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Clinical Studies |
Department of Medicine, Duke University Medical Center (M.J.E.), Durham, North Carolina 27710; and the Department of Pediatrics, University of Cincinnati Medical Center and Cincinnati Children’s Hospital (P.T.M.), Cincinnati, Ohio 45229
Address all correspondence and requests for reprints to: Michael J. Econs, M.D., Box 3298, Duke University Medical Center, Durham, North Carolina 27710. E-mail: Econs001{at}mc.duke.edu
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Abstract |
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Affected individuals have isolated renal phosphate wasting and inappropriately normal serum calcitriol concentrations. The inheritance pattern was consistent with autosomal dominant transmission with variable penetrance. The family contained two subgroups of affected individuals. Group 1 consisted of patients who presented with renal phosphate wasting as adolescents or adults. These patients presented with bone pain, weakness, and insufficiency fractures, but did not manifest lower extremity deformity. Group 2 consisted of patients who presented with phosphate wasting, rickets, and lower extremity deformity as children. Surprisingly, some individuals in group 2 lost the renal phosphate-wasting defect after puberty.
In conclusion, autosomal dominant hypophosphatemic rickets/osteomalacia is an inherited disorder of isolated renal phosphate wasting. The spectrum of disease includes delayed onset of penetrance and loss of the renal phosphate-wasting defect. Our results have implications in the evaluation of patients who present with renal phosphate wasting as either adults or children.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Serum concentrations of calcium, phosphorus, alkaline phosphatase, and creatinine were determined by automated methods (COBAS MIRA, Roch Diagnostic Systems, Branchburg, NJ). Values are from fasting specimens unless stated otherwise. In some instances (i.e. patients who are currently treated with vitamin D and phosphate), pretreatment serum values for calcium, phosphorus, bicarbonate, and creatinine were obtained by chart review. Tubular maximum reabsorption of phosphate per 100 mL glomerular filtrate (TMP/GFR) was calculated using the nomogram of Bivjoet and Walton (7). Serum for PTH, calcitriol, 25-hydroxyvitamin D, and alkaline phosphatase determinations was obtained from untreated affected individuals and controls and stored at -70 C until biochemical analysis was performed. Assays were performed using the following commercially available RIA kits: intact PTH Allegro (Nichols Institute, San Juan Capistrano, CA), 25-hydroxyvitamin D (Nichols Institute), calcitriol (Incstar, Stillwater, MN), and osteocalcin (Incstar). Serum concentrations of the various metabolites were compared between patients and family controls (unaffected family members and spouses) by t test using the computer program StatView (Abacus Concepts, Berkeley, CA).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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is an abbreviated diagram of the pedigree. All members of the family
are Caucasian. Affected individuals presented with hypophosphatemia for
age, normocalcemia (with the exception of subject V-38, who presented
with a serum calcium of 8.1 mg/dL), and normal renal function. In 6 of
7 patients tested there was no amino aciduria. In 1 patient (VI-2)
there was a urine amino acid report from 1963 with increased leucine
and valine, but this patient did not have other renal impairment or
glycosuria. None of the patients who were tested had glycosuria (n
= 7) or acidosis (n = 7).
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Group 1: delayed onset of clinically evident disease
Nine individuals (denoted by an asterisk in Fig. 1
) had
delayed onset of penetrance of clinically evident disease. Age at onset
ranged from 14.5 yr (patient VI-5) to 45 yr (IV-9). In general,
patients who presented after puberty complained of bone pain, fatigue,
and/or weakness. They did not have histories of rickets or manifest
lower extremity deformities. Pseudofractures and/or stress fractures
were occasionally seen on bone scans and radiographs. The mean serum
phosphorus concentration on presentation was 1.59 ± 0.49 mg/dL.
Of note, all of these individuals are female, and in several instances
the disease became evident shortly after pregnancy. Patient V-26
presented for routine screening at age 20 yr. At that time her serum
phosphorus level was 3.1 mg/dL. Five years later, after her third
pregnancy, she presented with ankle soreness and a serum phosphorus
level of 1.6 mg/dL. Similarly, patient V-24 had a serum phosphorus
concentration of 3.0 mg/dL at age 20 yr, but subsequently presented at
age 24 yr with bone and joint pain and a serum phosphorus concentration
of 1.6 mg/dL yr. Case reports from three individuals from group 1 are
presented below.
Patient VI-51. Patient VI-51 was brought to her pediatrician for routine screening at 3 months of age by her affected mother (V-38), who had been told that the disease was hereditary. At 3 months she had a normal nonfasting serum phosphorus level of 6.6 mg/dL. She grew and developed normally, but complained of back pain at 14.5 yr while she was a competitive swimmer. There was no history of lower extremity deformity, fractures, or tooth abscesses. She was found to have renal phosphate wasting with a serum inorganic phosphorus level of 1.2 mg/dL, a TRP of 85%, a serum calcium level of 8.9 mg/dL, and a serum creatinine level of 0.7 mg/dL. Repeat evaluation 1 week later demonstrated similar laboratory studies (calcium, 9.4 mg/dL; phosphorus, 1.4 mg/dL; TRP, 68%). She was placed on 50,000 U vitamin D/day. One year later, the dose of vitamin D was increased to 100,000 U/day, resulting in improvement in the phosphorus concentration (3.3–4.4 mg/dL). At 19.5 yr of age she was again noted to be hypophosphatemic (serum phosphorus, 1.4 mg/dL; calcium, 9.1 mg/dL; creatinine, 0.7 mg/dL) despite continued administration of 100,000 U vitamin D/day.
At age 22 yr she complained of ankle soreness, low back pain, and fatigue. She did not note significant weakness despite marked hypophosphatemia. She was evaluated after not taking vitamin D for 1 month (100,000 U/day). Her physical exam was essentially unremarkable. Height was 163.1 cm, and weight was 65.9 kg. There were no lower extremity deformities. There was full range of motion of the ankles, knees, hips, back, and shoulders. Motor testing failed to detect any weakness. Laboratory evaluation was significant for the following: calcium, 9.2 mg/dL; phosphorus, 1.4 mg/dL; magnesium, 1.3 mg/dL; blood urea nitrogen, 7 mg/dL; creatinine, 0.8 mg/dL; bicarbonate, 26 mmol/L; alkaline phosphatase, 229 IU/L (normal, 40–150); intact PTH, 24 pg/mL (normal, 13–64); TMP/GFR, 1.2 (normal, 2.5–4.2); 24-h urine: 106 mg calcium and 922 mg creatinine; urinalysis: specific gravity, 1.025; pH 7; negative for glucose and protein and negative microscopic. The karyotype was normal.
A bone scan (Fig. 2) demonstrated areas of increased
uptake in multiple ribs as well as bilateral increased uptake in the
medial femoral shafts and metatarsals. Plain films documented
pseudofractures in the medial aspects of the femurs and insufficiency
fractures in the metatarsals. A bone biopsy demonstrated marked
osteomalacia (osteoid volume, 13.5%; osteoid surface, 72.6%; osteoid
thickness, 39 µm; absence of tetracycline labels).
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Patient IV-9. Patient IV-9 was asymptomatic until age 43 yr, when she noted right hip pain. Over the next 2 yr she noted weakness and pain in both hips, elbows, and ribs. She developed a waddling gait and eventually used a walker to ambulate. At age 45 yr she came to medical attention. Serum calcium was 9.7 mg/dL, phosphorus was 1.3 mg/dL (nonfasting), creatinine was 0.7 mg/dL. Urinalysis showed a specific gravity of 1.025, pH 5, negative for glucose, trace protein, and negative microscopic. A chest x-ray demonstrated fractures of the lateral aspects of the right seventh and eighth ribs and a fracture of the lateral aspect of the left eighth rib. A bone scan reportedly showed increased uptake in the areas of the rib fractures, but no other areas of increased uptake. She was placed on 150,000 U vitamin D and supplemental phosphate and noted gradual improvement in her symptoms. Currently, she is 64 yr old and asymptomatic with high dose vitamin D therapy.
Group 2: onset of clinically evident disease during childhood
We identified nine individuals who presented with clinically
evident disease during childhood. These individuals presented with
lower extremity deformities. Radiographs or reports of radiographs were
available for six children. All six displayed radiographic evidence of
rickets. In some cases (Fig. 3, individual VI-2)
affected children had pronounced rickets. Age at presentation was
2 ± 0.7 yr and ranged from 1–3 yr. The mean serum phosphorus
concentration for the children was 2.57 ± 0.39 mg/dL, and all
patients were hypophosphatemic for age. Serum phosphorus concentrations
as adults are available for eight of nine individuals. In four
individuals hypophosphatemia has persisted into adulthood. In two
individuals adult serum phosphorus concentrations (off therapy) are in
the indeterminate range despite marked hypophosphatemia as children.
Surprisingly, two individuals presented with renal phosphate wasting,
but later lost the renal phosphate-wasting defect. Case reports from
these two subjects are presented below.
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) and knees (Fig. 4b). He
was treated with 25,000 U vitamin D/day, which was later increased to
50,000 U/day. At age 22 months he was admitted for vitamin D toxicity
(calcium, 16.8 mg/dL; phosphorus, 2.7 mg/dL). Vitamin D was
discontinued for 4 months. Subsequently, he was treated with
5,000–25,000 U vitamin D/day until 8.5 yr of age when all treatment
was discontinued and he was lost to follow-up. At age 14.5 yr serum
calcium was 9.4, and phosphorus was 4.1. At age 19 yr serum chemistries
were: calcium, 9.5 mg/dL; phosphorus, 3.8 mg/dL; and creatinine, 0.8
mg/dL. Currently, he is 20 yr old; denies complaints of bone pain,
joint pain, stiffness, or tooth abscesses; and has been off all
medication for over 5 yr. Repeat laboratory studies performed at 20 yr
of age are as follows: calcium, 9.4 mg/dL; phosphorus, 3.1 mg/dL;
creatinine, 0.9 mg/dL; alkaline phosphatase, 58 IU (normal, 30–135
IU); TMP/GFR, 3.1 (mean of two determinations); and creatinine
clearance, 120 mL/min (mean of two 2-h urine collections).
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Inheritance pattern
We identified 15 affected females and 8 affected males;
however, it is likely that we were unable to identify several affected
males because other males in the kindred lost the renal
phosphate-wasting defect. Some males (i.e. V-28, V-43, and
V-45) reported a history of rickets as children that could not be
documented and have either indeterminate or normal serum phosphorus
values as adults. These individuals are listed as unknowns on the
family tree, but are probably affected. Male to male transmission of
the disorder is evident, as illustrated in Fig. 1. Patients V-35 and
V-36 presented as children with hypophosphatemia and rickets. Both
patients were treated with high dose vitamin D (up to 200,000 U/day),
and patient V-35 required surgical intervention to correct lower
extremity deformity. Their father, patient IV-26, wore leg braces as a
child and took an unknown amount of vitamin D as a child. He has
moderate femoral and tibial bowing bilaterally. His most recent serum
phosphorus level was 1.8 mg/dL (off all medications). His wife, the
mother of V-35 and V-36, has had normal serum phosphorus on several
occasions. She has no family history of rickets or bone disease, and
there is no evidence of consanguinity. Other male to male transmission
of the defect includes from III-18 to IV-26 and from II-3 to III-10,
although adequate data on affected status is not available from the
earlier generations. Thus, the inheritance pattern is autosomal
dominant with variable penetrance.
Serum biochemistries
Table 1 contains serum biochemistries from
untreated affected adults and normal controls (spouses and normal
members of the kindred). Before therapy, serum calcium and creatinine
were normal in all affected individuals (except individual V-38, as
discussed above). Vitamin D deficiency was not present in any of the
affected individuals. Indeed, 25-hydroxyvitamin D concentrations were
slightly higher in patients than controls. There was a trend toward
higher PTH levels in the patients, but this was not statistically
significant (P > 0.05). Of note, calcitriol
concentrations were not different from control values despite
hypophosphatemia in the affected individuals. We noted similar
biochemical findings in three patients from a previously described (4, 5) ADHR family who have been off therapy for greater than 5 yr (data
not shown). Although it is possible that the untreated individuals in
the family that we describe are less severely affected than the treated
individuals, there was no trend toward an increased calcitriol
concentration in affected individuals. Thus, our data indicate that
ADHR is similar to X-linked hypophosphatemic rickets and different from
HHRH, in that the calcitriol concentration does not increase
appropriately in response to hypophosphatemia (2, 8, 9).
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Discussion |
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It is unclear why some patients present with the disease in childhood and others present with the disorder as adults. Apparently, individuals who presented as adults were able to compensate for the genetic defect and then lost the ability to compensate. In some instances the start of clinically evident disease was correlated to a physiological stress such as pregnancy; however, this was not always the case. Of note, all nine individuals with delayed onset of penetrance of the disease are female. Although we have no data to confirm or refute the contention, it is possible that postpubertal increases in sex steroid levels may play a role in the delayed onset of penetrance.
An additional novel feature of ADHR is the loss of the renal phosphate-wasting defect in some individuals. Data available for patients VI-26 and VI-5 indicate that they had renal phosphate wasting and rickets as children, but later lost the renal phosphate-wasting defect. Although less data are available for other members of the kindred, several other males appear to have lost the defect. Loss of the renal phosphate-wasting defect has been reported by Pettifor et al. (14) in one child. However, the diagnosis was never established in this child, who had been treated with a potentially nephrotoxic traditional South African remedy before coming to medical attention, and his disease resolved almost immediately after presentation without any therapeutic intervention. Thus, ADHR is the only hereditary disorder of renal phosphate wasting in which a patient may regain the ability to conserve phosphate. Unfortunately, the mechanism by which a few individuals regain their ability to reabsorb phosphate is currently unknown.
There are several other hereditary disorders of renal phosphate wasting, of which XLH is the most common. Although ADHR shares some phenotypic features with XLH, ADHR displays several phenotypic features that are not seen in XLH, and our family clearly demonstrates an autosomal dominant pattern of inheritance. However, individuals with ADHR may be inappropriately diagnosed as having XLH if families are too small to detect male to male transmission, and the clinician is unaware of the existence of ADHR. Indeed, now that the gene responsible for XLH (PEX) has been cloned (15), investigators may find patients from small families who have been thought to have XLH, but do not have mutations in the PEX gene. Many of these patients may turn out to have ADHR.
Another recently described disorder is HHRH. It is an autosomal disorder that results in renal phosphate wasting, increased calcitriol concentrations, hypercalciuria, and nephrolithiasis (2). Although it was originally thought to be an autosomal recessive disorder (2), more recent studies indicate that the inheritance pattern may be more complex (16). Additionally, Proesmans et al. have described a family with renal phosphate wasting, increased calcitriol concentrations, and hypercalciuria, but an autosomal dominant mode of transmission (17). Both of these disorders are clearly different from ADHR because patients with ADHR have inappropriately normal calcitriol concentrations and lack hypercalciuria. In many instances, these patients have not developed hypercalciuria despite treatment with high dose vitamin D.
Scriver et al. (3) described a disorder characterized by isolated renal phosphate wasting, which they term HBD. In one family (family 4) there was a male to male transmission, indicating an autosomal dominant pattern of inheritance. These investigators stated that HBD differed from ADHR because the children that they studied did not have radiographic evidence of rickets. In our study, affected children displayed radiographic evidence of rickets. However, in previous studies of children with XLH we determined that radiographic evidence of rickets is not an invariant feature of XLH (18). By analogy, it is possible that radiographic evidence of rickets may not be universal in children with ADHR. Of note, in the original description of HBD, family 4, which was the only family that demonstrated a father to son transmission, contained two members who were said to have a clinical picture consistent with XLH (including rickets in at least one of these individuals) in addition to the two individuals who had HBD (3). The paternal grandmother of the propositus, who was also the aunt of the two individuals who reportedly had XLH, had a serum phosphorus level of 3.1 mg/dL. In light of the incomplete penetrance observed in our ADHR family and the fact that the occurrence of two different uncommon renal phosphate-wasting disorders in the same family is unlikely, this family may have had ADHR. Our data suggest that HBD may not be a distinct clinical entity. Final resolution of this dilemma may await the eventual cloning of the ADHR gene and testing this gene for mutation in HBD families.
Our data are in agreement with those of Bianchine et al. (4), who described a small ADHR family. The father in their kindred was a markedly affected male who displayed renal phosphate wasting, short stature, and a windswept deformity (4, 5). He had two affected daughters and one affected son. Biochemical evaluation of three affected members of this family, who have been off treatment for several years, was similar to that of the untreated members of our family (data not shown). David et al. (19) also described a small kindred with autosomal dominant inheritance, hypophosphatemia, and normal calcitriol and PTH concentrations without hypercalciuria. Rickets was present in the one child who was studied. Wilson et al. (20) described a patient with renal phosphate wasting, short stature, and lower extremity deformity, but did not provide data for urinary calcium excretion. The patient was from a large family in which several members had hypophosphatemia without clinical evidence of bone disease. These investigators thought that the inheritance pattern was most consistent with an autosomal dominant mode of transmission, but were puzzled by the finding that several parents of affected children had normal serum phosphorus values. Our data expand the above findings considerably. The spectrum of disease in ADHR includes not only the classic presentation with early onset of hypophosphatemia and rickets, but also includes delayed onset of disease and resolution of the defect.
The delayed onset of phosphate wasting and the resolution of the phosphate-wasting defect in some affected individuals indicate that defects in the ADHR gene can be compensated for by other hormonal, genetic, or environmental factors. As mutations in the gene result in renal phosphate wasting, the ADHR gene probably plays an important role in maintaining normal phosphate homeostasis. The existence of other factors that can compensate for defects in this gene as well as the fact that mutations in other genes (i.e. PEX) can give rise to renal phosphate wasting indicate that control of phosphate homeostasis is a complex process. The isolation of these genes should lead to important insights into phosphate homeostasis and new therapies for these disorders.
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Acknowledgments |
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Received July 15, 1996.
Revised October 8, 1996.
Accepted October 28, 1996.
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References |
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