A case of reed syndrome with an unusually extensive cutaneous burden treated with fully ablative Erbium:YAG laser resurfacing therapy.

Reed Syndrome, or hereditary leiomyomatosis and renal cell carcinoma syndrome, is a rare, autosomal dominant genetic condition that predisposes individuals to a triad of cutaneous leiomyomas, uterine leiomyomas and renal cell carcinoma. Cutaneous leiomyomas are often the first manifestation of the syndrome, occurring in 76% of patients and average 26 in number. We present a case of a 47 year old female with Reed Syndrome with an unusually extensive cutaneous burden, with a total of 361 cutaneous lesions, far above the average reported number of 26. Due to the extent of her cutaneous burden, painful nature of the lesions and failure to respond to standard therapies, she was referred for fully ablative Erbium:Yag laser resurfacing therapy. The use of fully ablative Erbium:YAG laser resurfacing therapy for treatment of cutaneous leiomyomas has not been reported in the literature to date. One year following laser therapy, the treatment area not only began to repigment, but there was also no evidence of cutaneous leiomyomas recurrence or associated pain. Given the effectiveness of this unique therapy, fully ablative Erbium:YAG laser resurfacing should be kept in mind as a treatment option for both cosmetic and symptomatic cutaneous leiomyomas.

mTOR inhibitors reduce enteropathy, intestinal bleeding and colectomy rate in patients with juvenile polyposis of infancy with PTEN-BMPR1A deletion.

Ultra-rare genetic disorders can provide proof of concept for efficacy of targeted therapeutics and reveal pathogenic mechanisms relevant to more common conditions. Juvenile polyposis of infancy (JPI) is caused by microdeletions in chromosome 10 that result in haploinsufficiency of two tumor suppressor genes: phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and bone morphogenetic protein receptor type IA (BMPR1A). Loss of PTEN and BMPR1A results in a much more severe phenotype than deletion of either gene alone, with infantile onset pan-enteric polyposis and a high mortality rate. No effective pharmacological therapy exists. A multi-center cohort analysis was performed to characterize phenotype and investigate the therapeutic effect of mammalian target of rapamycin (mTOR) inhibition (adverse events, disease progression, time to colectomy and mortality) in patients with JPI. Among 25 JPI patients identified (mean age of onset 13 months), seven received mTOR inhibitors (everolimus, n = 2; or sirolimus, n = 5). Treatment with an mTOR inhibitor reduced the risk of colectomy (hazard ratio = 0.27, 95% confidence interval = 0.07-0.954, P = 0.042) and resulted in significant improvements in the serum albumin level (mean increase = 16.3 g/l, P = 0.0003) and hemoglobin (mean increase = 2.68 g/dl, P = 0.0077). Long-term mTOR inhibitor treatment was well tolerated over an accumulated follow-up time of 29.8 patient years. No serious adverse events were reported. Early therapy with mTOR inhibitors offers effective, pathway-specific and personalized treatment for patients with JPI. Inhibition of the phosphoinositol-3-kinase-AKT-mTOR pathway mitigates the detrimental synergistic effects of combined PTEN-BMPR1A deletion. This is the first effective pharmacological treatment identified for a hamartomatous polyposis syndrome.

Surgical Treatment of Brooke-Spiegler Syndrome.

ABSTRACT: Brooke-Spiegler Syndrome (BSS) is a very rare autosomal dominant hereditary disease which arises from heterozygous mutations in the CYLD gene. Patients with BSS are predisposed to multiple skin appendage tumors such as cylindromas, which are benign tumors occurring mainly on the scalp. The tumors mostly appear around puberty and usually show slow growth throughout life. Malignant cylindroma formation in BSS patients has been reported. Apart from the skin, major and minor salivary glands have rarely been involved.We here report a case of a 46-year-old female patient with BSS presenting with multiple aesthetically and functionally unpleasing cylindromas covering almost her entire hair-bearing scalp with further tumors on her face. Interestingly, her parotid glands were enlarged and showed multiple lesions with a diameter up to 18 to 20 mm. She was successfully treated by total subgaleal scalp excision and coverage through a dermal substitute and split thickness skin graft. Constant follow-up imaging was initiated to prevent unhindered tumor growth of salivary glands.

Case report: acute abdominal pain in a 37-year-old patient and the consequences for his family.

BACKGROUND: Hereditary diffuse gastric cancer is a rare condition that accounts for approximately 1-3% of all gastric cancer cases. Due to its rapid and invasive growth pattern, it is associated with a very poor prognosis. As a result, comprehensive genetic testing is imperative in patients who meet the current testing criteria in order to identify relatives at risk. This case report illustrates the substantial benefit of genetic testing in the family of a patient diagnosed with hereditary diffuse gastric cancer. CASE PRESENTATION: A 37-year-old patient was admitted to the emergency department with acute abdominal pain. Following explorative laparoscopy, locally advanced diffuse gastric cancer was diagnosed. The indication for genetic testing of CDH1 was given due to the patient's young age. A germline mutation in CDH1 was identified in the index patient. As a result, several family members underwent genetic testing. The patient's father, brother and one aunt were identified as carriers of the familial CDH1 mutation and subsequently received gastrectomy. In both the father and the aunt, histology of the surgical specimen revealed a diffuse growing adenocarcinoma after an unremarkable preoperative gastroscopy. CONCLUSION: Awareness and recognition of a potential hereditary diffuse gastric cancer can provide a substantial health benefit not only for the patient but especially for affected family members.

Screening and surgical prophylaxis for hereditary cancer syndromes with high risk of endometrial and ovarian cancer.

In the era of advanced cancer genomics, our recognition of hereditary cancer mutations continues to increase. Two of these conditions, which carry an increased risk of female cancers including endometrial, ovarian, breast, are hereditary breast and ovarian cancer syndrome and Lynch syndrome. Risk-reducing surgery, such as mastectomy, salpingo-oophorectomy, and hysterectomy may decrease cancer risk for mutation carriers. Background, indications, techniques, and consequences of these surgical procedures are reviewed.

Collagenoma of the Eyelid.

The rare case of an eyelid lesion comprised of hamartomatous dermal collagen, known as a collagenoma, is presented. Collagenomas may be sporadically acquired, or inherited as part of numerous autosomal dominant syndromes. In the appropriate clinical context, their diagnosis should prompt a thorough review of systems, systemic examination, and inquiry into family history, to assess for underlying autosomal dominant syndromes. Recognition of collagenomas may thus allow diagnosis of inherited syndromes, allowing patients to obtain appropriate genetic counseling, as well as screening and treatment of associated systemic pathology.

Is prophylactic gastrectomy indicated for healthy carriers of CDH1 gene mutations associated with hereditary diffuse gastric cancer?

INTRODUCTION: hereditary diffuse gastric cancer (HDGC) is a recently reported hereditary cancer syndrome. Patients with suspected HDGC must be under surveillance via endoscopy and multiple biopsies. As an alternative, some studies suggest prophylactic gastrectomy (PG) for disease carriers. The goal of this article was to report our experience with a CDH1 mutation positive family who underwent PG. PATIENTS AND METHODS: the index case was a 34-year-old female diagnosed with diffuse gastric adenocarcinoma and massive carcinomatosis. There was a family history of gastric adenocarcinoma in seven family members. A genetic study identified the c.1577G>A mutation, in exon 11 of the CDH1 gene via sequencing analysis. RESULTS: this mutation was also present in other six family members, who subsequently underwent prophylactic gastrectomy. The pathology study of resected gastric segments revealed multiple microscopic foci of adenocarcinoma in five of these individuals. These foci were not detected in the multiple endoscopies performed before surgery. CONCLUSIONS: we recommend prophylactic gastrectomy for CDH1 mutation carriers even in the absence of lesions during endoscopic screening.

[Free latissimus dorsi flap lacing and local care in two-stage scalp reconstruction]. / Laçage de lambeau libre de grand dorsal dans le cadre des soins locaux d'un lambeau en nourrice du cuir chevelu.

Surgical treatment of large and multiple lesions of irradiated scalp may require subtotal scalp exeresis and reconstruction in two-stage free flap surgery: harvesting and placing the flap first, then scalp removing and defect covering in a second step. This strategy raises the question of how to care the flap between the two surgeries. We report an original technique of free latissimus dorsi flap lacing. A 70-year-old male, afflicted with familial cylindromatosis and treated by brachytherapy 18years ago, received a free latissimus dorsi myocutaneous flap in two-stage surgery, allowing 25×25cm pathological scalp exeresis. During first step, suture clips were fixed in two rows around the future scalp defect, in order to be used as anchors for the flap lacing. Braided wire were chosen for a better steerability, and to prevent knots untightening. Thus, the flap were placed in "anatomical" place, next to the scalp, pending secondary procedure. This situation permitted to avoid flap or pedicle compression or plication, and to ease flap care. The wires were tighten as shoelaces, allowing them to be undone and done as desired. The two-stage free latissimus dorsi flap reconstruction of scalp large defect permitted us to assess the flap reliability before final reconstruction. The lacing solution allowed us regular local care and convenient flap handling, while favoriting its optimal placing next to its future location.

Quality-of-life implications of risk-reducing cancer surgery.

BACKGROUND: Modern advances in genetic sequencing techniques have allowed for increased availability of genetic testing for hereditary cancer syndromes. Consequently, more people are being identified as mutation carriers and becoming aware of their increased risk of malignancy. Testing is commonplace for many inheritable cancer syndromes, and with that comes the knowledge of being a gene carrier for some patients. With increased risk of malignancy, many guidelines recommend that gene carriers partake in risk reduction strategies, including risk-reducing surgery for some syndromes. This review explores the quality-of-life consequences of genetic testing and risk-reducing surgery. METHODS: A narrative review of PubMed/MEDLINE was performed, focusing on the health-related quality-of-life implications of surgery for hereditary breast and ovarian cancer, familial adenomatous polyposis and hereditary diffuse gastric cancer. RESULTS: Risk-reducing surgery almost uniformly decreases cancer anxiety and affects patients' quality of life. CONCLUSION: Although the overwhelming quality-of-life implications of surgery are neutral to positive, risk-reducing surgery is irreversible and can be associated with short- and long-term side-effects.

Outcomes after prophylactic gastrectomy for hereditary diffuse gastric cancer.

BACKGROUND: Patients with hereditary diffuse gastric cancer and a CDH1 mutation have a 60-80 per cent lifetime risk of developing diffuse gastric cancer. Total prophylactic gastrectomy eliminates this risk, but is associated with considerable morbidity. The effectiveness (removal of all gastric mucosa) and outcomes of this procedure were evaluated retrospectively. METHODS: All consecutive individuals undergoing a prophylactic gastrectomy for a CDH1 mutation or gastric signet ring cell foci at the authors' institute between 2005 and 2017 were included. RESULTS: In 25 of 26 patients, intraoperative frozen-section examination (proximal resection margin) was used to verify complete removal of gastric mucosa. All definitive resection margins were free of gastric mucosa, but only after the proximal margin had been reresected in nine patients. In the first year after surgery, five of the 26 patients underwent a relaparotomy for adhesiolysis (2 patients) or jejunostomy-related complications (3 patients). Six patients were readmitted to the hospital within 1 year for nutritional and/or psychosocial support (4 patients) or surgical reintervention (2 patients). Mean weight loss after 1 year was 15 (95 per cent c.i. 12 to 18) per cent. For the 25 patients with a follow-up at 1 year or more, functional complaints were reported more frequently at 1 year than at 3 months after the operation: bile reflux (15 versus 11 patients respectively) and dumping (11 versus 7 patients). The majority of patients who worked or studied before surgery (15 of 19) had returned fully to these activities within 1 year. CONCLUSION: The considerable morbidity and functional consequences of gastrectomy should be considered when counselling individuals with an inherited predisposition to diffuse gastric cancer. Intraoperative frozen-section examination is recommended to remove all risk-bearing gastric mucosa.

The Role of the Surgical Pathologist in the Diagnosis of Gastrointestinal Polyposis Syndromes.

Polyps of the gastrointestinal tract are very common lesions and most frequently sporadic in nature. Some polyp subtypes are associated with rare hereditary polyposis syndromes, including juvenile polyposis syndrome, Peutz-Jeghers syndrome, and Cowden syndrome. However, many sporadic benign lesions of the gastrointestinal tract can mimic some of these syndromic hamartomatous polyps. The role of the surgical pathologist is to raise the possibility of a hereditary condition in case of suggestive polyp histology and to look for clinical information to support the suspected diagnosis. In this review, the clinical presentation and the pathology associated with these rare hamartomatous polyposis syndromes are discussed in an attempt to provide pathologists clues in suggesting one such syndrome on the basis of histologic findings and clinical context. Identification of affected individuals is important because of the increased gastrointestinal and other malignancies. Recently, new adenomatous polyposis syndromes have been discovered, expanding the genetic causes of patient diagnosed with multiple colonic adenomas. By being aware of the clinical phenotype and the tumor spectrum associated with gastrointestinal polyposis syndromes, surgical pathologists can play a critical role in recommending genetic counseling when suspicious of such a diagnosis. This may lead to the identification of a genetic cause and appropriate surveillance of affected family members to screen for associated malignancies.

Therapeutic and prophylactic gastrectomy in a family with hereditary diffuse gastric cancer secondary to a CDH1 mutation: a case series.

BACKGROUND: Gastric cancer is the fifth most prevalent and the third most lethal cancer worldwide, causing approximately 720,000 deaths annually. Although most cases of gastric cancers are sporadic, one of its inherited forms, hereditary diffuse gastric cancer (HDGC), constitutes about 1-3% of cases. Interestingly, females in families with HDGC are also predisposed to developing lobular breast cancer (LBC). Recent analyses have identified loss-of-function germline mutations in cadherein-1 (CDH1) as a culprit in HDGC and LBC. This discovery fueled several sequencing analyses and case series reports analyzing the pattern of inheritance of CDH1 and its propensity to induce HDGC. In 2015, a multinational and multidisciplinary task force updated the guidelines and criteria for screening, diagnosing, and managing HDGC. CASE PRESENTATION: Here, we present a case series of three siblings with family history of HDGC who tested positive for the CDH1 mutation and describe their surgical treatment course, post-operative management, and follow-up as they pertain to the updated guidelines. CONCLUSIONS: Despite recent updates in guidelines in the diagnosis and management of HDGC, the disease remains challenging to address with patients given the high level of uncertainty and the comorbidities associated with prophylactic intervention. We strongly recommend that an interdisciplinary team inclusive of clinical and surgical oncologists, along with geneticists, social work, and psychological support, should follow the patients in a longitudinal and comprehensive manner in order to achieve full recovery and return to normalcy, as with our patients.

Hereditary leiomyomatosis and renal cell cancer without cutaneous manifestations in two Japanese siblings.

Hereditary leiomyomatosis and renal cell cancer is a rare genetic disorder characterized by cutaneous and uterine leiomyomatosis, and an aggressive type 2 papillary renal cell carcinoma. The disease is caused by a germline mutation in the fumarate hydratase gene. We report a familial hereditary leiomyomatosis and renal cell cancer in two siblings. A 34-year-old woman underwent nephrectomy for treatment of a renal cell carcinoma. The patient's sister had been diagnosed with renal cell carcinoma at 28 years-of-age and died of the disease. Neither sister had apparent skin tumors. Histopathology of the renal cell carcinomas of the siblings showed tubulocystic and papillary architectures with high nuclear grades. Immunostaining showed no fumarate hydratase expression in either tumor. Genomic DNA sequencing of the patient showed a germline mutation in the fumarate hydratase gene (c.675delT). Although there is no epidemiological information on Asian hereditary leiomyomatosis and renal cell cancer, physicians should be aware that typical cutaneous leiomyomatosis might not always be present in patients with hereditary leiomyomatosis and renal cell cancer.

Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) - a rare recently described gastric polyposis syndrome - report of a case.

In rare cases with multiple gastric polyps in the corpus and fundus, a recently described gastric polyposis syndrome called gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) has to be considered. We report on the findings in a patient fulfilling the criteria of this disease.A female patient born in 1977 underwent gastroscopy in 2005 due to recurrent abdominal pain. Endoscopy revealed more than 100 fundic gland polyps in the corpus and fundus. An ileocolonoscopy was inconspicuous. The patient did not take proton pump inhibitors. In follow-up biopsies, fundic gland polyps with low-grade dysplasia were observed. In 2015 gastroscopy with biopsy revealed for the first time high-grade dysplasia in a polyp, and the patient underwent prophylactic gastrectomy.Macroscopic examination of the gastrectomy specimen revealed hundreds of polyps predominantly measuring 3 mm in diameter covering the fundus and corpus. Histology showed fundic gland polyps, mainly covered by normal appearing foveolae. However, several of them were covered by lesions reminiscent of gastric foveolar adenomas with low- and focally high-grade dysplasia. Molecular pathology revealed a point mutation in the adenomatous polyposis coli promotor 1B. These findings in conjunction with the knowledge that the patient's father had died of gastric carcinoma in his 50 s led to the diagnosis of the autosomal dominant syndrome GAPPS, which has hitherto been described in 9 families.

Review of hereditary leiomyomatosis renal cell carcinoma with focus on clinical and pathobiological aspects of renal tumors.

The entity of hereditary leiomyomatosis renal cell carcinoma (HLRCC)-associated RCC has been proposed and integrated into the recent International Society of Urologic Pathology (ISUP) of renal tumors. This tumor is characterized by presence of cutaneous and/or uterine leiomyomas and RCC and autosomal dominant hereditary form. Grossly, HLRCC arising in the kidney show the solid tumor with frequent partial cystic area. Microscopically, the tumor typically shows papillary RCC, type 2, with eosinophilic large nucleoli reminiscent of cytomegaloviral inclusion and perinuclear clearing/haloes. Immunohistochemically, tumor cells show the overexpression for 2SC and reduced expression of FH. Germline mutation of fumarate hydratase (FH) gene, the HLRCC responsible gene mapped to chromosome 1q43, has been identified in patients with HLRCC. As the renal cancer in patients with HLRCC generally behave aggressively even in a small size, complete surgical resection and retroperitoneal lymph node resection should be performed promptly when the tumor is discovered. The surveillance of renal tumor in FH gene germline mutation-positive patients should be started from the early age using ultrasound sonography or magnetic resonance imaging.

JP-HHT phenotype in Danish patients with SMAD4 mutations.

Patients with germline mutations in SMAD4 can present symptoms of both juvenile polyposis syndrome (JPS) and hereditary hemorrhagic telangiectasia (HHT): the JP-HHT syndrome. The complete phenotypic picture of this syndrome is only just emerging. We describe the clinical characteristics of 14 patients with SMAD4-mutations. The study was a retrospective, register-based study. SMAD4 mutations carriers were identified through the Danish HHT-registry, the genetic laboratories - and the genetic departments in Denmark. The medical files from relevant departments were reviewed and symptoms of HHT, JPS, aortopathy and family history were noted. We detected 14 patients with SMAD4 mutations. All patients had polyps removed and 11 of 14 fulfilled the diagnostic criteria for JPS. Eight patients were screened for HHT-symptoms and seven of these fulfilled the Curaçao criteria. One patient had aortic root dilation. Our findings support that SMAD4 mutations carriers have symptoms of both HHT and JPS and that the frequency of PAVM and gastric involvement with polyps is higher than in patients with HHT or JPS not caused by a SMAD4 mutation. Out of eight patients screened for aortopathy, one had aortic root dilatation, highlighting the need for additional screening for aortopathy.

Hemangioma treatment with pulsed dye laser-distinct parameters used between neonatal and non-neonatal patients.

BACKGROUND: Pulsed dye laser (PDL) treatment remains the standard of care for infantile hemangiomas (IHs). However, the use of PDL to treat IHs in neonates has been hardly reported. In this study, the PDL treatments of IHs between neonatal and non-neonatal patients were retrospectively investigated. METHODS: All patients diagnosed with hemangiomas were treated by PDL. Their clinical data were collected, and the treatment outcomes and PDL parameters in neonates and non-neonates were analyzed using the Mann-Whitney U-rank test. RESULTS: All patients reached good or excellent scale in the treatment efficiency assessment. Laser energy used per treatment session was significantly lower in neonatal group than in non-neonatal group (Z = -8.980, P < 0.001). Total laser energy used in neonates was also markedly lower than that in non-neonatal patients (Z = -3.065, P = 0.002). However, treatment session numbers in these two groups were not significantly different (Z = -1.725, P = 0.085). Additionally, we observed that after each treatment, the purpura disappeared faster in neonates (2-4 weeks) than in non-neonatal patients (4-6 weeks), indicating neonates might have greater recovery ability. CONCLUSIONS: PDL, with distinct parameters, was effective in the treatment of IHs in neonates. After each laser treatment, neonates recovered faster than non-neonatal patients.