Treatment of chronic urticaria with colchicine.

BACKGROUND: Chronic urticaria (CU) is a cutaneous disease that can be debilitating, difficult to treat, and sometimes life-threatening. Treatment with antihistamines is often ineffective. Immunosuppressants are second line therapy but can have significant side effects. Data is needed on effective therapies with safer profiles. OBJECTIVES: To determine the efficacy and side-effects of colchicine in patients with CU. METHODS: Patients were identified through retrospective chart reviews at the University of Utah from 2002-2007. We identified 36 patients with a diagnosis of chronic urticaria based on history, physical examination, and a skin biopsy. Length of treatment ranged from one month to 17 months. RESULTS: Subjective clinical responses to colchicine therapy reported as complete (n=15) or partial (n=5) were found in 56 percent of patients. The mean±SD duration of treatment was 7±6 months. Three patients (15%) who had resolution of urticaria stopped colchicine secondary to diarrhea and hematuria. Of the complete responders, nine individuals (60%) have remained symptom free and four individuals (27%) had recurrence after colchicine was stopped. LIMITATIONS: Short-term follow-up and retrospective study design. CONCLUSIONS: This retrospective study demonstrated that colchicine was an effective and well-tolerated treatment for patients unresponsive to antihistamines. The data supports the use of colchicine for CU patients and further controlled studies are warranted to better characterize the use of colchicine in patients with CU refractory to antihistamines.

Paternal germ cell mosaicism in autosomal dominant pachyonychia congenita.

BACKGROUND: Pachyonychia congenita (PC) is a genodermatosis caused by mutations in 1 of 4 known keratin genes, including KRT6A, KRT6B, KRT16, or KRT17. The most common mode of inheritance is autosomal dominant. Families with an affected parent are routinely counseled about the 50% transmission risk to each offspring. In some cases, families with a rare disorder like PC can initially present with an affected child while both parents are unaffected. This is usually the result of a spontaneous in utero mutation, and the risk of subsequent offspring being affected with the same condition is negligible (but may be increased above the general population's risk, although the exact risk is not currently known for PC). OBSERVATIONS: We discuss a case of 2 affected children born to unaffected parents. We performed mutational analyses of all 4 individuals in the family on DNA extracted from lymphocytes. Owing to the unusual presentation of 2 affected siblings, we also extracted DNA from the father's sperm cells for keratin gene mutational analysis. We describe the first case, to our knowledge, of germ cell mosaicism in PC. CONCLUSION: Counseling of unaffected parents with a first child diagnosed as having PC should entail a discussion of the possibility of germ cell mosaicism contributing to an increased risk of having subsequent affected children.

Development of quantitative molecular clinical end points for siRNA clinical trials.

RNA interference (RNAi) is an evolutionarily conserved mechanism that results in specific gene inhibition at the mRNA level. The discovery that short interfering RNAs (siRNAs) are selective, potent, and can largely avoid immune surveillance has resulted in keen interest to develop these inhibitors as therapeutics. A single nucleotide-specific siRNA (K6a_513a.12, also known as TD101) was recently evaluated in a phase 1b clinical trial for the rare skin disorder, pachyonychia congenita (PC). To develop a clinical trial molecular end point for this type of trial, methods were developed to: (1) isolate total RNA containing amplifiable mRNA from human skin and callus material; (2) quantitatively distinguish the single-nucleotide mutant mRNA from wild-type K6a mRNA in both patient-derived keratinocytes and patient callus; and (3) demonstrate that repeated siRNA treatment results in sustained inhibition of mutant K6a mRNA in patient-derived keratinocyte cultures. These methods allow noninvasive sampling and monitoring of gene expression from patient-collected shavings and may be useful in evaluating the effectiveness of RNAi-based therapeutics, including inhibitors that specifically target single-nucleotide mutations.

Severe retention hyperkeratosis occurring with Susac syndrome.

A 50-year-old woman presented for asymptomatic yellow hyperkeratotic plaques limited to her face. The plaques reportedly arose over the six months prior to her clinic visit. She was healthy prior to the diagnosis of Susac syndrome (retinocochleocerebral vasculopathy) two years before. A punch biopsy was performed and revealed retention hyperkeratosis. Retention hyperkeratosis is a benign and commonly seen skin condition in primary care and dermatology. Retention hyperkeratosis occurs when there is abnormality of routine desquamation that can be associated with poor hygeine. It can be associated with acne or ichthyosis. Our case of retention hyperkeratosis is unique because of the profound presentation in a setting of an untreated psychiatric condition. Treatment consisted of daily topical exfoliative care. We also encouraged her family members to help her to seek medical attention for Susac syndrome.

Rapamycin selectively inhibits expression of an inducible keratin (K6a) in human keratinocytes and improves symptoms in pachyonychia congenita patients.

BACKGROUND: The macrolide sirolimus (rapamycin) selectively blocks translation of mRNAs containing a terminal 5' oligopyrimidine (TOP) tract by altering the activity of mammalian target of rapamycin (mTOR) and inhibiting downstream mTOR pathway components involved in TOP mRNA translation. The skin disorder pachyonychia congenita (PC) is caused by mutations in the inducible keratins (K) including K6a, K6b, K16 and K17. Published sequence data suggest the 5' untranslated regions of K6a and K6b mRNAs contain 5' TOP motifs and therefore may be sensitive to rapamycin treatment. OBJECTIVE: Determine if mTOR inhibitors (rapamycin, temsirolimus or everolimus) are viable drug candidates for treatment of PC and other disorders caused by inappropriate expression of K6a and K6b. METHODS: 5' RACE analysis was used to map the transcriptional start sites for K5, K6a, K6b, K14, K16 and K17. The sensitivity of these keratins to mTOR inhibitors was determined by Western and qPCR analysis following treatment of a human HaCaT keratinocyte cell line with rapamycin, temsirolimus or everolimus. A small off-label study was undertaken using orally administered rapamycin in three PC patients and the effects were monitored by clinical examination, photography, a validated Dermatology Life Quality Index (DLQI) and a pain and activity diary. RESULTS: Sequence comparison and 5' RACE analysis of the 5' untranslated regions of K6a and K6b revealed putative TOP regulatory elements. Treatment of a human HaCaT keratinocyte cell line with mTOR inhibitors (rapamycin, temsirolimus or everolimus) resulted in selective K6a repression. Furthermore, treatment of this HaCaT cell line with siRNAs targeting components of the mTOR pathway altered the levels of K6a expression. To test the ability of rapamycin to ameliorate PC symptoms, an off-label study was conducted. PC patient clinical responses to oral rapamycin showed a therapeutic response in callus character as well as subjective improvement. Of particular note, rapamycin greatly reduced the presence of painful cutaneous thromboses after reaching therapeutic serum levels. The well-known rapamycin side effects led to the early withdrawal of all of the patients from the study. CONCLUSION: Rapamycin selectively blocks K6a expression in human keratinocytes. The improvement of symptoms in PC patients following rapamycin treatment suggests rapamycin (or rapamycin analogs) may be a therapeutic option, particularly if topical formulations can be developed that avoid the side effects associated with systemic administration.

Abdominal desmoid in familial adenomatous polyposis presenting as a pancreatic cystic lesion.

A 17-year-old male with familial adenomatous polyposis (FAP) presented with chest pain and significant weight loss. An abdominal CT scan detected a cystic pancreatic lesion of unknown etiology. The patient therefore underwent surgical resection of the distal pancreas, which included the lesion, because of the known association of pancreatic cancer with FAP. Histopathological examination of the resected specimen showed a benign pancreatic cyst and fibrous plaque with desmoid fibromatosis adherent to the surface of the pancreas, serosa of the stomach, and colon. The fibrous plaque was histologically identical to the fibrous mesenteric plaque known to occur in FAP and associated mesenteric fibromatosis. We present pathologic evidence that the pancreatic cyst formation was induced by FAP-associated desmoid invasion. Desmoid growth should be considered in the differential diagnosis of a pancreatic cystic mass lesion in patients with FAP or its Gardner syndrome variant. This case report provides the first pathologic evidence for benign epithelial cyst formation in the pancreas caused by fibromatosis invasion of that organ as a part of FAP.

Current status of genetic testing for colorectal cancer susceptibility.

Over 130,000 new cases of colon cancer are diagnosed annually. Approximately 20% to 30% of these are attributable to familial risk, and 3% to 5% belong to a hereditary colorectal cancer predisposition syndrome. Recent discoveries of the genes responsiblefor the inherited colorectal cancer conditions have expanded the field of commercial genetic testing. Health-care providers who use genetic testing in clinical practice are aware of the benefits that genetic testing can confer on screening, prevention, and treatment options for patients with a personal and/or family history of colon cancer. When genetic test results are correctly interpreted, the information they provide can offer medical guidance for the entire family. The psychological impact, however, of presymptomatic testing can be multifaceted. There are unprecedented benefits but also complex issues surrounding genetic testing. For these reasons, the practice of offering genetic testing to individuals at high risk for colon cancer is heavily fortified with guidelines and recommendations. This review covers the current availability and limitations of genetic testing for inherited colorectal cancer syndromes and focuses on guidelines that address the psychological, ethical, and social concerns stemming from genetic testing.