Primary pachydermoperiostosis associated with Menetrier's disease

Introduction

Primary pachydermoperiostosis is a rare inherited disorder that manifests clinically by digital clubbing, extremely enlarged, painful and swollen joints, hypertrophic skin changes and periosteal new bone formation. This disorder usually has autosomal dominant mode of inheritance, although occasional autosomal recessive inheritance is reported and it occurs almost exclusively in men. The pathological mechanisms are still debated and proposed etiological factors include genetic influences, anomalies in fibroblast acitivity or alteration in peripheral blood flow.

Menetrier′s disease is a form of hypertrophic gastropathy occurring primarily in middle aged males. It is characterized by thickening of the gastric mucosa due to hyperplasia of gastric glands. Clinically, they present with dyspepsia, upper abdominal discomfort, loss of appetite, anemia, hypoproteinemia and its associated features, apart from weight loss. While the etiology of Menetrier′s diseas is still unknown, association of cytomegalovirus and Helicobactor pylori infection of gastric mucosa has been reported.[1],[2]

Some workers consider it as a precancerous condition.[2]

Here we report a case of primary pachydermoperiostosis with associated Menetrier′s disease.

Case Report

A 30 - year - old male presented to OPD of Dermatology, in June 1998, with the complaints of thickening and folding of skin of the scalp and face of 11 years duration. Initially, the thickening was limited to scalp and face which later extended on to extremities during past 6 years. Patient gave a history of pitting edema of lower extremities after prolonged standing, associated with mild pain. Family history revealed consanguineous marriage of parents with elder sister of patient suffering from acid peptic disease (APD) with malabsorption syndrome.

Patient has history of acid peptic disease with remissions and relapses of 14 years duration and history of treatment with H2 receptor antagonists and antacids with partial relief. Scrutiny of patients case records of 1987 revealed a history of gross anemia with hypoproteinemia associated with acid peptic disease for which he was subjected to endoscopy, gastric mucosal biopsy and jejunal biopsy at the department of Gastroenterology, PGIMS, Chandigarh, India. Upper gastointestinal endoscopy of 1987 reported prominent gastrict folds which however were effaceable with granularity of the mucosa, with associated multiple small erosions in stomach and multiple ulcers in duodenal bulb. Biopsy of gastric mucosa revealed active gastritis with mucosal infiltration with lymphomononuclear cells and eosinophils. Jejunal mucosal biopsy was normal. Surprisingly, cutaneous features of pachy-dermoperiostosis were not noted at the time of examination in 1987.

Presently, on examination of the patient, skin of the scalp, forehead and cheeks was thrown into folds with thickening of the eyelids giving the patient a weary look. There was spade like enlargement of hands and feet with skin at the sides of palms being thrown into folds. Clubbing of fingers was present. There was no macroglossia. Patient′s vital data were with in normal limits. Examination of other systems was normal. Haemogram, routine urine examination, serum proteins, routine blood biochemistry, serum T3, T4, and TSH and ECG were with in normal limits. Elisa for HIV & II was negative. Skin biopsy demonstrated epidermal hyperkeratosis and few follicular plugs with dermis showing dilated infundibule, hypertrophied sebaceous glands and round cell infiltration.

Skeletal survey revealed medullary widening of both clavicles, tibia and fibula with irregular periosteal reaction, diaphysial cortical thickening of both radio - ulna, metacarpals and phalanges associated with soft issue swelling and subarticular cystic erosions at both hip joints. Radiograph of the skull was normal.

Barium meal revealed markedly thickened and prominent gastric folds. Upper gastrointestinal endoscopy revealed thickened and hypertrophied

prolapsing non - effaceable gastric mucosa at the fundus and in the body of the stomach. There was also associated duodenal congestion. Gastric mucosal biopsy revealed changes of hyperplastic gastric mucosa with evidence of nonspecific inflammation.

Discussion

Pachydermoperiostosis also called primary hypertrophic osteoarthropathy, is characterized by pachyderma, periostosis, arthralgia and finger clubbing. Dermatological features usually found are coarse facial features, cutis vertices gyrata, hyperhydrosis of palms and soles, hyperplasia of sebaceous glands and seborrhoea. Associated features described are carpal and tarsal tunnel syndromes, chronic leg ulcerations, large calcifications of Achilles tendon, gynecomastia, opthalmological abnormalities, Crohn′s disease and mental retardation.[3]

The pathophysiology of this condition is not clear. Alteration of fibroblast biosynthetic activity and increased sensitivity of sex hormone steroid receptor and epidermal growth factor receptor system in the affected tissues were reported.[4] Usual age of onset of this condition is after puberty, though occasional cases are reported in children. Skin and bone changes usually progress for the first 5 to 10 years, although may continue to progress indefinitely.

Menetrier′s disease was first described in 1880, but in spite of more than 300 reported cases in the literature, the disease is almost as mysterious now as when it was first described. The existing data suggests that Menetrier′s disease might represent a common response to a number of endogenous and exogenous stimuli. The onset is insidious with peak incidence in fourth to sixth decade and the common clinical features associated are epigastric pain, vomiting, weight loss and peripheral edema. Most striking abnormality observed during endoscopy is the thick, tortuous gastric rugae which do not flatten with luminal air with occasional gastrict erosions and ulcerations. Menetrier′s disease has been previously reported in a family in association with primary pachydermoperiostosis.[3]

In the case under study, although this patient had clinical features of gastric mucosal hypertrophy in 1987, he did not reveal features of pachydermoperiostosis at that time. However when he came for re-evaluation in 1998 he had classical features of primary pachydermoperiostosis along with gastric mucosal findings of Menetrier′s disease. This indicates that both pachydermoperiostosis and Menetrier′s disease evolved and progressed over the period of 11 years to the present state. The symptoms of Menetrier′s disease though initially severe, were mild and intermittent later, as the patient was on therapy for APD.

Defects in the synthesis and degradation of regulatory macro molecules were observed in both these conditions. Abnormalities in the production of transforming growth factors (TGF) have especially been reported. Increased TGF - alpha immunoreactivity has been shown in gastric mucosa of patients of Menetrier′s disease,[5] whereas TGF-beta was observed to stimulate fibroblasts in patients of pachydermoperiostosis,[6] apart from the altered processing of plasminogen activator inhibitor I (PAI-I).

Not all patients of pachydermoperiostosis have gastrointestinal symptoms, hence are not investigated for its involvement. As both pachydermoperiostosis and Menetrier′s disease are hypertrophic conditions of the skin and gastric mucous membranes respectively and have at least some similarities in the abnormalities of growth factors, their association could be more frequent than reported. Routine upper gastrointestinal endoscopy in all patients of pachydermoperiostosis will help in assessing the actual incidence of gastric mucosal involvement in this condition.