Narayanan, Srinivasan MD*; Mohamed Gani, V. M. S. MD*; Sundararaju, Venmathi MD†
From the *Department of Medicine, SRM Medical College Hospital, SRM University, Chennai, India; and †Department of Internal Medicine, SUNY Upstate University, New York, NY.
V.S. was at SRM University when this work was done.
Correspondence: Srinivasan Narayanan, MD, Department of Medicine, SRM Medical College, SRM University, SRM Nagar, Kattankulathur, Chennai 603203, Tamil Nadu, India. E-mail: email@example.com.
Pachydermoperiostosis (PDP), or primary hypertrophic osteoarthropathy (PHO), is a rare genetic disease affecting both skin and bones. The 3 major diagnostic criteria include digital clubbing, periostosis, and pachydermia. The minor criteria include seborrhoea with sebaceous hyperplasia, folliculitis, acne, hyperhidorosis, and cutis verticis gyrata.1 Some of the earliest descriptions of the abnormalities caused by this syndrome were described by Hippocrates in 459 BC. We report the case of a 25-year-old man presenting with widening of the wrist and ankles, broadening of the fingers and toes, and clubbing for the previous 5 years who also had hypertrophic gastropathy.
A male patient aged 25 years from southern Tamil Nadu reported to the university hospital with progressive enlargement of the hands and legs and with broadening of fingers and toes since the last 5 years. In addition, he suffered from marked sweating especially of the hands and feet as well as persistent pain in the limbs and joints especially in the knee and ankles. He was born to nonconsanguineous parents with a healthy male sibling. On clinical examination the patients height was 157 cm with a weight of 44 kg. The patient had pronounced folds in the area of the forehead, between the eyes and in the nasolabial region with pseudoptosis, seborrhea and folliculitis. Noticeable folds (Cutis Vertis Gyrata) were also evident in the occipital region. Examination revealed grade IV pandigital clubbing with bilateral symmetrical enlargement of forearm and leg, widening of the wrist with tylosis (Fig. 1). The axillary and pubic hair were sparse with normal external genitalia, thyroid gland, and breasts. There was bilateral painless knee effusions with otherwise unremarkable systemic examination. Investigations revealed mild microcytic hypochromic anemia (Hb 10.3 g%) with ESR 28 mm in the 1st hour, normal blood biochemical tests including renal, hepatic, thyroid, and glucose tolerance tests. X-ray of both wrists with hands showed soft tissue thickening, widening of long ends of bone with normal joint space with periosteal thickening. X-ray of the skull showed cortical expansion with normal sella. X-ray of both hip with pelvis showed periosteal thickening with normal joint space. X-ray of both legs revealed normal symmetrical bones with periosteal thickening. X-ray of dorsolumbar spine showed mild reduction in disc space with sclerosis of vertebral bodies. Growth hormone and IGF levels were normal. Serum VDRL test was negative. Chest x-ray and computed tomography scan ruled out pulmonary lesions. ECG, echocardiogram, and abdominal with scrotal ultrasound were normal. Knee joint synovial aspirate was noninflammatory. Skin biopsy from the forehead showed mild hyperkeratosis and irregular acanthosis, hyperkeratotic plugs and pigment incontinence, focal acantholysis and multiple pustules within the epidermis with sebaceous hyperplasia. Upper GI scopy was done despite the absence of any dyspeptic symptoms because of the previous reported association of hypertrophic osteoarthropathy (HOA) with Menetrier's disease. It showed hypertrophic mucosa especially in the fundic region. Gastric biopsy revealed foveolar and polypoid hyperplasia of the surface epithelium, cystic changes, stromal edema with lymphoid collections, plasma cells, and eosinophils (Fig. 2).
Diagnosis of PHO with hypertrophic gastropathy was made and the patient was started on nonsteroidal anti-inflammatory drugs (NSAIDS) which have been tolerated with minimal benefit and is on regular hospital follow-up.
PHO was originally described by Friedreich in 2 affected brothers as “hyperostosis of the entire skeleton.”2 In 1935, Touraine, Solente and Gole individualized PDP as the primary form of the hypertrophic osteoarthropathy, distinct from the more common secondary hypertrophic osteoarthropathy (SHO) associated with various underlying causes like pulmonary or cardiac diseases.3 The primary form is considered to be hereditary with proved autosomal dominant inheritance and suggested autosomal recessive and X-linked inheritance.4
The disease typically appears without an underlying cause in infancy and adolescence, progresses for a number of years and then stabilizes with a near normal survival. The disease has a bimodal peak, with one in the first year of life and the other at puberty. Touraine et al3 described 3 forms of PHO (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.
It is important to distinguish between PHO/PDP and SHO. Secondary hypertrophic osteoarthropathy usually follows lung/cardiac/hepatic/intestinal/endocrinal disorders.
Bone lesions in the secondary form are more painful and progress more rapidly while the skin changes are slight to moderate. In SHO the underlying disease usually appears first but HOA can precede symptoms of the underlying disorder by more than a year, hence follow-up of patients is essential.5,6 In PHO the progress is slow and patients rarely report symptoms voluntarily as the skin manifestations and clubbing have over time become part of the patients body image, and the patient considers them to be more or less normal. The patients initially seek medical help for minor pains in the shoulder, hands, or recurrent swelling of a mechanical nature in the knees or ankles (effusions).7
Vascular endothelial growth factor is now postulated as the prototypic osteogenic-angiogenic coupling factor in the pathogenisis of HOA.8 Recent articles and studies have thrown light on the possible role of prostaglandins especially PG E2 in the pathogenesis of PHO.9,10 Uppal et al identified mutations in HPGD gene, which encodes 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a prostaglandin E2 (PG E2) catabolizing enzyme.11 This study has raised the key question as to whether treatment with NSAIDS, which block PG E2 synthesis, can arrest the progression of HO symptoms in patients with PHO.
A curious palindrome occurs in some cases of primary HOA as reported by Manuel Martinez-Lavin et al.12 They develop, as a late complication, diseases that in other circumstances are known to generate HOA. PHO patients developing patent ductus arteriosus, Crohn disease, and myelofibrosis have been reported as late as 6 to 20 years after the first diagnosis.12
Our patient presented at the age of 25 years with symptoms starting 5 years before presentation. He had a complete form of PHO with pachydermia and periostitis but without a family history. All work-up for secondary causes were negative and he remains free from any secondary causes as on 6-month follow-up. He had marginal improvement in the form of mild decrease in the swelling of the hands and legs without any intolerance to NSAIDs.
The association with hypertrophic gastropathy as seen in our patient is rarely reported.13,14 Lam et al have previously reported giant hypertrophic gastritis in a family with PDP and ulcer dyspepsia and suggested the possibility that PDP, hypertrophic gastropathy, and peptic ulcer may be genetically related.13,14 The levels of serum pepsinogen I and II were found to be markedly elevated. Symptoms usually appear in the twenties and are severe with gastric and duodenal ulcers.15 Our patient had no symptoms of ulcer dyspepsia or a family history of either PDP or dyspepsia.
PHO has a self-limiting course, and progression stops at the end of adolescence. There is no curative treatment for the skeletal abnormalities.
NSAIDS, colchicine may be helpful for the pain due to subperiosteal new bone formation. Recent isolated reports suggest that pamidronate (30–60 mg intravenous), Octreotide help in relieving bone pain in such cases.12 For correction of gross disfigurement plastic and reconstructive surgery may be indicated. Otherwise reassurance is all that is required. Prognosis for life is excellent but the effect on function depends on the degree of bone and joint involvement.
1. Once diagnosed patients with primary HOA require regular monitoring as in the long-term they may develop malignancies and complications due to the excessive growth in the soft tissues and bones.
2. PDP with hypertrophic gastropathy is a rarely reported combination and is important in view of the possible genetic link with ulcer dyspepsia.
3. NSAIDS can help in attenuating the hypertrophic osteoarthropathy in HOA by inhibiting PG E2 synthesis.
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Figure. No caption available.
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