Pachydermoperiostosis 

Updated: May 11, 2019
Author: Robert A Schwartz, MD, MPH; Chief Editor: William D James, MD 

Overview

Background

Hypertrophic osteoarthropathy is divided into primary and secondary forms. Pachydermoperiostosis (PDP), the primary form, accounts for 5% of all cases of hypertrophic osteoarthropathy. Secondary hypertrophic osteoarthropathy, also called pulmonary hypertrophic osteoarthropathy, is associated with underlying cardiopulmonary diseases and malignancies.[1] This latter condition is not discussed here but may be found in the article Dermatologic Manifestations of Pulmonary Disease.

Pachydermoperiostosis or primary hypertropic osteoarthropathy is a rare hereditary disorder that was first described in 1868. It is characterized by digital clubbing, pachydermia (thickening of the facial skin and/or scalp), and periostosis (swelling of periarticular tissue and subperiosteal new bone formation), as shown in the images below. Pachydermoperiostosis or primary hypertropic osteoarthropathy is associated with pain, polyarthritis, cutis verticis gyrata,[2] seborrhea, eyelid ptosis,[3, 4] and hyperhidrosis. Touraine et al[5] described 3 forms of pachydermoperiostosis or primary hypertropic osteoarthropathy: (1) a complete form with pachydermia and periostitis, (2) an incomplete form with evidence of bone abnormalities but lacking pachydermia, and (3) a forme fruste with prominent pachydermia and minimal-to-absent skeletal changes.

Clubbed fingernail. Clubbed fingernail.
Cutis verticis gyrata. Courtesy of DermNet New Zea Cutis verticis gyrata. Courtesy of DermNet New Zealand (http://www.dermnetnz.org/assets/Uploads/dermal-infiltrative/cvg2.jpg).

Pathophysiology

As reported in 2008, pachydermoperiostosis or primary hypertropic osteoarthropathy has been mapped to band 4q33-q34. Mutations in HPGD, encoding 15-hydroxyprostaglandin dehydrogenase, the main enzyme of prostaglandin degradation, have been identified.[6, 7] Deficiency of the prostaglandin transporter (SLCO2A1) has been characterized as the main cause of primary hypertrophic osteoarthropathy.[8, 9] Mutations in the prostaglandin transporter gene, SLCO2A1, have been documented in Koreans with pachydermoperiostosis.[10] A novel SLCO2A1 mutation in a Lebanese family,[11] a Saudi patient,[9] a Korean family,[12] and a Chinese family[13] have been documented, as have a novel nonsense mutation p.E141* of the SLCO2A1 gene in a Japanese one[14] and a novel homozygous truncating mutation in HPGD described in Turkey.[15]

Etiology

Pachydermoperiostosis or primary hypertropic osteoarthropathy is often familial. The condition is believed to be inherited in an autosomal dominant pattern with variable penetrance; however, autosomal recessive forms have been reported.

Pachydermoperiostosis or primary hypertropic osteoarthropathy has been mapped to band 4q33-q34, and mutations in HPGD, encoding 15-hydroxyprostaglandin dehydrogenase, the key enzyme of prostaglandin degradation, have been identified. Individuals with homozygous mutations have chronically elevated prostaglandin E2 levels. Milder biochemical and clinical manifestations are found in heterozygous individuals.

Vascular endothelial growth factor is abnormally expressed in some patients with pachydermoperiostosis or primary hypertropic osteoarthropathy.

Increased levels of interleukin 6 and receptor activator of nuclear factor–kappaB ligand (RANKL) have been reported in the serum of a patient with pachydermoperiostosis or primary hypertropic osteoarthropathy during the acute phase of the disease.[16]

Pachydermoperiostosis or primary hypertropic osteoarthropathy has been associated in case reports with a variety of other disorders, including the following:

  • Gastrointestinal pathology,[17] including gastric carcinoma, Crohn disease, peptic ulcer disease, chronic gastritis, Ménétrièr disease,[18] and protein-losing enteropathy[19]

  • Myelofibrosis[20, 21, 22, 23, 24]

  • Gynecomastia[25]

  • Compressive neuropathy

  • Hypoplastic internal genitalia

  • Psoriatic onychopathy[26]

  • Periodontal and alveolar bone abnormalities[27]

  • Spondylolisthesis of the L5-S1 vertebrae

  • Congenital cardiac disease[28, 29]

  • Atherothrombotic brain infarction[30]

  • Osteoporosis[25]

  • Rheumatoid arthritis[31]

  • Ankylosing spondylitis[32]

  • En coup de sabre (a form of localized scleroderma)[33]

In certain instances, several years after the onset pachydermoperiostosis or primary hypertropic osteoarthropathy, diseases generally known to result in secondary hypertrophic osteoarthropathy (Crohn disease, myelofibrosis, and congenital cardiac disease) have been reported to develop in patients with pachydermoperiostosis or primary hypertropic osteoarthropathy.[34]

Epidemiology

Frequency

United States

Pachydermoperiostosis or primary hypertropic osteoarthropathy is a rare disorder, and the precise incidence is unknown.

International

This rare paraneoplastic syndrome is most frequently associated with lung cancer. By analyzing clinical data of 6,151 patients with advanced lung cancer, a retrospective study found that 1.87% of patients showed characteristics of hypertrophic pulmonary osteoarthropathy.[35]

Race

Pachydermoperiostosis or primary hypertropic osteoarthropathy is more common in African Americans than in whites.

Sex

The male-to-female case ratio is approximately 7:1. Typically, men are affected more severely than women. Women often have milder findings, and their disease may remain undetected.

Age

Pachydermoperiostosis or primary hypertropic osteoarthropathy typically begins during childhood or adolescence and progresses gradually over the next 5-20 years before stabilizing.

Prognosis

The progression of pachydermoperiostosis or primary hypertropic osteoarthropathy typically ceases after 10 years, but patients may be left with chronic debilitating complications, which include severe kyphosis, restricted motion, and neurologic manifestations. Life expectancy may be normal, except in cases in which severe mental impairment is involved.

 

Presentation

History

Patients may report the following signs or symptoms:

  • Enlargement of the fingers and the toes

  • Swelling or pain of the large joints

  • Coarsening of facial features

  • Grooves or depressions in the scalp

  • Oily, scaly facial skin

  • Excessive sweating of the palms, soles, or other areas

  • A sensation of warmth or burning in the hands and feet

Physical Examination

Digital clubbing and/or paronychial thickening may be observed (see the image below).

Clubbed fingernail. Clubbed fingernail.

Coarse facial features may be reminiscent of acromegaly. Facial skin changes may include sclerodermoid thickening and furrowing of the skin on the forehead and the cheeks. Leonine facies may occur in advanced stages.

Cutis verticis gyrata (undulating grooved and thickened scalp) may become apparent during adolescence (see image below).

Cutis verticis gyrata. Courtesy of DermNet New Zea Cutis verticis gyrata. Courtesy of DermNet New Zealand (http://www.dermnetnz.org/assets/Uploads/dermal-infiltrative/cvg2.jpg).

Seborrheic dermatitis of the face and the scalp may be present.

Palmoplantar hyperhidrosis or generalized hyperhidrosis characterized by shiny and/or wet skin may be observed.

Dermatitis of the hands and the feet may be associated with hyperhidrosis.

Bilateral blepharoptosis may be present.

Facial acne may be present.

Complications

Patients with pachydermoperiostosis or primary hypertropic osteoarthropathy may develop severe kyphosis, restricted motion, and neurologic manifestations.

 

DDx

Diagnostic Considerations

Rosenfeld-Kloepfer syndrome, a variant of pachydermoperiostosis or primary hypertropic osteoarthropathy, is characterized by enlargement of the mandible and/or the maxilla; large hands, feet, nose, lips, and tongue; prominence of the upper part of the forehead; cutis verticis gyrata; and corneal leukoma.

Currarino idiopathic osteoarthropathy is a juvenile incomplete form of pachydermoperiostosis or primary hypertropic osteoarthropathy characterized by eczema and wide cranial sutures.[36]

A variant form of pachydermoperiostosis or primary hypertropic osteoarthropathy restricted to the lower extremities in the absence of digital clubbing or typical skin changes has been described. It affected 3 members of a single family and was characterized by pain, swelling, and hyperhidrosis of both feet. Radiographs revealed bony changes consistent with pachydermoperiostosis or primary hypertropic osteoarthropathy.[37]

Secondary hypertrophic pulmonary osteoarthropathy must be excluded.

Thyroid acropachy may cause diagnostic confusion. Unlike pachydermoperiostosis or primary hypertropic osteoarthropathy, thyroid acropachy is not painful.

Syphilitic periostosis can result in bony changes and symptoms similar to those seen in pachydermoperiostosis or primary hypertropic osteoarthropathy.

Differential Diagnoses

 

Workup

Laboratory Studies

Thyrotropin and growth hormone levels should be examined to exclude thyroid acropachy and acromegaly. Reactive plasma reagent and Venereal Disease Research Laboratory testing should be performed to check for syphilitic periostosis.

Imaging Studies

Radiographs of the long bones reveal subperiosteal new bone formation, which is a characteristic radiologic feature.[38] This feature is mainly seen in the distal tibia, the fibula, the radius, the ulna, the metacarpals, the phalanges, and, less frequently, the metatarsals. Acro-osteolysis and ossification of the ligaments and interosseus membranes may also occur.[39, 40]

Other radiographic abnormalities include the following[41] :

  • Patients may develop cortical thickening without narrowing of the medullary cavity.

  • Enlargement of the paranasal sinuses is reported.

Radionucleotide bone imaging (bone scanning) findings in patients with pachydermoperiostosis or primary hypertropic osteoarthropathy demonstrate increased radiopharmaceutical uptake in the diaphyses and the metaphyses of long bones along the cortical margins.[42, 41] Uptake may result from hyperemia occurring prior to subperiosteal proliferation. Periarticular regions may also have increased uptake because of associated synovitis. Scintigraphic findings (such as those described above) often precede changes noted on radiographs.[43]

Bone scan abnormalities, found in 15% of patients, less commonly involve the mandible, the maxilla, the clavicles, the scapulae, and the patellae.

Ultrasound may document echogenic tissue surrounding the long bones; Doppler sonograms may show increased vascularity on the surface of some superficial bony structures.[38]

 

Treatment

Medical Care

Nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroids may alleviate the polyarthritis associated with pachydermoperiostosis or primary hypertropic osteoarthropathy. Most patients treated with NSAIDs had clinical improvement.[44] Etoricoxib, a selective COX-2 inhibitor not approved for use in the United States, has also be successfully used.[45] Methotrexate may be considered too if there is a large inflammatory component.[46]

Thickened skin on the glabellar region may benefit from botulinum injections.[47]

In isolated cases, pamidronate and tamoxifen citrate have been reported as effective therapies for the painful osteoarthropathy associated with pachydermoperiostosis or primary hypertropic osteoarthropathy.[48, 49, 50, 51]

In a single case report, pachydermoperiostosis or primary hypertropic osteoarthropathy associated arthritis was treated with the combination of oral administration of risedronate sodium and arthroscopic synovectomy.[52]

A study from Shanghai found that etoricoxib, a selective cyclooxygenase-2 inhibitor, may improve the pachydermia, clubbing finger, and joint swelling.[53]

Surgical Care

Vagotomy may improve the articular pain and swelling associated with pachydermoperiostosis or primary hypertropic osteoarthropathy.

Plastic surgery may improve the appearance of the face and scalp by excising redundant skin and correcting the cutis verticis gyrata. Bilateral blepharoplasties, tarsal wedge resections, excision of skin furrows, and facial rhytidectomy have been described as methods of providing cosmetic improvement.[54, 55, 56]

Surgical correction of the clubbing through bilateral resection and shortening of the nail bed, nail matrix, and soft tissue has been reported.[57]

If anti-inflammatory therapy is insufficient with knee arthritis, arthroscopic synovectomy and radiosynoviorthesis performed consecutively may be an option.[58]

 

Medication

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Nonsteroidal anti-inflammatory drugs

Class Summary

These medications have analgesic, anti-inflammatory, and antipyretic activities. Their mechanism of action in pachydermoperiostosis or primary hypertropic osteoarthropathy is not known. In general, NSAIDs inhibit cyclo-oxygenase activity and prostaglandin synthesis. Other mechanisms may exist; these include inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell membrane functions.

Ibuprofen (Ibuprin, Motrin, Advil, Excedrin IB)

Ibuprofen is the drug of choice for patients with mild to moderate pain. It inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.

Indomethacin (Indocin, Indochron E-R)

Indomethacin is rapidly absorbed; metabolism occurs in the liver by demethylation, deacetylation, and glucuronide conjugation; it inhibits prostaglandin synthesis.

Meloxicam (Mobic)

Meloxicam decreases the activity of cyclo-oxygenase, which, in turn, inhibits prostaglandin synthesis. These effects decrease formation of inflammatory mediators.

Celecoxib (Celebrex)

Celecoxib primarily inhibits COX-2. COX-2 is an isoenzyme induced during pain and inflammatory stimuli. Inhibition of COX-1 may contribute to NSAID GI tract toxicity. At therapeutic concentrations, the COX-1 isoenzyme is not inhibited, thus GI tract toxicity may be decreased. Seek the lowest dose for each patient.

Naproxen (Aleve, Naprosyn, Naprelan, Anaprox)

Naproxen is used for the relief of mild to moderate pain; it inhibits inflammatory reactions and pain by decreasing the activity of cyclo-oxygenase and prostaglandin synthesis.

Antidote, Hypercalcemia

Class Summary

These agents inhibit bone resorption and increase renal calcium excretion.

Pamidronate (Aredia)

Pamidronate acts principally by inhibiting osteoclastic bone resorption.

Bisphosphonate Derivative

Class Summary

These agents inhibit osteoclastic bone resorption.

Risedronate (Actonel)

Risedronate is a potent aminobisphosphonate. It inhibits bone resorption via actions on osteoclasts or osteoclast precursors. Supplementation with adequate calcium and vitamin D is required for effectiveness.

Risedronate has been shown to reduce bone resorption and increase bone mineral density of the spine by 5% and femoral neck by 1.6%. It has also has been shown to reduce the incidence of vertebral fractures by 41% and nonvertebral fractures by 39% over a period of 3 years in postmenopausal women.

In men with osteoporosis, significant mean increases in bone mineral density at the lumbar spine, femoral neck, trochanter, and total hip compared with placebo were shown after 2 years of treatment. It is indicated for prevention or treatment of osteoporosis.

Antineoplastic Agent, Hormone Antagonist

Class Summary

These agents inhibit estrogen effects.

Tamoxifen (Nolvadex, Tamofen, Tamone)

Tamoxifen competitively binds to the estrogen receptor, producing a nuclear complex that decreases DNA synthesis and inhibits estrogen effects.