Olmsted syndrome with squamous cell carcinoma of extremities and adenocarcinoma of the lung: failure to detect loricrin gene mutation

ARTICLE

Auteur(s) : Fumihide Ogawa¹, Masako Udono¹, Hiroyuki Murota¹, Kazuhiro Shimizu¹, Hidetoshi Takahashi², Akemi Ishida-Yamamoto², Hajime Iizuka², Ichiro Katayama¹

¹ Department of Dermatology, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan
² Department of Dermatology, Asahikawa Medical College, Midorigaoka-Higashi 2-1-1-1, Asahikawa 078-8510, Japan

Article accepted on 11/08/03

Case report

A 48-year old woman, first presented to the dermatology department at a 7-year old with a lifelong complaint of severe palmoplantar and periorificial keratoderma. The hyperkeratotic erythema had first appeared on her neck and continuously spread to the perioral, inguinal and perianal areas when she was 3-months old. The marked palmoplantar keratoderma was detected when she was 2 years old, and that resulted in a flexion and walking disorder. When she came to our department, hyperkeratotic lesions had developed around the perioral and perianal body orifices. We could also detect hyperkeratotic lesions in nares and inguinal areas. The lesions had borders which were sharply margined with erythematous inflammation. The soles were affected by a diffuse, thick keratoderma. Marked dystrophy, hyperkeratosis and paronychia of the nails also occurred. (Fig. 1) There was a growth retardation, her height and weight placed her outside the – 2 standard deviation at this time, and resulted in short stature, 136 cm, 30.6 kg. No joint laxity was observed. IQ and neuro-sensory evaluation (including hearing) were normal. The mutilating changes of the fingers progressed with age resulting in contractions of the fingers and in difficulty in grasping because of severe deformities. We did not observe ainhum-like constriction bands during the course of her disease.
At the age of 19, she had a trans-tibial amputation of the left leg because of squamous cell carcinoma (SCC). SCC next appeared on the right inner malleolus area at the age of 31, and then she had excision of the SCC and a skin graft. (Fig. 2a) Histological examination of SCC showed eosinophilic cytoplasm with abnormal nucleus that promoted the formation of obvious horn pearls. (Fig. 2b,c) Metastasis of SCC to the left inguinal lymph node was identified by lymphadenectomy, and intramuscular administration of methotrexate was applied to this metastasis.
At the age of 43, she was diagnosed as suffering from Olmsted syndrome based on clinical and histological findings. Histological examination of her keratoderma showed a thickened epidermis, hyperkeratosis with parakeratosis and absence of granular layer in most parts of the epidermis. (Fig. 3a,b) Previous electron microscopy revealed that cells which have keratohyaline granules and nucleus, were detected in the stratum corneum, furthermore, we could detect cells that equipped organelles in the horny layers (Fig. 4).
Laboratory tests showed no significant abnormality. Serum zinc levels were normal. A hormonal workup (growth hormone, somatomedin C, plasma cortisol, thyroid and parathyroid hormone, TSH) proved normal.
X-ray analysis of the hands showed complete osteolysis of the proximal phalanx of each finger of the hands at the age of 31 years which extended with complete lysis of the metacarpal bones of the hands at the age of 43. (Fig. 5) Diffuse hyperkeratosis of the soles and tendons was also observed. The toes showed similar deformities to those seen in the fingers, but the progression of the toes was more gradual than that of the fingers.
Several ointments, such as corticosteroid, vitamin A, salicylic acid, urea ointment or zinc ointment, showed no significant improvement of the abnormal keratinization. Radiation therapy on the palms and soles was performed at 8-years old with unsatisfactory clinical results. She was treated up to 57.6 Gy with 230KV roentgen on her extremities.
At the age of 47, we detected a small mass on the right upper lobe of the lung about 1.5 cm in diameter, by computed tomography. Needle biopsy revealed the lesion to be adenocarcinoma. She did not smoke. Further studies clarified it as a metastasis to the right occipital lobe, 1.5 cm diameter. She was treated with stereotactic radiosurgery of brain mass up to 30 Gy in total dose, instead of systemic chemotherapy. In contrast, systemic chemotherapy for the lung adenocarcinoma was not undertaken because she was concerned about the side effects of this and we could not get her consent for treatment.

Materials and methods

To differentiate loricrin keratoderma, including Vohwinkel's syndrome, loricrin gene mutation was analyzed after informed consent. DNA was isolated from peripheral blood of the patient and the entire coding sequence of the loricrin gene was amplified by PCR from genomic DNA. High-molecular weight DNA was isolated from peripheral leucocytes with proteinase K digestion following phenol/chloroform extraction. The sequence of exon 2 of the loricrin gene from genomic DNA was amplified by polymerase chain reaction (PCR) using the LA PCR kit (Takara shuzo, Ohtsu, Japan). The primers, designed from the published sequence (GenBank M94077), were 5'-GCTGAGGCTCTGGCACCTAAAAG-3' (forward) and 5'-GCCGGAGAGCTCAATGGCTTCT-3' (reverse). PCR conditions were 95°C for 2 min, then 35 cycles of 95°C for 1 min, 65°C for 2 min and 72°C for 2 min, followed by a 7-min extension at 72°C using thermal cycler 400 (Perkin Elmer Cetus, Norwalk, USA). PCR products were purified on agarose gel and directly sequenced using the Big Dye Termination Cycle FS Ready Reaction Kit (PE Biosystems, Tokyo, Japan). The sequences were run in a 373-A Sequencer (PE Biosystems). The PCR product was subcloned to pCRTM2.1 vector (Invitrogen, San Diego, CA, U.S.A.) and sequenced with 5'-TCTCCTTCCTTCTCAGACAA-3' or 5'-CGCTGAGGCTCTGGCACCTGAAGG-3' using the dideoxy nucleotide method.

Results

PCR amplified a 1235-bp product, which contained the entire coding region of the loricrin gene. Direct sequencing analysis revealed that no mutation was found in this case.

Discussion

We here present a patient suffering from Olmsted syndrome, complicated by SCC and osteolysis. Twenty-two cases of Olmsted syndrome have been reported in the literature [3-6]. 17 of the 22 patients reported were males [4, 5, 7-9]. Although inheritance of this syndrome is mostly sporadic, autosomal dominant cases [9, 10] and monozygotic twins cases [11] have been reported. Perry summarized previous reports of Olmsted syndrome [12] and categorized this disease as follows; The two major findings that classify the Olmsted syndrome as distinctive and independent are (1) symmetrical involvement of keratoderma of the palms and soles, and (2) the presence of symmetrical hyperkeratotic plaques around the body orifices. The less classical manifestations are scaly dermatosis of the scalp, various degrees of alopecia, nail dystrophy (mild to severe), chronic paronychia, contracture deformities of digits with spontaneous amputations, leukokeratosis, transgradiens keratoderma of hands, verrucous plaques in axillae and nuchal areas and small stature. Furthermore, unusual or incidental findings in this syndrome have been summarized in this report. These are large joint laxity, absent premolars or gaps in dentition, high frequency hearing loss, supprativa dacrocystitis, corneal epithelial dysplasia, primary sclerosing cholangitis and linear hyperkeratosis on the extensor surface of extremities, axillae and cubital areas. We observed two major manifestations, many minor manifestations and linear hyperkeratosis as incidental features in our case. For the differential diagnosis, Mal de Meleda, Norbotten type recessive palmoplantar keratoderma and Vohwinkel's syndrome (including the Camisa variant) should be considered. Most of these can be easily differentiated from Olmsted syndrome by the absence of periorificial keratoderma. We investigated the loricrin gene mutation that has been detected in some pedigrees of variant Vohwinkel's syndrome [2, 13, 14] and one case of progressive symmetric erythrokeratoderma [15]. Loricrin is the major protein component of the cornified cell envelope of terminally differentiated keratinocytes. Therefore loricrine gene mutation might cause palmoplantar keratoderma such as Vohwinkel's syndrome. Only three mutations in the loricrin gene have been reported to date. The clinical presentation of loricrin keratoderma is distinct from typical Vohwinkel's syndrome, which causes specific connexin 26 gene mutations and has a feature of deafness. No loricrin mutation was detected in our case. There are previous reports, which have investigated keratin expressions in Olmsted syndrome [4, 7, 16]. They checked the immunoreactibility of the epidermis by anti keratin antibodies, and suggested abnormality in the terminal differentiation of keratinocytes that is directly related to the disease in Olmsted syndrome. Although we did not investigate keratin expression, the results of histopathology and electron microscopy in our case also might support their suggestion.
X-ray studies of the hands and feet in our case showed pronounced osteoporosis and osteolysis. The developments of osteolysis in the hands were faster than in the foot. Radiographic studies in the previous reports [8, 16-18] found similar results. In previous reports, osteolysis in this syndrome is not frequently described and the causes of osteolysis were not mentioned. It is unclear whether it might be a consequence of the genetic effect or the consequence of an inflammatory process. As for the former possibility, there is a syndrome such as pycnodysostosis [19] and Papillon-Lefevre syndrome [20]. In those syndromes, osteolysis is a part of their phenotypes and is caused by cathepsin K and cathepsin C gene mutations respectively. On the other hand, there is another syndrome, hypotrichosis-osteolysis-periodontitis-palmoplantar keratoderma (HOPP) syndrome [21]. This syndrome resembles Haim-Munk syndrome that is also caused by cathepsin C gene (CTSG) mutations and has osteolysis as a phenotype, but there are no CTSG mutations in HOPP syndrome. Authors suggested that the syndrome is caused by mutations in a gene that has a functional or structural relation with CTSC. As a latter possibility, there are previous investigations that preinflammatory cytokines such as TNF-α, IL-1α, IL-1β, TGFα and IL-6 play an important role for activating osteoclast formation and bone resorption [22, 23]. Furthermore, there is an interesting investigation suggesting that so-called surface-associated material (SAM) eluted from S.aureus and S. epidermidis in saline was able to induce osteolysis by activating proinflammatory cytokines [24]. Some infection on the skin surface of keratoderma in Olmsted syndrome might enhance osteolysis. In either possibility, activating osteoclasts seems to play an important role in osteolysis in Olmsted syndrome.
We observed two separate SCCs on the extremities and adenocarcinoma of the lung. The patient did not smoke and no one in her family suffered from cancer. It might be argued that the radiation therapy for keratoderma she received in her childhood could predispose to the development of SCC on her extremities. In this respect, SCC on the right foot [25] and four epitheliomata cuniculatum (EC) on the both soles in Olmsted syndrome [26] have been reported. These two cases had no radiation therapy. Furthermore, our patient suffered from lung cancer diagnosed as adenocarcinoma not metastasis of SCC. Although lung adenocarcinoma might suggest cancer proneness in Olmsted syndrome, there is no direct proof of it. Because of the facts mentioned above, we suggest that Olmsted syndrome has a higher potential to develop tumors such as SCC, EC and adenocarcinoma. However, it is unclear why other palmoplantar keratoderma such as Meleda, Vohwinkel's syndrome including Norbotten type are not cancer prone and Olmsted syndrome is different. The severe, unstable palmoplantar lesions, and some cancer predisposition might cause cancer proneness in this syndrome.
The treatment of Olmsted syndrome remains undefined. We found mild improvement of the keratoderma with oral etretinate and topical carcipotriol at present. Even radiation therapy applied to our case, failed to relieve the symptoms. Radiation therapy must not be selected because of its ineffectiveness and cancer proneness in this syndrome.
The management of Olmsted syndrome must be undertaken carefully considering the development of tumors and advancing osteolysis which are observed following keratoderma. n

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