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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2006-0479
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 5 1897-1901
Copyright © 2007 by The Endocrine Society

Sporadic Hyperphosphatasia Syndrome Featuring Periostitis and Accelerated Skeletal Turnover without Receptor Activator of Nuclear Factor-{kappa}B, Osteoprotegerin, or Sequestosome-1 Gene Defects

Suat Simsek1, Natalja M. Basoski1, Nathalie Bravenboer, Xiafang Zhang, Steven Mumm, Michael P. Whyte and J. Coen Netelenbos

Departments of Endocrinology (S.S., N.B., J.C.N.) and Rheumatology (N.M.B.), VU University Medical Center, 1007 MB Amsterdam, The Netherlands; Division of Bone and Mineral Diseases (X.Z., S.M., M.P.W.), Washington University School of Medicine, St. Louis, Missouri 63110; and Center for Metabolic Bone Disease and Molecular Research (S.M., M.P.W.), Shriners Hospitals for Children, St. Louis, Missouri 63131

Address all correspondence and requests for reprints to: Dr. Suat Simsek, Department of Endocrinology/Diabetes Center, VU University Medical Center, P.O. Box 7057, 1007 MB, Boelelaan 1117, Amsterdam, The Netherlands. E-mail: Simsek{at}vumc.nl.


   Abstract
Top
 Abstract
Introduction
 Patient and Methods
 Results
 Discussion
 References
 
Context: A middle-aged woman with recent-onset painful swollen fingers and widespread periostitis, elevated serum alkaline phosphatase (ALP) activity and erythrocyte sedimentation rate, and accelerated skeletal turnover was found not to have mutations in the gene sequences for exon 1 of receptor activator of nuclear factor-{kappa}B (RANK), osteoprotegerin (OPG), or sequestosome-1.

Introduction: Hyperphosphatasia refers to disorders that feature elevated serum ALP activity (hyperphosphatasemia) usually from excesses of the bone isoform of ALP. Such conditions include familial expansile osteolysis, expansile skeletal hyperphosphatasia, and a familial form of early-onset Paget’s disease of bone (PDB2), all from constitutive activation of RANK, and juvenile Paget’s disease from OPG deficiency.

Patient and Methods: A 38-yr-old woman developed painful swollen fingers and achy bones after an episode of unexplained pericarditis and restrictive lung disease. Sequence analysis of exon 1 of TNFRSF11A encoding RANK, TNFRSF11B encoding OPG, and SQSTM1 encoding sequestosome-1 searched for mutations responsible for familial expansile osteolysis, expansile skeletal hyperphosphatasia, or PDB2, juvenile Paget’s disease, or Paget’s disease of bone (PDB), respectively.

Results: Serum ALP and osteocalcin and urinary hydroxyproline were increased. Radiographs showed widespread, symmetric hyperostosis in the limbs where bone scintigraphy demonstrated enhanced radionuclide uptake. Iliac crest histology revealed accelerated skeletal turnover. No mutations were detected in the three genes examined. Three years of therapy with 70 mg alendronate orally once weekly improved symptoms, radiographic abnormalities, and biochemical markers.

Conclusions: Our patient manifested a unique, sporadic hyperphosphatasia syndrome. Unexplained, transient inflammation seemed to cause her pericarditis, restrictive lung disease, and periostitis with accelerated skeletal turnover that responded well to antiinflammatory drugs and alendronate therapy.


   Introduction
Top
 Abstract
 Introduction
Patient and Methods
 Results
 Discussion
 References
 
HYPERPHOSPHATASIA REFERS TO disorders that feature elevated serum alkaline phosphatase (ALP) activity (hyperphosphatasemia) as their biochemical hallmark (1). This grouping includes several rare genetic diseases of the receptor activator of nuclear factor-{kappa}B ligand (RANK-L)/osteoprotegerin (OPG)/RANK/nuclear factor-{kappa}B (NF-{kappa}B) signaling pathway, with hyperphosphatasemia from accelerated skeletal turnover sometimes complicated by focal bone lesions (2).

Familial expansile osteolysis [FEO; Online Mendelian Inheritance in Man (OMIM) #174810] (3) is a rare autosomal dominant disorder due to an activating, 18-base pair (bp) tandem duplication (84dup18 or 83dup18) in exon 1 of TNFRSF11A, the gene encoding RANK (4, 5, 6, 7). Either duplication lengthens the signal peptide of RANK by six identical amino acids enhancing osteoclast-mediated bone resorption and causing pathological osteoclast attack on teeth (5, 8, 9, 10, 11, 12, 13). FEO manifests clinically with early-onset deafness (11), destruction of adult dentition (12, 13), and focal, progressive, painful osteolysis that leads to fracture and deformity (5, 8, 9, 10).

Early-onset Paget’s disease of bone (PDB2; OMIM #602080), an autosomal dominant disorder described in one Japanese family (14), features a 27-bp tandem duplication (75dup27) in exon 1 of TNFRSF11A (4). Patients with PDB2 have hearing impairment, tooth loss starting in the second or third decade of life, and facial deformity due to distortion of the maxilla and the mandible (14). Radiographs show lytic and sclerotic lesions with bone enlargement and deformity (14).

Expansile skeletal hyperphosphatasia (ESH), reported in a mother and daughter (15), features early-onset deafness, premature loss of adult dentition, and painful phalanges in the hands. Progressive hyperostotic widening of long bones is the principal radiographic feature (15). Absence of large osteolytic lesions in major long bones and periodic hypercalcemia suggested that ESH was not a variant of FEO (15). Nevertheless, a 15-bp tandem duplication (84dup15) in exon 1 of TNFRSF11A was identified in 2002 (16).

Juvenile Paget’s disease (JPD; OMIM #239000), previously called idiopathic hyperphosphatasia, manifests in infancy or early childhood with painful, fragile bones, skeletal deformities, and deafness (1, 17, 18, 19, 20). Since 2002 (18, 20), it has been recognized that homozygous, deactivating mutations in TNFRSF11B, the gene encoding OPG, cause most cases of JPD (21).

As these heritable disorders of the RANK-L/OPG/RANK/NF-{kappa}B signaling pathway were characterized (2), interest grew in their similarities to Paget’s disease of bone (PDB; OMIM #167250 and #602080) (22). PDB is a common, focal, late-onset skeletal disease that can cause bone pain, deformities, fractures, and neurological symptoms (23). In some PDB families exhibiting autosomal dominant inheritance, as well as some sporadic cases, domain-specific mutations in SQSTM1/p62, the gene encoding sequestosome-1, have been identified (24, 25).

Here, we describe an acquired, sporadic hyperphosphatasia syndrome featuring generalized acceleration of skeletal turnover and expanded, painful phalanges in the hands with periostitis yet without mutations in TNFRSF11A, 11B, or SQSTM1. Instead, this unique condition seems to result from a transient inflammatory process associated also with pericarditis and restrictive lung disease. Alendronate was a highly effective therapy for the bone manifestations.


   Patient and Methods
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 Abstract
 Introduction
 Patient and Methods
Results
 Discussion
 References
 
Case history

A previously healthy, 38-yr-old woman was referred for a 6-month history of painful and stiff fingers that had slowly and progressively swelled together with an inability to extend her elbows because of pain. Serum ALP activity was considerably elevated.

Five months earlier, she was seen elsewhere by a rheumatologist for increasingly painful tibiae, elbows, and right shoulder that compromised her activities at work. She recalled no skeletal disease in her family and denied hearing, dental, or previous joint problems. She had recently seen a cardiologist and a pulmonologist because of pericarditis and severe restrictive lung disease [forced vital capacity (FVC), 40% of predicted; forced expiratory volume in 1 sec/FVC ratio, 94% of predicted], both of unknown cause. Physical examination was remarkable for swollen bones around the interphalangeal joints and limitation in extension of both elbows. Erythrocyte sedimentation rate (ESR) was elevated to 70 mm/h (normal, <10). Serum calcium level was normal, but ALP activity was four times the upper limit of the reference range. Liver enzymes and kidney and thyroid function testing were unremarkable. Autoimmune antibodies, including antinuclear antibodies, rheumatoid factor, antiphospholipid antibodies, anti-extractable nuclear antigen antibodies, and anti-double-stranded DNA antibodies, were not detected. Within 1 month, the ESR had normalized during treatment with nonsteroidal antiinflammatory drugs (NSAIDs), which relieved her pain, and 20 mg prednisone daily given for 3 months.

At the VU Medical Center, her cardiac and pulmonary symptoms (FVC, >80%) had resolved. However, hyperphosphatasemia was still manifest with serum ALP values elevated up to 400 U/liter (normal, <120), and serum osteocalcin was 6.7 nmol/liter (normal, 0.2–1.9). Serum PTH and 25-hydroxyvitamin D levels were normal. In a 2-h fasting urine specimen, the hydroxyproline (OHP)-creatinine ratio was elevated at 139 µmol/mmol (normal, <24), but the calcium-creatinine ratio was unremarkable at 0.35 mmol/mmol (normal, <0.45) (Table 1Go).


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  		TABLE 1. Improvement in biochemical markers of bone turnover during treatment with alendronate

 
Radiographs of her shoulders, elbows, hands (Fig. 1AGo), hips, knees, legs, and ankles showed dense periosteal calcifications. After 698 MBq Tc-99m hydroxymethylene-diphosphate administered iv, total body bone scintigraphy revealed multiple "hot spots" with symmetric distribution involving the areas with periosteal calcification (Fig. 2Go).


Figure 1
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  		FIG. 1. Hands. A, Before alendronate treatment, periosteal thickening is marked in the middle and proximal phalanges and in the metacarpals. Note the sclerosis in these same areas. B, Hyperostosis has nearly resolved during alendronate therapy.

 

Figure 2
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  		FIG. 2. Skeletal scintigraphy shows enhanced radionuclide uptake, especially in both hands and wrists before alendronate treatment.

 
Histological examination of a nondecalcified iliac crest specimen, obtained by biopsy after double tetracycline labeling, revealed many osteoid seams, osteoblasts, and resorption lacunae with tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts that appeared more abundant in the cortex than on the surfaces of trabecular bone (Figs. 3Go and 4Go). Fluorescence microscopy showed many double fluorescent labels (data not shown). Bone histomorphometry was performed according to previously described methods using abbreviations according to the American Society for Bone and Mineral Research (ASBMR) nomenclature committee (26). Bone volume was 18.0%, osteoid volume was 16.9%, osteoid surface was 31.4%, mineralizing surface was 93.9%, osteoclast number was 0.18%, and mineral apposition rate was 0.23 µm/d. These data are compatible with high bone turnover.


Figure 3
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  		FIG. 3. Goldner-stained, nondecalcified, iliac crest trabeculum shows abundant osteoid seams with active osteoblasts before treatment.

 

Figure 4
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  		FIG. 4. Bone multicellular unit. A, Goldner stain, bottom right side, osteoclasts resorbing bone; upper part, osteoblasts filling up the resorption cavity with osteoid (red). B, TRAP. Stain: TRAP-positive osteoclasts resorbing bone.

 
Because of the patient’s accelerated skeletal turnover, treatment with alendronate (70 mg/wk orally) was begun. Soon after, she noted decreased swelling of her fingers and less pain. After 1 yr, serum ALP activity had gradually normalized from 400 IU/liter to 120 IU/liter, and the urine OHP ratio of 31 had nearly corrected. After 3 yr, urinary OHP was normal (Table 1Go). Radiography after 12 months of alendronate treatment showed significant skeletal improvement (Fig. 1BGo). Currently, she is at her former job and continues the bisphosphonate therapy.

Mutation analysis of the TNFRSF11A, TNFRSF11B, and SQSTM1 genes

Because our patient had skeletal pain, expansion of fingers and long bones, and biochemical and histopathological features of systemic acceleration of bone turnover as seen in heritable disorders of the RANK-L/OPG/RANK/NF-{kappa}B signaling pathway (2), especially ESH (15), we amplified by PCR and sequenced exon 1 of TNFRSF11A encoding RANK (16). We also studied the entire coding region and adjacent splice sites of the TNFRSF11B gene encoding OPG (18) that is deactivated in JPD. Finally, we studied SQSTM1, encoding sequestosome-1, responsible for some cases of familial or sporadic PDB (24, 25).

Genomic DNA was obtained from blood leukocytes using the Puregene DNA Purification Kit (Gentra Systems, Minneapolis, MN).

Exon 1 of TNFRSF11A was amplified by PCR using previously reported primers and conditions (4). The PCR amplicon was purified by low-melt, 1% agarose gel electrophoresis, visualized by ethidium bromide staining, and then sequenced in both directions.

The entire coding region (exons 1–5) and adjacent mRNA splice sites of TNFRSF11B were amplified by PCR and sequenced in both directions using primers and conditions as previously described (18).

The entire coding region (exons 1–8) and adjacent mRNA splice sites of SQSTM1 were also amplified and sequenced in both directions using previously described primers (25). Some primers were modified, and some were redesigned (sequences available on request).


   Results
Top
 Abstract
 Introduction
 Patient and Methods
 Results
Discussion
 References
 
Three candidate genes (TNFRSF11A, TNFRSF11B, and SQSTM1) for our patient’s disorder were examined.

The TNFRSF11A amplicon, purified by agarose gel electrophoresis and visualized by ethidium bromide staining, showed only a single band. In ESH, FEO, and PDB2 (caused by 15-, 18-, and 27-bp extensions in exon 1, respectively), two bands are seen on agarose gel electrophoresis; one is the normal allele and the other is the expanded allele. Furthermore, we excised the PCR product and sequenced in both directions to show only normal DNA sequence throughout exon 1, including the signal peptide. Therefore, our patient did not have an expansion in the signal peptide of exon 1 of the RANK gene.

Similarly, no mutation was detected in TNFRSF11B, the OPG gene. We did find two 11B polymorphisms: heterozygous Lys3Asn in exon 1 and homozygous Leu256Leu in exon 4, which have been reported at frequencies of 48 and 15%, respectively, in control populations (27, 28).

Mutations in exons 7 and 8 of SQSTM1 have been associated with PDB in some families and sporadic cases (24, 25, 26, 27). Therefore, we also sequenced the entire coding region and mRNA splice sites for SQSTM1 but did not find any mutations. Two heterozygous polymorphisms were detected in exon 6 (916C>T, E292E; 976G>A, R312R) (24).


   Discussion
Top
 Abstract
 Introduction
 Patient and Methods
 Results
 Discussion
References
 
We describe a sporadic hyperphosphatasia syndrome with sufficient resemblance to the heritable disorders of the RANK-L/OPG/RANK/NF-{kappa}B signaling pathway (2, 22) to prompt a search for an associated gene defect. However, our sequencing studies revealed no genetic predisposition to accelerated bone turnover from an aberration in exon 1 of TNFRSF11A, 11B, or SQSTM1. For TNFRSF11A, only exon 1 was sequenced because this is where gain-of-function duplications that extend its signal peptide have activated RANK (4). It was, however, necessary to sequence the entire coding region and mRNA splice sites of TNFRSF11B encoding OPG and SQSTM1 encoding sequestosome-1 to show no deactivating mutation consistent with JPD or PDB, respectively. In fact, our patient had adult-onset skeletal disease, but did not have deafness, which is a characteristic complication of the heritable disorders of RANK-L/OPG/RANK/NF-{kappa}B signaling (2) (Table 2Go).


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  		TABLE 2. Patient features of select hyperphosphatasia syndromes1

 
Because our patient’s condition was acquired and followed an episode of pericarditis and restrictive lung disease, it seems to result instead from inflammation of an unknown cause that somehow accelerated skeletal turnover and led to remarkable periosteal new bone formation. There was marked elevation in ESR, and the disorder was responsive to NSAIDs and prednisone treatment. Her hyperostosis on radiographic and scintigraphic examination occurred together with elevated serum ALP activity and osteocalcin levels as well as urinary OHP. Although high levels of markers of bone turnover hypothetically could have emanated solely from her focal bone lesions, histopathological examination of an iliac crest specimen revealed systemic acceleration of bone remodeling.

We did consider hypertrophic osteoarthropathy (HOA) in the differential diagnosis. HOA features periostitis causing painful swollen joints, focal bony enlargement of the extremities, and symmetric clubbing of the fingers and toes (29, 30). Bilateral periostitis is the hallmark involving mainly the radii and fibulae (31), although the femora, metatarsals, humeri, and metacarpals can also be affected. The heritable, primary form of HOA, called pachydermoperiostosis or Touraine-Solente-Golé syndrome, is an autosomal dominant disorder (3) whose genetic basis is not known (32). Secondary HOA, also called Pierre-Marie-Bamberger syndrome, is more prevalent and associated with pulmonary metastases from a variety of cancers, chronic infections (e.g. arterial grafts), pulmonary fibrosis, Pneumocystis carinii pneumonia in AIDS, cystic fibrosis, cardiopulmonary disease such as cyanogenic congenital heart disease (33), and gastrointestinal disorders (34). Successful treatment of the underlying condition can lead to resolution of the osteoarthropathy. However, our patient’s negative family history, adult-onset disease, and responsiveness to treatment excluded primary HOA (32). Secondary HOA was excluded because she had no persistent cardiac, pulmonary, or gastrointestinal disease. Furthermore, significant enlargement and/or clubbing of the digits/extremities is expected in severe secondary HOA but was not observed in our patient. Pericarditis and restrictive pulmonary disease had resolved, whereas the skeletal abnormalities persisted, indicating a protracted pathogenetic effect of this syndrome on skeletal remodeling.

Hyperostosis-hyperphosphatemic syndrome features juvenile-onset pain, swelling, tenderness, and heat in the limbs caused by a marked periosteal bone formation along the shafts of tubular bones (e.g. radius and ulna). Here, serum ALP activity is increased, sometimes with hyperglobulinemia and anemia (35). Hyperphosphatemia results from decreased renal excretion of phosphate (36). However, this syndrome was excluded for our patient because her disorder developed during adult life and was without anemia or impaired renal excretion of phosphorus (data not shown).

Hence, our patient’s clinical presentation, course, and responsiveness to treatment as well as the lack of mutation in TNFRSF11A, 11B, or SQSTM1 supports an inflammatory basis for her disorder without predisposition from defects in genes within the RANK-L/OPG/RANK/NF-{kappa}B signaling pathway (2, 21) or causing PDB (24, 25, 27). We tentatively call this seemingly unique disorder "sporadic hyperphosphatasia syndrome" until more is known. With future occurrences, serum OPG and RANK-L and inflammatory cytokines known to accelerate bone turnover should be measured to advance our understanding of this condition. Although we do not know the etiology of this syndrome, there seems to be effective treatment. Our patient’s symptoms improved with NSAID and prednisone therapy, and the biochemical and radiographic changes of the skeletal disturbances corrected during alendronate therapy.


   Acknowledgments
 
We are grateful to Shriners Hospitals for Children, The Clark and Mildred Cox Inherited Metabolic Bone Disease Research Fund, and the Hypophosphatasia Research Fund for financial support. Cynthia Webster, an expert volunteer at Shriners Hospitals for Children (St. Louis, MO), helped prepare the manuscript. Paulien Holzmann and Paul Lips performed the bone histomorphometry and assessments, respectively.


   Footnotes
 
Disclosure Summary: The authors have nothing to disclose for this publication.

First Published Online February 6, 2007

1 The contributions of authors S.S. and N.M.B. are equal. Back

Abbreviations: ALP, Alkaline phosphatase; bp, base pair; ESH, expansile skeletal hyperphosphatasia; ESR, erythrocyte sedimentation rate; FEO, familial expansile osteolysis; FVC, forced vital capacity; HOA, hypertrophic osteoarthropathy; JPD, juvenile Paget’s disease; NF-{kappa}B, nuclear factor {kappa}B; NSAID, nonsteroidal antiinflammatory drug; OHP, hydroxyproline; OMIM, Online Mendelian Inheritance in Man; OPG, osteoprotegerin; PDB, Paget’s disease of bone; PDB2, early-onset Paget’s disease of bone; RANK, receptor activator of NF-{kappa}B; RANK-L, RANK ligand; TRAP, tartrate-resistant acid phosphatase.

Received March 2, 2006.

Accepted January 31, 2007.


   References
Top
 Abstract
 Introduction
 Patient and Methods
 Results
 Discussion
 References
 

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