either due to nutritional
causes, or defective Vitamin D metabolism or defective Vitamin D function. Light was
shed on hereditary Vitamin D dependent rickets (VDDR)-alopecia disorder, in this condition
the 25 Vitamin D level can be variable from patient to other but they all characteristically
have very high 1, 25 Vitamin D >350 nmol/l. Phosphopenic rickets can be either due
to nutritional causes, or increased phosphate loss in the urine whether FGF-23 mediated
or not. XLH is FGF-23 mediated condition that resulted in phosphate wasting. Different
mutations have been identified for XLH. Male and female are affected at a ratio of
1:2 with no male to male transmission but father can transmit it to his daughters.
There are also Autosomal recessive DMP1, ENP1 mutations.[[7]],[[8]],[[9]]
Illustrative clinical cases
The session ended with illustrative clinical cases. Dr. Anya Rothenbuhler (France)
presented a case of 1-a-hydroxylase deficiency to illustrate dental abscesses are
specific to XLH. Low phosphate in a calcipenic rickets patient can be due to high
parathyroid hormone (PTH). Also 1, 25 Vitamin D assay is not invariably accurate and
the normal range of 1, 25 Vitamin D in calcipenic rickets patients may not be true
as they have high PTH and later is already converting all Vitamin D to active form.
Suggested starting dose of 1 alpha Vitamin D 2–8 ug/day and maintenance of 1.5–3 ug/day,
where the starting dose of 1, 25 Vitamin D 1–4 ug/day and maintenance of 0.75–1.5
ug/day. Patients with VDDR-1 will also be treated by Vitamin D (substrat) and calcium
(age appropriate dose) during the 1st year. The presented case had CYP27B1, ch. 12
mutation which is autosomal recessive. Laboratory findings include hypocalcaemia,
hypophosphatemia, high PTH and very low calciuria. Professor Agnès Linglart (France)
and Dr. Volha Zhukouskaya (Italy) presented a case of 25-hydroxylase deficiency who
was treated by Dedrogyl (25 Vitamin D); 8 drops, each drop is 5 ug. Liver dysfunction
is one of the causes of functional defect of 25 hydroxylation. The presented case
was for a neonate who had transitional cholestasis that led to raised liver enzymes
as well as dysfunction of 25 hydroxylase mechanism leading substantially to hypocalcemia.
The 1, 25 Vitamin D in these cases is very sensitive and it degrades quickly.
Session 2: Presentation and diagnosis of X-linked hypophosphatemia
The afternoon session was dedicated for describing the clinical presentations and
radiological diagnosis of XLH, clinical presentation of XLH in children, How to improve
growth in XLH children and how to succeed in transition of care for XLH from childhood
to adulthood and the final presentation focused on the management of pregnancy and
newborns.
Clinical presentations of XLH were discussed by Professor Justine Bacchetta (France).
Normal values of interest in XLH were presented including phosphate levels and TmP/glomerular
filtration rate [[Table 3]]. A case of 5.5-year-old, short female with bowing of legs, growth retardation and
dental caries, thought to have tyrosinemia was presented. Hepatomegaly with raised
alpha-fetoprotein was noted. Hypophosphatemia was evident and thought to be related
to the bowing of legs. Aims of treatment were discussed in similar cases; clinicians
should not attempt to normalize the phosphate level, but rather to normalize serum
alkaline phosphatase (ALP) and PTH levels and to ensure that no calciuria to be developed.
A 3 monthly follow up was recommended. Use of Vitamin D analog in patients with normal
renal function could lead to nephrocalcinosis; hence, this practice was discouraged.
It was thought difficult or even impossible to correct the serum ALP according to
personal observation from one of the colleagues. The expert suggested that if one
wishes to check patients are they are taking alfacalcidol, measurement of 1, 25 Vitamin
D level can be helpful. However, monitoring the adherence to phosphate therapy can
be readily made by measuring urinary phosphate which will be high. Even changing from
the conventional therapy can still be associated with high ALP. Burusomab use should
continue until the closure of growth plates becomes evident. However, it may continue
life-long. There is a limited experience with Cinacalcet in this condition. Adolescents
with persistently high phosphate levels two times above the upper end of the normal
range lead to tertiary hyperparathyroidism which may respond well to Cinacalcet as
an off-label use, Haffnar commented.
Table 3: Normal values of interest in X-linked hypophosphatemia, phosphate levels, and TmP/glomerular
filtration rate
Radiological diagnosis of XLH was illustrated by Professor Catherine Adamsbaum, (France).
She stressed the radiological ALADA principle, of using radiation “As Low As Diagnostically
Acceptable”. She then shed light on the metrics 3Ms when looking to the radiological
images of patients with rickets (3Ms; Mineralization, morphology and modeling, and
maturity of bones). In rickets, apoptosis of chondrocytes does not happen hence the
epiphysis gets bigger. However, in XLH mineralization is preserved. Differential diagnosis
of XLH from radiological point of view was discussed and that include (1) metaphyseal
chondrodysplasia (Schmid disease), where there is widening of the growth plate and
preserved mineralization but mild increase of height of the physis. (2) Blount disease,
where there is developmental bowing but no increase in height of growth plates. (3)
Hypophosphatasia, which is characterized by abnormal metaphysis but radiolucent, gives
the “Tulip-like” image. Magnetic resonance imaging (MRI) can be a good model for imaging
in XLH; it shows bone marrow abnormalities of the epiphysis and “Harris lines” - the
thin transverse metaphyseal lines - which are related to the growth. Hence, MRI could
provide good details for the XLH patients' follow up. No contrast is needed. EOS®
imaging system; which is biplane X-ray imaging system using a technology based on
the Nobel prize-winning work of physicist Georges Charpak on multiwire proportional
chambers, characterized by (a) radiological images with less radiation, (b) reconstruction
of three-dimensional model and (c) full length body imaging in standing position.
Overall, it gives images with limited resolution, so it is good imaging model for
follow up but not really for diagnosis of XLH. The discussion continues as it is known
for XLH patients could have Chiari 1 malformation; so it was advised to look for syrinx
that could be related to the impairment of the cerebrospinal fluid (CSF) circulation.
Low cerebral tonsils would be considered when they are more than 5 mm below the foramen
magnum. Interestingly, Vitamin C deficiency radiological features can be one of the
differential diagnoses for XLH.
Special features for clinical presentation of XLH in children was elaborated by Dr.
Anya Rothenbuhler (France), dental abscesses in healthy looking teeth is characteristic
feature among XLH patients. A positive family history is present in 26% but de novo
rickets 56%. Late diagnosis occurs in 12%. They have hyperlax joints. She noted that
children will not develop limb deformities if they were diagnosed early. Less known
features in XLH; Hearing loss due to abnormal mineralization of inner ear resembling
otosclerosis also malformation of the skull and craniovertebral junction. If there
is a family history of XLH that is transmitting in the family, therefore, it is advisable
to do genetic testing for babies of these families at birth. Biochemical investigations
to be arranged at 1 month of age, if normal repeat in 3 months, if normal repeat at
6 months – by then you should have the genetic testing results. Biochemical changes
take some time to develop. For further reading, the clinical practice recommendations
for the diagnosis and management of XLH can provide you with more detailed information.[[10]]
How to improve growth in XLH children was the theme of a presentation by Professor
Dieter Haffner (Germany) who is the lead author of the latest evidence-based consensus
guidelines.[[10]] In Denmark despite conventional therapy but their patients got shorter. Sitting
height index is increasing as leg length is getting worse when the sitting height
remained steady. How to improve growth in XLH children was the theme of a presentation
by Professor Dieter Haffner (Germany) who is the lead author of the latest evidence-based
consensus guidelines.[[10]] In Denmark despite conventional therapy but their patients got shorter. Sitting
height index is increasing as leg length is getting worse when the sitting height
remained steady. The progress in body disproportion is usually noted despite conventional
treatment. Certainly, early conventional treatment improves growth in XLH patients;
An experience from a single-center study, Toronto-Canada was shared during the presentation[[11]] Professor Haffner recommended to start the treatment within the first 6 months
of life as that would lead to better results. Growth starts to deteriorate at 6–9
months of age in untreated patients with XLH. Data were presented showing the spontaneous
growth in 127 XLH patients from Germany (collected in 1991 and 1992 from 49 paediatric
centres). The mean height standard deviation score (SDS) in girls were −2.0, −1.9
and −2.1 and for boys they were −2.2, −1.6, and −3.0 for 3 different age groups, respectively;
before the age of 1 year, between 1 and 5 years, and after the age of 5 years.[[12]]
Growth can be kept within the lower normal range by conventional treatment in the
majority of patients. Large doses may promote growth but are associated with an increased
risk of side effects. 64 week Burosumab treatment increased mean height by 0.19 SDS
in XLH patients aged 4–12 years with prior conventional treatment. It did not result
in catch-up growth but prevented early declines in growth in XLH patients aged 1–4
years with previous conventional treatment. Three-year growth hormone treatment increased
mean height by 1.1 SDS in short prepubertal XLH patients with concomitant conventional
treatment, but final height was not increased compared to control. So, it was suggested
that if the growth hormone would be considered by the treating clinician, then perhaps
it is better to be given early in the prepuberty period rather than during puberty.
Although, he stressed that it is not the routine recommendation to start growth hormone
for all XLH patients.
The transition of patients care of XLH from childhood to adulthood and how best to
succeed in transition was addressed by Dr. Raja Padidela from the (UK). He started
by sharing the results of a study on the relative burden of disease at various stages
of life. Taking conventional therapy was most “annoying” to children, growth becomes
a concern during adolescence, whereas later on in life, fractures and need for pain
and need for corrective surgery operations become the major issue for adults. Moving
patients from paediatrics to adults like moving from the pond into the sea. Dr. Padidela
emphasized the importance of CQC transition document that promotes “ready steady go”
approach for transitioning service. Symptomatology of XLH can be shared between pediatrics
and adults, for example, short stature, deformity of weight bearing limbs, teeth abscesses,
excessive dental caries, osteomalacia, bone and joint pain, joint stiffness, muscle
pain and weakness, Chiari malformation, gait abnormalities and diminished quality
of life (QoL) including psychological impact. However, there are some features which
are more apparent in pediatrics such as rickets, craniosynostosis, delayed and disproportionate
growth, delayed motor development and gait abnormalities. Other evident symptoms for
adults with XLH include fractures (including insufficiency fractures and looser zones),
osteoarthritis, extraosseous calcification (including enthesophytes, enthesopathy,
and spinal stenosis), hearing loss and disability that impacts ability to work. The
goals of XLH treatment were reiterated as to (a) compensate for hypophosphatemia and
low to low-normal 1, 25 Vitamin D levels that result from increased FGF-23 level,
(b) improve the progressive bowing, anteromedial rotational torsion of tibiae and
short stature in growing children, (c) to reduce the risk of dental and periodontal
defects, (d) to reduce the need for surgical intervention, and (e) to screen for neurosurgical
complications of XLH. Hence, to improve the outcomes, children should be diagnosed
and treated as early as possible. Successful conventional treatment should not aim
to normalize the serum phosphate as aiming to do so may result in overtreatment and
secondary hyperparathyroidism. ALP is a useful biomarker for skeletal response. Blood
PTH, ALP and calcium levels with urinary calcium creatinine ratio were suggested as
useful biomarkers for efficacy and safety assessment. They should be measured every
3 months in infancy, every 3–6 months in childhood, every 3 months during puberty,
and every year or 6 months if on treatment for adults. The renal ultrasound for nephrocalcinosis
is to be done every year. There are some challenges to be addressed during adolescence;
it is important for this cohort of patients to understand their disease, adhere to
the treatment to prevent the complications. There should be some motivation for the
treatment. Of course, support from family, friends, and school is of great value.
In regards of XLH management in adults; usually, no treatment is required for asymptomatic
adults with XLH. It is important to manage Vitamin D deficiency. Treating symptomatic
adults by giving oral phosphorus 750–1600 mg daily, calcitriol 0.5–0.75 ug daily,
or alfacalcidol 0.75–1.5ug daily.
The final presentation focused on the management of pregnancy and newborns. Professor
Agnès Linglart (France) revised the physiology and changes happen during pregnancy
as total calcium is usually at lower levels (2.0–2.2 mmol/L) due to hypoalbuminemia.
Whereas, ionized calcium remain the same. Calciuria can be present and increased due
to hyperfiltration. Interestingly 1, 25 Vitamin D increases by 2–3 folds by the end
of pregnancy (200 pmol/L). PTH is normally lower but the PTH related protein is higher
than usual.
Session 3: Burden of disease
The morning session of the second day started by reviewing the endocrine features
in adults, Vitamin D in XLH and other rickets, rheumatological complications, neurosurgical
complications of rickets, dental features in XLH and other rickets and the ear, nose
and throat (ENT) features in XLH and management. Dr. Peter Kamenicky reviewed the
complications of hypophosphatemic rickets. He highlighted the fact that in XLH; hyperparathyroidism
is linked to long-term phosphate supplementation. On the other side, untreated patients
who have hypophophatemia and high FGF23 would have suppressed PTH. Prevention, diagnosis
and treatment of hyperparathyroidism is crucial for clinical management of XLH patients
as the hyperparathyroidism can increase the risk of renal and bone complications.
The exact prevalence of hyperparathyroidism in adults with genetic hypophosphatemia
is not known as large studies are lacking. Creatinine clearance was found higher in
hypophosphatemic patients. Hypercalcemic hyperparathyroidism is a likely result of
PHEX mutation – nephrocalcinosis was reported. Young-onset hypercalcemic hyperparathyroidism
can be effectively and safely cured by surgical resection. PTH adenoma and chief cells'
hyperplasia occur more often, but adenomatous hyperplasia and oncocystic adenoma were
also reported. The metabolic effect of raised FGF-23 (similar structure to FGF-19
and 21) is increasing of fat mass, large waist circumference, and lipid metabolism
defect. Glucose metabolism in genetic hypophosphatemia is not normally affected –
no association with diabetes or insulin resistance. Raised FGF23 induces left ventricular
hypertrophy. It was suggested that cardiac MRI is more suitable for assessment of
cardiac condition rather than echocardiogram because of deformities of the thoracic
cage.[[13]]
Professor Wolfgang Hogler addressed the current challenges in nutritional rickets
as he thinks it is a socioeconomic problem. Migration and global public health, policy
and politics are the major challenges for effective prevention. He believes that the
burden of the disease is mainly caused by ethnicity, culture, poverty, and geography.
Those factors can result in low calcium diets, low sunshine exposure or inadequate
sunshine exposure especially for the dark skin and poor public health standards. Nutritional
rickets can lead to hypocalcemic seizures and tetany, hypocalcemic dilated cardiomyopathy,
severe muscle weakness, growth plate abnormality, osteomalacia, obstructed labor due
to bone deformities and fractures, disability, low QoL, unemployment, and even mortality.
The issues start early in life as Vitamin D of baby is 75% of his mum's level. Sufficient
Vitamin D was considered when serum 25OHD is more than 50 nmol/L, insufficient when
30–50 nmol/L and deficient when it is <30 nmol/L. The recommended calcium intake for
0–6 months' infants is 200 and 260 mg/day for 6–12 months' infants. The daily calcium
intake otherwise for other age groups is sufficient when it is more than 500 mg, insufficient
300–500 mg, and deficient when it is <300 mg/day. It was proposed to supplement Vitamin
D to all infants in their 1st year of life (minimum 400 IU/day; independent of mode
of feeding), all pregnant women, and all ethnic risk groups (minimum 600 IU/day).
It was recommended to have national Vitamin D supplementation policies to incorporate
universal supplementation policies regardless of the mode of feeding, monitor adherence
at recommended childcare visits, and provide family financial support. Fortification
of food was discussed; it can prevent rickets and improve Vitamin D status if appropriate
food was used, sufficient fortification was used, supported by relevant legislation,
adequate monitoring of the process, and indigenous food sources of calcium are promoted
and subsidized.
Rheumatology complications were then discussed by Dr. Karin Briot (France). Indeed,
the emphasis was on the impaired QoL. Various QoL scoring system in adults were presented
such a HAQ, RAPID 3, short form (SF)-36 physical component score (PCS) and VAS pain
score all of which can help in assessing the degree of impairment. Altered QoL was
defined by HAQ >0.5, RAPID 3 >6 or SF-36 (one domain PCS or mental component summary
> median). She confirmed that recognized risk factors for altered QoL include age,
female gender, fatigue, and enthesopathies.
Neurosurgical complications of rickets were reviewed by Professor Federico Di Rocco
(France). Sagittal suture loss seem to be the main type of craniosynostosis seen in
XLH (59% will have complete or partial suture loss). Synostosis also seen in pseudohypoparathyroidism,
osteopetrosis, and hypophosphatasia. The outcome of syringomyelia in XLH can be improved
by improving the CSF circulation. This can be achieved by surgical intervention. XLH
patients ought to be seen regularly by the neurosurgeon, regularly evaluated the surgeon
can decide on who needs surgery; usually only <10% who would get operated. Fundus
examination from year 1 is essential to roll out papilloedema; if fundus is normal;
further imaging can be delayed.
Professor Catherine Chaussain (France) discussed the dental features in XLH patients.
The hypophosphatemia directly affects the tooth structure. Children and adolescents
are prone to multiple dental infections. Spontaneous dental necrosis with severe abscesses
on deciduous and permanent teeth was noted in XLH. For necrosis and cellulitis, biantibiotic
therapy as first line is recommended (metronidazole and amoxicillin if no allergy).
Periodontitis occurs usually at the age of 40s, particularly in diabetic patients.
However, XLH patients are more susceptible and they ever start having it even in their
third decade. There is some cementum; so, it is unlike hypophosphatasia there will
be no spontaneous tooth loss. Patients with XLH could have normal enamel but thin
with cracks, dentin hypodensity or hypomineralization with unmerged calcospherites,
enlarged pulp chambers. Children with XLH should have regular follow-up (every 3–6
months); they should be monitored and managed the spontaneous abscesses. Sealing the
pits and fissures with resins on temporary and permanent molars is recommended. Rigorous
systemic treatment of XLH improves dental health. Prof. Chaussain has asked insurance
companies to include oral care and orthodontic treatment under the provided cover.
The ENT features in XLH and management were covered by Dr. Jérôme Nevoux (France).
Session 4: Practical management of X-linked hypophosphatemia
The practical aspects of managing XLH included initiation, adjustments and outcomes
of conventional therapy were outlines by Dr. Anya Rothenbuhler (France). Limiting
the effect of FGF-23 in treatment of XLH was covered by Professor Agnès Linglart (France)
and Dr. Volha Zhukouskaya (Italy). Expectations of patients were given by Dr. Pol
Harvengt (Belgium). Following the state of the art management, the principles were
applied on 4 clinical cases with suspected or confirmed XLH.
It was recommended for patients aged 5 years and older to have hearing assessment
and musculoskeletal function assessment (gait). All patients otherwise including those
younger than 5 years old, to have growth charts, bone deformities and signs of rickets
to be reviewed, measurement of intermalleolar distance and intercondylar distance,
head circumference and skull shape to be assessed, neurological examination (consequences
of craniosynostosis and spinal stenosis) to be reviewed and to have dental and oral
examination as part of the workup.
It was underscored that the objectives of treating XLH in children are healing or
preventing rickets and reducing pain, improving or correcting leg deformities, improving
the musculoskeletal function, increasing the growth velocity to improve the final
height, avoiding treatment-related complications, and preventing adult rheumatological
complications. There should be a transitioning of care service. It was emphasized
that improvement of the patients' QoL is very important.
The standard therapy strategy of managing XLH, otherwise known as conventional therapy
is based on compensating the renal defects, by giving Vitamin D analogs and phosphate
supplements. That ideally should help in healing the rickets, mineralization and growth.
Clinicians should be cautious and careful when they treat XLH, Vitamin D analogs can
lead to the development of hypercalciuria that subsequently could lead to nephrocalcinosis.
Phosphate therapy can lead to hyperparathyroidism. So, the treating physicians should
be carefully monitoring the development of hypercalciuria and hyperparathyroidism.
Three important rules were reiterated. First, do not aim for correcting the hypophosphatemia,
(2) regular adjustments (every 3 months) for efficacy and toxicity, and third, giving
the phosphate supplement in divided doses.
ALP usually get normalized within 1 year of starting the conventional therapy. Leg
bowing correction (1 cm/6 months) and restoring the optimal growth should be achieved
within 2–3 years. The initial dose of elemental phosphorus for infants or preschool
children is 20–60 mg/kg/day, adjusted according to improvement of rickets, growth,
ALP, and PTH levels. Young patients who have high ALP level will need frequent administration
of phosphate (4–6 times/day, lowered to 3–4 times/day when ALP is normalized). The
dose can be increased if progressive disease but it should not exceed 80 mg/kg/day
to prevent gastrointestinal discomfort and hyperparathyroidism. Consider low dose
in milder phenotypes (e.g., infants diagnosed by family screening).
Burosumab is monoclonal antibody to treat XLH with radiographic evidence of bone disease
in children of 1 year of age and older. It was shared by the speakers that in France,
it is given based on these conditions: (a) approval by a reference center expert in
rare bone and mineral diseases, (b) children with complication of the conventional
therapy, (c) children with severe disease, or (d) children with late diagnosis. Burosumab
is given subcutaneously every 2 weeks.
Session 5: Management of X-linked hypophosphatemia: Clinical cases from the Gulf
The last session of the program was dedicated to discussion of the preceptorship focused
on the challenges and special needs for XLH patients in the Arabian Gulf region and
was moderated by the host expert. The discussion considered the various types of hypophosphatemic
disorder seen in the region, available resources for diagnostic testing, building
capacity for collaboration between all concerned specialties and how best to identify
the right type of adult specialists to allow a seamless transition. For-most part,
adult endocrinology seemed the most appropriate specialty to undertake this role.
Concerns about medical insurance coverage were discussed and experiences were shared
among delegates from various countries. Perhaps, most importantly was the discussion
on how best to identify such patients who may be suffering from this rare condition.
Potential low awareness of physicians of XLH was raised. Reportedly, a survey of the
physicians' perceptions and practices in identification and management of rare genetic
and metabolic bone disorders is ongoing; narrative review of the literature from the
Middle East and North Africa is also being contemplated. Furthermore, a Gulf-dedicated
guidance statement, with educational slide deck is also being developed by a group
of experts, it was revealed. At the end of the day, the delegates were escorted by
the host to visit the rare diseases unit in the hospital to identify the various clinical,
epidemiological and laboratory resources and ongoing research projects. With its long
track record, the unit was obviously very equipped with [[Figure 2]].
Figure 2: The Bicetre Paris Sud Hospital, France where the event took place
Final Remarks
The preceptorship was a high quality, in depth review of the subjects of rare metabolic
and genetic bone diseases. In summary, phosphate is a cornerstone of several physiological
pathways including skeletal development, bone mineralization, membrane composition,
nucleotide structure, maintenance of plasma pH, and cellular signaling. The kidneys
have a key role in phosphate homeostasis with three hormones having important functions
in renal phosphate handling or intestinal absorption namely, PTH, FGF-23, and 1, 25(OH)
2D. FGF-23 is a direct phosphaturic factor that also inhibits 1, 25(OH) 2D and PTH.
FGF-23 also has effects on the cardiovascular, immune, and central nervous systems.
Genetic diseases may affect the FGF-23 pathway, resulting in either increased FGF-23
levels leading to hypophosphatemia or defective secretion/action of intact FGF-23
inducing hyperphosphatemia. Understanding the biochemical and physiological background
of such disorders sharpens the focus of physicians' diagnostic and therapeutic abilities.
The content was undoubtedly superb, and the faculty members were world class. The
selection of the delegates was fairly appropriate by selecting academics and practicing
clinicians involved in the care of rare genetic and metabolic disorders or those with
an interest in research and education in the area. From an organization point of view,
few issues could have been conducted in a better manner. For instance, with such a
heavy curriculum and specialized group, abstracts or outlines of the presentations
could have been made available in a booklet for the delegates. Furthermore, an audience
participation system with fully interactive sessions would have been valuable and
encouraging more focus. Accommodation could have also been nearer to the venue of
the lectures to waste less time in transportation to and from the meeting venue. Finally,
with such”star-studded” meeting, a high quality clear audio recording of the lectures
could have been used to produce a valuable and unique set of educational videos to
be made available elsewhere.
Authors' contribution
Equal contribution in perception of the idea, drafting and finalizing the report.
Compliance with ethics principles
Not applicable.
Reviewers:
NA (Solicited)
Editors:
Elmahdi A Elkhammas (Columbus, OH, USA)
Elhadi H Aburawi (Al Ain, UAE)
