Complete primary pachydermoperiostosis: A case report from Jordan and review of literature

Key Clinical Message Complete Primary Pachydermoperiostosis is a rare syndrome that presents with skin and skeletal manifestations. Though diagnosis can be made on the basis of the classic clinical and radiological features, it is often missed due to variable presentations. Therefore, it is important to know about this syndrome to reach correct diagnosis.


| INTRODUCTION
, also known as primary hypertrophic osteoarthropathy or Touraine-Solente-Gole syndrome, is a rare genetic disease with primary clinical features of pachydermia (thickening of skin) and periostosis (new bone formation). In 1935, three French dermatologists, Touraine et al, classified this condition as a familial disorder with three forms: complete (periostosis and pachyderma), incomplete (without pachyderma), and the forme fruste (pachydermia with minimal skeletal changes). 1 The development of the disease usually starts during adolescence with gradual thickening of facial skin, which eventually resembles that of an elephant (pachyderm) and hence the name. The diagnosis should only be made when at least two out of a family history, hypertrophic skin changes, bone pain/radiographic changes, or clubbing are existing. 2 The exact incidence is not known but estimated prevalence of the disease is 0.16%. 3 We report a case of complete primary PDP that presented to Jordan University Hospital which is the second reported case of its kind in Jordan. 4

| CASE REPORT
An 18-year-old male Caucasian referred to plastic surgery clinic from dermatology department as a case of extensive skin folding on the forehead and depressed nasolabial fold. He also complained of bilateral knee joint pain and swelling. These symptoms were first noted at 16 years of age. No history of similar condition in family and consanguinity. No history of trauma and fractures.
On examination, he had pronounced folds in the area of forehead, between the eyes, in the nasolabial grooves and on the chin, furrowing on his forehead skin and first one inch of the scalp posterior to hairline, and bilateral partial ptosis ( Figure 1). The development of the patient's skin folds was insidious and progressive. Clubbing of his fingers and toes ( Figure 2) was noticed. Patient has swollen knee joints ( Figure 3). Patient has profuse sweating and seborrhea in his axillae, hands, and feet.
Examination of the cardiovascular, respiratory, and gastrointestinal systems revealed no significant abnormalities.
Laboratory analysis showed a mild increase in ESR (18 mm/first h; normal < 15) and significant increase in Creactive protein (31.5 mg/L; normal < 5). The following | 347 SALAH et AL. parameters were normal: random blood sugar, serum calcium, growth hormone, and thyroid function tests.
Radiographic investigations were done to look for skeletal abnormalities. Plain X-rays revealed thickening of the bone indicating increased bone formation, symmetric shaggy subperiosteal bone formation with the involvement of epiphyseal regions, acro-osteolysis of the tufts of distal phalanges, irregularity in the superiolateral borders of both scapulae, and diffuse soft tissue thickening ( Figure 4).
According to the data available from history, examination, and investigation, the patient was diagnosed with complete primary form of PDP.
Two weeks after diagnosis, the patient underwent frontal rhytidectomy to remove excess skin in the forehead and to decrease the prominent nasolabial folds. A frontal rhytidectomy was performed through a brow lift incision, with dissection into forehead in the subgaleal and subfrontalis planes ( Figure 5). Excision of 2 inches of excess forehead skin was achieved and sent for histopathological examination. Closure of skin with 3-0 Nylon was done without tension.
Autologous dermal-fat graft from the lower abdomen was placed in the nasolabial fold bilaterally through a small nasolabial incision, due to lack of enough fat available for liposuctioning and grafting. Postoperative recovery was unremarkable.
Hyaluronic acid (1.6 mL of Juvederm ® filler) was injected in the forehead area 1 week after the operation, and Botulinum toxin type A (120 IU of Dysport ® ) was injected in the forehead muscles 4 weeks postoperatively ( Figure  6).
He was satisfied with the operation cosmetic outcome. Future interventions might be needed with further progression of the disease.
Microscopic evaluation of the excised skin revealed unremarkable epidermis and thickening of the dermis with fibrous bands extending into subcutaneous tissue surrounded by thick collagenous bundles with increased amount of ground substance. Well-controlled alcian blue and colloidal iron special stains highlight dermal per adnexal mucin deposition. Features of skin with deep dermal fibrosis, increased fibroblasts, and neuronal hyperplasia were consistent with the clinical diagnosis of Pachydermoperiostosis ( Figure 7).

F I G U R E 3 Swollen knee joints
F I G U R E 4 Hand X-ray: periostosis, enlarged phalanges and metacarpals; Foot X-ray: enlarged phalanges and metatarsals; Shoulder X-ray: enlarged both clavicles and irregularity in the superiolateral borders of both scapulae indicating periostosis; and Knee X-ray: symmetric shaggy subperiosteal bone formation with the involvement of epiphyseal regions, and speculated periostosis | 349 SALAH et AL.

| DISCUSSION
Pachydermoperiostosis also known as Touraine-Gole-Solente syndrome was first described as "Hyperostosis of the entire skeleton" by Friedreich in 1868. 5 In 1907, Unna suggested the term "cutis verticis gyrate" for thick, transversely folded skin of scalp and forehead. 6 Three forms of this disease were described: classic or complete form, presented with skin and skeletal changes; incomplete form, with skeletal changes but no dermal findings; and forme fruste with dermal changes but no skeletal findings. 7 When an affected person exhibits one or few features commonly associated with this syndrome, the diagnosis could be confirmed by thorough examination of other family members. 8 Pachydermoperiostosis has a gradual onset. The disease usually starts at puberty, progresses variably for the next 5-20 years, and then stays stable. 9 It occurs more commonly in young male patients (M:F ratio of 7:1). In addition, males were found more severely affected. Major findings in this disease include pachydermia, periostosis, and finger clubbing. Other minor findings include hyperhidrosis, seborrhea, cutis verticis gyrate, blepharoptosis, joint effusion, arthralgia, column-like legs, elephant feet, acne, and gastric ulcer. 10 PDP makes 3%-5% of cases of hypertrophic osteoarthropathy and should be distinguished from the secondary form before a diagnosis of PDP is established. 11 The secondary form usually results from cardiopulmonary diseases (eg, bronchiectasis, cystic fibrosis, congenital heart diseases, and tuberculosis), hepatic diseases (eg, portal and biliary cirrhosis), gastrointestinal diseases (eg, inflammatory bowel disease and polyposis), and certain malignancies (eg, Hodgkin's disease, nasopharyngeal carcinoma, and chronic myeloid leukemia).
Clinically, in secondary form, the cutaneous findings (pachydermia, seborrhea, oiliness) are less frequent than primary PDP; the osteoarthropathy is more severe and painful, especially with congenital cyanotic heart disease. 12 In secondary form due to neoplasia, only treatment of the underlying illness causes improvement of the associated symptoms. 13 Other differential diagnoses include acromegaly, thyroid acropachy, van Buchem's disease (in which there is absence of clubbing and skin changes), psoriasis, and rheumatoid arthritis. Patients with forme fruste have to be differentiated from the rare hyperelasticity disorders such as Ehler-Danlos syndrome, cutis laxa, Meretoga's syndrome, Marfan's syndrome, and pseudoxanthoma elasticum, which may cause forehead furrows. 14 In up to 30% of the patients, PDP presents as a hereditary disease with autosomal dominance of variable penetrance.Although pathogenesis is currently unknown, an increased level of prostaglandin E2 which motivates the overexpression of the vascular endothelial growth factor has been proposed as a main factor. Due to high M:F ratio, Xlinked transmission and role of testosterone hormone have been suggested as other factors. 15 Recently, hydroxyprostaglandin dehydrogenase (HPGD) and solute carrier organic anion transporter family member 2A1 (SLCO2A1) were described as pathogenic genes responsible for PDP. When germline SLCO2A1 mutations are detected, myelofibrosis, a life-threatening complication, should be suspected and individual followed up periodically. Alcoholic consumption might be a contributing factor by alteration of prostaglandin metabolism. 16 Unfortunately, genetic testing for our reported case was not available at our center.
Histopathological examination of skin samples taken from patients with PDP shows epidermal acanthosis and hyperkeratosis, different degrees of fibrosis and capillary ectasia of the dermis as well as sebaceous gland hypertrophy.
Bone biopsy showed cortical hyperostosis and thickening of the periosteum with bands of partially hyalinized connective tissue in addition to vascular hyperplasia, with a reduction in trabecular bone. In cases with arthritis, the synovial membrane showed vascular congestion and stromal edema, lymphocytic and monocytic infiltration, and formation of solitary lymphatic follicles. 17