Congenital Primary Pachydermoperiostosis and Striate

CASE REPORTS Serbian Journal of Dermatology and Venereology 2014; 6 (2): 81-92 DOI: 10.2478/sjdv-2014-0008 Congenital Primary Pachydermoperiostosis and Striate Palmoplantar Keratoderma - a Case Report Slobodan STOJANOVIĆ1*, Nada VUČKOVIĆ2 , Marina JOVANOVIĆ1, Kosta PETROVIĆ3

1Clinic of Dermatovenereology Diseases, Clinical Center of Vojvodina, Faculty of Medicine, University of Novi Sad 2Center of Pathology and Histology, Clinical Center of Vojvodina, Faculty of Medicine, University of Novi Sad 3Center of Radiology, Clinical Center of Vojvodina, Faculty of Medicine, University of Novi Sad

*Correspondence: OPEN UDC 616.5-002.52 :616.594.1

Abstract The authors present a rare case of congenital pachydermoperiostosis associated with striate palmoplantar keratoderma in a 55-year-old female. Pachydermoperiostosis (PDP) is a heterogeneous syndrome characterized by hypertrophic changes involving predominantly the skin and bones of the extremities: pachydermia, clubbing of the fi ngers and toes, and hypertrophic osteoarthropathy. Primary pachydermoperiostosis (Touraine–Solente–Gole syndrome) (PPDP) or primary hypertrophic osteoarthropathy (PHO) is a rare congenital disorder and is one of two types of hypertrophic osteoarthropathy. In addition to the three main criteria, which are confi rmed clinically, histologically, and by X-ray, there may be other additional clinical features. Hyperhidrosis of the hands and feet may be troublesome. The skin of the face, forehead and scalp becomes grossly thickened and thrown into folds. The folding of the scalp produces a form of cutis verticis gyrata. Additional clinical features include hypohidrosis, seborrhea, sebaceous gland hyperplasia and folliculitis, carpal and tarsal tunnel syndrome, chronic leg ulcers and calcifi cation in the Achilles tendon. Our patient presented with most of these additional clinical features, such as acro-osteolysis of the fi ngers and toes, which generally occurs occasionally. In regard to palmoplantar keratoderma, we have not found reports of its association with PPDP in the available literature. Unlike PPDP, secondary pachydermoperiostosis (secondary hypertrophic osteoarthropathy -SHO) occurs in association with severe pulmonary disease such as bronchiectasis, abscess, bronchial carcinoma, pleural mesothelioma, or thymic, esophageal or stomach cancer, which were all excluded in our patient. In conclusion, this paper presents a congenital form of pachydermoperiostosis in a female also suffering from striate keratoderma. According to the available literature, this is the fi rst case report of comorbidity between these two dermatoses.

Key words Osteoarthropathy, Primary Hypertrophic; Keratoderma, Palmoplantar; Diagnosis; Signs and Symptoms; Comorbidity

achydermoperiostosis (PDP) is a heterogeneous autosomal recessive inheritance has been demonstrated Psyndrome characterized by hypertrophic changes (1, 3). In 2008, the primary genetic defect in this involving predominantly the skin and bones of the disease was mapped to chromosome 4q33-q34 extremities: pachydermia, clubbing of the fi ngers identifying mutations in the HPGD gene, encoding and toes and hypertrophic osteoarthropathy (1, 2). the NAD+dependent 15-hydroxyprostaglandin Primary pachydermoperiostosis (Touraine-Solente- dehydrogenase (3). Th is is the main enzyme of Gole syndrome) (PPDP) or primary hypertrophic prostaglandin degradation, so homozygous individuals osteoarthropathy (PHO) is a rare inherited disorder with truncating mutations of HPGD may also have with no hard evidence of inheritance related to X persistent patent ductus arteriosus, secondary to the chromosome: in some families, autosomal dominant elevated levels of prostaglandin, while mild clubbing inheritance with incomplete penetrance and variable of the digits can be present in heterozygous carriers of expressivity was detected, while in other families, HPGD mutations (3).

Th e three major criteria of this syndrome include miotomes; no signs of acute injury, corresponding to pachydermia (thickening of the skin), hypertrophic radicular syndrome. X-ray examination showed diff use osteoarthropathy with periostitis (excessive bone osteoporosis of the hands, feet and knee joints. Bone formation) and the so-called ”clubbing” (swelling of mineral density (BMD) was measured by dual-energy the soft tissues of the terminal phalanx of a digit that X-ray absorptiometry (DEXA) and spinal osteoporosis obliterates the angle between the base of the nail and was excluded. the digit) with idiopathic acromegaloid features (1, 4). Apart from this, it was found that the patient was It has a marked predominance in males (5). treated by a cardiologist for compensated cardiomyopathy. Th e authors present a rare case of congenital Th e family history revealed that her father’s mother pachydermoperiostosis associated with palmoplantar suff ered from ”arthritis” and changes similar to hers, and keratoderma in a 55-year-old female. that her father died of a myocardial infarction. On the fi rst visit, general physical examination Case report showed that the patient was in good general condition, A 55-year-old female with a lifelong history of but having mobility diffi culties. Th e pertinent fi ndings clubbing of the fi ngers and a diagnosis of congenital were confi ned to the skin of palms and soles, ngers,fi toes pachydermoperiostosis was fi rst referred to our Clinic and nails as well as bones and joints on the hands and in 2011. Th e diagnosis was made in childhood by a feet: hyperkeratosis on the palms and soles with a clinical physiatrist, based on x-rays, but since then the patient picture of palmoplantar striate keratoderma (Figures was not treated or examined thoroughly. On admission, 1,2); signs of hypertrophic osteoarthropathy on the she complained of pain in muscles and joints, especially fi ngers with clubbing of the nails (Figure 3); subungual in the small joints of the hands and feet, as well as of hyperkeratosis of the toenails and hands with thickened, toenail changes and inability to stand on a fl at surface, dystrophic dark yellow nail plates and onycogryphosis forcing her to wear high heels. Over the last ten years she (Figure 4); inguinal follicular hyperkeratosis; keratotic - noticed yellowish thickening of the skin on the palpms thickened skin around the Achilles tendons and swelling and feet with nail damage and deformities of the fi ngers of the ankles. and toes. She experienced walking diffi culties and pain in the joints of knees, feet, and along the lumbosacral spine. Investigations History data showed that during childhood the Laboratory tests revealed the following abnormal test patient was admitted to the Endocrinology Department results: sedimentation rate 44/74 mm/h, red blood cell of the Institute for Mother and Child Health Care count 3.19 x1012/L, hemoglubin: 10.5 g/L, osteocalcin: in Novi Sad on two occasions, and at the Institute of 54.3 ng/ml (normally 12-41 ng/ml), Cross Laps: 572 Internal Medicine in Novi Sad 20 years ago. pg/ml (normally 162-436 pg/ml). Based on the submitted data, we learned that she Aff ected skin samples were positive for: Klebsiella underwent benign breast tumor surgery in 2003, and pneumoniae, Pseudomonas aeruginosa, and had regular 6-month check-ups with her oncologist: an Stenotrophomonas maltophiia, which are sensitive to intraductal papilloma was removed from the left, and an several antibiotics. atheroma from the right breast. Th e following check-ups Mycological examination: Candida albicans was indicated removal of new tumors in both breasts, and isolated between the toes of both feet. after magnetic resonance imaging and histopathological Oncomarkers: Th e following serum levels of tumor analysis, the diagnosis of fi bro-micro-cystic dysplasia/ markers were estimated: carcinoembryonic antigens adenosis without extensive changes was made; 6-month (CEA) 9,7 ng/ml (normally < 5,0 ng/ml), alpha check-ups with her oncologist continued. fetoprotein antigens (AFP), CA 19-9 carbohydrate Patient data also revealed that a tumor was removed antigen, CA 15-3 carbohydrate antigen, and CA 125 from the palm of her right hand in 2008, histologically carbohydrate antigen were all within normal levels. consistent with intradermal pigmented nevus and X-ray of the hands, feet and long bones: Prominent syringoma. Due to a reduced passive and active mobility diff use osteoporosis. Hand X-ray: bilateral narrowing of of the right hand, electromyography test showed: axonal the proximal interphalangeal joint space, pronounced on moderate to severe lesion of the C8, Th 1 right-sided the third, fourth and fi fth fi ngers on the right hand, and

Figure 1. Striate palmar keratoderma with pachyonyichia

on the fi ft fi nger on the left hand; marked narrowing of the distal interphalangeal joint space, with subluxation of the distal phalanges of the fi fth fi nger of the right hand; acro-osteolysis of distal phalanges present on all fi ngers, with almost complete lysis of the distal phalanges of the fi fth fi nger of the left hand; edema of the surrounding soft tissue - clubbing fi ngers (Figure 5). X-ray of the feet: Bilateral talocrural joint and metatarsophalangeal joint space narrowing of the fi rst toe; acro-osteolysis of distal phalages present on all toes, with nearly complete lysis of ditstal phalanges of the fi fth, third toes of the left foot, and on the third, fourth and fi fth toes of the right foot; bilateral periosteal reaction of the calcaneus and the fi rst metatarsal bone, more prominent on the right foot; rough exostoses on the distal heads of the fi rst metatarsal bone of both feet; bilateral calcaneal spurs at the site of the insertion of the plantar aponeurosis of the Achilles tendon, more pronounced on the right foot (Figure 6). X-ray of long bones: Bilateral periosteal reaction in the tibia, fi bula with bone bridge formation (Figure 7). X-ray of the knee and long bones: Marked diff use osteoporosis; bilateral asymmetric narrowing of the joint space of the tibiofemoral joint, prominent laterally with a lateral notch, and intercondylar Figure 2. Plantar keratoderma with subungual eminences and subchondral sclerosis of the articular hyperkeratosis and onychogryphosis surfaces; periosteal reaction of both the femur(with a

Figure 3. Clubbed fi ngers (digiti hippocratici) with osteohypertrophic arthropathy “sunburst” appearance), including the tibia and fi bula; – sacrum acutum; intervertebral disc space height calcifi cation in the knee pits; bilateral narrowing of and confi guration of the lumbar spine preserved. the patellofemoral joint (Figure 8). Incidental fi nding: abdominal aortic calcifi cation; Lumbosacral spine X-ray: Corrected physiological calcifi ed fi broid in the small pelvis. lordosis of the lumbar spine, with a sharp transition Mammography in two directions: Predominantly

Figure 4. Subungual hyperkeratosis with onychogryphosis and osteoarthropathic foot deformity

Figure 7. X-ray of the left calf: pronounced periosteal deposits on the tibia and fi bula with bone bridge formation

Figure 5. X-ray of the left hand: clubbing of the digits with acrolysis of the distal phalanges; distal phalange of the fi fth fi nger with prominent lysis; visible bone fragments in the soft tissue of the second fi nger after acrolysisdeformity fi broglandular tissue in both breasts; perimammilar area of the left breast presents with thickened skin, while grouped polymorphic microcalcifi cations are present in the retromammary region; oval, vaguely demarcated condensed parenchyma observed in the

Figure 6. X- ray of the right calcaneus: rough periosteal Figure 8. X-ray of the right femur: a periosteal bone deposits along the edge of the calcaneus reaction with a “sunburst” appearance

Figure 9. Photomicrograph of the skin with a thick keratotic layer, moderately thick granular layer of the epidermis and mild acanthosis and papillomatosis (HE x 40)

Figure 10. Photomicrograph of a skin biopsy specimen with moderately elongated epidermal papillae and thickened collagen fi bers in the papillary dermis (HE x 100)

86 © 2014 Th e Serbian Association of Dermatovenereologists CASE REPORTS Serbian Journal of Dermatology and Venereology 2014; 6 (2): 81-92 center line requiring ultrasound evaluation; there are no Pulmonologist: No pulmonary fi brosis. tumor shadows in the right breast, nor pathognomonic Recommendation – 6-month check-up. microcalcifi cations; no visible axillary node enlargement. Radiologist: Skeletal X-rays revealed changes, Breast ultrasound: A round cyst 14x9 mm, along predominantly in the long bones, hands and feet with a smaller one 6 mm in diameter, were found in consistent with severe pachydermoperiostosis. the retroareolar region of the left breast; moderate duct Physiatrist: Orthopedic shoes with a platform are ectasia; no visible signs of pathological condensation recommended. Postural imbalance is part of the of breast parenchyma; the right breast presented with underlying disease; clubbing fi ngers - functional. sporadic microcysts up to 5 mm in diameter; axillary Scoliosis - T4L, the right leg is longer, the right hip is fi brolipomatous lymph nodes. higher set; contracture of the right knee, swelling of both Chest X-ray fi nding (PA): Normal. lower legs; impaired walk. Gastroduodenal X-ray fi nding: Normal. Upper abdomen X-ray: Signs of gallbladder Therapy polyps and cholesterolosis. Uterus myomatosus was an Th e proposed treatment with systemic and local incidental finding. Findings on the liver, pancreas, and retinoids was rejected by the patient. After the kidneys were normal. potential chronic and malignant causes of secondary Th oracic CT (native): Normal. hypertrophic osteoarthropathy were excluded, Arterial and venous duplex ultrasound of the lower nonsteroidal antiinfl ammatory drugs (NSAID) and extremities: Normal fi ndings on the arteries and veins, local keratolytic treatment was initiated, as well as with a slightly pronounced Cockett’s perforator on the Tamoxifen, an anti-oestrogenic drug which may be left leg; enlarged lymph nodes visible bilaterally in the useful in the treatment of fi brocystic disease of the proximal part of the thigh; distal soft tissue swelling breast, prescribed by the gynecologist. below the knee, more pronounced on the left leg. Histological fi ndings of palmar keratoderma (thenar Discussion of the left hand from May 27, 2011; PH fi nding Primary pachydermoperiostosis (PPDP), or primary no.13072/11): pronounced hyperkeratosis of the hypertrophic osteoarthropathy (PHO), is a rare inherited epidermis with acanthosis (Figure 9); a prominent disorder with a characteristic triad: clubbing of the fi ngers granular layer and regularly elongated rete ridges; and toes, periostosis, and pachydermia (1, 3), as well as moderate edema of the papillary dermis; collagen fi bers elevated levels of prostaglandin E2 (PGE2) , which can be are tough and the dermis is slightly thickened (Figure 10); considered as a consequence of cytokine-mediated tissue septa of the subcutaneous adipose tissue are extremely remodeling and vascular stimulation. In PHO, these visible and thick; sweat glands are normal. Conclusion: eff ects are associated with hyperhidrosis, acroosteolysis, Cutaneous and subcutaneous changes are consistent pachydermia, periostosis and arthritis (6,7). PGE2 with pachydermoperiostosis. may aff ect the activity of osteoblasts and osteoclasts (ie Specialist consultations: Otorhinilaryngologist, promote osteoclasia). For these reasons, acroosteolysis and dentist, gynecologist, gastroenterologist, cardiologist, periosteal new bone formation are explained by eff ects ophthalmologist, pulmonologist, physiatrist. of PGE2 (8). Moreover, PGE2 has vasodilator eff ects, Otorhinolaryngologist: Hypoacusis mixta gradus levis. which is consistent with prolonged local vasodilation in No focus. Bilateral light mixed hearing loss - 25 dB. clubbing fi ngers (8). Apart from elevated levels of PGE2, Gynecologist: Menopause - the last cycle in 2009. studies including patients with PDP showed increased Postmenopause. Myoma uteri. Other fi ndings – normal. plasma levels of several other mediators, such as von Dentist: Periodontal disease. Willebrand factor, and vascular endothelial growth factor Ophthalmologist: Normal. (VEGF) (1, 9). Th ese mediators play a signifi cant role in Endocrinologist: Dual-energy X-ray absorptiometry PDP progression and periosteal proliferation (1). Unlike (DEXA) - indicates left hip osteoporosis. mutations in 15-hydroxyprostaglandin dehydrogenase Vascular surgeon: Feet problems are not vascular in nature. (HPGD), mutations in the genes encoding synthesis of Orthopedic surgeon: contractura genus bilateralis these factors have not been established so far (1, 9). gravis. PPDP is one of the two types of hypertrophic Cardiologist: Chronic cardiomyopathy. osteoarthropathy. It represents approximately 5% of

© 2014 Th e Serbian Association of Dermatovenereologists 87 S. Stojanović et al. Serbian Journal of Dermatology and Venereology 2014; 6 (2): 81-92 Primary Pachydermoperiostosis and Striate Keratoderma the total hypertrophic osteoarthropathy cases with a but usually not folded. Hyperhidrosis of the hands and prevalence of 0.16% (4, 10). Contrary to PPDP, secondary feet may be troublesome. Th e skin of the face, forehead pachydermoperiostosis (secondary hypertrophic and scalp becomes grossly thickened and thrown into osteoarthropathy - SHO) occurs in patients with severe folds. Th e folding of the scalp may produce one of the pulmonary diseases such as bronchiectasis, lung abscess, forms of cutis verticis gyrata. Additional clinical features bronchial carcinoma, pleural mesothelioma, or thymic, include hypohidrosis, seborrhoea, sebaceous gland esophageal and stomach cancer. Th e bone changes are hyperplasia and folliculitis, carpal and tarsal tunnel often painful, develop rapidly and are usually presented syndrome, chronic leg ulcerations and calcifi cation in the as a pertinent fi nding. Skin changes may be absent or Achilles tendon. Our patient presented with most of the mild. Th e bone and skin changes regress after appropriate additional clinical features. treatment of the primary disease (2). Our case report Skin biopsy is another way to diagnose PDP. is about a patient with a congenital hypertrophic Histology shows cutaneous sclerosis and hyalinosis, with osteoarthropathy, without signs of malignancy or perivascular infi ltration of lymphoid cells in the dermis cardiopulmonary conditions that might have caused it. (5); apart from hypertrophy of collagen and epidermal Based on the phenotypic expression, three clinical appendages, an increase of acid mucopolysaccharides subtypes of PDP have been proposed: 1) a complete form, may also be seen (2). However, it is not an absolutely presenting the full-blown phenotype which includes specifi c fi nding, because changes similar to those in all thus far described signs ad symptoms of PDP, but PDP may be found in some other diseases such as necessarily pachydermia, periostosis and clubbing fi ngers; myxedema, hypothyreoidism, acromegaly (4). However, 2) an incomplete form, accounting for 54% of cases skin biopsy helps to diagnose PDP in patients with skin with isolated bone involvement, limited skin changes, manifestations (4, 14). Histological tests of skin samples while pachydermia is less pronounced; 3) a fruste form, taken from palms with changes in the dermis and which accounts for only 6% of cases with pachydermia subdermis that match pachydermoperiostosis confi rmed and minimal or absent periostosis (1). Th e cause of the clinical diagnosis of palmoplantar keratodrma and diff erent forms of the disease is unknown (1). In our pachydermoperiostosis. case, it was a complete phenotype associated with striate In order to diagnose PPDP, other diseases palmoplantar keratoderma. Pachydermoperiostosis has often need to be excluded. For example, secondary a familial aggregation in 25 to 38% of cases (5), but it hypertrophic osteoarthropathy must be excluded, as has not been verifi ed in our case. Autosomal dominant well as cardiovascular, pulmonary, hepatic, intestinal model with incomplete penetrance, with extremely and mediastinal diseases (12). In diff erential diagnosis, variable expression, has been proved in about half of the detailed hormone tests are necessary (eg. thyrotropin families with incomplete type of the disease (1). Several and growth factor levels), and they were carried out in families with confi rmed autosomal recessive model of our patient. In our case thyroid gland disorders were inheritance, presented with a complete phenotype with excluded. severe osteo-skeletal and cutaneous manifestations. In regard to the course and prognosis of PPDP, Considering the fact that medical history data indicated skin and bone manifestations tend to progress for 5–20 the existence of the disease only in her father’s mother, years before stabilizing. Life expectancy may be the same, our patient can be included in the group with a recessive regardless of the fact that many patients have functional model of inheritance. and esthetic complications, including restriction of Pachydermoperiostosis is clinically diagnosed if the movements, neurological manifestations and the lion- following symptoms are present: pachydermia, clubbing like appearence with facial folds (leonine facies) (1, 15). of the fi ngers and toes, and periostosis (predominantly Non-steroidal anti-infl ammatory drugs (NSAID) aff ecting the distal ends of long bones) (1, 12, 13). are employed as symptomatic treatment, while New bone formation is seen on long bone X-rays as corticosteroids are used to relieve infl ammation and pain. symmetrical, irregular periosteal ossifi cations (13). Digital By inhibition of cyclooxygenase enzymes, NSAIDS clubbing is associated with cylindrical thickening of the reduce prostaglandin levels. Other medications are used legs and forearms. Acroosteolysis of the fi ngers and toes, to improve skin manifestations of patients with PPDP which may occasionally occur, was also present in our (5). Retinoids are preferably used to improve skin lesions patient. Th e skin of the hands and feet is also thickened, (5). By their systemic action on nuclear receptors of

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Kongenitalna primarna pahidermoperiostoza udružena sa strijatnom keratodermijom − prikaz slučaja Sažetak Uvod. Pahidermoperiostoza (PDP) predstavlja malih zglobova šaka i stopala, promene na noktima heterogeni sindrom za koji su karakteristične prstiju stopala i nemogućnost stojanja na ravnoj podlozi, hipertrofi čne promene prvenstveno kože i kostiju što je primoravalo da nosi samo obuću sa potpeticama. ekstremiteta: pahidermija, klabing (clubbing) prstiju Primetila je tokom poslednjih desetak godina žućkaste šaka i stopala i hipertrofi čna osteoartropatija. Primarna deblje naslage na dlanovima i stopalima sa oštećenjem pahidermoperiostoza − sinonim Turen−Solent−Goleov noktiju i deformitetima na prstima šaka i stopala. Takođe, sindrom (Touraine–Solente–Golé) (PPDP), ili primarna imala je i otežan hod i osećaj bolova u zglobovima kolena, hipertrofi čna osteoartropatija (PHO), redak je nasledni stopala, duž lumbosakralne kičme. Na osnovu priložene poremećaj i predstavlja jedan od dva tipa hipertrofi čne dokumentacije došlo se do podatka da je operisala osteoartropatije. benigne tumore na obe dojke 2003. godine, da se od Za razliku od PPDP, sekundarna pahidermoperiostoza tada redovno kontrolisala na 6 meseci kod onkologa; (sinonim sekundarna hipertrofi čna osteoartropatija − iz leve dojke odstranjen je intraduktalni papilom, a iz SHO) javlja se u sklopu teških bolesti pluća (karcinom, desne dojke aterom. Tokom narednih kontrola kod bronhiektazije, apsces), pleuralnog mezotelioma, ili onkologa indikovano je odstranjenje novih tumorskih karcinoma timusa, ezofagusa ili želuca. formacija na obe dojke, te je nakon snimanja magnetnom Primarna pahidermoperiostoza (PPDP) ili primarna rezonanicijom i histopatološke analize postavljena hipertrofi čna osteoartropatija (PHO) redak je genetski dijagnoza fi bromikrocistične displazije/adenoze, poremećaj koji pogađa i kosti i kožu, sa nesigurnim bez prisusustva ekspanzivnih promena i indikovane načinom genetskog prenosa (autozomnodominantnim šestomesečne kontrole kod onkologa. ali i autozomnorecesivnim), bez sigurnih dokaza o Na osnovu priložene dokumentacije takođe se saznalo da X-hromozom vezanom nasleđivanju. Primarni genetski je 2008. godine odstranjena tumorska promena na dlanu defekt kod ove bolesti je 2008. godine mapiran na desne šake koja je po patohistološkoj analizi odgovarala 4q33-q34.15 pri čemu je identifi kovna mutacija intradermalnom pigmentnom nevusu i siringomu. Zbog na genu HPGD koji kodira hidroksiprostaglandin- redukovane pasivne i aktivne pokretljivosti desne šake u dehidrogenazu, glavni enzim degradacije prostaglandina. celini, tada je indikovan i elektromiografski pregled desne Jedna od glavnih karakteristika bolesti je uglavnom ruke: lezija aksonskog tipa srednjeg do težeg stepena mišića pahidermija (zadebljanje kože), upala pokosnice C8, Th 1 miotoma desnostrano, bez znakova aktuelizacije, (prekomerno formiranja kosti) i tzv. klabing (oticanje tkiva što odgovara radikularnom sindromu. Pomoću RTG sa gubitkom normalnog ugla između noktiju i nokatnog pregleda utvrđena je difuzna osteoporoza šaka, stopala i ležišta), sa idiopatskim akromegaloidnim promenama kolenih zglobova. Na osnovu merenja mineralne gustine udruženim sa hipertrofi čnom osteoartropatijom.Češće kostiju (BMD) aparatom DEXA (eng. Dual Energy obolevaju muškarci. X-ray), isključena je osteoporoza kičmenog stuba. Prikaz slučaja. Bolesnica starosti 55 godina, sa Iz porodične anamneze saznalo se da je očeva mati dugogodišnjiim prisustvom maljičastih prstiju i bolovala od „kostobolje“ sa promenama i tegobama koije dijagnozom kongenitalne pahidermoperiostoze, koju je su slične njenim, a da je otac umro od infarkta miokarda. postavio fi zijatar na osnovu ogovarajućih RTG snimaka Na prvom pregledu, objektivni fi zički nalaz je pokazao još u detinjstvu, prvi put nam se javila 2011. godine; da je bolesnica bila u dobrom opštem stanju, ali teško nije se do tada ozbiljnije lečila i ispitivala. Na prijemu je pokretna. Relevantni zaključci su ograničeni na kožu imala bolove u mišičima i zglobovima posebno u predelu dlanova i tabana, prste i nokte, kao i kosti i zglobove

90 © 2014 Th e Serbian Association of Dermatovenereologists CASE REPORTS Serbian Journal of Dermatology and Venereology 2014; 6 (2): 81-92 na rukama i nogama: hiperkeratoza na dlanovima na jetri, pankreasu, bubrezima uredan. šaka i tabanima sa kliničkom slikom palmoplantarne CT toraksa nativno: uredan. keratodermije strijatnog tipa; znaci osteoartropatije Dupleks sken vena i arterija donjih ekstremiteta: uredan hipertrofi čnog tipa na prstima šaka sa slikom maljičastih nalaz na arterijama uz nalaz na venama, jedino nešto prstiju; subungvalna hiperkeratoza na noktima stopala naglašenijeg Koketovog (Cockett) perforatora levo; u i šaka sa zadebljalim delom, distrofi čnim nokatnim proksimalnom delu natkolenice, femoralno obostrano su pločama žutomrke boje sa pojavom slike onihogripoze vidljivi po jedan uvećan limfni nodus; evidentan je otok − kandžasti nokti; ingvinalna folikularna hiperkeratoza; mekih tkiva distalno potkoleno, izraženije levo. keratotična i zadebljala koža oko Ahilovih tetiva i na Histološki nalaz biopsije sa keratodermijskih promena skočnim zglobovima sa otokom skočnih zglobova. na dlanovima šaka (tenar leve šake od 27.05. 2011. Laboratorijski i drugi nalazi. Imala je abnormalne PH nalaz br.13072/11): epidermis je naglašeno nalaze: sedimentacija 44/74 mm/h, broj eritrocita 3,19 hiperkeratotičan, prominentnog granularnog sloja, x 1012/L, hemoglobin: 10,5 g/L, osteokalcin: 54,3 ng/ izduženih epidermalnih prečki; papilarni dermis je ml (normalno 12−41ng/ml), crossLaps: 572 pg/ml umereno edematozan; kolagena vlakna su grublja i demis (normalno 162−436 pg/ml). CEA karcinoembrioni je blago povećane debljine; u supkutanom masnom tkivu antigen 9,7 ng/ml (normalno < 5,0 ng/ml). septa su naglašena i deblja; znojne žlezde su pravilne. RTG snimak šaka i stopala i dugih kostiju: Izražena Zaključak: promene u dermisu i subdermisu odgovaraju difuzna osteoporoza snimljenih koštanih struktura. pahidermoperiostozi. Radiografi ja šaka: obostrano prisutno suženje Specijalističke konsultacije: ORL, stomatolog, ginekolog, proksimalnih interfalangealnih zglobnih prostora, gastroenterolog, kardiolog, oftalmolog, pulmolog, izraženije na III, IV i V prstu desno, kao i na V prstu fi zijatar levo; izrazito suženje svih distalnih interfalangealnih Radiolog: na osnovu RTG pregleda skeleta, nađene zglobnih prostora, uz subluksaciju distalne falange V promene na skeletu predominantno na dugim prsta desno; na svim prstima pisutna je akroosteoliza kostima, šakama i stopalima defi nišu izraženu formu distalnih falangi, uz gotovo potpunu lizu distalne falange pahidermoperistoze. V prsta leve šake; prisutan otok okolnih mekih tkiva − Fizijatar: Dolazi u obzir prepisivanje ortopedske obuće batičasti prsti. Radiografi ja stopala: obostrano prisutno po meri sa povišicom. Postoji posturalni disbalans u suženje talokruralnog zgloba kao i metatarzofalangealnih sklopu osnovne bolesti, maljičasti prsti sa očuvanom zglobnih prostora I prsta; na svim prstima je prisutna funkcijom. Skolioza T4L, desna noga duža, desni kuk akroosteoliza distalnih falangi, uz gotovo potpunu lizu višlje postavljen, kontraktura desnog kolena, otoci distalne falange V, III prsta levog stopala, kao i III, potkolenica obe noge. Hod izmenjen. IV i V prsta desno; obostrana periostalna reakcija na Terapija. Predloženu terapiju sistemskim i lokalnim kalkaneusu, I metatarzalnoj kosti, izraženije desno, u vidu retinoidima pacijentkinja je odbila. Nakon što su grubih egzostoza na distalnim glavicama I metatarzalne isključeni mogući hronični ili maligni uzroci za kosti oba stopala; spina kalkanei obostrano u projekciji sekundarnu hipertrofi čnu osteoartropatiju, u terapiju je, plantarne aponeuroze i Ahilove tetive, masivnije desno. pored NSAID i lokalne terapije keratoliticima, uključen Rtg snimak dugih kostiju: obostrana periostalna reakcija tamoksifen (prepisao ginekolog), antiestrogeni lek koji na tibiji, fi buli. bi mogao biti koristan u tretmanu cistične fi broze dojke RTG snimak kolena i dugih kostiju: izražena difuzna i prevenciji karcinogeneze. osteoporoza snimljeih koštanih struktura, obostrano Diskusija. Primarna pahidermoperiostoza (PPDP) prisutno asimetrično suženje zglobnog prostora ili primarni oblik hipertrofi čne osteoartropatije tibiofemoranlnog zgloba; periostalne reakcije oba femura (PHO), predstavlja retku naslednu bolest za koju i snimkom obuhvaćene tibije i fi bule; kalcifi kacije u je karakteristična trijada: maljičasti prsti na šakama zatkolenim jamama; suženja patelofemoralnog zgloba i palčevima stopala, periostoza i pahidermija, kao i obostrano. povišen nivo prostaglandina E2 (PGE2), što se može Mmamografi ja i UZ dojku: promene odgovaraju smatrati posledicom delovanja citokina na tkiva i krvne fi brocistično izmenjenim dojkama sudove. Kod PHO se ova dejstva povezuju sa pojavama Rtg srca i pluća u PA pravcu: uredan. hiperhidroze, akroosteolize, pahidermije, periostoze i Rtg gastroduodenuma: uredan. artritisa. PGE2 može uticati na aktivnost osteoblasta i UZ gornjeg abdomena: znaci polipoze i holesteroloze osteoklasta (odnosno izgradnju i osteoklaziju koštanog holeciste. Uterus miomatozus je uzgredan nalaz. Nalaz tkiva). Iz ovih razloga se akroosteoliza i periostalno

© 2014 Th e Serbian Association of Dermatovenereologists 91 S. Stojanović et al. Serbian Journal of Dermatology and Venereology 2014; 6 (2): 81-92 Primary Pachydermoperiostosis and Striate Keratoderma obrazovanje kostiju objašnjavaju dejstvom PGE2. biopsija kože pomaže postavljanju dijagnoze PDP u Štaviše, PGE2 ima vazodilatorne efekte, što je u skladu nejasnim slučajevima. Histološki, analiza kože uzete sa produženom lokalnom vazodilatacijom prisutnom sa keratodermijskih promena na dlanovima šaka kod u maljičastim prstima. Osim povišenog nivoa PGE2, naše pacijentkinje, zajedno sa promenama u dermisu studije o bolesnicima sa PDP pokazale su i povećane i subdermisu, koje odgovaraju pahidermoperiostozi, nivoe u plazmi nekoliko drugih mdijatora, kao što su potvrdila je kliničku dijagnozu palmoplantarne Von Vilebrandov (Von Willebrand) faktor i vaskularni keratodermije u sklopu pahidermoperistoze. endotelni faktor rasta (VEGF). Ovi medijatori bi mogli Radi postavljanja dijagnoze PPDP, često moraju biti imati značajnu ulogu u progresiji i širenju PDP (1). isključene druge bolesti. Na primer, isključuje se Za razliku od HPGD mutacija, nije do sada utvrđeno sekundarna hipertrofi čna osteoartropatija u sklopu postojanje mutacija na genima koji kodiraju sintezu kardiovaskularnih, plućnih, jetrenih, crevnih i navedenih faktora. medijastinalnih bolesti. Radi postavljanja diferencijalne Na osnovu fenotipske ekspresije, razlikuju se tri podtipa dijagnoze, potrebna je detaljna hormonalna pretraga (npr. PDP: 1) kompletan fenotip, koji u 40% slučajeva može tirrotropni i nivo hormona rasta) što je je sprovedeno uključivati sve do sada opisane simptome i znake PDP, kod naše bolesnice. U našem slučaju isključene su ali obavezno pahidermiju, periostozu i maljičaste prste, endokrinološke abnormalnosti štitne žlezde. što je puni fenotip bolesti; 2) Nepotpuni fenotip se javlja Kada govorimo o toku i prognozi bolesti, PPDP u 54% slučajeva, a karakterišu ga uglavnom koštane i obično napreduje tokom 5 do 20 godina, dok tok ne skeletne promene, dok je pahidermija slabije izražena; 3) postane stabilan. Očekivano trajanje života može biti frusta fenotip javlja se u samo 6% slučajeva; kliničkom nepromenjeno, bez obzira na to što bolesnici imaju mnogo slikom dominiraju promene na koži sa manje izraženim funkcionalnih i estetskih komplikacija, uključujući skeletnim promenama i ograničenom periostozom ograničeno kretanje, neurološke manifestacije i „lavlje (1). Nepoznat je uzrok nastanka ovako različitih formi lice“ sa naborima (facies leontina). bolesti (1). U našem slučaju se radilo o kompletnom Konvencionalna terapija PPDP je u osnovi simptomatska, fenotipski ispoljenom obliku bolesti udruženom sa najčešće se bazira na nesteroidnimantiinfl amatornim palmoplantarnom keratodermijom strijatnog tipa. U lekovima (NSAIL) i kortikosteroidima koji se daju 25−38% slučajeva, pacijenti imaju familijarnu pojavu sa ciljem smanjenja upale i bola. NSAIL inhibicijom PDP (4), što nije siguran podatak u našem slučaju. enzima ciklooksigenaze smanjuju nivo prostaglandina. Autozomnodominantni model nasleđivanja, sa izrazitom Drugi lekovi se koriste kod bolesnika sa PPDP sa ciljem penetrantnošću i varijabilnošću, potvrđen je kod oko delovanja na kosti i promene na koži. Retinoidi se koriste polovine porodica sa nepotpunim oblikom bolesti (1). prvenstveno za poboljšanje kožnih promena. Infl iksimab, Nekoliko porodica, sa poznatim autozomno recesivnim biološki inhibitor faktora tumorske nekroze alfa (TNF- modelom nasleđivanja, imalo je kompletno fenotipski alfa) može biti efi kasan u resorpciji novostvorene ispoljen oblik bolesti sa izraženim koštano-skeletnim i kosti. Hirurški tretman služi za poboljšanje estetskih i kožnim oblikom bolesti. S obzirom na postojanje samo funkcionalnih sposobnosti obolelih. anamnestičkih podataka o pojavi oboljenja samo kod Kada je palmoplantarna strijatna keratodermija u očeve majke, i naša bolesnica mogla se ubrojati u ovu pitanju, do sada nismo našli, u nama dostupnoj literaturi, grupu sa recesivnim modelom nasleđivanja PDP. njenu udruženost sa PPDP. Baro−Klenovsek (Barraud− Biopsija kože predstavlja još jedan način da se Klenovsek) objavili su slučaj 30-godišnje žene sa dijagnostikuje PDP. Histologija otkriva kutanu palmoplantarnom keratodermijom i maljičastim prstima sklerozu, hijalinozu, perivaskularni infi ltrat limfoidnih 1997. godine. Nedavno, Perić i saradnici, objavili su slučaj ćelija; takođe mogu biti prisutni hipertrofi ja kolagena pahidermoperiostitisa kod bolesnika sa psorijazom. i epidermisa i epidermalnih adneksa, kao i povećanje Zaključak. U radu je prikazan kongenitalni oblik nivoa kiselih mukopolisaharida. Međutim, to nije pahidermoperiostoze kod ženske osobe kod koje se apsolutno specifi čan nalaz, jer se i kod drugih bolesti tokom života razvila strijatna keratoderma. Prema nama mogu u koži ispoljiti slične promene kao kod PDP, npr. dostupnoj literaturi, ovo bi bio prvi objavljeni slučaj kod miksedema, hipotireoze, akromegalije. Međutim, udružene pojave ove dve dermatoze.

Ključne reči Primarna hipertrofi čna osteoartropatija; Palmoplantarna keratodermija; Dijagnoza; Znaci i simptomi; Komorbiditet