Johanna Sheu

Voriconazole phototoxicity in children: A retrospective review

BACKGROUND Voriconazole, an antifungal agent, is associated with various cutaneous reactions, including phototoxicity, accelerated photoaging, and skin cancer. Incidence and risk factors for these reactions in children have not been well described. OBJECTIVE We sought to determine the incidence of and factors associated with phototoxic reactions and nonmelanoma skin cancer in pediatric patients treated with voriconazole. METHODS This was a retrospective analysis of 430 pediatric patients treated with voriconazole between 2003 and 2013 at Boston Childrens Hospital. RESULTS Incidence of phototoxicity was 20% in all children treated with voriconazole and 47% in children treated for 6 months or longer. Factors associated with phototoxicity included white race, cystic fibrosis, cumulative treatment time, and cumulative dose. Four patients (1%) had nonmelanoma skin cancer; all experienced a phototoxic reaction during voriconazole treatment. Of those with phototoxicity, 5% were discontinued on voriconazole, 6% were referred to dermatology, and 26% received counseling about sun protection from their primary physician. LIMITATIONS Our study is limited by its retrospective design and potential referral bias associated with a tertiary-care center. CONCLUSIONS Voriconazole-associated phototoxicity is relatively common in children and may lead to nonmelanoma skin cancer. However, those with phototoxic reactions are often continued on therapy, rarely referred to dermatology, and infrequently counseled on sun protection.

Polycystic ovary syndrome: A review for dermatologists Part II. Treatment

Dermatologists are in a key position to treat the manifestations of polycystic ovary syndrome (PCOS). The management of PCOS should be tailored to each womans specific goals, reproductive interests, and particular constellation of symptoms. Therefore, a multidisciplinary approach is recommended. In part II of this continuing medical education article, we present the available safety and efficacy data regarding treatments for women with acne, hirsutism, and androgenetic alopecia. Therapies discussed include lifestyle modification, topical therapies, combined oral contraceptives, antiandrogen agents, and insulin-sensitizing drugs. Treatment recommendations are made based on the current available evidence.

Ponatinib-induced pityriasiform, folliculocentric and ichthyosiform cutaneous toxicities

DEAR EDITOR, Ponatinib, a potent third-generation tyrosine kinase inhibitor (TKI), has demonstrated significant efficacy in chronic myelogenous leukaemia (CML) and Philadelphia chromosome-positive acute lymphocytic leukaemia (ALL), and is currently being employed in solid organ tumour trials. Among the most common side-effects reported are a nonspecific rash or dry skin. We report five patients treated with ponatinib who developed prominent pityriasis rubra pilaris (PRP)-like, hyperkeratotic, folliculocentric and ichthyosiform eruptions. Case 1 is a 59-year-old man with refractory metastatic gastrointestinal stromal tumour (GIST). He presented with asymptomatic, red–orange, follicular-based papules and plaques with

Mosaic focal dermal hypoplasia caused by a novel somatic mutation in PORCN detected in affected skin

DEAR EDITOR, Focal dermal hypoplasia (FDH), or Goltz syndrome, is an ectodermal and mesodermal disorder characterized by dermatological, skeletal, ocular, dental and craniofacial involvement. Cutaneous findings often present along Blaschko lines of cell migration and include atrophic skin, aplasia cutis, dermal fat nodules, papillomas and pigmentary changes. The hair can be sparse and brittle. Nail findings include ridging, dysplasia or hypoplasia. Other organ involvement has also been reported including abdominal wall defects, diaphragmatic hernias and renal abnormalities. FDH is caused by mutations in PORCN. PORCN encodes a protein-cysteine N-palmitoyltransferase, required for palmitoylation of Wnt family members. To date, there are 119 PORCN mutation variants identified on the Leiden Open (source) Variation Database, and our review of the literature added two unique mutations (see Supporting Information; Table S1). The term ‘genetic mosaicism’ describes the coexistence of two or more genetically distinct cell populations in one individual. Genetic mosaicism results from sporadic mutations occurring during embryonic development. Hemizygous PORCN mutations are considered to be lethal in men, therefore male patients with FDH represent mosaic cases. Comparatively, over 200 cases of FDH in women have been reported in the literature, most with functional mosaicism secondary to Xchromosome inactivation. Thirteen women with genetic mosaicism have been identified. In cases of genetic mosaicism, if the proportion of mutated blood cells is too low, a genetic analysis of peripheral blood may yield negative results. An alternative diagnostic approach is to test the affected skin. A 38-year-old woman presented to the dermatology clinic with a burning rash on her trunk and extremities. The skin lesions first appeared on her left leg as vesicles along Blaschko lines when she was 6 months of age. It was also noted that as a child she had small teeth and brittle nails, but lacked any other indicators of FDH. Bone radiography, ophthalmological examination and renal ultrasound were all within normal limits. The patient was considered to have ‘mild’ FDH based on physical examination and a skin biopsy performed in childhood (pathology report/specimen not available). A diagnosis of incontinentia pigmenti was also considered given the patient’s history of vesicles along Blaschko lines in infancy. Previous genetic testing of peripheral blood-derived DNA showed no PORCN or IKBKG (OMIM 300248; formerly NEMO) mutations. Given that her rash had erythema, slight scaling and was pruritic, the patient was treated episodically with topical steroids for an inflammatory component of her lesions. Topical steroids were effective for short-term symptom relief, but were not used for long-term treatment due to side-effects. Treatment with topical tacrolimus and pimecrolimus did not result in any improvement. At the time of presentation, the patient used emollients daily and topical steroids for severe burning as required. She did not have any other significant past medical history. There was no family history of FDH. Both her mother and maternal grandmother had two miscarriages, with unknown fetal sex. On initial physical examination, the patient had erythematous, atrophic plaques in a Blaschkoid distribution on the lower extremities, with the left side significantly more affected than the right and a mildly erythematous linear patch on the left arm. No changes to the patient’s hair or nails were observed. She returned 4 months later with worsening burning pain, which was most prominent on the left lower extremity. A follow-up examination revealed multiple erythematous, atrophic plaques along Blaschko lines on her trunk and arms; the atrophic plaques on the legs were much more brightly erythematous than on previous examination (Fig. 1a, b). Dermoscopy revealed diffuse proliferation of dilated capillaries within the affected areas (Fig. 1c). Written informed consent for skin biopsies and genetic analysis was obtained. Mutational analysis was performed solely for clinical purposes. Three 4-mm full-thickness punch biopsies were obtained from the affected skin of the left thigh. The tissues were placed in a sterile Eagle’s minimum essential medium with 1% penicillin and streptomycin and were transported at ambient temperature. The specimens were minced, placed in additional culture media supplemented with fetal calf serum and incubated at 37 °C. The cells were harvested for DNA extraction, polymerase chain reaction amplification and Sanger sequencing. The mutational analyses were conducted by a laboratory that was certified by Clinical Laboratory Improvement Amendments and accredited by the College of American Pathologists using proprietary standard procedures. The sequencing revealed a GCAC duplication in the PORCN gene that resulted in a frameshift mutation with an alanine substitution of glutamine388 and a premature stop codon at position 32 (c.1158_1161dupGCAC, p.Gln388AlafsX32). This novel mutation is predicted to cause loss of function through protein truncation; its presence is consistent with the diagnosis of mosaic FDH.

Dapsone Therapy for Pustular Psoriasis: Case Series and Review of the Literature

Background: Pustular psoriasis is an uncommon psoriasis variant, clinically characterized as small sterile pustules on an erythematous base. Evidence for therapy is lacking, and many currently employed systemic therapeutics carry risks of significant side effects, without specifically targeting disease etiology which includes the aggregation of neutrophils. Observations: We report therapy with the anti-neutrophil agent dapsone in 5 patients with pustular psoriasis and provide a brief review of the literature. Four patients responded to oral dapsone and 1 to topical dapsone therapy. All 5 patients had previously failed multiple topical and systemic treatments. In 2 cases, oral dapsone allowed for the discontinuation of other systemic agents. One patient stopped oral dapsone due to a side effect of sleep disturbance. Conclusion: Dapsone has a much safer side effect profile and may target the pathophysiology of pustular psoriasis more directly than many other systemic agents. As such, dapsone should be considered for the treatment of patients with pustular psoriasis.

Papulopustular Acneiform Eruptions Resulting From Trastuzumab, a HER2 Inhibitor

The epidermal growth factor receptor (EGFR) family, human epidermal growth factor receptor (HER)1/ EGFR, HER2, HER3, and HER4, has been the target of an increasing number of oncologic therapies. It is wellknown that medications targeting HER1/EGFR commonly cause a papulopustular acneiform eruption. Despite the increasing use of HER2 inhibitors, including trastuzumab, in breast cancer management, reports of papulopustular eruptions in patients treated with HER2 inhibitors have been rare. Four women undergoing HER2-directed breast cancer therapy with trastuzumab developed papulopustular eruptions 7 to 22 days after therapy initiation. In 1 case, the eruption prompted treatment interruption. All patients’ eruptions resolved with skin-directed treatment and did not recur. At the last follow-up visit, all were alive with no evidence of breast carcinoma. These cases show that HER2 inhibitors might cause papulopustular reactions, similar to those classically reported with HER1/EGFR inhibition, possibly through HER2 homodimer and/or HER1-HER2 heterodimer inhibition. With the increasing use of targeted inhibition of the EGFR family, especially HER2, in patients with breast cancer, increased awareness of these reactions is imperative. Prompt recognition and appropriate treatment of patients receiving HER2 inhibitors, such as trastuzumab, could avoid treatment interruption, dose reduction, and impairment of patient quality of life.

Bone marrow engraftment and associated dermatologic sequelae in a three‐yr‐old after liver transplantation

We present a case of a three‐yr‐old child with a history of multisystem Langerhans cell histiocytosis treated with systemic chemotherapy, who developed progressive liver failure and received an orthotopic split liver transplant while continuing on chemotherapy. One month following transplant, he developed acute graft‐vs.‐host disease of the skin and gastrointestinal tract. Peripheral blood chimerism studies post‐transplant demonstrated an increasing predominance of donor lymphocytes and granulocytes. Shortly after, the patient developed vitiligo, and two yr after transplantation, the patient developed skin manifestations of psoriasis. We discuss and review the current literature, which demonstrates that chimerism following liver transplantation is rare and in our patient may be related to his profound immunosuppression around the time of liver transplant as well the development of acute graft‐versus‐host disease. While autoimmune disease can occur after solid organ and stem cell transplant, our patient developed skin manifestations of autoimmunity after liver transplantation, which is also rarely described.

Skin Diseases Associated with Stem Cell Transplantation

Hematopoietic stem cell transplantation (HSCT) has been used as curative treatment in both children and adults for hematologic malignancies, immunodeficiencies, autoimmune disorders, and other rare indications. While HSCT has revolutionized patient care, following HSCT, patients are at risk for several secondary cutaneous side effects. In this chapter, we discuss indications for HSCT, conditioning regimens before transplantation, and types of HSCTs. While there is a large range of cutaneous sequelae, we focus on three main topics and their histopathologic correlations in order to help practitioners identify them: (1) the different stages of acute and chronic cutaneous graft-versus-host disease as well as available treatment options; (2) the risk of cutaneous malignancies including nonmelanoma skin cancers and melanoma, as well as additional factors which may increase a patient’s risk; and (3) autoimmune and inflammatory skin diseases associated with HSCT. In transplant recipients, the diagnosis and management of acute and chronic skin diseases after HSCT are vital. We recommend full skin examinations annually and appropriate referral to dermatology when needed, especially in patients who may be at higher risk for skin cancer. Continued research is needed to better understand the pathogenesis and treatment of post-transplant effects on the skin.