Hypertrophic Osteoarthropathy: Skin, Bone, and Digit Swelling

Introduction

Hypertrophic osteoarthropathy (HOA), also known as Pierre-Marie syndrome, Bamberger syndrome, osteoartropatia hipertrofia, Mankowski syndrome, or Hagner syndrome, is a rare pathological condition that is characterized by clubbing and increased periosteal activity of the tubular bones, especially the digits.

Who Is Susceptible to Hypertrophic Osteoarthropathy?

Hypertrophic osteoarthropathy shows autosomal dominant and recessive patterns of inheritance with a bimodal age of onset during the first year of birth and puberty. The condition is predominant in males, but the exact incidence and prevalence have not been studied in detail.

What Are the Types of Hypertrophic Osteoarthropathy?

Hypertrophic osteoarthropathy is of two types based on its origin:

• Primary hypertrophic osteoarthropathy.

• Secondary hypertrophic osteoarthropathy.

What Causes Hypertrophic Osteoarthropathy?

Primary hypertrophic osteoarthropathy has a genetic origin from the genes encoding 15-hydroxyprostaglandin dehydrogenase and solute carrier organic anion-transporter-family member-2A1, resulting in abnormal accumulation of prostaglandin E2.

Secondary hypertrophic osteoarthropathy is observed in association with various cardiac, pulmonary, gastrointestinal, endocrine, adrenal, and lung carcinomas. Due to its close association with non-small-cell lung carcinomas, the condition is often considered a paraneoplastic rheumatic syndrome. Although the exact etiology of secondary hypertrophic osteoarthropathy is vague, a potent etiology similar to that of primary hypertrophic osteoarthropathy is hypothesized, which involves abnormally elevated levels of circulated hormones, and an alternative etiology of neurogenic etiology has also been proposed.

What Is the Pathophysiology of Hypertrophic Osteoarthropathy?

Both primary and secondary hypertrophic osteoarthropathy present similar clinical and pathological features, which suggest identical pathogenicity in both variants. Increased capillary density, capillary dilation, edema, and hyperplasia of both fibroblasts and vascular smooth muscle happen to be associated with clubbing in both subtypes. Abnormal vascularization, hypoxia (deficient oxygen), and chronic inflammation result in the stimulation and release of VEGF (vascular endothelial growth factor). VEGF is the prime pathophysiological agent of clubbing. The affiliation of VEGF is to the capillaries present in the extremities, especially that of the upper limbs. Lower limbs are spared partly owing to the distance variation between upper and lower limb extremities.

In secondary hypertrophic osteoarthropathy, there is an aggregation and entrapment of megakaryocytes and platelets in the pulmonary circulation. In predisposing cases like left-to-right shunts, malformations in existing vasculature (like hepatopulmonary syndrome), or aberrant vessel formation (bronchogenic neoplasms), these aggregates can bypass the pulmonary capillary beds, which lead to the interaction of the aggregates with the endothelium in the peripheral circulation. This results in hypoxia and the release of inflammatory and growth-promoting factors, which in turn increases VEGF.

The function of VEGF are:

• Stimulates angiogenesis (formation of new blood vessels).

• Increases capillary permeability.

• Promotes stimulation.

• Migration of osteoblasts (bone-forming cells).

• New bone formation.

• Edema (swelling).

This coincides with the characteristic features of hypertrophic osteoarthropathy. Hence, VEGF acts as a prime mediator of the condition. It is observed that treatment or management of the underlying condition in secondary hypertrophic osteoarthropathy leads to a marked decrease in VEGF levels and a drastic reversal of skeletal abnormalities.

Mutations in the 15-hydroxyprostaglandin-dehydrogenase (HPGD) encoding gene from the etiology of the primary variant of hypertrophic osteoarthropathy. The main responsibility of HPGD is to break PGE2 prostaglandin in the peripheral vasculature. Improper breakdown or lack thereof leads to abnormal accumulation of PGE2, which induces transcription of VEGF in osteoblasts and stimulates bone formation, activates endothelial cells, which increases further transcription of VEGF, and promotes local angiogenesis. This leads to the characteristic features of hypertrophic osteoarthropathy.

What Is the Histopathology of Hypertrophic Osteoarthropathy?

The histopathological specimen obtained from the digits shows excessive deposition of collagen fibers, interstitial edema, increased number of arteriovenous anastomoses, small vessel dilation, vascular hyperplasia, and vessel wall thickening with perivascular lymphocytic infiltration.

Under a higher magnification of electron microscope, the presence of Weibel-Palade bodies, perivascular infiltrate endothelial activation, and thickened, reduplicated basal capillary membranes confirm structural damages.

What Are the Signs and Symptoms of Hypertrophic Osteoarthropathy?

• Digital Clubbing: Digital clubbing is the most prominent sign of hypertrophic osteoarthropathy, which might be the only manifestation in early and mild cases. The bulbous deformity, also known as drumstick appearance, of the fingertips is evident on a physical examination which is caused due to progressive convexity of the nail and soft tissue deposition at the nail base. As a result, the nail base becomes shiny and thin, and the fingertips lose their creasing. In addition, there is a marked rocking of the nail bed on palpation due to increased edema. Clubbing can be diagnosed with a positive Lovibond sign on examination, which differentiates between actual and pseudo clubbing.

• Cutaneous Manifestation: Skin lesions involve dermal and glandular hypertrophy, which results in coarse facial features and skin furrowing on the face and scalp. ‘Elephant legs’ can be seen due to non-pitting, cylindrical soft tissue swelling of both legs. Tubular bones of extremities are muscle free, so the thickening of these bones is very evident. Other symptoms like seborrhea, blepharoptosis, acne, and hyperhidrosis manifest due to the hypertrophy of sweat and oil glands.

• Periostosis: Also called the inflammation of the periosteum (covering of the bones). The bones may be asymptomatic or tender on palpation. Joint effusion is evident in larger joints and lesser in small joints due to camouflage from tubular thickening.

How to Diagnose Hypertrophic Osteoarthropathy?

• Serological and Physical Examination:

There are no confirmatory serological tests for hypertrophic osteoarthropathy. The diagnosis of HOA is based on physical manifestations like leg swelling and tubular bone thickening. The underlying conditions of secondary hypertrophic osteoarthropathy should be considered, especially lung cancers since HOA is often a paraneoplastic rheumatic syndrome.

The presence of a positive Lovibond sign differentiates the observed clubbing from pseudo-clubbing. When the angle between the proximal nail fold and the nail at the junction of the nail bed is greater than 180°, the Lovibond sign is positive. Increased Lovibond angle results in Schamroth sign (obliteration of diamond-shaped windows between the nails.

• Radiographic Studies:

Radiographic studies should be done to detect any intrathoracic abnormality in the case of isolated clubbing. In the case of unilateral clubbing, a neurogenic etiology can be suspected, and angiography should be ordered. A radiograph of a periostitis-affected bone shows thickening without any change of shape, giving an onion skin appearance. The film may even show the ossification of ligaments and interosseous membranes.

• Synovial Fluid Study:

Synovial fluid is thick and viscous with spontaneous clotting even in the absence of any inflammatory cells.

• Other Tests:

Radionuclide bone scanning can detect early evidence of periostitis, but it cannot detect the origin of the symptom. F-fluorodeoxyglucose positron emission tomography with CT (computed tomography) may show periostitis with increased uptake of reagent in internal organs, indicating secondary hypertrophic osteoarthropathy.

How to Treat or Manage Hypertrophic Osteoarthropathy?

The treatment of secondary hypertrophic osteoarthropathy is primarily focused on treating the underlying disorder. When the underlying condition is managed, the VEGF levels drastically decline, which results in the remission of the condition. Such improvements are observed through treatments like removing lung tumors, correcting congenital heart malformations, treating infective endocarditis (heart wall or valvular infection), and lung transplants in cystic fibrosis. Pain can be managed by octreotide prescriptions.

Primary HOA is of genetic etiology resulting in over-accumulation of prostaglandins which can be managed by COX-2 inhibitors. Bisphosphonates are effective in the case of refractory bone pains.

What Is the Differential Diagnosis of Hypertrophic Osteoarthropathy?

• Secondary hyperparathyroidism.

• Chronic kidney disease.

• Scleroderma (chronic hardening and skin tightening).

• Sarcoidosis (collection of inflammatory cells or granulomas in various parts).

• Acromegaly (excessive growth hormone).

• Thyroid acropachy (changes in the fingers with autoimmune thyroid disease).

• Trauma.

• Multifocal osteomyelitis (inflammation of bone without infections).

• Hypervitaminosis A (chronic vitamin A poisoning).

• Fluorosis (excessive intake of fluoride).

• Leukemia (blood cancer).

• Juvenile idiopathic arthritis (arthritis in ages below 16 years).

• Psoriatic arthritis (joint inflammation with psoriasis-autoimmune skin disorder).

• Polyostotic bone tumors (uneven bone growth, bone replaced by fibrous tissues).

• Sickle cell dactylitis (severe digit pain in sickle cell patients).

What Is the Prognosis of Hypertrophic Osteoarthropathy?

The primary variant of the condition is self-restricting and often undergoes remission after an adolescent age. But the prognosis of the second variant is dependent on the treatment viability of the underlying condition. The prognosis is good in primary and secondary variants with a treatable underlying predisposing condition. Poor to worse prognosis is observed in cases of underlying cystic fibrosis, tuberculosis, idiopathic pulmonary fibrosis, extrinsic allergic alveolitis, and asbestosis. The prognosis of the condition accompanied by malignancy is unclear.

What Are the Complications of Hypertrophic Osteoarthropathy?

• Pain.

• Loss of range of motion.

Other complications are related to the underlying conditions respectively.

Conclusion

Patients may present with a suspected swelling which requires a specialized diagnosis of exclusion as the presented symptoms may be secondary to any serious underlying condition, including malignancies. A thorough medical history, physical examination, and radiographs should be undertaken to rule out probable differentials. An interdepartmental approach is the best bet against countering the condition along with its underlying illness.