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Autosomal Dominant Hypophosphatemic Rickets/Osteomalacia: Clinical Characterization of a Novel Renal Phosphate-Wasting Disorder

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

	Abstract

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Renal phosphate-wasting disorders are the most common form of hereditary rickets and osteomalacia in western countries. Although autosomal dominant transmission of renal phosphate wasting has been described, previous studies included too few affected individuals to adequately characterize the disorder. We performed clinical and biochemical evaluations of individuals from a large kindred with autosomal dominant hypophosphatemic rickets/osteomalacia. We identified 23 affected members in this family, and for some individuals, follow-up was up to 25 yr. As patients were all members of the same kindred, we had the opportunity to determine the clinical manifestations of the disorder in patients who presumably all have the same genetic mutation.

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.

	Introduction

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DISORDERS of renal phosphate wasting are the most common hereditary forms of rickets and osteomalacia in western countries. Isolated renal phosphate wasting may result from a number of genetic disorders including X-linked hypophosphatemic rickets (XLH), hereditary hypophosphatemic rickets with hypercalciuria (HHRH); hypophosphatemic bone disease (HBD); and autosomal dominant hypophosphatemic rickets/osteomalacia (ADHR) (1, 2, 3, 4, 5). Although ADHR has been described, previous studies included only a few affected individuals and have not been able to adequately characterize the manifestations of the disorder. To understand the clinical manifestations of ADHR, we studied a large kindred from southern Ohio with 23 affected individuals. The presence of a large number of affected individuals in 1 kindred allowed us to explore the phenotypic variability of the disease in individuals who all have the same mutation. Our findings indicate that ADHR frequently displays features that are not seen in other hereditary phosphaturic disorders, and this may lead to difficulties in establishing the presence of the disorder.

	Subjects and Methods

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Several family members presented independently for treatment of rickets and/or osteomalacia. The family tree was determined by obtaining detailed family histories from members of the kindred and by using established genealogy techniques. Individuals were defined as having ADHR if they had hypophosphatemia, normocalcemia, and normal renal function. In adult subjects we considered a fasting serum phosphorus concentration equal to or less than 2.4 mg/dL to indicate hypophosphatemia. Serum phosphorus values over 3.1 mg/dL were considered normal in adults. Those individuals who had serum phosphorus values between 2.4–3.1 mg/dL were considered to have indeterminate values and were asked to have repeat testing and/or measurement of urinary phosphate excretion. Serum phosphorus values for children were interpreted using age-specific normal ranges (6). Histories and physical exams were performed during family reunions, at the subject’s home, at the out-patient facilities of Children’s Hospital Medical Center, or in the General Clinical Research Centers of Children’s Hospital Medical Center of the University of Cincinnati Medical Center and Duke University Medical Center. Several patients have been followed since the mid-1970s. Medical records, radiographs, and bone scans dating back to the 1960s were reviewed when available. We used multiple microsatellite repeat polymorphisms to verify paternity.

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).

	Results

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We identified 23 affected family members. Figure 1 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).

View larger version (51K): [in this window] [in a new window]   Figure 1. Abbreviated family pedigree. Roman numerals denote generations, squares indicate male family members, circles indicate female family members, solid symbols show affected subjects, an asterisk by a symbol indicates delayed onset of penetrance, diagonal lines indicate an obligate affected or carrier, open symbol denotes not tested, ? indicates indeterminate disease status, N indicates tested and normal, and slashes show people who have died. Individuals whose children are not shown (i.e. III-1) are indicated by a line extending down from their symbol.

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).

View larger version (107K): [in this window] [in a new window]   Figure 2. Bone scan from patient VI-51 demonstrating several areas of increased uptake, including the ribs, medial aspects of both proximal femurs, and metatarsals. Also note the absence of lower extremity deformity.

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.

View larger version (127K): [in this window] [in a new window]   Figure 3. Wrist (A) and knee (B) radiographs from individual VI-2, demonstrating severe rickets.

View larger version (123K): [in this window] [in a new window]   Figure 4. Wrist (A) and knee (B) radiographs from individual VI-26, demonstrating rickets.

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).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

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.

	Acknowledgments

 
We are indebted to the study subjects for their participation in these studies. We thank Dr. Eugene Kovalik for partial translation of the paper by David et al.

Received July 15, 1996.

Revised October 8, 1996.

Accepted October 28, 1996.

	References

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