|
Infantile hypophosphatasia: Treatment options to control
hypercalcemia, hypercalciuria, and chronic bone demineralization
John P Barcia.
MD, C , Frederic Strife, MD, and Craig B, Langman,MD
From the Department of Pediatrics, Division of Nephrology.
Children's Hospital Medical Center and the Universlty of
Cincinnati College of Medicine, Cincinnati,Ohio, and the Department of
Pediatrics, Division of Nephrology and Mineral Metabolism, Children's
Memorial Hospital, Northwestern University, Chlcago,Illinois
A 2-month-old child with infantile hypophosphatasia had
hypercalcemia (3.49 mmol/L (14 mg/dl]), nephrocalcinosis, and diminished
bone mineral content.
Hypercalcemia was corrected with calcitonin.
Hypercalciuria and bone demineralization abated with chlorothiazide.
Hypercalcemia is hypothesized to be related to normal bone resorption in
conjunction with impaired bone mineralization.
Chlorothiazide may alleviate this impairment.
(J Pediatr 1997;130:825-8)
Hypophosphatasia is a clinical disorder marked by a
deficiency of tissue-nonspecific alkaline phosphatase enzymatic activity.
The disorder arises as a recessive genetic defect caused by point
mutations in the gene for tissue-nonspecific ALP located on the short arm
of chromosome 1 (1p36.11p34).
Absence of tissue-nonspecific ALP is associated with defective skeletal
mineralization.
Phenotypic expression varies considerably, with earlier age at
presentation being associated with more severe skeletal involvement and a
higher mortality rate.
Hypophosphatasia presenting in infancy is associated with a 50% mortality
rate by the age of 1 year, with no known cure.
We describe an infant with this disorder and discuss treatments used to
control hypercalcemia, hypercalciuria, and chronic bone demineralization.
CASE REPORT
At presentation a 2-month-old white girl born of
nonconsanguineous parents had weight loss, constipation, and anorexia for
1 month.
Physical examination findings were normal except for a palpable rachitic
rosary.
Weight was 3.8 kg (10th percentile) and length 55.8 cm (20th percentile).
Pertinent laboratory values were as follows: Serum measurements included
total calcium, 3.49 mmol/L (14 mg/dl);
phosphorus, 1.8 mmoUL (5.7 mg/dl);
ALP activity, 0.65 kat/L (39 IU/ml) (normal range, 2.3 to 5.4 kat/L [140
to 325 IU/ml]);
parathyroid hormone, less than 0.62 pmol/L (<5.9 pg/ml);and
1,25-dihydroxyvitamin D, 25.2 pmol/L (10.5 pg/ml) (normal range, 40.8 to
105.6 pmol/L [17 to 44 pg/ml]).
Urinary measurements included a calcium/creatinine ratio of 3.19 (when
measured in micromoles per micromole; ratio of 1.13 when measured in
milligrams per milligram) (upper 95% normal value: 2.42 [molar ratio] ;
0.86 [milligram-measurement ratio]) and a value for phosphoethanolamine (a
substrate for ALP) of 1500 mmol/gm creatinine (normal range, 80 to 220
mmol/gm creatinine).
Renal ultrasonography revealed echogenic medullary pyramids consistent
with nephrocalcinosis.
Subsequent test results and their relation to therapeutic trials are shown
in Fig.1
A representative x-ray film from the initial skeletal survey, showing bony
changes consistent with hypophosphatasia, and follow-up x-ray films are
shown in Fig.2
DISCUSSION
Hypophosphatasia was first described by Rathbun in 1948
and has since been separated into four clinical categories based on age at
presentation.
The "infantile" variety occurs during the first 6 months of life
and is associated with severe progressive bony demineralization, leading
to flail chest, pulmonary insufficiency, and death in about half of the
affected children.
The pathophysiology of this disorder is centered around an imbalance in
bone mineralization.
Osteoclasts appear normal and are involved in age-appropriate bone
resorption.
Osteoblasts, although morphologically normal, lack membrane-associated ALP
activity on histochemical analysis.
It appears that the absence of ALP in this disorder impedes theproper
incorporation of calcium into newly formed bone matrix.
Bone demineralization and hypercalcemia result when the impaired matrix
calcification process occurs with a rapid rate of bone resorption.
Seemingly at odds with this schema are the observations that long-term
survivors with "infantile " hypophosphatasia have some
improvement in the disordered bone mineralization despite continued low
serum ALP levels.
However, it is likely that progressive bone demineralization and
hypercalcemia are greatest during the rapid-growth phase of infancy and
decrease in parallel with decreasing growth velocity.
A variety of approaches to manage the hypercalcemia associated with
hypophosphatasia have been tried.
Reduction of gastrointestinal absorption of calcium by dietary calcium
restriction, as used briefly in our patient, or treatment with prednisone,
reduce serum calcium levels minimally or not at all and have been
associated with even further skeletal demineralization.
Increasing urinary calcium excretion with a salt diuresis (saline
solution/furosemide) reduced serum calcium levels in our patient, but
nephrocalcinosis associated with long-term use precludes this management
approach.
Rather, we took the approach of reducing the rapid rate of bone resorption.
Inhibition of osteoclastic activity with calcitonin rapidly returned the
serum calcium concentration to normal in our patient and in two others.
These observations support our speculation that the elevated serum calcium
concentration in hypophosphatasia is a result of a mineralization
imbalance, with "normal" bone resorption occurring in the
presence of impaired bone mineralization.
Efforts to effect improved mineralization in patients with
hypophosphatasia have not been successful, either with treatment with
vitamin D or prednisone or with mineral supplementation.
Plasma infusions designed to supplement ALP activity or induce ALP
production have not consistently improved bone mineralization.
Demineralization continued in our patient, despite the return to normal of
the serum calcium concentration, as evidenced by the worsened bone mineral
density z score at 5 months of age.
Chlorothiazide was begun primarily to lower the urinary calcium
concentration but also potentially to increase bone mineralization.
Whereas we observed improved mineralization using serial densitometry
studies (Fig. 1) and plain radiographs (Fig. 2), it remains unclear
whether this effect was in fact due to the chlorothiazide.
Although the possibilities are speculative, bone mineralization may have
improved without treatment, or calcitonin may have reduced bone resorption
enough to maintain sufficient mineralization until growth slowed, allowing
a balance to be established between mineralization and resorption.
The variable clinical course seen in this disease limits the conclusions
that can be drawn from experience with any one patient.
However, the evidence in our patient and others suggests that inhibition
of osteoclast activity with calcitonin corrects the pronounced
hypercalcemia seen in this disease.
Saline solution furosemide diuresis, steroid therapy, or a low calcium
diet should be avoided because these therapeutic approaches may actually
worsen bone mineralization and nephrocalcinosis, whereas chlorothiazide
use was associated with improved bone mineralization in our patient.
Further observations are warranted.
Supported in part by U.S. Public Health Service grant No.MO1 RR08084 from the General Clinical Research Centers Branch, National Institutes of Health.
Submitted for publication June 10, 1996;
accepted Oct. 11, 1996.
Reprint requests: C. Frederic Strife, MD.
Division of Nephrology, Children's Hospital Medical Center, 3333 Bumet Ave.
, Cincinnati, OH 45229-3039.
Copyright C 1997 by Mosby-Year Book, Inc. OO2-3476/97/$5.00 + O 9/22/78631
fig1 fig2
|