Primary Hypertrophic Osteoarthropathy

By Manuel Martinez-Lavin, Carlos Pineda, Tirso Valdez, Juan-Carlos Cajigas,

Michael Weisman, Niklaus Gerber, and Daniel Steigler

S INCE THE ORIGINAL description of the

syndrome almost a century ago, hypertro- phic osteoarthropathy (HOA) has been consid-

ered an ominous sign, the herald of a severe

underlying illness. Bamberger’ and Marie’ asso-

ciated HOA with chronic infectious lung condi-

tions. However, despite the advances in medical

therapy during the first half of this century, including the discovery of antibiotics and the

decreased incidence of infectious illnesses in

developed countries, HOA did not disappear. Presently, HOA is often a paraneoplastic syn- drome, most commonly a sign of lung cancer.

During the past 8 years we had the opportu- nity to study seven patients with longstanding HOA unassociated with any systemic disease.

We observed a totally different articular picture

in these cases compared with other chronic rheu-

matic syndromes. We also noted the confusion

that exists in the literature regarding nomencla- ture, clinical features, and diagnostic criteria for

primary HOA. Thus, the objective of the present investigation

of seven cases and literature review is to define the outstanding clinical characteristics of HOA in its primary or idiopathic form and, on this

basis, to propose nomenclature and diagnostic criteria for this entity.

CASE REPORTS

Patient No. I

A 17-year-old man was referred for evaluation of digital clubbing. This deformity was noted for the first time at age

10. Several months later the patient had the insidious onset of

aching pain along the tibia1 shafts. He also noticed bony

enlargement of the wrists and ankles. He denied symptoms

that would suggest chest or abdominal illness. The patient’s

family history includes a brother with digital clubbing. On

physical examination skin was oily and wet, especially

throughout the hands. No coarse facial features or gyneco-

From the Institute National de Cardiologia Ignacio Chbvez, Mexico; the University of California, San Diego; and Universittitsklinik Inselspital. Bern, Switzerland.

Address reprint requests to Manuel Martinez-Lavin. MD, Chief Rheumafology Service. Institute Nacionaf de Cardio- logia, Juan Badiano # I, 14080 Mexico D. F. Mexico.

0 I988 by Grune & Stratton, Inc. 0049-O I72/88/1703-0003$5.00/O

mastia were detected. There was drumstick deformity of all

20 digits with a clubbing index of I. 17 (measured as the ratio

of the circumference of the fifth left finger at the base of the

nail over the perimeter of the same finger at the distal

interphalangeal joint) being the normal value .I I .I There was bony enlargement of the wrists, knees, and ankles. and

synovial effusion was detected in both knees. The range of

motion was decreased by ten degrees in the wrists and knees.

Examination of the chest and abdomen was unremarkable.

Laboratory examination including complete blood count.

sedimentation rate, SMA-I 2. urinalysis, rheumatoid factor,

and antinuclear antibodies were negative or normal. Serum

growth hormone levels performed during a glucose tolerance

teqt were normal. Electrocardiogram and chest x-rays were

normal. Radiographic bone survey showed multilayered type

of periostitis involving all appendicular bones. Arthrocentesis

of the right knee yielded a thick viscous fluid with 200

leukocytes/ml. Biopsy of the synovial membrane of the same

joint showed no evidence of inflammatory cell infiltrate. The

patient was given indomethacin 25 mg three times a day and

propranolol 20 mg three times a day; with these measures the

bone pain and the hyperhydrosis improved. We have followed

the patient for 8 years and no illnesses have developed.

Repeated skeletal radiographs demonstrated mild pro-

gression of the extent of periostitis.

Patient No. _?

The mother of this l2-year-old boy noted digital clubbing

since birth and enlargement of the knees and ankles since the

age of I. The child complained of chronic aching pain along

the tibia] shafts; otherwise he was healthy. Physical examina-

tion demonstrated a clubbing index of I .23. There was bony

enlargement of the knees and ankles without evidence of

synovial effusion. .Ioint range of motion was normal. No skin

abnormalities were detected. All laboratory studies were

normal. Radiographic bone survey showed a monolayer type

of periostitis in both ulnae. The patient was administered

naproxen 2.50 mg twice daily with symptomatic improve-

ment. We have followed this patient for 5 years and his

clinical condition remains stable.

Patient No. 3

This &year-old boy has similar history to his brother

(patient no. 2) with clubbing since birth and bony enlarge-

ment of knees and ankles. Physical examination was normal

except for the skeletal abnormalities. Bone radiographs dem-

onstrated a multilayered type of periosteal new bone forma-

tion in both ulnae, metacarpals, and metatarsals. Treatment

with naproxen yielded good symptomatic results.

Patient No. 4

A 42.year-old man was referred for evaluation of asymp-

tomatic digital clubbing discovered during a physical exami- nation. He denied a history of bone or joint pain or any

change in the skin. His family history was negative. On

156 Seminars in Arthritis and Rheumatrsm, Vol 17, No 3 (February), 1988: pp 156-162

PRIMARY HYPERTROPHIC OSTEOARTHROPATHY 157

physical examination his clubbing index was 1.2 1 and there was hyperhydrosis of the palms and soles. Joint examination was normal. Comprehensive clinical and laboratory studies failed to reveal any systemic illness. Skeletal radiographs showed an irregular type of periostitis involving femorae, tibias, and tibulae. He has been observed for 3 years without appreciable change. No treatment has been prescribed.

Patient No. 5

This 34-year-old man first noted digital clubbing at the age of 16. Later he suffered from progressive aching pain in the lower extremities accompanied by painful swelling of his knees and ankles. He also noticed progressive skin hypertro- phy more prominent in the hands and face with hyperhydro- sis. His family history was negative. On physical examination his clubbing index was 1.31. His hands were broad, fleshy, and wet. He had coarse facial features and cutis verticis gyrata; the legs displayed cylindrical swelling resembling “elephant feet.” No gynecomastia was detected. Joint exami- nation failed to reveal evidence of inflammation. Range of motion of the wrists, knees, and ankles was decreased; the rest of the physical examination was unremarkable. Radiographic bone survey disclosed an irregular type of periostitis involving all tubular bones (Fig 1). The patient was administered

indomethacin and propranolol with symptomatic improve- ment of the skeletal pain and hyperhydrosis.

Patient No. 6

This 20-year-old man was referred for evaluation of recently discovered digital clubbing. At age 16 he first noticed deformity in the tips of his fingers. He was otherwise asymptomatic. Clubbing was present on physical examina- tion. Joint examination was normal. He had oily wet skin without hypertrophic changes. Chest and abdominal exami- nations were negative. Growth hormone determination was normal. Radiographic bone survey disclosed an irregular type of periostitis.

Patient No. 7

This 38-year-old man was seen by the dermatology service because of prominent and generalized skin hypertrophy that began at age 16. Findings were more evident in the head, with deep furrowed skin and hypertrophy of the eyelids that obstructed his vision (Fig 2). Seborrhea was evident. The patient had clubbing of his 20 digits and effusions were present in both knees. Radiographic studies demonstrated a widespread irregular type of periostitis. The patient was lost to follow-up.

SUMMARY OF THE CASE REPORTS

Our seven patients were all Mexican mestizo men except one (patient no. 6) who had an immediate Spanish ancestry. Three of the seven had a family history of similar disorder. Our cases displayed a wide spectrum of skeletal and skin abnormalities. From the articular point of

Fig 1. Patient no. 6. Radiograph of the right ankle showing advanced irregular periosteal proliferation with ossification of the inter-osseous membrane (arrow).

Fig 2. Patient no. 7. Severe hypertrophic skin changes with blepharoptosis end cerebroid appearance of the fore- head.

158 MARTiNEZ-LAWN ET AL

view, patients no. 4 and 6 were asymptomatic

whereas in patients no. 1, 2, 3, and 5, pain required treatment. These four patients had a

symptomatic response to nonsteroidal antiin-

flammatory agents. The cutaneous changes also

showed great variability from glandular dysfunc-

tion manifested as hyperhydrosis, seborrhea, and acne, to hypertrophic skin changes manifested by

coarse facial features. In two instances (patients no. 5 and 7), this abnormality reached the extreme of cutis verticis gyrata, represented in

patient no. 7 as the most advanced changes that we have observed with report cases (Fig 2).

Propranolol provided symptomatic improvement

for the hyperhydrosis. We have followed five patients for a mean period of 4.6 years. There

was no indication that the treatment altered the natural course of their illness. Discrete pro-

gression of the periosteal apposition in some patients has been noted. The arthropathy was

located mostly in the knees and ankles. Patients complained of achiness that involved both joints and adjacent bone. The most impressive finding on physical examination was the hard periarticu- lar bony enlargement that mildly diminished the

range of motion of the joints. There was no thickening of the synovial capsule. Joint effu-

sions were present in three of seven patients; two

on physical examination and one by history.

REVIEW OF THE LITERATURE

Methods

The MEDLINE data bank was used to iden- tify cases classified as pachydermoperiostosis,

Table 1. Outstanding Clinical Features of 125 Patients

With Primary Hypertrophic Osteoarthropathy Described in

the Literatures

Finding Percentage

Man

Positive family history

Digital clubbing

Radiographic periostitis

Synovial effusion

Skin involvement

Hypertrophic skin changes

Coarse facial features

Cutis verticis gyrata

“Elephant feet”

Hyperhydrosis

Seborrhea

Acne

89

38

89

97

41

73

61

24

24

36

33

13

Fig 3. Age of onset of hypertrophic osteoarthropathy.

primary HOA. familial HOA. or idiopathic HOA and that were published in the English.

French, or German literatures. The bibliography

of each article was reviewed, searching for addi-

tional cases not included in MEDLINE. A total of 125 cases of primary HOA were collected.J~9”

The salient clinical findings are summarized in Table 1.

The male/female ratio was 8.9 to 1 and the age of onset of the illness was defined in 67% of

the patients. In some instances, as in our case no. 2, patients were unable to relate the time of onset. When the onset could be ascertained, there was a bimodal distribution with one peak during

the first year of life and the other at age 15 (Fig

3). Familial clustering of the syndrome is evident by 38% of the cases reporting a relative with

similar abnormalities. Digital clubbing was not

reported in 14 of the 125 cases (1 I%).“. 18.30,34.42,49.54,61.64.67.72,73.79,82 In eight of the cases, ‘“~30*34~42~49~6’~64~72 the absence of clubbing was

explicitly stated. Nevertheless, these patients dis- played periostitis as well as typical cutaneous changes. A joint effusion was described in 41% of patients with predilection for knees, ankles, and

wrists. All, except for four patients,9,34*65 had radiographic signs of periostitis. Tibiae and fibu- lae were the bones most frequently affected.

Synovial fluid examination in nine in- Stances14.16.29.46.48.53.55.78.83 was noninllammatory except for one (hemarthrosis).29 Characteristi- cally, the fluids were thick and viscous with low WBC counts. The histology of the synovium in eight patients 14,16.25,33,39,46.48.53 showed mild cell_

lining hyperplasia,25.33.39,48 thickening of the small blood vessels with fibrosis,25,48 or mild nonspecific inflammatory cell infiltrate.‘4*‘6.48.53

Most patients with primary HOA had skin involvement (Table 1). The most frequent abnor-

PRIMARY HYPERTROPHIC OSTEOARTHROPATHY 159

mality was coarse facial features, an alteration commonly associated with blepharoptosis.

No specific abnormality was found on labora- tory examination. Parameters that measure inflammation were absent in almost all instances, as were studies of immune dysfunction such as rheumatoid factor, anti-nuclear antibodies or serum levels of immunoglobulins. Growth hor- mone was elevated in one6’ of the five patients meaSUred.6,45,47,61.89

There is little information in the literature regarding treatment. The therapy most widely used was nonsteroidal antiinflammatory drugs; radiation therapy was favored in the older arti- cles. 10,‘1*85 There was no claim of treatment alter- ing the course of the illness.

A variety of associated abnormalities have been described such as cranial suture de- fects 1,4*5~1g.20,64*78 female escucheon,12s54*64 bone , marrow failure, 54 hypertrophic gastropathy,45*57 and chromosomal abnormalities.71 In the fol- low-up reports, it appeared that the disease had a self-limited course with an “active” period dur- ing childhood and adolescence, adults were asymptomatic.

DISCUSSION

HOA not associated with an internal illness was recognized even before the classical descrip- tion of pulmonary HOA by Bamberger’ and Marie.2 In fact, the only patient with HOA personally seen by Marie and erroneously diag- nosed by him as “pulmonary,” was a patient with primary HOA admitted to the hospital with a minor respiratory ailment.87 Although described earlier, credit for the recognition of the primary syndrome has been attributed to Touraine et al who masterfully described the clinical features of the illness.6g Subsequently, many additional names have been given to this condition,87 each emphasizing different clinical features, adding confusion to the subject. We believe that primary HOA is the most appropriate term; it emphasizes the lack of associated illness and also encom- passes patients without hypertrophic skin changes and without family history.

Primary HOA contains a hereditary predispo- sition and it is clearly sex-linked, over one-third of the reported cases have a relative with similar illness. It is not presently possible to ascertain the type of inheritance. The onset of the illness has a

bimodal distribution, with a second peak that coincides with the rapid growth period of puberty (Fig 3) and the appearance of secondary sexual characteristics. Clinically, the disease seems to have a self-limited course ending in adulthood.

The main clinical features of primary HOA are in the skeleton and the skin. The most conspicuous, but not uniform, abnormality was digital clubbing in 89% of cases. It appears that bona fide cases of primary HOA exist without clubbing. The periosteal proliferation of HOA display diverse patterns,g’ with a predilection for the lower extremities. Literature review confirms our impression that a minority of patients have synovial effusion; studies of the synovial fluid and synovial histology have not shown significant inflammatory cell-infiltration or exudation. These data suggest that HOA is not a primary synovial disease; it is suggested that synovial effusions are a contiguous sympathetic reaction to the neighboring periostitis, analogous to syno- vial effusions in juxtaarticular osteomyelitisg2 or bursitisy3

We propose diagnostic criteria for HOA to include the combined presence of digital club- bing and radiographic periostitis. In this review of 125 patients, including our seven patients, the sensitivity of these combined criteria is 86%. Specificity was not tested.

The cutaneous involvement of primary HOA could be divided into two expressions: (1) glan- dular abnormalities such as acne, hyperhydrosis, and seborrhea and (2) hypertrophy of the soft tissues such as clubbing, coarse facial features, elephant feet, ptosis of the lids, and cutis verticis gyrata.

There were no other clinical differences among the group of patients with or without hypertrophic skin changes, suggesting that HOA is a single disease entity with variable cutaneous expression. Cutis verticis gyrata represents the most advanced stage of hypertrophy, histological examination reveals only excessive skin or glan- dular hypertrophy.4g,6g*87 The cutaneous changes are not limited to the primary form of the syndrome, as they have been reported in HOA associated to lung malignancies.g4 When con- fronting a patient with clinical features of HOA, it still remains of utmost importance to rule out any associated illness before the consideration of a primary case. However, the long-standing pres-

160

ence of clubbing and a positive family history suggest the primary form of the syndrome. The

clinical features of primary HOA suggest that a genetically determined hormonal factor related

to maleness plays a role in its pathogenesis. The recent discovery of other growth-inducing factors

different from growth hormone have opened an interesting line of investigation.95

SUMMARY

We describe seven patients with primary

HOA and review 125 cases reported in the English, French, and German literature.

The salient clinical features of primary HOA

are: a bimodal distribution of disease onset with one peak during the first year of life and the other at age 15, a male predominance (nine to

one), uncommon benign joint effusion, and a

MARTiNEZ-LAViN ET AL

variety of skin abnormalities resulting from cuta-

neous hypertrophy or glandular dysfunction.

We concluded that HOA is not a synovial disease. It is suggested that synovial effusions.

when present, are perhaps a sympathetic reac- tion to the neighboring periostitis. Proposed diag- nostic criteria for HOA, including digital club- bing and radiographic periostitis, appear 86%,

sensitive.

The clinical features, age of onset, and sex distribution suggest that a genetically controlled

growth promoting factor, different from growth

hormone, plays a role in the pathogenesis of this

syndrome.

ACKNOWLEDGMENT

We wish to thank Dr Clara Shumski, Dr Maria dcl

Carmen Moreno, and Dr Jaime Sabanes for allowing us to

study and to describe their patients.

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