Hereditary osteodysplasia with acro-osteolysis (the Hajdu-Cheney syndrome)

Hereditary Osteodysplasia with Acre-Osteolysis

(The Hajdu-Cheney Syndrome)

ALAN N. ELIAS, MB., B.S.*

ROBERT S. PINALS, M.D.+

Syracuse, New York

H. CLARKE ANDERSON, M.D.t

Brooklyn, New York

LEO V. GOULD, M.D.

DAVID H. P. STREETEN, M.B.,

Syracuse, New York

D. PHIL.

A mother and son with acre-osteoiysis (Hajdu-Cheney syndrome) are described. in addition to osteolysis of the distal phalanges, these patients have a generalized osseous dysplasla wlth osteoporosis, premature loss of teeth, short stature and a dlstlnctlve facial appearance. In one of the cases an enlarged sella turclca was associated with no abnormality of endocrine function. A biopsy specimen taken from an area of active osteolysls in a phalanx was studied by light and electron mlcroscopy. There was active replacement of central medullary bone by a fibrous and anglomatous process characterized by the presence of small, thick-walled vessels and an unusual number of interspersed nerve fibers and mast cells. A neurovascular dysfunction with local release of osteolytk mediators may be involved in the pathogenesis of the disorder, but the nature of the osteolytic factor is unknown.

From the Departments of Medicine, Rehabilitation Medicine and Radiology, S.U.N.Y. Upstate Medical Center, Syracuse, New York, and the Department of Pathology, S.U.N.Y ., Downstate Medical Center, Brooklyn. New Yti. This paper was supported by a graduate training grant in Endocrinology (AM 07146) from the National Institute of Arthritis, Metabolism and Digestive Diseases, and a Clinical Research Center grant (RR 00229) from the Di- vision of Research Facilities and Resources, U.S. Public Health Service, Bethesda, Maryland. Re- quests for reprints should be addressed to Dr. David H. P. Streeten, Department of Medicine, Upstate Medical Center, Syracuse, New York 13210. Manuscript accepted April 26, 1978.

l Present address: University of California, Levine, Department of Medicine, 101 City Drive South, Orange, California 92668.

+ Present address: Department of Medicine, University of Tennessee, 858 Madison Avenue, Memphls, Tennessee 38 163.

t Present address: Department of Pathology, University of Kansas Medical Center, Rainbow Bldg. at 39th, Kansas City, Kansas 66103.

The term acre-osteolysis has been used to describe a diverse group of idiopathic disorders in which iysis of the bones of the distal extremities is an outstanding feature. There are differences related to the presence or absence of genetic transmission and the association with familial renal disease, neuropathy and ulcerative skin lesions (Table I). There are also several distinctive patterns and appearances of the osseous lesions.

In this report we describe the occurrence in two members of the same family of acre-osteolysis of the type described as the Hajdu- Cheney syndrome. This is a generalized osseous dysplasia in which the lytic process in the digits is most striking, but which also includes short stature, osteoporosis, premature loss of teeth and a distinctive facial appearance. Only three other families and several similar, sporadic cases have been described before [g-22]. Since there have been few studies of bone pathology and of potential endocrine factors in the pathogenesis of this disorder, we describe in this report the histologic and electron microscopic abnormalities in involved bone and the results of endocrine studies in one of these patients.

Case 1. A white woman, now 35 years old, was evaluated in 1963 for shortening and discomfort of the distal phalanges of the fingers, first noticed at the age of five. She complained of pain and swelling of the finger tips, especially after mild trauma or prolonged manual work, and blanching on exposure to the cold. Other problems included severe frontal headaches and

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HAJDU-CHENEY SYNDROME-ELIAS ET AL.

TABLE I

Syndrome

Primary Acre-osteoiysis Syndromes

Major Inheri- Character- Locations tance’ istics

Winchester Carpals, Recessive Contractures, syndrome [l] tarsals. osteoporosis,

elbows cornea1 clouding, thick skin

Carpal and tarsal Carpals, Recessive Contractures. osteolysis- tarsals, osteoporosis, recessive [ 21 phalanges subcutaneous

nodules Carpal and tarsal Carpals, Dominant Osteoporosis,

osteolysis- tarsals hand deformity, with hypertension, nephropathy nephropathy

]31 Carpal and tarsal Carpals, Sporadic Osteoporosis,

osteolysis [4] tarsals cornea1 clouding, muscle weakness, platybasia

Neurogenic Phalanges Dominant Sensory osteolysis [ 51 and neuropathy,

recessive skin ulcerations Acro-osteolysis Distal Recessive Otherwise

of Joseph [6] phalanges healthy Acro-osteolysis Phalanges Dominant Skin ulcerations

of Schinz [7] Massive Variable Sporadic Unifocal with

osteolysis extreme of Gorham [S] destruction

Hajdu-Cheney Distal Dominant Generalized syndrome phalanges and bone dysplasia,

sporadic osteoporosis

l All are autosomal.

back pain, premature loss of teeth and short stature. Her height was reported tc have been 155 cm previously but was found to be only 148lcm. in 1977,she,sustained a fracture of one metatarsal which had not completely healed when a second roentgenogram was taken seven months later. The face showed flared nostrils and a receding chin (Figure 1). The ears were low-set and the eyebrows were sparse, although they were said to have been “bushy” during childhood. Elbows and knees were hyperextensibie. The most striking physical abnormality was shortening of the distal phalanges of the fingers and a curvature of the nails which resembled cjubbing (Figure 2). There were similar changes in the toes. These changes have progressed slightly during 14 years of observation. There has never been joint swelling. The skin was of normal texture and was not hyperelastic. Hearing was normal. The palate was not high or arched. Hypertelorism was absent.

Routine hematoiogic and blood chemical measurements have been normal. Normal or negative results have been found in the urinalysis, creatinine clearance, excretion of mucopoiysaccharides and hydroxyproiine, sedimentation rate, C-reactive protein, antinuclear antibody, rheumatoid factor, protein eiectrophoresis. cryogiobulins, serum thy- roxine and triiodothyronine, and plasma cortisoi.

An enlarged seiia turcica and generalized osteoporosis prompted an endocrine investigation, with essentially negative results. The serum calcium (9.4 to 10.0 mg/lOO ml), serum inorganic phosphorus (3.8 to 5.1 mg/lOO ml), serum alkaline phosphatase (7.8 to 10.0 KA units), serum parathy- roid hormone level (281 pg/mi, when serum calcium was 10.0 mg/lOO ml) were all normal. Serum caicitonin level was normal (400 pg/mi) and did not rise after stimulation with pentagastrin (0.5 mg/kg). Adrenal stimulation with (r-1-24 ACTH increased the plasma cortisol concentration from 9.3 to 44 pg/lOO ml. in an insulin tolerance test using 0.15 U regular insulin/kg intravenously, plasma cortisol increased normally from 8.8 to 34.5 pg/lOO ml, and growth hormone from 1.1 to 33 ng/ml. After an intravenous injection of 500 pg of thyrotropin-releasing hormone, the serum thyroid- stimulating hormone (TSH) increased from 1.8 to 6.8 $J/mi in 30 minutes whereas serum triiodothyronine (Ts) increased from 113 to 158 ng/lOO ml in 3 hours (both normal re- sponses).

Case 2. The 12 year old son of the patient described began to notice finger shortening and pseudoclubbing at age seven. There have been progressive changes and mild finger discomfort associated with overuse of the hands. His fingers develop pallor in cold weather. He has noticed lumbar aching after performing heavy work, but has had no headaches.

On examination he was a pubescent male, 157 cm in height (75th percentile). His facial appearance resembled that of his mother, with low-set ears, large ear lobes, bushy eyebrows, a broad nose without hyperteiorism and a receding chin (Figure 3). Sexual development was normal. There was shortening of most of the distal phalanges with pseudoclubbing of the nails, clearly seen in the second, third and fifth fingers, but sparing the fourth finger of the left hand (Figure 4). The elbows and knees were hyperextensibie, but the skin was normal and not excessively elastic. There was no abnormal loss of teeth. The palate was normal in shape.

INHERITANCE (Figure 5)

We examined another son of the propositus (Case l), who was 15 years old; he showed no evidence of acre-osteolysis. This boy and his brother (Case 2) had different fathers, and have little resemblance to each other. The mother and brother of the propositus (Case 1) had no evidence of acre-osteolysis on roentgenograms of the hands, although the mother had a strong resemblance in general appearance to the propositus. She was 148 cm in height and had a long history of low back pain. Roentgenograms of the lumbar spine showed lumbosacral disc narrowing but no vertebral collapse or spondylolisthesis. The father of the propositus had no acre-osteoiysis on physical examination. His height was 168 cm. A sister was unavailable for study.

HLA typing was performed on both patients. The propositus (Case 1) was positive for A9, 10 and B8.27. Her son (Case 2) was positive only for A10 and 88. No abnormalities were detected on chromosome analysis in Case 2.

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Figure 1. Case 7. Profile of patient showing the receding chin.

Figure 3. Case 2. Note the bushy eyebrows, broad nose, large ear lobes and pointed, receding chin.

Figure 2. Case 1. Hands of patient in 1977. The striking shortening of the nails and terminal phalanges of several fingers is evident. The fourth finger of the right handand the third and fourth fingers of the left hand are relatively less affected, but show increased curvature and “pseudoclubbing” of the nails.

Figure 4. Case 2. Fingers of the patient’s left hand. The shortening of the distal phalanges and the curved, “pseudo-clubbed” nails of the second, third and fifth fingers contrast with the relatively unaffected 4th finger.

-_

n @ Acre-osteolys

0 0 Normal

1/1 @ Not examihed

is

L ___.._ .____

Figure 5. Family tree of patients (Cases 1 and 2).


HAJDU-CHENEY L SYNDROME-ELIAS ET AL.

6

6

ROENTGENOLOGIC FINDINGS

The x-ray appearances in this syndrome are so interesting that it is not surprising to find the first and many of the later reports in the roentgenologic literature. There is a strong similarity between the reported cases. Acre-osteolysis results from two abnormal patterns of bone resorption, which may occur together or inde- pendently (Figures 6-8). One pattern is a terminal resorption of the distal end of the phalanx, occurring first in the terminal phalanx. Much later, when the resorption in this bone is severe, the change begins in the adjacent phalanx. The other pattern is the appearance of transverse lytic lesions producing a zone of “absent

Figure 6. Case 1. Roentgenogram of hand, January 4, 7969. There is marked acre-osteolysis involving all the terminal phalanges and the distal ends of the in- termediate phalanges of the index and middle fingers.

Figure 7. Case 1. Roentgenogram of hand, October 4, 1976, showing pro- gression of the marked acre-osteolysis involving all terminal phalanges but also the adjacent phalanges of the thumb, index and middle fingers.

Figure 6. Case 2. Roentgenogram of hand, February 2, 1973. Acre-osteolysis is seen to be eroding the distal ends of the terminal phalanges of the thumb, and all fingers. There is a transverse band of ra- diolucency evident in the distal phalanx of the thumb.

bone” across the long axis of the affected bone, seen especially in the terminal phalanx. These changes are not associated with roentgenographic evidence of periosteal activity. The interface with remaining bone shows little reaction, but it may be irregular with slight fragmentation. The subungual tuft may be preserved intact or may disappear. Bone adjacent to either type of abnormal area is gradually absorbed over many years (Figures 6 and 7). These changes tend to be more severe in the hands than in the feet. The process starts in the more distal bones and progresses proximally. Me- tacarpal and metatarsal involvement has not occurred in our patients and is unusual, but in a case described by Papavasiliou et al. [ 121 lytic defects were seen in

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HAJDU-CHENEY SYNDROME--ELIAS ET AL.

two metatarsals. Growth impairment is not reflected roentgenologically, although the long bones tend to be somewhat shorter than the average, even when not involved in the osteolytic process.

Abnormalities in the skull (Figure 9) include persistent separation of the sutures with Wormian bone formation, hypoplasia of the nasal sinuses and the maxilla, platybasia, sellar elongation, bathrocephaly and dolicho- cephaly. The skull changes in the original case were more severe than in our cases, but qualitatively identi- cal, making allowance for age difference. The separation of sutures does not resemble that produced by increased intracranial pressure. The interdigitations fit loosely so that the bones of the vault appear to be settling like the sagging walls and roof of an old building. In most cases the teeth are lost early, and this is associated with alveolar atrophy. In the case described by Chawla [ 131, but not in ours, the angle between the horizontal and vertical rami of the mandible was markedly obtuse.

In the remaining parts of the skeleton there tends to be moderate demineralization, sometimes leading to vertebral collapse or biconcavity, as in our Case 1. The long bones may show some alteration in tubulation and bowing which does not appear to be necessarily related to the degree of demineralization. In two cases in the literature the patients had subluxation or dislocation of the radial head; one of these appears to have been due to an old Monteggia fracture (a fracture of the ulnar shaft associated with dislocation of the radial head) [ 13,191. Subluxation was not seen in our patients but lumbosacral spondylolisthesis, which was reported previously in one case [ 181, was present in both of ours.

PATHOLOGIC FINDINGS

A 1 cm length of bone was removed from the distal aspect of the middle phalanx of the left index finger for microscopic studies. The major portion of the specimen was processed by a special procedure utilizing cyanuric chloride fixation [23] which allows a distinction to be made between calcified bone matrix and uncalcified osteoid. Small fragments from the central portions of the phalangeal bone were fixed in 2.5 per cent glutar- aldehyde in cacodylate buffer, postfixed in 1 per cent osmium tetroxide and embedded in Epon@ for transmission electron microscopy. The gross impression was that of a lack of density in the central medullary bone.

By light microscopy, the central portion of the phalangeal bone was shown to be replaced by small blood vessels (Figures 10 and 1 l), often with very thick walls. The vessels were separated by fibrous tissue containing many small nerves (Figure 11). At the margin of the invasive vascularized tissue, resorption of bone spicules

Figure 9. shows edentulous upper and lower jaws, hypoplastic frontal sinuses and a shallow elongated se/la turcica (7 by 7 mm). The basal angle is 154 degrees as depicted (normal shown). The cranial sutures are prominent and still patent, with multiple Wormian bones and bathrocephaly.

was apparent; sometimes it was associated with osteoclasts. There was no evidence of osteomalacia.

Electron microscopy of the vascularized center of the bone lesions confirmed the presence of small blood vessels and a striking number of small nerve bundles (Figure 12) a few of which showed areas of myeliniza- tion (Figures 12 and 13). The nerve bundles were ar- ranged with layers of 2 to 3 cells lying side to side and separated from the adjacent bundle of cells by a collagen-filled space (Figure 13). A basal lamina-like membrane was interposed between cells and collagen, and hemidesmosomes were present between nerve cells and basal lamina. The cytoplasm of the nerve cells contained parallel arrays of intermixed microtubules and fine filaments, the latter resembling tonofilaments. The structural difference between these two types of filaments was well demonstrated in cross sections in which central lucencies were seen in the microtubules (Figure 13). Typical fibroblasts were also present with prominent rough endoplasmic reticulum and Golgi complexes lying amid large accumulations of mature collagen fi- brils. Granulated cells, resembling mast cells, were seen scattered about (Figure 14).



The over-all impression gained was that of an active replacement of central medullary-bone and bone marrow by a fibrous and angiomatous process characterized by the presence of small, often thick-walled vessels and a surprising number of interspersed nerve fibers.

COMMENTS

The patients described here bear a strong resemblance to the sporadic case of acre-osteolysis reported by Hajdu and Kauntze in 1948 [9] and the family described by Cheney in 1965 [ 141. The characteristics of Hajdu-

Ffgure IO. Case 1. Photomicrograph of bone biopsy specimen (Figures IO- 14) showing central portion of phalanx. Vas- cularired fibrous tissue has replaced much of the medullary bone and bone marrow. Residual bone spicules are seen at 12, 6 and 9 o’clock. Magnification X 255, reduced by 20 per cent.

Figure 71. The fibroangiomatous process which replaced medullary bone was composed of many, frequently thick- walled blood vessels plus multiple small nerve bundles (N) with interspersed dense fibrous tissue. Magnification X 510, reduced by 20 per cent.

Cheney syndrome are summarized in Table II. Twenty-two similar cases have been described in the literature, with approximately equal sex incidence. Five of these, in a mother and four children, were in the family described by Cheney [ 141. Two other families each had two cases [ 16,191, and in the remaining patients the disorder occurred sporadically but with similar clinical features. The abnormalities were usually evident in the first decade. Short stature has resulted both from diminished growth in early life and from loss of height in adulthood due to vertebral compression. Adult height has ranged from 140 to 170 cm. Pain related to skeletal lesions may occur in the extremities,

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F&um 12. Electron micrograph of small nerve fiber which was a part of the angiomatous process. Although most nerve cells were nonmyelinated, two nerve cells in the upper portion of the field possess my&n sheaths. Myelin is shown in greater detail in Figure 13. Magnification X 11,200, reduced by 20 per cent.

Figure 13. Electron micrograph of my- elinated nerve fiber which was cut in cross section. The orderly Iamellae of myelin at left show an interlamellar dis- tance of 175 A. Cross-sectioned mi- crotub&s arnd interspersed fine filam9nts are present and were characteristic of the nerve cell cytoplasm. Sectioned profiles of three mitochon&ia are present at lower right. Magnification X 88,000, nxluced by 20 per cent.

spine and skull, and is often aggravated by motion and use, particularly in the hands. Generalized osteoporosis may lead to fractures of the long bones as well as the vertebrae. Delayed healing of a fracture, seen in one of our patients, appears to be unusual. Early loss of teeth, often during the second decade of life, has usually been caused by alveolar bone resorption, probably enhanced by chronic occlusal trauma secondary to dental malposition and mandibular shortening.

The abnormal nail curvature occurs only in digits with osteolytic lesions and is probably due to shortening of the distal phalanges. It is more marked in the fingers than in the toes. It has been described as “clubbing” in

some reports, but since it is unrelated etiologically we prefer the term “pseudoclubbing.” Joint laxity, mainly in the knees and elbows, is mild in comparison with that seen in the Ehlers-Danlos and Marfan syndromes. The distal interphalangeal joints are markedly hypermobile, but this is probably due to osteolysis rather than to lig- amentous laxity. Several reports have referred to a peculiar or distinctive facial appearance. The hair is thick and straight, with prominent eyebrows and lashes. The ears are low-set and, in our patients, the lobes are unusually large. A broad nose and receding chin com- plete the picture, Altered skull configuration due to aberrant growth and closure in the cranial sutures may


HAJDU-CHENEY SYNDROME-ELIAS ET AL

result in neurologic disorders. The patient originally described by Hajdu and Kauntze [9] had headache, blurred vision and basilar impression, and may have died as a result of increased intracranial pressure [ 13,171. Visual field defects, optic disc pallor, nystagmus, sixth nerve palsy and slurred speech have been reported [17,18].

Laboratory studies have been consistently normal, including serum calcium, phosphorus, alkaline phosphatase and proteins. Enlargement of the sella turcica

TABLE II Features of the Hajdu-Cheney Syndrome

Common

Fipe 14. Electron micrograph of mast cell. These were frequently encountered in the fibroangiomatous process. Magni- fication X 24,000, reduced by 20 per cent. An inset at lower right shows details of scroll-like mast cell granules. Magni- fication X 88,000, reduced by 20 per cent.

has been reported in five cases, exclusive of our own [13,14]. However, neither clinical features nor the endocrine studies in our first patient has revealed evidence of pituitary or other endocrine dysfunction. It seems likely that the sellar enlargement and other reported roentgenologic changes in the base of the skull, such as sellar elongation with a sleep clivus, are a part of the skeletal dysplasia. Renal function is normal in this syndrome, in contrast to other types of acre-osteolysis [4]. Autoantibody tests and indicators of an inflam-

Short stature Osteolysis of distal phalanges Early loss of teeth Pseudoclubbing Joint laxity Recessed mandible and malocclusion of teeth Low set ears Coarse hair, thick eyebrows and lashes Generalized osteoporosis and vertebral compression Fractures of long bones Skull deformity and basilar impression Enlarged sella turcica with normal endocrine function Persistent wide cranial sutures and multiple Wormian bones Hypoplastic frontal sinuses Decreased tubulation of long bones

Diminished hearing Headache Valgus deformity of knees Spondylolisthesis Scoliosis Spina bifida occulta Joint dislocations Hirsutism High-arched palate Hernias Recurrent infections Epicanthal folds Dental maleruption Visual abnormalities Syndactyly

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matory process, such as sedimentation rate and C- reactive protein, have seldom been mentioned in pre- vious reports but were repeatedly negative in our first case over a period of 14 years. It should be pointed out that acre-osteolysis may occur not only as a primary disorder of various types (Table I) but also as an associated abnormality in a large number of connective tissue, metabolic and vascular diseases (Table Ill).

There is little published evidence on the pathogenesis of acre-osteolysis. It appears to be a generalized osseous dysplasia, occurring sporadically or with autosomal dominant inheritance. An abnormality of bone mineral metabolism does not appear to play a primary role, and no alteration in bone matrix has been demonstrated. Bone and skin collagen had a normal appearance on electron microscopy in the case reported by Brown et al. [20]. Some negative studies suggest that the Hajdu-Cheney syndrome is not a mucopoly- saccharidosis [20]. A discrepancy between bone formation and removal, persisting into adult life, must be present if one is to account for the generalized osteoporosis. Brown et al. [20) performed iliac crest biopsies on two patients and found that the percentage of en- dosteal bone surfaces characteristic of bone formation was diminished in both patients; in one, resorptive surfaces were increased. These findings differed from those in hyperparathyroidism in which increased bone resorption predominates. However, the striking osteolysis in the distal extremities, which is the hallmark of the syndrome, suggests that the rate of bone removal may be accelerated, at least locally if not throughout the skeleton.

The biopsy specimen of bone from our patient (Case 1) showed a rather striking fibrous and angiomatous process associated with numerous nerve fibers and some mast cells. Marrow fibrosis and medial thickness of small arteries similar to that seen in our case were reported by Hollister et al. [24] in the carpal bone of one patient with Winchester syndrome and acre-osteolysis. We did not see a particular dilatation of fibroblast mi- tochondria and rough endoplasmic reticulum as described in the Winchester syndrome, and there was not a noticeable prominence of lysosomes in fibroblasts.

The phalanges in acre-osteolysis have rarely been biopsied and never before analyzed with the electron microscope. In one of Cheney’s reported cases [ 141 a phalanx was examined which showed “striking ne- crosis” of bone tissue and adjacent soft tissue. On examination of the published photomicrograph in this case, one detects no noticeable reduction in the size of bone spicules. Thus, it is possible the center of the erosive lesion was not sampled microscopically. It is interesting that Cheney did not attach much significance to this biopsy report and preferred to think of the disease process as being vascular. In another study by

HAJDU-CHENEY SYNDROME -ELIAS ET AL.

TABLE III

_-

Disorders in Which Secondary Acro- osteolysis May Occur

Scleroderma Systemic lupus erythematosus Rheumatoid arthritis Juvenile rheumatoid arthritis Sjogren’s syndrome Gout Raynaud’s disease Frostbite Burns Electrical injuries Occlusive vascular disease Ergot and vinyl chloride toxicity Neuropathic arthritis Diabetes mellitus Syphilis Porphyria Leprosy Neurogenic ulcerative acropathy Psoriasis Pityriasis rubra Epidermolysis bullosa Lipodermatoarthritis Disseminated lipogranulomatosis Werner’s syndrome and progeria Sarcoidosis Osteomalacia Hyperparathyroidism Mucopolysaccharidoses

Fycnodysostosis

Greenberg and Street [ 1 I], a nonunited fracture site of the metatarsal was examined and reported to show “nonspecific fibrosis.” The published photomicrograph in that case showed only dense fibrous tissue with very infrequent small blood vessels, raising the possibility that only reactive scar tissue rather than the actual osteolytic process was sampled. Brown et al. (1976) reported light and electron microscopic studies of bone taken at random from the iliac crests of two patients with acre-osteolysis. These biopsy specimens may not have been reflective of the more active localized osteolysis occurring in the phalanges. Therefore, our study appears to be the first detailed light and electron microscopic description of an involved bone. It is also the first report of an angiomatous osteolysis somewhat reminiscent of the changes described originally by Gorham and Stout [25] in the condition of massive osteolysis, and subsequently reviewed and enlarged upon by Halliday et al. [26]. In several of these reported cases the vessels were described as thick-walled and widely separated by fibrous tissue; this, of course, corresponds to the appearance of our patient’s vascular lesion. Osteoclastic resorption and infiltration of in- flammatory cells were not prominent. Aberrant or in- appropriate neurogenic vasomotor activity might, therefore, have been involved in some manner. The mild Raynaud’s phenomenon reported by both of our patients


HAJDUCHENEY SYNDROME-ELIAS ET AL.

may be related to an imbalance between blood flow in cause osteoporosis in some circumstances [27,28], the superficial (cutaneous) and deep (osseous) circu- and prostaglandins [29] or collagenase [30] from en- lations. It might be suggested that endothelial or mast dothelial or connective tissue cells. This material might

cells were releasing a mediator or activator of osteo- be released and inactivated locally, thus escaping de- lysis. A number of mediators could be suspected, in- tection in the circulation, even if appropriate technics eluding heparin or histamine from mast cells, which can for measurement were available.

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Documents

Hereditary osteodysplasia with acro-osteolysis (the Hajdu-Cheney syndrome)