Chronicity and diagnostic doubts of Melkersson-Rosenthal syndrome. Analysis of developing ways in 5 cases]

In order to demonstrate the variability of the muco-cutaneous and neurovegetative signs and symptoms of Melkersson-Rosenthal syndrome (MRS), we report the cases of five out of 80 patients suffering from this complex oro-facial syndrome. In the majority of our patients the major symptoms, and in particular recurrent labial or intraoral swellings and/or facial palsy, did not occur simultaneously, which delayed the definite diagnosis of either complete or incomplete type of MRS. However, more than 80 p. 100 of our patients complained of various relapsing cranio-facial neurovegetative troubles that constitute the so-called minor symptoms of MRS, whereas a history or sequelae of facial palsy were found in only 35 p. 100 of our patients followed up for years or decades. In patients with solitary facial palsy or oro-facial oedemas as the initial symptom of putative MRS, the uncovering of concomitant minor symptoms proves to be helpful for substantiating the recognition of incomplete MRS. Thus, in questionable cases of MRS attention should be paid to seemingly incidental disturbances of the cranio-facial neurovegetative system (e. g., relapsing disorders of lacrimation, sweating, migraine-like headache) forming minor but characteristic hints to incomplete or unusual cases of MRS.     

Recurrent chancriform mucous membrane ulcer in plasmacytoma with secondary IgA deficiency. Pyoderma chancriforme of the tongue

A 66 year old patient presented with a nine month history of recurrent oral ulcerations involving the tongue. We diagnosed chancriform pyoderma and a previously not identified multiple myeloma with secondary immunoglobulin deficiency. Clinically and histologically we excluded a necrotizing ulcerative stomatitis as found in individuals with cellular immunodeficiency as in late-stage HIV-infection. On culture only Neisseria catarrhalis was found. Chancriform pyoderma is often associated with local bacterial infections, especially Staphylococcus aureus. The most common sites are the genitalia and periorbital region; involvement of the oral mucosa is uncommon. To the best of our knowledge, this is the fourth reported case with tongue lesions. The multiple myeloma-associated immunoglobulin deficiency might have facilitated the oral manifestations of chancriform pyoderma.     

Melkersson-Rosenthal Syndrome with Genitalia Involved in a 12-Year-Old Boy

Melkersson–Rosenthal syndrome (MRS) is an uncommon granulomatous disease characterized by the triad of relapsing facial paralysis, orofacial swelling, and fissured tongue. Genital swelling in MRS is rarely reported. We presented the first case of complete MRS with genital swelling in a child. Biopsy examinations of both the child''s lower lip and penis showed noncaseating granuloma and intralymphatic granuloma infiltration. No symptoms or signs of other systemic disease (Crohn''s disease or sarcoidosis) were observed after 2 years of follow-up. Genetic screening for CARD15/NOD2 in this patient showed negative, which further confirmed the diagnosis of MRS. Eleven other cases of suspected complete or incomplete MRS with genitalia involved were reviewed. Our case emphasizes the specific clinical feature of MRS with genitalia involved, which was genetically different from Crohn''s disease and could be an independent entity. Lymphatic obstruction is responsible for localized edema in MRS.     

Complete Melkersson–Rosenthal syndrome with multiple cranial nerve palsies

Melkersson–Rosenthal syndrome (MRS) is an uncommon, complex neuromucocutaneous disorder characterized by recurrent orofacial oedema, facial palsy and fissured tongue. Complete MRS is uncommon. A case of complete MRS with multiple cranial nerve palsies is reported.     

Oral-cutaneous CD4-positive T-cell lymphoma: a study of two patients

We describe two slowly progressive cases of T-cell lymphoma that involved both acral skin and oral cavity. One patient presented with a tongue nodule, completely responded to chemotherapy and then developed recurrent lymphoma involving tongue and skin a few months later that also responded to therapy. The second patient presented with a skin nodule that spontaneously resolved without therapy, and subsequently recurred in tongue and skin a few years later. In both cases, the neoplasms were composed of atypical lymphoid cells with epidermotropism and were of T-helper cell lineage (CD4+). The initial lesions were also negative for CD30. Identical T-cell receptor gene rearrangements were detected in the initial and recurrent lesions of one case. Although these neoplasms were classified as unspecified peripheral T-cell lymphoma because of the unusual distribution of disease, both cases also had histopathologic features of mycosis fungoides. These cases are strikingly similar, and may represent an unusual clinicopathologic type of T-cell lymphoma that can hone to cutaneous and oral mucosal sites with a slowly progressive natural history.     

Orofacial granulomatosis treated with intralesional triamcinolone

Orofacial granulomatosis (OFG) is an uncommon disease, usually presenting as recurrent or persistent swelling of the soft tissues in the orofacial region, predominantly lips (cheilitis granulomatosa). The cause of this illness is unknown. OFG may also be part of the triad of Melkersson-Rosenthal syndrome (MRS) and some consider it a monosymptomatic form of MRS. We describe a case of a Croatian male patient with recurrent swelling limited to the upper lip for the past 6 years. After establishing the diagnosis, we performed intralesional triamcinolone injections (16 mg, twice on a weekly schedule), resulting in complete remission. OFG differential diagnosis and treatment modalities are discussed.     

Characterization of LHTric-1, a new monospecific monoclonal antibody to the trichocyte keratin Ha1

The hair follicle is a heterogeneous tissue involving differentiation of both hair forming (trichocyte) and non-hair forming (root sheath) cells; while there are many antibody markers available which can determine the distribution of ‘soft’ epithelial keratins, fewer have been described which are truly monospecific for hair specific ‘hard’ keratins. We employed the proven strategy of raising monoclonal antibodies to a short synthetic peptide from the carboxy-terminal sequence of mouse Ha1 and report here the successful production of a monospecific monoclonal antibody which we have called LHTric-1. We have characterized the antibody using immunostaining on rat and human tissues and by immunoblotting against an extract of human follicles. The antibody cross-reacted between rat and human tissue but did not stain formalin-fixed tissue. LHTric-1 localized very specifically to the pre-cortical region of the hair follicle in early anagen and to pre-cortical cells in the upper bulb in anagen. Telogen follicles did not react. LHTric-1 immunoreacted within tongue and nail, staining being restricted to the mid-line above the connective tissue core in tongue and to the suprabasal layers of the nail matrix. The antibody did not react with the fully keratinized hair or nail plate. Finally, in immunoblotting. LHTric-1 reacted with a single band of 44kDa, suggesting that a single protein was recognized. We conclude that this antibody, by virtue of its known antigen sequence specificity, will be useful in research into the formation of hair and nail in normal and diseased states.     

Cheilitis granulomatosa

Melkersson-Rosenthal Syndrome (MRS) is a rare syndrome that is characterized by a triad of facial paralysis, chronic edema of the lip, and a fissured tongue. Most commonly, one element of the triad precedes the development of the other symptoms. We present a case of cheilitis granulomatosa (CG) as a manifestation of incomplete MRS. As the etiology remains unknown, treatment of CG is challenging. Intralesional glucocorticoids remain the first-line treatment, but recurrences are common. We discuss alternative treatment strategies that include combination therapy with other anti-inflammatory agents and biologics, such as infliximab.     

The ''Dirty Neck''—a reticulate pigmentation in atopics

Reticulate pigmentation of the neck is seen in some subjects with atopic eczema. It involves the anterior or antero-lateral aspects. It is often interpreted as an unwashed appearance and we have called it the ‘Dirty Neck’. Two patterns have emerged. One is found in mildly eczematous, young patients who have a marked increase in pigment during the summer months; it may be confluent in some parts and reticulate in others. The second pattern is a feature of severe atopic eczema, develops after puberty and shows little seasonal variation. Neither pattern is necessarily associated with eczema of the affected area. The morphological and histological characteristics of the ‘Dirty Neck’ are described and possible aetiologies discussed. Distinctions are drawn from ichthyotic ‘dirty necks’ and other types of reticulate pigmentations.     

Treatment and follow-up of persistent granulomatous cheilitis with intralesional steroid and metronidazole

Granulomatous cheilitis (GC) is a chronic edema which frequently affects the upper lip due to granulomatous inflammation. Its etiology is currently unknown. This rare disease is generally accompanied by Melkersson-Rosenthal syndrome (MRS), characterized by scrotal tongue, orofacial edema and facial paralysis. However, it is also known to develop only with orofacial edema. Granulomatous cheilitis is a difficult disease to treat because of recurrences. There are contradictory reports about the results of treatment without surgical intervention and the rates of recurrence. Our case was a 57-year-old female patient who was characterized by orofacial edema only. The edema and erythema had persisted for 1 year before admission. In the present case, application of intralesional corticosteroid treatment as a total of three injections over 3 consecutive months (one injection per month) and the accompanying metronidazole treatment brought about successful results. No recurrence was observed in the follow-up.     

Oral lymphangiectasia and gastrointestinal Crohn disease

Lip edema with non-caseating granulomas or lymphangiectasia pose a clinical and pathological challenge. These findings can be attributed to cheilitis granulomatosa (CG), Melkersson-Rosenthal syndrome (MRS), or Crohn disease (CD) depending on the appropriate clinical context. Lymphangiectasis, in particular, is a common pathological finding in CD due to lymphatic obstruction by granulomas and intralymphatic granulomas. Because oral symptoms can precede gastrointestinal symptoms of CD or be seen in patients with asymptomatic gastrointestinal disease, the identification of lymphangiectasia should raise the possibility of underlying CD. We present a case of a young woman with several years of lip swelling, with notable lymphangiectasia and subtle granulomas on pathological evaluation. The patient was diagnosed with MRS at an outside institution and treated with systemic steroids, without further systemic evaluation. We believe that early recognition of lymphangiectasia and consideration of CD early in the work-up are critical for early diagnosis and appropriate management. Neither clinical nor histopathological findings should be used in isolation to diagnose GC, MRS, or CD as there is significant debate as to the etiology and overlapping findings of these conditions. We highlight the importance of lymphangiectasia in diagnosing underlying CD in the appropriate clinical context.     

Melkersson-Rosenthal syndrome caused by saprodontia: a case report

A 24-year-old female patient with Melkersson-Rosenthal syndrome (MRS) in association with saprodontia is reported. She presented with lower labial swelling and left facial edema. Histological examination of the involved oral mucosa showed a noncaseating epithelioid granuloma. Results from the laboratory and imaging examinations were normal or negative. Her orofacial swelling disappeared after treatment of the saprodontia of the left first molar.     

In search of oral psoriasis

Even though psoriasis is a common skin disorder, reports of it involving the oral cavity are exceedingly rare, with less than 100 publications in the literature. Biopsy-proven oral psoriasis has been reported in the oral medical literature, but the commonest oral mucosal findings in most studies are associated non-specific features including fissured and geographic tongue. Case series on this entity have not provided any definitive data to support its existence. From the evidence available to date, it is still unclear if oral psoriasis is a distinct entity or if, indeed, it exists.     

Treatment of mucocutaneous presentations of herpes simplex virus infections

Infections by herpes simplex virus (HSV) types I and II are diverse and quite frequent. After primary infection, the virus establishes a life-long latency in the sensory ganglia and recrudescences may occur at an unpredictable rate. Recurrent labial and genital herpes infections represent the majority of clinical manifestations of HSV infections. Their management is currently well established using evidence-based medicine data. Primary labial herpes is generally not treated with antivirals in otherwise healthy children, although intravenous aciclovir may be offered in severe primary infections, particularly in the immunocompromised patient. The decision whether or not to treat recurrent labial herpes should be evaluated individually and depends on the frequency and severity of relapses, the impairment of the quality of life, and the cost of therapy. Patients with mild disease may benefit from topical therapy, and those with severe and frequent recurrences may be considered for intermittent or long-term oral antiviral therapy. Primary genital herpes is treated with oral or intravenous antivirals, depending on the severity of the infection and associated symptoms. Recurrent genital herpes can be managed with episodic short courses of oral antivirals in patients whose recurrences are moderate to severe and rare, and have a clear prodrome. Patients with >5 episodes/year, severe recurrences or unrecognisable prodromes may be best managed with long-term suppressive antiviral prophylaxis. HSV is also responsible for a variety of other clinical manifestations, including herpetic whitlow, neonatal infection, disseminated and atypical cutaneous infections, traumatic herpes, eczema herpeticum, and HSV-associated erythema multiforme. HSV infection may also represent a complication following cosmetic procedures of the oro-facial region, surgical and dental interventions, sun exposure and burns. Precise treatment guidelines for these HSV infections are not firmly established.     

Persistent unilateral orbital and eyelid oedema as a manifestation of Melkersson–Rosenthal syndrome

Melkersson-Rosenthal syndrome (MRS) is a complex neuromucocutaneous disorder characterized by localized orofacial oedema and cranial nerve dysfunction, frequently associated with minor signs, including furrowed tongue. Complete forms are rare whereas mono- and oligosymptomatic variants are more common. A 71-year-old man presented with a 2-year history of relapsing and progressively persistent oedema of the right eyelids and periorbital region. A fissured tongue and telangiectatic rosacea had been present since the age of 50 and 60 years, respectively. The patient was also affected by essential hypertension and diabetes mellitus. A skin biopsy showed a marked upper dermal oedema, and small epithelioid cell granulomas arranged in perivascular and perilymphatic location. Collections of small epithelioid cells were occasionally observed within lymphatic spaces. No acid-fast bacteria, fungi or foreign bodies were detected. Intralesional corticosteroids induced transient improvement, whereas minocycline, clofazimine and dapsone have been ineffective. MRS may present with unilateral eyelid and periorbital swelling. Differential diagnoses of such cases may include a variety of cutaneous, ophthalmic and systemic diseases.     

Melkersson Rosenthal syndrome: a histopathologic mystery and dermatologic challenge

Melkersson Rosenthal syndrome (MRS) is rare disease of unknown etiology characterized by orofacial edema, facial nerve palsy and fissured tongue. Microscopically, it shows epithelioid non‐caseous granulomas; however, edema and perivascular lymphocytic infiltrates have been described. Two different clinical forms of MRS are presented in this report. In the complete form (Case 1), the main histopathologic finding was a non‐necrotizing granulomatous inflammation with 56% of the total number of cells composed of B cells (CD 20⁺) principally located in the granuloma's center and 33% being T cells predominating in the surrounding area, of which 48% were CD 4⁺ and 16% were CD 8⁺ lymphocytes. In the monosymptomatic form (Case 2), the inflammatory cells were dispersed into the connective tissue without granulomatous formation. B cells were scanty, and 78% of the cells were CD 45⁺ T cells, with 46% and 34%, CD 8⁺ and CD 4⁺ phenotype, respectively. These cases showed different clinical, histopathological and immunohistochemical forms of MRS, suggesting different host immune responses. Kaminagakura E, Jorge J Jr. Melkersson Rosenthal syndrome: a histopathologic mystery and dermatologic challenge.     

Chondroma of the tongue

Chondroma is a remarkably rare lesion of the oral soft tissues. Most previously reported chondromas of this area have been associated with varying percentages of fibrous, adipose or bone tissues, and the occurrence of such neoplasms exclusively composed of chondromatous tissue is exceedingly rare. We report the clinicopathological features of a pure chondroma of the dorsum of the tongue, occurring in a 51-year-old woman and discuss the possible origin of the tumour.     

Amalgam tattoo

A 53-year-old woman with a history of melanoma status-post excision two years prior presented with a 4-month history of 4, dark-brown macules on the inferior surface of her tongue. A biopsy specimen showed a squamous mucosa with chronic submucosal inflammation and brown pigment. The clinical and histopathologic findings were consistent with a diagnosis of amalgam tattoo. Amalgam tattoos are common, oral pigmented lesions that clinically present as isolated, blue, grey, or black macules on the gingivae, the buccal and alveolar mucosae, the palate, and/or the tongue. They are due to deposition of a mixture of silver, tin, mercury, copper, and zinc, which are components of an amalgam filling, into the oral soft tissues. Amalgam tattoos can either be treated surgically or with a Q-switched ruby laser. In the case of our patient with the history of melanoma, her oral lesions proved not to be the more dire diagnosis of malignant melanoma.     

Mucous membrane pemphigoid, thymoma, and myasthenia gravis

In November 1997, approximately 1 year before being evaluated at the Mayo Clinic, Rochester, a 63‐year‐old woman presented with erosive tongue lesions that were diagnosed by her physician as oral lichen planus. The lesions responded well to 3 months of treatment with systemic and topical corticosteroids and topical antiyeast medication. She stopped taking the medications and had a relapse. A few months after the oral lesions developed, her left eyelid became ptotic. Results of magnetic resonance imaging of her brain were normal, and the ptosis resolved spontaneously after 2 weeks. One year later, her right eyelid began to droop, and the results of edrophonium testing were positive. She was prescribed prednisone, 30 mg daily, and pyridostigmine, as needed. The ptosis improved, but never fully resolved. Radiography revealed a left ‘‘thyroid nodule,’' but computed tomography did not show a mediastinal mass. She was advised to have the ‘‘nodule’' removed surgically and came to the Mayo Clinic, Rochester, for a second opinion. Her medical history was significant for the following: tinnitus, glaucoma, early bilateral cataracts, and long‐standing hypertension, for which she took losartan, 50 mg twice daily. Other medications included: prednisone, 30 mg daily; pyridostigmine as needed; famotidine, 40 mg daily; and eyedrops for glaucoma. She denied any history of hyperthyroidism or hypothyroidism, head and neck irradiation, family history of thyroid disease, or diplopia. Hepatitis serologic studies revealed hepatitis B exposure and recovery, hepatitis C immunity, and a previous hepatitis A viral infection. On examination at the Mayo Clinic, Rochester, an erosive hypertrophic plaque was noted on the posterior dorsal half of the tongue, and vesicles and erythematous erosions on the hard and soft palates ( Fig. 1a ). A lace‐like white pattern was seen on the buccal mucosa bilaterally, and a small erosive patch on the left buccal mucosa ( Fig. 1b ). Ocular and nasal mucous membranes were normal in appearance, and there were no pertinent skin findings. Dermatopathologic examination of an excisional biopsy specimen from the left dorsum of the tongue demonstrated an ulcer with epitheliomatous hyperplasia and a granulomatous reaction, presumably due to yeast infection. Silver staining showed hyphae and yeast at the base of the tongue ulcer. The results of the direct immunofluorescence study were negative and revealed no lichenoid changes on hematoxylin and eosin staining. Indirect immunofluorescence testing of the serum revealed a 1 : 80 titer of basement membrane zone antibodies, reflecting pemphigoid. This test was positive on repeat study. Salt‐split skin on monkey esophagus revealed an epidermal pattern of basement membrane zone antibodies. Treatment included fluocinonide gel applied to the involved areas four times daily and oral antiyeast therapy (fluconazole, 200 mg once daily by mouth) while the rest of the evaluation was being completed.

Figure 1(a) Open in figure viewer PowerPoint Erosive hypertrophic tongue plaque.     

Cutaneous candidiasis – an evidence‐based review of topical and systemic treatments to inform clinical practice

Cutaneous candidiasis is a common skin disease, and several treatments have been investigated within the last fifty years. Yet, systematic reviews are lacking, and evidence‐based topical and systemic treatment strategies remain unclear. Thus, the aim of this review was to summarize efficacy and adverse effects of topical and oral therapies for cutaneous candidiasis in all age groups. Two individual researchers searched PubMed and EMBASE for ‘cutaneous candidiasis’ and ‘cutaneous candidiasis treatment’, ‘intertrigo’, ‘diaper dermatitis’ and ‘cheilitis’. Searches were limited to ‘English language’, ‘clinical trials’ and ‘human subjects’, and prospective clinical trials published in abstracts or articles were included. In total, 149 studies were identified, of which 44 were eligible, comprising 41 studies of 19 topical therapies and four studies of three systemic therapies for cutaneous candidiasis. Topical therapies were investigated in infants, children, adolescents, adults and elderly, while studies of systemic therapies were limited to adolescents and adults. Clotrimazole, nystatin and miconazole were the most studied topical drugs and demonstrated similar efficacy with complete cure rates of 73%–100%. Single‐drug therapy was as effective as combinations of antifungal, antibacterial and topical corticosteroid. Four studies investigated systemic therapy, and oral fluconazole demonstrated similar efficacy to oral ketoconazole and topical clotrimazole. Limitations to this review were mainly that heterogeneity of studies hindered meta‐analyses. In conclusions, clotrimazole, nystatin and miconazole were the most studied topical drugs and demonstrated equal good efficacy and mild adverse effects similar to combinations of antifungal, antibacterial and topical corticosteroids. Oral fluconazole was as effective as topical clotrimazole and is the only commercially available evidence‐based option for systemic treatment of cutaneous candidiasis.