Coats plus syndrome (cerebroretinal microangiopathy with calcifications and cysts-1): A case report.

We present a 6-year-old girl with skin hyperpigmentation, leukoplakia, and onychodystrophy, the classic mucocutaneous triad usually associated with dyskeratosis congenita. The patient also had premature graying of the hair, bone marrow failure, hepatitis, exudative retinopathy, osteopenia with multiple long bone fractures, and intracranial calcifications and brain cysts. Coats plus syndrome is a rare disease with a clinical and genetic overlap with dyskeratosis congenita. This disease is reviewed, with a focus on the pathogenesis of the genetic anomalies and its background as a telomere biology disorder.

Tumoral melanosis after immunotherapy with pembrolizumab - a response sign mimicking melanoma.

Tumoral melanosis is a rare histopathological finding characterized by aggregates of melanophages, in the absence of melanocytes, usually observed in sites of regressed melanocytic lesions, including melanoma. A 72-year-old woman with a history of a completely excised melanoma on her right arm (T3bN0M0, Stage IIb) presented with clinically-evident regional lymph node metastasis. This was treated with right axillary lymphadenectomy. Subsequently, a 2-centimeter blue-colored patch over the excision scar was identified, along with a blue nodule within the posterior aspect of the same arm, consistent with in-transit metastases. Additional metastases on the right hilar region of the lungs were detected by PET/CT. Hence, the patient began immunotherapy with pembrolizumab. After three months, a second PET/CT revealed a complete response, but the patient maintained the blue-colored patch previously observed. Given the discrepancy between the clinical and metabolic response she underwent a skin biopsy; histological examination showed findings compatible with tumoral melanosis resulting from complete regression of a metastatic lesion. In cases of metastatic melanoma under immunotherapy with anti-PD1 agents, especially pembrolizumab, tumoral melanosis has been anecdotally associated with tumor regression and favorable treatment response. The patient has been maintained on pembrolizumab, accomplishing 15 cycles, and has had a complete response to date.

Demyelinating disease of the central nervous system associated with Pembrolizumab treatment for metastatic melanoma.

Immune checkpoint inhibitors are used in metastatic melanoma with good efficacy and safety profile. We report the first case of an inflammatory demyelinating disease of the central nervous system during treatment with Pembrolizumab and discuss the evidence in the literature supporting its causative role. The patient had a good clinical recovery after intravenous steroids, plasma exchange and discontinuation of Pembrolizumab. Due to the expected increase in the importance of immune checkpoint inhibitors in cancer treatment, it is important to be aware of neurological adverse events, as early treatment usually leads to good clinical responses.

Erythema nodosum and sarcoid granulomas - letting the cat out of the bag.

A 41-year-old woman presented with a violaceous papule on the dorsum of the hand, large ipsilateral axillary lymphadenopathy, and tender, erythematous, subcutaneous nodules on the legs. Accompanying signs included fever, ankle swelling, and bilateral red eye. She recalled having a previous exposure to kittens one month before and had a positive family history for sarcoidosis. Histological examination of the hand lesion showed sarcoidal granulomas with positive Bartonella henselae DNA, whereas a biopsy done on the leg nodules was compatible with erythema nodosum. Cat scratch disease (CSD) typically presents as a tender regional lymphadenopathy preceded by an inoculation papule with spontaneous resolution occurring between 8-16 weeks. Cutaneous manifestations of CSD are rare, with erythema nodosum accompanying only 0.6% of cases. Although speculative, the background of a positive family history for sarcoidosis may explain the atypical presentation of this case, with red eye, persistent arthralgia, and associated sarcoidal granulomas.

A challenged case of Vogt-Koyanagi-Harada syndrome: when dermatological manifestations came first.

INTRODUCTION: Vogt-Koyanagi-Harada syndrome (VKHS) is an inflammatory systemic autoimmune disease principally affecting pigmented tissues in the ocular, auditory, integumentary and central nervous systems. Patients are generally women in the fourth decade of life. The prognosis is correlated mainly with the time between diagnosis and the start of treatment and number of recurrent episodes of inflammation. Most complications are mainly ocular. The purpose of this paper is to describe a clinical case of VKHS. MATERIAL AND METHODS: A child with a challenging clinical presentation in which the dermatological symptoms occurred before ocular manifestations. DISCUSSION AND CONCLUSION: VKHS is rare in children and can be a diagnostic challenge. It seemed interesting to share this case as an opportunity to expand our knowledge of the clinical spectrum of diseases and reflect about current diagnostic criteria.

Long-term reproducibility of positive patch test reactions in patients with non-immediate cutaneous adverse drug reactions to antibiotics.

BACKGROUND: As in contact allergy, T cell-mediated hypersensitivity in non-immediate (NI) cutaneous adverse drug reactions (CADRs) to antibiotics is considered to be lifelong, but, in this setting, patch tests have rarely been repeated after long time intervals. OBJECTIVE: To evaluate the long-term reproducibility of positive patch test reactions to antibiotics in patients with NI CADRs. METHODS: Fifty-six patients with NI CADRs to antibiotics who had relevant positive reactions during patch testing were invited to repeat patch tests with a similar antibiotic series 2-15 years thereafter. RESULTS: Twenty patients were included (9 males and 11 females; mean age 54.6 years): 18 with maculopapular exanthema, 1 with drug hypersensitivity syndrome, and 1 with acute generalized exanthematous pustulosis. Results were reproducible in 17 of 20 patients after a mean interval of 6.0 years (range 2-14.7 years). Concerning ß-lactams, 7 of 8 patients remained positive for aminopenicillins, 4 of 4 for isoxazolyl penicillins, and 1 for cefoxitin. Patch test results were also reproducible for clindamycin in 5 of 7 patients, for vancomycin in 1 patient, and for spiramycin in 1 patient. Reproducibility was not affected by the time interval between tests, sex, or age at testing. CONCLUSIONS: In the context of NI CADRs, we showed high reproducibility of positive patch test reactions to various antibiotics, even after several years.

Histopathology of the Exanthema in DRESS Is Not Specific but May Indicate Severity of Systemic Involvement.

OBJECTIVE: Exanthema in drug reaction with eosinophilia and systemic symptoms (DRESS) has no specific clinical diagnostic hallmark and there are few histopathologic studies. The aim of this study was to describe dermal-epidermal histopathologic features in DRESS and correlate them with the culprit drug, viral reactivation, or systemic organ involvement. METHODS: Skin biopsies were independently evaluated by 2 dermatopathologists who characterized the main histological patterns and scored dermal and epidermal changes, which were further correlated with clinical and laboratorial data. RESULTS: In 15 DRESS patients (9 male/6 female patients, mean age 53.3 years), the main observation was lymphocyte exocytosis (1.87 ± 1.25), spongiosis (0.93 ± 0.94), scattered keratinocyte necrosis (1.70 ± 1.44), basal cell vacuolization (2.13 ± 1.42), lymphocyte infiltration around dermal vessels (2.93 ± 0.92) or at the dermal-epidermal junction (2.07 ± 1.12), often with eosinophils and extravasated erythrocytes, swollen endothelial cells, and intravascular neutrophils but no vasculitis. Histopathologic patterns were classified mainly as spongiotic (5), erythema multiforme-like (3), or lichenoid (2). There was a significant positive correlation between the intensity of lymphocyte infiltration and the severity of hepatic cytolysis (r = 0.51; P < 0.05) and eosinophilia (r = 0.51; P < 0.05). No correlation was observed between the intensity and type of dermal inflammation and the degree of epidermal damage or the culprit drug. Human herpes virus type 6-positive patients had a pseudolymphomatous reaction or a perifollicular localization of the infiltrate. CONCLUSIONS: Histopathology in DRESS is variable with no specific diagnostic aspect, but there is a possible correlation between the intensity of the lymphocyte infiltrate and DRESS severity, namely, liver cytolysis.

Interstitial Granulomatous Dermatitis: A Clinicopathological Study.

INTRODUCTION: Interstitial granulomatous dermatitis (IGD) is an uncommon granulomatous dermatitis occurring in the setting of highly reactive immune states, with a polymorphic clinical presentation. Because there is overlap with other entities [namely palisading neutrophilic granulomatous dermatitis (PNGD)], controversy exists regarding its classification. OBJECTIVE: To understand if there are features allowing clear-cut distinction between IGD and PNGD. MATERIAL AND METHODS: Retrospective analysis of 10 cases previously diagnosed as IGD or PNGD, from 2000 to 2013, with review of the histopathologic findings and clinical correlation. RESULTS: Six females and 4 males presented mostly with erythematous papules/nodules (n = 7) but also with erythematous annular plaques (n = 3). In 2 patients, the lesions coexisted. They were mostly distributed symmetrically on the limbs. Associated disease was observed in 6 patients. Regarding histopathology, an inflammatory infiltrate occupying the superficial and mid dermis was present in 40% of cases, with an interstitial component in all biopsies and a palisaded arrangement in 60%. Neutrophils and mononuclear cells were present in all cases in varying proportions. Necrobiosis was found in 70%, and leukocytoclasia was observed in 80% of biopsies. CONCLUSIONS: Coexistence of the interstitial and palisaded inflammatory patterns occurred in 90% of cases, with no correlation between tissue neutrophilia and the predominant pattern of the infiltrate. There was also no clear-cut correlation between the infiltrate pattern and semiologic aspect of the lesions. Therefore, the features described in our study suggest that IGD and PNGD belong to the same clinicopathological spectrum.

Actinomycosis of the Forearm: An Unusual Presentation of an Early Event.

Actinomycosis is a rare chronic infectious disease, most commonly affecting the cervicofacial, pulmonary, or genitourinary areas. It is caused by the Actinomyces spp. bacteria, which are facultative anaerobes and gram-positive, nonsporing rods. The disease is characterized by the formation of cold abscesses or fistulas, as well as granulomatous tissue, reactive fibrosis, and necrosis, which can resemble local malignancy. Cutaneous actinomycosis in the trunk or extremities is extremely rare and is usually related to previous surgical procedures or trauma. However, we report one such rare case of cutaneous actinomycosis of the forearm without previous precipitating factors, which was successfully treated with prolonged antibiotherapy.

Tubulointerstitial Nephritis and Uveitis in a Pediatric Patient.

Tubulointerstitial nephritis and uveitis syndrome (TINU) is a rare autoimmune disease. It is characterized by uveitis and kidney damage. The presentation of uveitis is typically anterior and bilateral, while the renal lesion is an acute interstitial nephritis. We report a case of an adolescent diagnosed with this disease, who presented with ocular and constitutional symptoms. An ophthalmologic examination confirmed the diagnosis of uveitis, and subsequent systemic evaluation revealed impaired renal function. The findings of the renal biopsy established the diagnosis after ruling out other systemic diseases. Given the rarity and nonspecific clinical presentation of this condition, a high level of suspicion is required for early diagnosis and treatment. Clinicians should consider this diagnosis in a pediatric patient with uveitis and impaired renal function.

Current management of inherited retinal degenerations in Portugal (IRD-PT survey).

Inherited retinal dystrophies/degenerations (IRDs) are the leading cause of visual impairment and incurable familial blindness in the Western world. Given the clinical and genetic heterogeneity, establishing a molecular diagnosis is especially relevant. The aim of this study was to perform the first nationwide survey to understand the prevalence and current management of IRDs in Portugal. A response was obtained from 26 healthcare providers (HCP) (76.5% response rate). Only 4 respondents reported not managing IRD patients. Most HCPs (68.1%) reported managing up to 100 patients, while three currently manage between 501 and 1000 patients. Based on the Portuguese population, an estimated IRD prevalence of 0.031%, i.e., about 1 in 3000 individuals, was calculated. In most HCPs (86.3%), most patients are adults, and non-syndromic retinitis pigmentosa is the most frequent diagnosis. Only 4 HCPs currently use the national, web-based IRD registry (IRD-PT). However, all but one respondent expressed interest in participating in such a registry. Genetic testing is available in 54.5%, with 58.3% HCPs reporting solved rates between 61-80%, but 4 to 9 months to get a genetic test result in 83.4% of cases. Based on this survey, the prevalence of biallelic RPE65-associated disease in Portugal is 0.00031%, i.e., approximately 1:300,000 individuals. Data from this study provide vital background information on national differences in the diagnosis and management of IRD patients. Nationwide implementation of the IRD-PT registry should be encouraged and supported to provide population-based reference data and to identify patients eligible for current and future therapies.

A Challenging Case of Metastatic Crohn's Disease Without Gastrointestinal Manifestations.

Metastatic Crohn's disease (MCD) is a rare cutaneous manifestation of Crohn's Disease (CD), defined as non-caseating, granulomatous skin lesions non-contiguous with the gastrointestinal (GI) tract. Most patients with MCD either have concomitant classic manifestations of CD or develop them within a few months to years. We report a case of MCD without known involvement of the GI tract, after more than three years from diagnosis. After failure or intolerance to several conventional treatments, including oral corticosteroids and azathioprine, adalimumab was initiated with a good response.  Diagnosis of cutaneous CD is made by a combination of clinical and histopathological findings. Therapeutic options include topical, intralesional, and systemic corticosteroids as well as topical and systemic immunosuppressants and immunomodulators. Surgical excision may be considered for refractory cases.

Case for diagnosis. A pruritic eruption of keratotic papules over the face and neck.

Generalized eruptive keratoacanthoma of Grzybowski is a rare variant of multiple keratoacanthomas counting with about 40 cases reported. It is a chronic and progressive disease for which none of the described therapeutic options has been entirely satisfactory. We report a case of an 83-year-old female who presented with a 3-month history of extremely pruritic, multiple, skin-coloured to erythematous to brownish, millimetric papules, with a keratotic centre. Histological examination of an incisional biopsy was consistent with the diagnosis of keratoacanthoma. The patient started acitretin 25 milligrams daily with a complete resolution of pruritus and regression of numerous lesions.

Complete Multilineage CD4 Expression Defect Associated With Warts Due to an Inherited Homozygous CD4 Gene Mutation.

Idiopathic T-CD4 lymphocytopenia (ICL) is a rare and heterogeneous syndrome characterized by opportunistic infections due to reduced CD4 T-lymphocytes (<300 cells/µl or <20% T-cells) in the absence of HIV infection and other primary causes of lymphopenia. Molecular testing of ICL has revealed defects in genes not specific to CD4 T-cells, with pleiotropic effects on other cell types. Here we report for the first time an absolute CD4 lymphocytopenia (<0.01 CD4+ T-cells/µl) due to an autosomal recessive CD4 gene mutation that completely abrogates CD4 protein expression on the surface membrane of T-cells, monocytes, and dendritic cells. A 45-year-old female born to consanguineous parents consulted because of exuberant, relapsing, and treatment-refractory warts on her hands and feet since the age of 10 years, in the absence of other recurrent infections or symptoms. Serological studies were negative for severe infections, including HIV 1/2, HTLV-1, and syphilis, but positive for CMV and EBV. Blood analysis showed the absence of CD4+ T-cells (<0.01%) with repeatedly increased counts of B-cells, naïve CD8+ T-lymphocytes, and particularly, CD4/CD8 double-negative (DN) TCRαß+ TCRγδ- T-cells (30% of T-cells; 400 cells/µl). Flow cytometric staining of CD4 using monoclonal antibodies directed against five different epitopes, located in two different domains of the protein, confirmed no cell surface membrane or intracytoplasmic expression of CD4 on T-cells, monocytes, and dendritic cells but normal soluble CD4 plasma levels. DN T-cells showed a phenotypic and functional profile similar to normal CD4+ T-cells as regards expression of maturation markers, T-helper and T-regulatory chemokine receptors, TCRvß repertoire, and in vitro cytokine production against polyclonal and antigen-specific stimuli. Sequencing of the CD4 gene revealed a homozygous (splicing) mutation affecting the last bp on intron 7-8, leading to deletion of the juxtamembrane and intracellular domains of the protein and complete abrogation of CD4 expression on the cell membrane. These findings support previous studies in CD4 KO mice suggesting that surrogate DN helper and regulatory T-cells capable of supporting antigen-specific immune responses are produced in the absence of CD4 signaling and point out the need for better understanding the role of CD4 on thymic selection and the immune response.

Extraocular Muscles Involvement as the Initial Presentation in Metastatic Breast Cancer.

Orbital metastasis is a rare event, and metastatic disease affecting the extraocular muscles is an even less frequent complication of solid tumors. Herein, we report an unusual case of ptosis as the initial presentation of an invasive breast cancer. A 68-year-old woman presented with III and VI partial nerve paresis, secondary to a compressive retrobulbar mass. Magnetic resonance imaging revealed an infiltrative lesion involving the extraocular muscles. Tissue biopsy yielded a result compatible with metastasis to the orbit, with immunohistochemistry analysis suggesting breast as the primary organ. Mammography identified an area of architectural distortion; stereotactic wire-guided biopsy confirmed the result of the previous orbital biopsy. A positron emission tomography scan demonstrated disseminated disease. Palliative chemotherapy with bone-modulating agents and subsequent hormonal therapy was proposed. Unfortunately, the patient did not respond to therapy and died 38 months after diagnosis.

A Rare Case of Bilateral Proptosis.

A 65-year-old man presented with a 2-year history of severe bilateral proptosis, palpable lymphadenopathy and moderate hepatosplenomegaly. A blood test was positive for hepatitis C infection. CT showed palpebral infiltrative lesions with regional progression through the temporal and masticatory spaces to the pharynx and hypopharynx causing almost complete airway obstruction. A palpebral biopsy was consistent with low-grade Bcl-2+ extra-nodal MALT non-Hodgkin B-cell lymphoma. The patient received six cycles of rituximab-based chemotherapy with clinical remission at 9-month follow-up. Bilateral proptosis is a rare presentation of several diseases. When brain CT excludes cavernous sinus pathology, thyroid ophthalmopathy or haematological malignancy should be considered. LEARNING POINTS: Bilateral proptosis is a rare presentation with a broad differential diagnosis, and is most frequently is caused by cavernous sinus disease, thyroid ophthalmopathy or haematological malignancy.Hepatitis C may be associated with MALT lymphoma and presents mainly at non-gastric locations even with few hepatic manifestations of the infection.Long-term low-grade lymphoma may present with severe disseminated disease at diagnosis, but treatment response is generally good.