Presented in part at the 21st Annual Meeting of the American Society for Bone and Mineral Research, St. Louis, Missouri, U.S.A., September 30-October 4, 1999 [J Bone Miner Res 14(Suppl 1):S224, 1999]
Article first published online: 1 DEC 2000
Copyright © 2000 ASBMR
Journal of Bone and Mineral Research
Volume 15, Issue 12, pages 2330–2344, December 2000
How to Cite
Whyte, M. P., Mills, B. G., Reinus, W. R., Podgornik, M. N., Roodman, G. D., Gannon, F. H., Eddy, M. C. and Mcalister, W. H. (2000), Expansile Skeletal Hyperphosphatasia: A New Familial Metabolic Bone Disease. J Bone Miner Res, 15: 2330–2344. doi: 10.1359/jbmr.2000.15.12.2330
The opinions expressed are those of the authors and do not necessarily represent those of the Department of Defense
- Issue published online: 2 DEC 2009
- Article first published online: 1 DEC 2000
- Manuscript Accepted: 28 JUL 2000
- Manuscript Revised: 11 MAY 2000
- Manuscript Received: 3 DEC 1999
- alkaline phosphatase;
- Paget's bone disease
We describe a new familial metabolic bone disease characterized by expanding hyperostotic long bones, early onset deafness, premature tooth loss, and episodic hypercalcemia. The condition affects a mother and daughter studied at the age of 36 years and 11 years, respectively. Both individuals lost all hearing in early childhood and suffered premature shedding of teeth. Skeletal pains began just before puberty. Swelling and aching of most middle phalanges in the hands is an especially troublesome manifestation. The mother also had episodes of symptomatic hypercalcemia first documented in late childhood and subsequently during intercurrent illness and postpartum lactation. Radiographs show hyperostosis and/or osteosclerosis predominantly in the skull and appendicular skeleton. Long bones also are expanded considerably, especially the middle phalanges in the fingers. The mother's skeletal abnormalities are more severe. Biochemical parameters of bone turnover, including serum alkaline phosphatase (ALP) activity, are elevated substantially. In the proposita, dynamic histomorphometry of nondecalcified sections of iliac crest revealed rapid skeletal remodeling. In the mother, who had been treated with bisphosphonates, electron microscopy (EM) showed disorganized collagen bundles as well as necrotic and apoptotic bone cells but no osteocytic osteolysis. Measles virus gene transcripts were not detected in peripheral blood monocytes. Karyotyping was normal, 46,XX. Hyperphosphatasia with bone disease previously has been reported as either a sporadic or autosomal recessive condition. Expansile skeletal hyperphosphatasia (ESH) is probably inherited as an autosomal dominant trait with a high degree of penetrance.
HYPERPHOSPHATASIA REFERS generically to a group of rare disorders featuring marked elevation in serum alkaline phosphatase (ALP) activity (i.e., hyperphosphatasemia).(1) Included among the hyperphosphatasias are several conditions in which focal or generalized acceleration of skeletal remodeling engenders this biochemical disturbance by selectively increasing circulating levels of the bone isoform of the tissue-nonspecific isoenzyme of ALP. Examples are severe polyostotic fibrous dysplasia (POFD), including the McCune-Albright syndrome (MAS), and juvenile Paget's disease (JPD).(1)
Here, we report a new familial form of hyperphosphatasia characterized by expansile hyperostosis, early onset deafness, premature tooth loss, and episodic hypercalcemia. This metabolic bone disease that we call expansile skeletal hyperphosphatasia (ESH) seems to be inherited as a highly penetrant, autosomal dominant trait (throughout our article, we refer to heritable disorders by their McKusick number provided in Mendelian Inheritance In Man [MIM](2)).
MATERIALS AND METHODS
A mother and daughter are affected. Their skeletal disturbance features expanding and painful tubular bones containing areas of thickened and coarsened cortical and trabecular osseous tissue (i.e., hyperostosis and osteosclerosis, respectively).(3) The daughter was our patient and is described first.
This 11-year-old Australian-born girl was referred for investigation of recently discovered hyperphosphatasemia and skeletal disease. She weighed 8 lb 10 oz at birth. Gestation was uneventful, but she was delivered 10 days past due by Caesarian section because of her mother's small pelvis. Iron supplements only had been taken during the pregnancy.
At 13 weeks of age, the mother suspected that her daughter also was deaf. Subsequently, the patient suffered the “usual” number of ear infections. When fluid accumulation was found in both ears, myringotomy tubes were inserted. Nevertheless, at the age of 5 years, she became deaf. Hearing aids were not helpful. Ostensibly, her physicians attributed the condition to the deafness in both her parents, and no further diagnostic studies were performed.
At the age of 6 years, when hospitalized for a viral illness, an unspecified “abnormal blood test” was mentioned. She always appeared somewhat underweight from being an “active child.”
Except for deafness, the patient was well until 10 years of age when she broke her left forearm after leaping from a swing. The fracture healed uneventfully. However, 2 months later she began to have constant pain contralaterally in her right index finger and right heel. The discomfort gradually resolved, but then the joints in the fingers of both hands appeared to enlarge. She was ridiculed by her deaf classmates because of her difficulty in using sign language. At another medical center, blood studies for arthritis were negative, but her serum ALP activity (709 IU/liter) was elevated markedly. When widespread skeletal abnormalities were then discovered on radiographic examination, she was referred to us.
At the Metabolic Research Unit (MRU), we learned she was a good student. No medication was taken. Premature loss of deciduous teeth occurred at 4 years of age (>5 years, normal), although tooth structure was unremarkable. Pain in various bones, rather than joints, limited her participation in sports. However, it was unclear where she felt discomfort. Features of arthritis reportedly occurred only in her fingers. Like her mother, she experienced bone pain in cold weather, but there was no Raynaud phenomenon. Several days before admission, her right middle finger began to swell without injury. Her mother commented that these problems were reminiscent of her own difficulties. Review of symptoms was positive for increasingly frequent headaches occurring almost daily. She was premenarchal.
Physical examination revealed a well-developed white girl. Vital signs were normal. Height was 151 cm (60th percentile), weight 37 kg (50th percentile), and head circumference 54.5 cm (90th percentile). Her face appeared somewhat broad and flattened. Sclerae were white. The teeth were in good condition. Gentle squeezing elicited bony tenderness at her left antecubital fossa and left anterior midforearm. Finger joints appeared swollen, especially the proximal interphalangeal (PIP) joints (Fig. 1). At the PIP joints, especially involving her right middle finger, there was tender, nonerythematous bony expansion. Her femoral condyles, tibial plateaus, and feet also appeared large, and her ankles seemed to be widened. The skin was unremarkable. Except for profound deafness, neurological examination was intact.
This 36-year-old woman has the same (but more advanced) condition as her daughter. A case report from Australia in 1991(4) described some of her clinical, radiographic, biochemical, and histopathological findings up to that time and concluded that she suffers from a mild form of JPD. It emphasized her difficulties with hypercalcemia while breast feeding each of her two daughters (see Discussion). She was deaf since infancy because of absence of middle ear ossicles. Hypercalcemia was detected at the age of 11 years and remitted spontaneously after puberty but recurred with intercurrent illnesses, immobilization, or lactation.(4) She had progressive skeletal pain, swelling, and deformity, especially in her legs and in several fingers. Symptoms diminished during pregnancy. Osteotomy had corrected significant bowing of her left femur. Etidronate treatment was not beneficial. Intravenous infusions of pamidronate lowered serum ALP activity but did not alleviate symptoms. Salmon calcitonin given subcutaneously helped to control postpartum hypercalcemia that was postulated to reflect lactation-associated estrogen deficiency superimposed on accelerated bone remodeling from JPD.(4)
At the MRU, she told us that surgery had been considered at 3 years of age for her deafness, but was not performed. She had suffered a fracture of her left wrist with trauma at the age of 12 years. She did not know the age when she shed her deciduous teeth. However, complete dentures were necessary by the age of 18 years because of tooth loss from “bone disease”; the teeth themselves were ostensibly normal. Four years before study, medical insurance problems after coming to the United States led to no further treatments, although her skeleton was becoming increasingly painful. Bones were tender and ached each day at various skeletal sites. Occasionally, her joints seemed to be hot, sore, and swollen, especially her knees and in her middle fingers.
Limited physical examination showed more advanced skeletal changes compared with her daughter. She also had broader and more flattened facial features with mild hypertelorism ( Figs. 2A and 2B). Her fingers appeared expanded at most PIP joints (Fig. 3). There was remarkable swelling within the middle digits and contractures especially on the left. Lower extremity long bones appeared widened, particularly near the knees and ankles, and there was bowing on the right.
The father was in good health except for deafness. The proposita had a younger full sister who was well and reportedly had normal serum ALP activity and hearing. The mother has three full siblings and four maternal half siblings who, like the maternal grandmother, had no history suggestive of this disorder.
At the MRU, the proposita consumed a constant diet(5) that matched her poor ad libitum intake of ∼350 mg calcium per day as assessed by our research dietitian. Blood was obtained after an overnight fast, and two successive urine collections each spanned 24 h. Biochemical investigations were performed as published.(6) Radiographic studies included skeletal surveys of both the proposita and her mother. Bone densitometry involved dual-energy X-ray absorptiometry (DEXA) using a QDR-2000 instrument (Hologic, Inc., Waltham, MA, U.S.A.). Skeletal scintigraphy was not requested. A search for viral transcripts in peripheral blood leukocytes utilized published methods.(7) Before transiliac crest biopsy was performed, the proposita and her mother each received two 3-day courses of oxytetracycline orally separated by 2 weeks.(8) An extra core of iliac crest from the mother was obtained for electron microscopy (EM). Karyotyping involved Giemsa-stained chromosomes (450-band stage) derived from peripheral blood lymphocytes (Department of Genetics, St. Louis Children's Hospital, St. Louis, MO, U.S.A.).
During her 2-day hospitalization, she consumed 207 mg and 242 mg of calcium and 445 mg and 587 mg of phosphorus each day.
Complete blood count and leukocyte differential were unremarkable, except for slightly low hemoglobin at 11.9 g/dl and mild leukocytopenia at 3.2 × 103 cells/μl (normal, 4.8 × 103 cells/μl to 10.8 × 103 cells/μl). Platelet count was normal at 188 × 103 cells/μl. Erythrocyte sedimentation rate (ESR) was unremarkable at 9 mm/h (normal, 0-15 mm/h). The serum cholesterol concentration was low at 111 mg/dl (normal, 120-200 mg/dl). Routine urinalysis and overnight fasting urine osmolality (963 mOsm/liter) were unremarkable.
Complete blood count was notable only for mild anemia with hemoglobin at 11.9 mg/dl and hematocrit at 35%. The ESR was slightly elevated at 24 mm/h. The serum parathyroid hormone-related protein (PTH-rP) level (Corning Nichols Institute, San Juan Capistrano, CA, U.S.A.) was not elevated at 0.6 pmol/liter (normal, <1.3 pmol/liter). Serum cholesterol concentration was low at 97 mg/dl (normal, 120-200 mg/dl).
Both the proposita and her mother had normal fasting levels of serum total and ionized calcium, phosphate, creatinine, and intact PTH as well as electrolytes, blood urea nitrogen (BUN), glucose, magnesium, uric acid, total protein, albumin, total and direct bilirubin, aspartate aminotransferase (AST), and lactate dehydrogenase (LDH). In both, urinary calcium levels were also normal. However, abnormal parameters of skeletal homeostasis indicated rapid skeletal turnover and are summarized in Table 1.
Proposita: Axial skeleton:
The skull was normal except for some thickening of the frontal diploic space. Mastoids were well aerated. The chest was unremarkable except for sclerotic clavicles with hyperostosis especially medially. Scapulae were dense in the coracoid processes and in the glenoids. The spine was normal. The pelvis showed sclerosis at the lateral aspect of the left sacroiliac joint but was otherwise unremarkable.
Proposita: Appendicular skeleton:
Each proximal humerus had an irregular, mushroom shape with a fused epiphyseal line, patchy sclerosis, lucencies, and irregularity of the metaphysis (Fig. 4). The greater tuberosity was prominent. The forearm bones showed cortical thickening in their middiaphyseal portions. The trabecular pattern, particularly in the radial metaphyses, was coarse (Fig. 5). Carpal bones were not involved. Metacarpals (most notably the third) were undertubulated causing expansion of the medullary cavities (Fig. 6). All proximal and middle phalanges were abnormal with areas of sclerosis, cortical thickening, small lucencies, and metaphyseal flaring. Epiphyses of the proximal phalanges were relatively enlarged and flattened, and they overlapped metacarpal heads probably because of mild flexion. The tubular bones of the hand were shortened, especially the middle and distal phalanges. Epiphyses of the distal first phalanges were fused. The femurs had coarse trabeculation proximally giving rise to linear striations distally. The right midtibia was sclerotic with some loss of definition of the inner cortex. The distal tibias showed some sclerosis and undertubulation (Fig. 7). Both feet exhibited sclerosis, thick trabeculae, lucencies especially in the first metatarsals and proximal phalanges, and metatarsal undertubulation.
Mother: Axial skeleton:
The skull showed calvarial thickening with patchy sclerosis and small lucencies throughout the diploic space in the frontal, parietal, and superior portion of the occipital bones (Fig. 8). Sinuses and mastoids appeared well aerated. The mandible was edentulous. The clavicles showed marked irregular cortical thickening with the greatest thickening medially. Diffuse, patchy sclerosis affected the ribs, which were not expanded. The sternum was unremarkable, but the scapulae had some sclerosis laterally. Multiple biconcave deformities involved the thoracic vertebral bodies, which appeared markedly osteopenic with prominent vertical trabeculae. The lumbar vertebrae were relatively spared without significant fractures or end plate thickening. Their trabecular pattern was unremarkable. The pelvic flat bones showed some sclerosis on the inner aspects of the iliac bones. Visualized portions of the sacrum appeared normal.
Mother: Appendicular skeleton:
The humeri were shortened and undertubulated with irregular cortical thickening throughout the diaphyses (Fig. 9). Humeral heads were deformed, especially the left. Lucent and sclerotic areas were seen at both ends of the humeri. The radii and ulnas had marked, irregular, cortical thickening and focal, linear, lytic and sclerotic areas in the distal radii (Fig. 10). The hands showed some irregular cortical thickening, metaphyseal widening, marked expansion of the right third proximal phalanx, some phalangeal shortening, patchy areas of sclerosis in the carpals, and narrowing of the radiocarpal and intercarpal joints (Fig. 11). The left third digit was dislocated at the PIP joint. The hip joint space was mildly narrowed with hypertrophic changes in the femoral head. The femora showed some coarsening of the load-bearing trabeculae, patchy areas of sclerosis and lucencies, and distally had Erlenmeyer flask deformities. Cortical thickening caused a waviness of both the endosteum and periosteum. More proximally in the femora, periosteal surfaces were smooth. An area of soft-tissue ossification extended cranially from the left greater trochanter. The left femur was mildly bowed. The tibias and fibulae showed undertubulation and expansion with mild valgus bowing deformities (Fig. 12). The cortices were widened with some wavy periosteal and endosteal thickening. Metaphyseal trabeculae were coarse. Linear lucent and sclerotic areas were present. No Looser's zones were seen in the femora or tibias. Some narrowing involved the tibiotalar joints bilaterally, likely because of secondary osteoarthritis. The feet showed forefoot varus and cortical thickening of the metatarsals, especially medially. Proximal phalanges had metaphyseal flaring with thin sclerotic diaphyses. Patchy areas of sclerosis were noted in the tarsal bones. A Morton's deformity (shortening of the first metatarsal relative to the second) was present bilaterally.
Low bone mineral density (BMD), compared with age-matched normals, was recorded in the lumbar spine in both the proposita and her mother. Appendicular (radius and hip) BMD was normal in the mother (Table 2).
Iliac crest sections, embedded in methylmethacrylate, showed strikingly increased cortical porosity with cutting cones containing abundant osteoclasts and osteoblasts (Fig. 13A). Elsewhere, numbers of osteoclasts and osteoblasts were also excessive. Many of the osteoclasts appeared enlarged, but not to the extent seen in Paget's bone disease (PBD). Numerous resorption bays were present in the trabecular bone, leading to a considerable increase in the surface-to-volume ratio. This was most pronounced in the cortex with loss of cortical volume. The osteoid thickness was increased. Polarized-light microscopy showed only lamellar collagen. UV-light microscopy revealed a larger than normal percentage of the trabecular bone surface having single or double labels of tetracycline fluorescence indicating that the rate of bone formation was enhanced. There was no peritrabecular fibrosis. Additionally, there was no mosaic pattern found in PBD. Dynamic histomorphometry showed the mineral appositional rate was normal (Table 3).
Paraffin-embedded sections, stained with either the Masson or Goldner method, showed resorption cavities in lamellar bone containing osteoclasts and osteoblasts on opposite sides of the trabeculum. Enlarged osteocyte lacunae and “reversal lines” (mosaic pattern) were not observed.
Mother: Light microscopy:
Light microscopy of the iliac crest specimen embedded in methylmethacrylate showed an increase in the cortical width and an overall excess of bone (Fig. 13B). Trabecular bone mass was increased markedly (Table 3). The numbers of osteoblasts and osteoclasts were increased. However, osteoid and eroded surfaces were decreased. Osteocyte morphology was normal. Polarized-light microscopy showed all bone collagen was lamellar. UV-light microscopy indicated a markedly decreased rate of bone formation with scattered single fluorescent labels and few double labels. Dynamic histomorphometry showed a markedly decreased mineral appositional rate (Table 3).
Thick (1 μm), toluidine blue-stained sections showed small chips of trabecular bone with adjacent fibrous bone marrow containing fat globules. No resorption cavities, osteoclasts, or osteoblasts were found. Osteocytes were absent from lacunae, some of which appeared slightly enlarged. Only lamellar bone was observed. No cement lines or reversal lines were noted. However, the lamellae were structurally abnormal. In some areas, collagen bundles ran in groups curving through the bone across the usual parallel layers.
Thin sections, stained with lead and uranyl acetate, showed cells on the bone surface that were elongated with scant cytoplasm. Their dark nuclei appeared compressed and necrotic or apoptotic. Marrow spaces contained lipid droplets and abundant amorphous material. Sometimes, remnants of cytoplasm containing mitochondria and a few lysosomes were seen. Erythrocytes and polymorphonuclear leukocytes appeared well preserved, despite proximity to necrotic bone cells (Fig. 14). No active osteoblasts or osteoclasts were found, and, therefore, presence of viruslike nuclear inclusions resembling those observed in PBD could not be investigated. Lacunae containing remnants of osteocytes were embedded in necrotic areas. Often, there was a thin lamina limitans on an irregular surface in which collagen bundles protruded. Most osteocytes showed no evidence of osteocytic osteolysis, although apparently enlarged lacunae were seen occasionally in the thick sections. Flocculent debris and occasional apoptotic nuclei were found in the osteocyte lacunae. The bone matrix was interesting also. Collagen fibers were sometimes aligned forming lamellar bone, but more often they were arranged in small bundles randomly dispersed like broken columns.
Viral transcript studies
Measles virus transcripts were not detected in peripheral blood leukocytes from the proposita or her mother (Fig. 15).
The proposita's karyotype was normal (46,XX).
We describe a new familial metabolic bone disease. After an overview of this condition, a brief discussion follows summarizing the differential diagnosis and how the candidate disorders differ from ESH.
The principal features of ESH are consistent in the proposita and her mother and include early onset deafness, premature loss of teeth, and progressive expansion of long bones that is especially painful in the fingers. Episodic hypercalcemia has been documented only in the mother, but her daughter just recently developed skeletal symptoms and is reaching the age when this complication might manifest. Serum ALP activity and additional markers of bone remodeling are elevated considerably in both individuals and are in keeping with the histopathological findings indicating rapid skeletal turnover before treatment. Apparently, the mother's skeletal disturbance was influenced by intercurrent illnesses and pregnancies.(4) Her bony changes are more severe. Hence, ESH seems to be a progressive disorder, with periods of exacerbation, at least until middle age.
Deafness is the earliest clinical problem. Both the mother and the daughter developed a hearing deficit in infancy that was complete by early childhood. Unfortunately, we were unable to investigate this complication. Nevertheless, compression in the VIIIth cranial nerve does not seem to be at fault because the proposita essentially had unremarkable skull radiographs at the age of 11 years. Instead, there may be a dysostosis—the mother reportedly has absence of middle ear bones.(4) Of interest, early-onset deafness occurs in other disorders that feature rapid skeletal remodeling. In familial expansile osteolysis (FEO), necrotic degeneration of middle ear bones and other abnormalities can lead to deafness.(9,10) Hearing loss is frequent in JPD, and conductive deficits have been reported.(11) Finally, deafness from a variety of mechanisms is common when PBD involves the temporal bone.(12)
Premature tooth loss during childhood or early adult life also seems to characterize ESH. The pathogenesis is unclear. We did not see radiographic abnormalities in the mandible of the proposita. However, the mother's X-rays showed edentia and osteosclerosis. Early tooth loss is also a feature of FEO(13) and JPD(14,15) and sometimes occurs in PBD.(16)
Skeletal symptoms in ESH begin before puberty, at about 10 years of age. Bony expansion at the PIP joints understandably can be mistaken as “arthritis,” yet articular surfaces do not feel hot, although they can be tender. The hands suffer the greatest discomfort and deformity. Possibly, the pain is caused by periosteal stretching or joint distortion. We do not know if the proposita's abnormal blood test at the age of 6 years indicated elevated serum ALP activity. If so, the generalized bone disturbance of ESH could be present and detected long before symptoms manifest. However, it is interesting that the proposita's bone pain and finger swelling started soon after a fracture at a remote skeletal site. Perhaps the fracture provoked a sustained, global, skeletal reaction leading to symptoms. In fact, skeletal trauma has been postulated to cause the focal osteolytic defects of PBD.(16) However, we were unable to find this speculation in the literature for the osteolytic lesions of FEO.
Radiographic survey of the mother showed that ESH eventually disturbs the entire skeleton. Her calvarium (excluding the basal occiput), thoracic vertebral bodies, and long bones were affected most. The major abnormalities are a combination of hyperostosis (cortical thickening) and expansion (undertubulation) of long bones whether large or small. In fact, the most remarkable changes involve the fingers in which phalangeal expansion can be extraordinary. Squaring occurred in the proximal phalanx of her right third digit. In addition, bowing of long bones, particularly the femora, and an unusual mushroom-shaped deformity of the humeral heads were noted. The daughter's radiographic changes were similar but less severe. Her principal findings were early, distinctive changes in the feet and, less so, in the hands.
Biochemical parameters of mineral homeostasis in ESH are usually normal. However, the mother experienced episodic, marked hypercalcemia spontaneously during childhood as well as during intercurrent illness and lactation.(4) Chosich and colleagues postulated that her hypercalcemia was caused by these perturbations acting on rapid skeletal turnover because of JPD(4); accelerated skeletal remodeling was uncoupled by factors that enhanced osteoclastic activity, including lowered estrogen levels during lactation.(4) Elevated markers of skeletal turnover in both the proposita and her mother suggest that osseous tissue is in fact remodeling rapidly in ESH. Histological studies showed increased numbers of osteoblasts and osteoclasts. In the proposita, accelerated skeletal turnover was also suggested by the increase in cellular resorptive activity.(8) Dynamic histomorphometry after tetracycline labeling showed that her mineral apposition rate was normal.(8)
It is interesting that the total bone volume in the iliac crest specimen was markedly increased in the mother and was normal in the proposita despite her active skeletal turnover. In the mother, resorption was noted primarily in the cortex. Although trabecular erosion was observed, it was much less than in the cortices. In the daughter, active resorption of cortical and trabecular bone was occurring; however, there were no morphological signs of true osteopenia (i.e., “button” islands of bone, cutting cones, etc.). The daughter's iliac crest specimen appeared osteopenic compared with her mother's specimen, but this was an illusion caused by significant “Haversianization” of the cortex; the total bone volume was normal. Peritrabecular fibrosis was not present. There were reversal lines, but not those of PBD. The reversal lines suggest an episodic pattern of activity. Puberty may, through hormonal factors, influence the expression of ESH.
These morphological features are consistent with the radiographic studies. The coarse trabecular lines evident on skeletal survey could result from cortical bone loss, providing a “window” showing comparatively thicker trabecular struts. Also unexplained is the swelling of the middle fingers and the reason for the osteopenia in the lumbar region documented by DEXA. Because DEXA provides an areal measurement of BMD, there could be some inaccuracy produced by widened bones.
The location of the bone resorption is of interest. The mother manifests early erosion of the Haversian canals in the cortex without corresponding resorption in the trabecular compartment. There is a lack of formation (i.e., osteoid production) as well, although the bone volume is almost twice normal. There is no indication as to the mechanism of the initial increased bone deposition, but she had received bisphosphonate treatment years earlier. The daughter shows significant resorption of the cortex suggesting progressive cortical bone loss. Her trabecular bone shows increased bone loss, but not to the same degree as the bone loss in the cortex. It is unclear as to the mechanism of predilection for osteoclastic activity in that compartment.
The etiology of ESH is unknown, but the disorder is familial and likely heritable. Because two females in successive generations are affected, either autosomal or X-linked dominant transmission is possible, although the former is more common.(2) The mother had no similarly affected family member. Therefore, she seems to represent the new mutation for this highly penetrant condition. Unfortunately, routine karyotyping did not reveal a chromosomal defect, and this nonconsanguineous family is too small for genetic mapping. Hence, it will be necessary to investigate candidate genes.
Although the mother's skeletal symptoms did not diminish during treatment with antiresorptive therapy (synthetic salmon calcitonin, etidronate, or pamidronate), the treatment seemed helpful for her hypercalcemia.(4) A trial of alendronate treatment—effective in JPD,(17) FEO (M.P.W., personal observation, 1998), and PBD(18)—was recommended to the proposita and her mother, but they returned to Australia and were lost to follow-up.
The candidate disorders in the differential diagnosis for ESH comprise progressive diaphyseal dysplasia (PDD), FEO, PBD, and the mild form of JPD. As reviewed briefly in the following paragraphs, each condition seems to be excluded in our patients.
PDD (MIM 131300), also called Camurati-Engelmann disease, is a well-characterized autosomal dominant disorder.(2,19) Recently, PDD was mapped to chromosome 19q13.1-q13.3.(20) PDD features acquired hyperostosis of the major long bones.(3,21) The principal symptom, pain in the major limb bones, typically occurs in the lower extremities and responds to glucocorticoid therapy.(19,22) In addition, pamidronate given orally may help.(23) Myopathy is also characteristic.(19, 22, 23) Deafness can occur in adult life when axial involvement includes the skull.(24) We did not find reports of discomfort in the hands or premature loss of teeth in PDD. Biochemical parameters of mineral homeostasis usually are within normal ranges, although serum ALP activity and urinary hydroxyproline can be increased mildly.(19, 22, 23) A key distinguishing radiographic feature of PDD is that hyperostosis does not spread to the ends of long bones.(3,21) Furthermore, undertubulation of long bones is not characteristic.(3,21) Hence, ESH seems to be different from PDD.
FEO (MIM 174810) has been reported in just two families(2) and described in detail in only the large Northern Ireland kindred.(9,25) For the past 30 years, we have investigated and followed a five-generation family with FEO in St. Louis, MO (FEO(Am)). However, only the audiological findings have been reported.(10) In 1994, FEO was mapped to chromosome 18q21.1-22.(26) This year, the molecular defect causing FEO was discovered in both reported families and the American kindred. The mutation is an 18 base pair tandem duplication in the signal peptide sequence of the TNFRSF11A gene, which encodes receptor activator of nuclear factor κB (RANK).(27)
FEO is inherited as a highly penetrant, autosomal dominant disorder(2,9) and features acquired, painful, deforming expansion of one or a few major long bones.(9,25) Occasionally, bones in the hands are involved.(9) FEO is also associated with acquired deafness, premature tooth exfoliation caused by root resorption, and generalized osteopenia.(13) Hearing loss can be caused by spontaneous necrosis of middle ear ossicles(10) as well as by absence, thinness, or replacement by fibrous tissue of the long process of the incus, fixation of the stapes footplate, or compression of the auditory nerve.(9) Serum ALP levels and other biochemical markers of bone remodeling indicate accelerated skeletal turnover.(9,25) FEO(Am) responds well to alendronate therapy (M.P.W., personal observation, 1998), whereas in the Northern Ireland family various drugs helpful for PBD have not produced sustained improvement.(9) On radiographic and histopathological assessment, the lytic skeletal lesions of FEO resemble the early, destructive phase of PBD.(9,25) Eventually, however, the osteolytic areas become filled with fat.(28) As in PBD, measles virus transcripts have been obtained from circulating leukocytes from FEO(Am) patients.(29)
ESH resembles FEO in several important ways, but the episodic hypercalcemia, extraordinary painful involvement of fingers, obvious changes in the mother's skull, and considerable nonosteolytic expansion of multiple long bones are not characteristic of FEO.(9) Hence, ESH does not seem to be a form of FEO.
PBD (MIM 167250) often affects family members,(2, 18, 30) yet rarely troubles three or more generations.(30) At a few sites (e.g., her tibias), the radiographic appearance of the mother's skeletal lesions is typical of PBD.(16,21) Furthermore, in ESH numerous osteoblasts and increased numbers of osteoclasts are noted—histopathological features consistent with PBD.(18) Skeletal turnover is accelerated in both PBD and ESH.
However, other skeletal sites featuring hyperostosis in ESH do not have the “tracked” radiographic appearance typical of PBD.(21) Unlike in PBD,(18) iliac crest osteoclasts in ESH were not extremely large. Furthermore, the mosaic pattern of reversal lines characteristic of PBD(16,18) was not found in the trabecular bone. However, we did not biopsy focal skeletal lesions. Chosich and colleagues reported that the cystic area in the mother's left hand showed marked osteoblastic and osteoclastic activity.(4) In ESH, the young age at presentation, hypercalcemia, eventual diffuse nature of the skeletal disease, and undertubulation of major long bones with remarkable expansion of phalanges in the hand are not features of PBD.(16, 18, 21) No osteoclasts were observed by EM in the mother's bone, precluding further search for the viral inclusion bodies identified in PBD.(31) However, paramyxovirus gene transcripts found in PBD blood(7) were not detected in circulating mononuclear cells from either the proposita or her mother. Hence, ESH does not seem to be a form of PBD.
JPD (MIM 239000), also called hereditary hyperphosphatasia, usually is diagnosed in infants or young children.(1,2) Approximately 40 cases have been reported(1, 2, 32) and several reviews have been published recently.(32,33) Skeletal remodeling is rapid, causing hyperphosphatasemia.(1,32) Skeletal disease usually does not manifest until childhood.(32) Accordingly, there are severe and especially rare mild forms of JPD.(1,32) Both disorders are considered autosomal recessive conditions.(2) Like ESH, JPD affects the entire skeleton.(21) The chromosomal location(s) of the defective gene(s) is unknown.(2)
Severe (congenital) JPD manifests in infants who suffer fracture and deformity.(1, 2, 21) Radiographs show marked expansion (undertubulation) of long bones with thin cortices.(21) These changes reflect extremely rapid skeletal remodeling inferred by markedly elevated biochemical markers of bone turnover(1) and supported by histopathological findings.(32) Severe JPD responds to antiresorptive therapy, including human calcitonin(1) and bisphosphonates.(17)
Mild JPD causes less bony deformity and fewer fractures.(32) There is diffuse, acquired hyperostosis and osteosclerosis associated with biochemical and histological evidence of rapid skeletal turnover.(32) Indeed, Chosich and colleagues suggested that the proposita's mother had a mild form of JPD.(4)
Some of the clinical, radiographic, biochemical, and histopathological abnormalities of ESH resemble mild JPD.(1, 20, 32) Hyperphosphatasemia, undertubulation of long bones, hyperostosis, osteosclerosis, and bowing deformity associated with increased serum ALP activity from accelerated bone remodeling would fit well with JPD. Premature loss of teeth(14,15) and deafness(11) also occur. Furthermore, a mosaic pattern in bone is not found in JPD. Measles virus transcripts, commonly found in PBD,(7) have not been detected in peripheral blood leukocytes in mild(34) or severe JPD (M.P. Whyte, S.V. Reddy, and G.D. Roodman, unpublished observation, 1998).
However, to our knowledge, the deformities of the greater tuberosities of the humeri in our patients, and especially the bony expansion in their hands and feet, have not been described in JPD.(21) Furthermore, ESH seems to be transmitted as a highly penetrant autosomal dominant trait, whereas JPD is an autosomal recessive disorder.(2) We note that in first-cousin parents with two affected offspring with severe JPD, the mother had a large head, wide face, and radiographic changes in several skeletal areas similar to, but less severe, than in her children.(35) Perhaps these were manifestations in a carrier mother. However, we did not find any report of autosomal dominant transmission of JPD. Hence, ESH does not seem to be a form of JPD.
Solitary, expansile lesions of bone can occur in several benign or malignant skeletal neoplasms and in a variety of disorders that produce tumorlike lesions.(36) However, these conditions are readily excluded, especially by the diffuse nature of the skeletal disease in ESH.
In 1999, a three-generation family was reported with expansile bone lesions, cortical thickening of the proximal long bones, and pathological features most like genochondromatoses, a form of symmetric chondromata.(37) However, the lesions affected the distal radius and ulna.
Pseudorheumatoid dysplasia causes painful expansion of bones in the hands(21) due to mutations involving the WISP3 gene,(38) but this is an autosomal recessive form of spondyloepiphyseal dysplasia.(2)
Kashin-Beck disease is an endemic, degenerative, chronic osteoarticular disorder prevalent in China.(39) This condition features short stature caused by multifocal necrosis in the growth plates and metacarpal and phalangeal widening(39) caused by high concentrations of fulvic acid and selenium in drinking water.(40)
ESH seems to be distinctly different from all these additional disorders.
We are grateful to Dr. Peter Schlesinger, Hennepin County Medical Center, Minneapolis, MN, for referring the proposita. Dr. S.V. Reddy helped search for measles virus transcripts. Dr. S.L. Teitelbaum reviewed the iliac crest light microscopy. Darlene Harmon provided expert secretarial help. This report was made possible by the dedication and skill of the nursing, dietary, and laboratory staffs of the MRU, Shriners Hospital for Children, St. Louis, MO. This work was supported in part by grant 15958 from Shriners Hospital for Children and by the Clark and Mildred Cox Inherited Metabolic Bone Disease Research Fund.
- 11996 Hyperphosphatasia syndromes. In: CohenMMJr, BaumBJ (eds.) Studies in Stomatology and Craniofacial Biology. IOS Press, Amsterdam, The Netherlands, pp. 245–272.,
- 21998 Mendelian Inheritance in Man: A Catalog of Human Genes and Genetic Disorders, 12th Ed. Johns Hopkins University Press, Baltimore, MD, U.S.A.
- 31987 Osteosclerosis, Hyperostosis, and Related Disorders. Elsevier, New York, NY, U.S.A., ,
- 41991 Post-partum hypercalcemia in hereditary hyperphosphatasia (juvenile Paget's disease). J Endocrinol Invest 14:591–597., , , ,
- 51973 Clinical research diets: Definition of terms. J Am Diet Assoc 62:47–51.,
- 61999 Polycystic bone disease: A new, autosomal dominant disorder. J Bone Miner Res 14:1261–1271., , ,
- 71996 Detection of measles virus nucleocapsid transcripts in circulating blood cells from patients with Paget's disease. J Bone Miner Res 11:1602–1607., , ,
- 81996 Biopsies. In: BilezikianJP, RaiszLG, RodanGA (eds.) Principles of Bone Biology. Academic Press, San Diego, CA, U.S.A., pp. 1333–1342.
- 91996 Familial expansile osteolysis: A genetic model of Paget's disease. In: SharpePT (ed.) The Molecular Biology of Paget's Disease. RG Landes, Heidelberg, Germany, pp. 179–199.,
- 101996 Conductive hearing loss caused by hereditary incus necrosis: A study of familial expansile osteolysis. Otolaryngol Head Neck Surg 114:639–641., ,
- 111978 Chronic familial hyperphosphatasia. Radiology 129:669–676., , , ,
- 121992 MRI of Paget's disease with temporal bone involvement presenting with sensorineural hearing loss. J Comput Assist Tomogr 16:314–316., ,
- 131990 Dental abnormalities associated with familial expansile osteolysis: A clinical and radiographic study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 70:301–307., ,
- 141968 Congenital hyperphosphatasia: A clinical, pathological, and biochemical study of two cases. J Bone Joint Surg Am 50:1099–1117.,
- 151977 Familial idiopathic hyperphosphatasia: A study of two young siblings treated with porcine calcitonin. J Bone Joint Surg Br 59:421–427., , ,
- 161981 Paget's Disease of Bone: Assessment and Management. Praeger Publishers, New York, NY, U.S.A.
- 171996 Hereditary hyperphosphatasia: Response to oral alendronate in a 5 year old child. J Bone Miner Res 11(Suppl 1):S254. (abstract), , ,
- 181998 Pathophysiology and Treatment of Paget's Disease of Bone, 2nd Ed. Blackwell Science, Malden, MA, U.S.A.
- 191977 Clinical and biochemical studies in Engelmann's disease (progressive diaphyseal dysplasia). QJM 46:273–294., , ,
- 202000 Genetic mapping of the Camurati-Engelman disease locus to chromosome 19q13.1-q13.3. Am J Hum Genet 66:143–147., , , , , , , , , ,
- 211995 Diagnosis of Bone and Joint Disorders, 3rd Ed. WB Saunders, Philadelphia, PA, U.S.A.
- 221985 Progressive diaphyseal dysplasia: Evaluation of corticosteroid therapy. Pediatrics 75:321–323., , ,
- 231997 Clinical, humoral and scintigraphic assessment of a bisphosphonate as potential treatment of diaphyseal dysplasia: Ribbing and Camurati-Engelmann diseases. Medicina 57(Suppl 1):56–60., ,
- 241994 Otolaryngological aspects of Camurati-Engelmann disease (progressive diaphyseal dysplasia): Review of literature and report of one case. Acta Otorrinolaringol Esp 45:207–213., , , , ,
- 251988 Familial expansile osteolysis: A new dysplasia. J Bone Joint Surg Br 70:255–260., , , , , , , , ,
- 261994 Genetic linkage of familial expansile osteolysis to chromosome 18q. Hum Mol Genet 3:359–361., , , , , , ,
- 272000 Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis. Nat Genet 24:45–48., , , , , , , , , ,
- 281991 Familial expansile osteolysis: A morphological, histomorphometric and serological study. Bone 12:331–338., , , , ,
- 291996 Evidence of a locus for Paget's disease of bone on human chromosome 18q. J Bone Miner Res 11(Suppl 1):S99. (abstract), , , , , ,
- 301997 Paget's bone disease involving young adults in 3 generations of a Korean family. Medicine (Baltimore) 76:157–169.., , , , , , , , , , ,
- 311976 Nuclear inclusions in Paget's disease of bone. Science 194:201–202.,
- 321996 Juvenile Paget's disease: Life-long features of a mildly affected young woman. J Bone Miner Res 11:132–142., , , , , , ,
- 331994 Hereditary hypophosphatasia and hyperphosphatasia. Curr Opin Rheumatol 6:336–339.
- 341996 Absence of paramyxovirus transcripts in juvenile Paget's bone disease. J Bone Miner Res 11:1041. (letter), , ,
- 351964 Familial osteoectasia with macrocranium. Am J Roentgenol 91:609–617., ,
- 361993 Reeder and Felson's Gamuts in Bone, Joint, and Spine Radiology: Comprehensive Lists of Roentgen Differential Diagnosis. Springer-Verlag, New York, NY, U.S.A.,
- 371999 Expansile bone lesions in a three-generation family. Am J Med Genet 82:1–5., , ,
- 381999 Mutations in the CCN gene family member WISP3 cause progressive pseudorheumatoid dysplasia. Nat Genet 23:94–98., , , , , , , , , , , , , , ,
- 391998 Kashin-Beck osteoarthropathy in rural Tibet in relation to selenium and iodine status. N Engl J Med 339:1112–1120., , , , , , , , ,
- 401999 The role of humic substances in drinking water in Kashin-Beck disease in China. Environ Health Perspect 107:293–296., , , , , ,