Henry Ford Hospital Medical Journal Henry Ford Hospital Medical Journal

Volume 36 Number 3 Article 7

9-1988

Paget Bone Disease and Heredity: A Case Report Paget Bone Disease and Heredity: A Case Report

Donato Agnusdei

Roberto Civitelli

Angelo Camporeale

Carlo Gennari

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Recommended Citation Recommended Citation Agnusdei, Donato; Civitelli, Roberto; Camporeale, Angelo; and Gennari, Carlo (1988) "Paget Bone Disease and Heredity: A Case Report," Henry Ford Hospital Medical Journal : Vol. 36 : No. 3 , 150-152. Available at: https://scholarlycommons.henryford.com/hfhmedjournal/vol36/iss3/7

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Paget Bone Disease and Heredity: A Case Report

Donato Agnusdei, MD,* Roberto Civitelli, MD,̂ Angelo Camporeale, MD,* and Carlo Gennari, MD*

Evidence on familial aggregation of Paget disease of bone shows that the trait is controlled by a single dominant gene .Due to the late onset ofthe disease, the primary biochemical abnormalities leading to the characteristic roentgenographic features are still unknown. We report the case of a 24-year-old woman who had an elevated serum alkaline phosphatase on routine analysis. Family history revealed that her father arui paternal grandmother had Paget bone disease. This pattern is compatible with an autosomic dominant inheritance. Complete laboratory workup confirmed high heat labile alkaline phosphatase values, along with high serum osteocalcin and urinary hydroxyproline excretion. Skeletal x-ray and bone scan were negative. The 24-hour body retention o/""Tc-methylenediphosphonate was elevated, suggesting high bone turnover. Dual photon densitometry of distal radius, femoral shaft, and lumbar spine revealed lower than normal bone density at all sites. The existence ofa high bone turnover disease and osteopenia in a member of a family with high incidence of Paget disease might represent an abnormality linked to the "Pagetic trait," although an occasional association cannot be ruled out. (Henry Ford Hosp Med J 1988;36:150-2)

S ir James Paget, in his original description of osteitis defor­mans, wrote in 1889: " I have tried in vain to trace any hered­

itary tendency to the disease. 1 have not found it twice in the same family" (1). However, the observations of familial ag­gregation reported from even before that time are fairly numer­ous, and the role of heredity in the production of this disease has been stressed repeatedly (2-13). Familial history of the disease has been identified in several instances, with reports indicating that several members of a family in various generations and identical twins may be affected (11,14,15).

There is no agreement regarding the mode of inheritance. In general the data are consistent with the view that the trait for Paget disease is controlled by a simple autosomal Mendelian dominant gene (9,16). However, some authors suggested that it is inherited as a sex-linked recessive or incompletely dominant gene (10,14,17).

Case Report A 24-year-old white woman (weight 53 kg [116.6 lb], height 164 cm

[65.6 in]) was referred to us because she had an elevated semm alkaline phosphatase on routine analysis. Family history revealed that her father, her patemal grandmother, and two brothers of her grandmother were affected by Paget bone disease. Details of the family are depicted in the genealogical diagram shown in Fig 1.

The patient was asymptomatic and did not complain of bone pain. Clinical evaluation was unremarkable. No bowing or deformities of ex­tremities were present. No areas of increased skin temperature were noted. Her calcium intake was calculated at about 800 to 1,000 mg/day. The neurologic examination was negative, and no Trousseau or Chvostek signs were present.

Complete metabolic laboratory workup revealed reduction of total semm calcium with normal values of ionized calcium, normal levels of phosphate, and increased parathyroid hormone circulating levels sug­gesting a secondary hyperparathyroidism associated with a slight in­crease in l,25(OH)2D3 semm levels. An elevated alkaline phosphatase was confinned along with increased hydroxyproline/creatinine ratio ex­cretion, semm osteocalcin, and 24-hour whole-body retention of'''"'Tc-methylenediphosphonate, suggesting a high tumover bone disease.

An important decrease in urinary calcium/creatinine ratio excretion and severe impairment of intestinal calcium absorption, evaluated by calcium-47 oral test, were also observed. Bone mineral content, mea­sured by dual photon absorptiometry at three different sites—lumbar spine, femoral shaft, and distal radius—showed a reduction of bone mineral below the normal range of normal, age-matched women. Func­tional and biochemical features are shown in the Table.

A complete skeletal x-ray survey was performed. No bone lesions were observed in the axial skeleton and upper limbs. X-rays of both femurs showed a "lance-like" appearance of distal extremity (Fig 2). Although not diagnostic, this radiographic finding may be suggestive of initial "Pagetic" osteodystrophy.

A bone scan with '̂ '"Tc-methylenediphosphonate revealed an in­creased uptake of the radioactive tracer, especially in the long bones. There was no evidence of localized areas of increased uptake. Whole-body retention was 48%. This picture is compatible with high bone tumover.

*Institute of Medical Semeiotics. University of Siena, Italy. tDivision of Endocrinology and Bone and Mineral Metabolism. Washington University

Medical Center. St Louis. MO. Address correspondence to Dr Civitelli. Division of Endocrinology and Bone and Min­

eral Metabolism, Washington University Medical Center. 216 S Kingshighway, St Louis. MO 63110.

150 Henry Ford Hosp Med J—Vol 36, No 3, 1988 Paget Bone Disease and Heredity—Agnusdei et al

I O j « 9 ®

11 o m o o o

... (D- f 9 cf

9 d 9

• REPORTED CASE

@ PAGET BONE DISEASE

O NON PAGET

Fig I—Pedigree of four generations.

Table Functional and Biochemical Features

Normal Range

BMC: Lumbar spine (g/cm )̂ 0.69 (0.85-1.11) BMC: Femoral shaft (g/cm )̂ 1.20 (1.35-1.55) BMC: Distal radius (mg/cm )̂ 307 (411-529) Ca2+ Intestinal absorption (fx) 0.092 (0.220 ± 0.040) 24-hour '»'"Tc-MDP WBR (%) 48 (34 ± 7) Serum total Ca (mg/dL) 7 (8.6-10.4) Serum Ca^^ (mEq/L) 2.20 (2-2.30) Alkaline phosphatase (UKA) 33.5 (5-14) Urinary Ca/Cr (mg/g) 10.8 (35-160) Urinary HOP/Cr (mg/g) 82.2 (7-19) PTHC-ter(ng/ml,) 0.70 (0-0.88) PTH MM (ng/mL) 0.40 (0.05-0.31) Osteocalcin (ng/mL) 14 (2.2-6.6) 25(OH)Di (ng/inL) 71.2 (50-90) l,25(OH)2D3 (pg/mL) 41.7 (29.4 ± 6.5)

An iliac crest bone biopsy was also performed. Undecalcified I mi­cron thick slices were stained with Azur II , methylene blue, which stains the osteoid and leaves the calcified matrix unstained. Histological examination showed several trabeculae almost completely surrounded by a large osteoid seam (Fig 3) and resorption lacunae with active os­teoblasts inside. The electron microscopy evaluation showed no evi­dence of viral inclusions in the nuclei of osteoclasts examined.

Discussion Although the clinical findings do not allow a precise diag­

nosis in this case, the radiologic findings and the family history of Paget disease may be indicative of a disease in the initial phase. The high turnover bone disease might be the conse­quence of the extremely reduced intestinal calcium absorption with associated hypocalcemia.

Reduced calcium bioavailability may partly explain the min­eralization defect which was present in this patient despite nor­mal serum phosphate and slightly elevated l,25(OH)2D3 serum levels. The reasons for impaired intestinal calcium transport and its possible link with the "Pagetic trait" are obscure. Regarding the inheritance of Paget bone disease, further genetic studies are needed to clarify the primary biochemical abnormalities leading to the characteristic roentgenographic features of the disease.

Fig 2— "Lance-like" aspect of distal femur.

Fig 3—Resorption lacuna with active osteoclasts inside (arrow) (Azur II, methylene blue staining).

References 1. F̂ get J. Remarks on osteitis deformans. Illus Med News 1889;2:181-2. 2. Evens RG, Bartter FC. The hereditary aspects of Paget's disease. JAMA

1968;205:900-2. 3. Galbraith HJ. Familial Paget's disease of bone. Br Med J [Clin Res]

1954:2:29. 4. Irvine RE. Familial Paget's disease with early on.set. J Bone Joint Surg

1953:358:106-12. 5. KayHD, Levy-Simpson S, RiddochG, VilvandreGE. Osteitis deformans,

with roentgenologic section. Arch Intern Med 1934:53:208-48. 6. Koller F. Uber die Hereditat per ostitis deformans Paget. Helv Acta Med

1946;13:389-400. 7. LasserreC. Les osteopathies hypertrophiantes. Revue d'Orthopalmologie

1931;18;457-543.

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8. Martin E. Considerations sur la maladie de Paget. Helv Acta Med 1947:14:319-33.

9. McKusick VA. Inheritable disorders of connective tissue. 4th ed. St. Louis: CV Mosby Co, 1972.

10. Montagu MFA. F^get's disease and heredity. Am J Hum Genet 1949; 1:94-5.

11. Rast H, Weber PF. Paget's bone disease in three sisters. Br Med J [Clin Res] 1937;1:918.

12. Ravault P, Lejeune E, Robert J, Maitrepierre J. Les formes familiales de la maladie osseuse de Paget. Revue de Rhumatisme et des Maladies Osteo-articulaires 1963;30:824-31.

13. Seze S, Welfing J. Maladie de Paget familiale. Revue de Rhumatisme et des Maladies Osteoarticulaires 1950:17:23-5.

14. Aschner B, Hurst LA, Roizin L. A genetic study of Paget's disease in monozygotic twin brothers. Acta Geneticae Medicae ed Gemellologiae 1952;1:67-9.

15. Jones JV, ReedMF. Paget's disease: A family with 6 cases. BrMed J [Clin Res] 1967;4:90-1.

16. Lievre JA. Donnees cliniques et etiopathogeniques sur la maladie de Paget. J Beige de Rheumatologie et de Medecine Physique. 1974;29:322-32.

17. Hamdy RC. Paget's disease of bone: Assessment and management. New York: Praeger, 1981.

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