Download Hypophosphataemic rickets in children and adults

Abstracts
1918
Hypophosphataemic rickets in children and adults
Jochen H. H. Ehrich, Guido Filler
Paediatric Nephrology, Charite Children's Hospital, Humboldt University, Berlin, Germany
X-linked vitamin D3 resistant hypophosphataemic
rickets (HPR) is a X-chromosomal dominant inherited
kidney disease occurring in approximately 1 in 20000
births. The HPR gene is found on the distal short arm
of the X chromosome in the Xp22.1-p22.2 region. The
function of the normal gene and the molecular defects
of the HPR locus are not known. It is possible that
HPR may be a heterogeneous disorder leading to
variable severity and additional clinical symptoms such
as hearing loss. HPR leads to renal hyperphosphaturia,
hypophosphataemia and inadequately low 1,25-dihydroxy-cholecalciferol concentration in the plasma. The
major symptoms of rickets during childhood are severe
bone deformation and disproportionate growth. Oral
phosphate supplementation and vitamin D3 during
infancy may prevent rickets and bone deformation.
After manifestation of the disease in children, treatment may cure rickets and accelerate growth in many
patients. In previously treated or untreated adult
patients with HPR, phosphate and vitamin D3 were
able to reduce bone pain which is the dominating
complaint in adults. Nephrocalcinosis was the main
side effect of treatment. There are only a few articles
on the course of HPR in both children and adults.
Therefore, we report on nephrological, orthopaedic,
radiological, dental and psychosocial aspects of 44
patients treated at the Medizinische Hochschule
Hannover and the Charite Hospital in Berlin. The
potential beneficial effects and side effects of treatment
on the course of the disease are analysed.
Forty-four patients (33 females, 11 males) with HPR
were regularly undergoing clinical examinations by a
paediatric nephrologist in the renal outpatient clinic.
There were 13 families with two to five affected members and four sporadic cases. At the last examination,
12 patients were less than 18 years old, 18 patients
were aged 18-29 years and 14 patients were 30-56
years old. All patients fulfilled the criteria of reduced
tubular phosphate reabsorption (TP/GFR below 2SD
of normal for age), hypophosphataemia, normocalcaemia and a history of rickets. Patients with other types
of vitamin D resistant rickets and other tubular disorders were excluded. The median observation period
was 17 years. Mean age at diagnosis of HPR was
11 years. Age at start of treatment and dosage
of vitamin D plus phosphate therapy varied considerably. Patients received either vitamin D3 (range
Correspondence and offprint requests to: J. H. H. Ehrich, Paediatric
Nephrology, Charite Children's Hospital, Humboldt University,
Berlin, Germany.
10000-40000 units per day) or 0.125-0.5 ug 1,25 dihydroxy cholecalciferol (1,25 vitamin D) per day.
Phosphate dosage ranged from 10-100 mg/kg/day.
Duration of therapy was 3-20 years. Eight patients
had not been treated.
Final height of female patients ranged from
140-170 cm. Final height of males was 144-168 cm.
HPR resulted in a final body height < 155 cm in 20/32
adult patients. Within single families the variability of
final height was relatively mild. Female and male
patients with a Tp/GFR <0.45 umol/ml were shorter
than those with a higher value. Final height of patients
receiving therapy before the age of 10 years was higher
than in patients never treated or at a later age. Growth
failure is among the most severe consequences of HPR.
Some of our families were more affected than others,
indicating a heterogeneity of HPR.
At last investigation, kidney function was normal in
all with the exception of a 56-year-old patient who
showed a creatinine clearance of 77 ml/min/1.73 m2.
Renal tubular dysfunction including disturbances of
acid-base metabolism, glucosuria and low-molecular
weight proteinuria were absent in all other patients.
With the exception of phosphate, serum electrolytes
were normal in all patients. Hypophosphataemia
(<0.83 mmol/1) was found in untreated adult patients
at the last investigation. Three patients had secondary
hyperparathyroidism. Ultrasonography revealed that
14 out of 40 patients had a mild to moderate medullary
nephrocalcinosis. None of the eight untreated patients
had nephrocalcinosis.
Decreased joint mobility was found in all adult
patients with HPR, affecting mostly hips and shoulders.
Older patients with HPR suffered from functional
limitations during every day situations such as walking,
dressing and personal hygiene. A deviation of the leg
axis (range 6-40°) was seen in three quarters of
patients. Genu valgum was found more frequently
than genu varum. Scoliosis was generally mild.
Radiologically, only one patient showed scoliosis of
grade II. There was a trend that patients with early
treatment had milder orthopaedic problems according
to an orthopaedic score including pain, deformation
of leg axis, and number of orthopaedic operations.
The rate of inadequate fractures was increased in only
one of our patients. Increased fragility of the bone is
only to be expected in patients with severe bone
deformation. Fractures and recurrence of deformities
were seen after osteotomies and following immobilisation. Thus, osteotomies should be delayed until ado-
1919
Abstracts
lescence when growth has come to an end. Adult
patients with HPR need persistent follow-up in an
orthopaedic unit to treat prearthrotic deformities, to
sustain and restore joint mobility and to receive physiotherapy. Patients should not be excluded from school
sport. On the contrary, they should be encouraged to
do sports such as swimming and bicycling which will
contribute to the patient's wish of being 'normal'.
Mean bone mineral density was increased in our
patients. In five patients with vitamin D and phosphate
therapy, it was more than 2 SD above the normal agedependent average. Adult patients with HPR had
increased mineralisation, especially of the cortical bone
of the lumbar vertebrae bodies.
Radiographic examination of the teeth revealed
unusually large dental pulp chambers and multiple
apical lesions without visible carious defects. It is
suggested that microorganisms or pathological substances may be able to penetrate the enamel layer in
microscopic tubular clefts and lead to apical lesions.
Early bone deformities, decreased final height, multiple operations and side effects of treatment affected
the patients health and psychosocial rehabilitation
during early adulthood and secondary degenerative
alterations of the skeletal system worsened when
patients got older. Episodes of pain and limitations of
joint mobilities developed in our patients during adulthood. HPR is clearly a chronic disease with an important psychosocial impact extending into adulthood.
Patients judged themselves less well able to cope with
physical and psychological stress than healthy controls.
This was mainly contributed to bone-pain, dysproportionate growth failure, waddling gait and multiple
hospitalisations leading to a lack of schooling and
vocational training. Although our study group may be
too small for demographic analyses, there was an
indication that unemployment and early retirement
were more frequent than in the healthy population.
Almost all patients were married or wanted to be
married, however, a proportion of women refused to
have their own children because of the risk to have an
affected baby.
Treatment of children with HPR with vitamin D
and phosphate had a positive effect on growth, frequency of operations of bone deformities, bone density
and bone pain, however, many patients were still
growth retarded and showed bone deformities in spite
of therapy. Treatment should begin at an early age to
prevent the development of severe rickets. It is, however, difficult to identify the young patients with a
future severe course of the disease requiring more
intensive drug treatment. The abnormal height at dia-
gnosis may be a good indicator of a poor prognosis.
The present data show that patients with a low
Tp/GFR may be at a special risk for developing severe
disease. Once the full clinical picture in a previously
untreated patient has developed, treatment with
vitamin D and phosphate may cure the radiologically
detectable rickets, but bone deformation and growth
failure may persist in spite of therapy in these cases.
The dosages of 1,25 vitamin D and phosphate are a
matter of debate and the ideal level of serum phosphate
concentration to be achieved is still unknown. There
are no controlled studies on the use of growth hormone
and the risks of deterioration of bone mineralisation
and the costs of growth hormone therapy have to be
considered with respect to a possible gain of height.
Approximately one half of the HPR patients treated
with vitamin D and phosphate developed nephrocalcinosis. Untreated patients did not develop nephrocalcinosis. The present study does not clarify the
pathogenetic mechanisms of nephrocalcinosis in
patients with HPR, however, it was shown that our
adult patients did not develop renal dysfunction in
spite of persistent nephrocalcinosis. Our patient with
mild renal insufficiency had no nephrocalcinosis, but a
long history of analgesic use and congenital urinary
abnormalities.
In summary, the present study shows that children
with HPR remain chronically ill during adulthood.
There was a trend that patients with a moderate
urinary loss of phosphate and early vitamin D and
phosphate treatment did better than children with a
severely reduced Tp/GFR and no or late therapy.
Therefore, we conclude that children with HPR should
be treated with vitamin D and phosphate. There is
little doubt regarding the beneficial effect of treatment
on rickets, height and bone pain in children and
adolescents. The dosage can be reduced after puberty
and the beneficial effect in adults, however, remains to
be established. Life long interdisciplinary care for all
patients should be provided by nephrologists, orthopaedic surgeons, physiotherapists and dentists.
References
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Whyte MP. X-linked hypophosphatemia: a clinical, biochemical
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