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Importance: Propranolol for infantile hemangiomas (IH) has been shown to be effective and relatively safe. However, other less lipophilic β-blockers, such as nadolol, may be preferable in individuals who experience propranolol unresponsiveness or adverse events., Objective: To document the noninferiority and safety of oral nadolol compared with oral propranolol in infants with IH., Design, Setting, and Participants: This double-blind noninferiority prospective study with a noninferiority margin of 10% compared propranolol with nadolol in infants aged 1 to 6 months with problematic IH. The study was conducted in 2 academic pediatric dermatology centers in Canada between 2016 and 2020. Infants aged 1 to 6 months with a hemangioma greater than 1.5 cm on the face or 3 cm or greater on another body part causing or with potential to cause functional impairment or cosmetic disfigurement., Interventions: Oral propranolol and nadolol in escalating doses up to 2 mg/kg/d., Main Outcomes and Measure: Between-group differences comparing changes in the bulk (size and extent) and color of the IH at week 24 with baseline using a 100-mm visual analog scale., Results: The study included 71 patients. Of these, 36 were treated with propranolol. The mean (SD) age in this group was 3.1 (1.4) months, and 31 individuals (86%) were female. Thirty-five infants were treated with nadolol. The mean (SD) age in this group was 3.2 (1.6) months, and 26 individuals (74%) were female. The difference in IH between groups by t test was 8.8 (95% CI, 2.7-14.9) for size and 17.1 (95% CI, 7.2-30.0) for color in favor of the nadolol group, demonstrating that nadolol was noninferior to propranolol. Similar differences were noted at 52 weeks: 6.0 (95% CI, 1.9-10.1) and 10.1 (95% CI, 2.9-17.4) for size and color improvement, respectively. For each doubling of time unit (week), the coefficient of involution was 2.4 (95% CI, 0.5-4.4) higher with nadolol compared with propranolol. Safety data were similar between the 2 interventions., Conclusions and Relevance: Oral nadolol was noninferior to oral propranolol, indicating it may be an efficacious and safe alternative in cases of propranolol unresponsiveness or adverse events, or when faster involution is required., Trial Registration: ClinicalTrials.gov Identifier: NCT02505971.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant syndrome wherein affected individuals are at risk for the development of cutaneous leiomyomas, early-onset multiple uterine leiomyomas, and an aggressive subtype of renal cell cancer. HLRCC is caused by germline mutations in the fumarate hydratase (FH) gene, which inactivates the enzyme and alters the function of the tricarboxylic acid/Krebs cycle. This article reviews the hitherto described morphologic features of HLRCC-associated renal cell carcinoma (RCC) and outlines the differential diagnosis and ancillary use of immunohistochemistry and molecular diagnostics for these tumors. The morphologic spectrum of HLRCC-associated RCC is wide and histologic features, including tumor cells with prominent nucleoli, perinucleolar halos, and multiple architectural patterns within the same tumor, which are suggestive of this diagnosis. FH immunohistochemistry in conjunction with genetic counseling and germline FH testing are the important parameters for detection of this entity. These kidney tumors warrant prompt treatment as even smaller sized lesions can demonstrate aggressive behavior and systemic oncologic treatment in metastatic disease should, if possible, be part of a clinical trial. Screening procedures in HLRCC families should preferably be evaluated in large cohorts., Competing Interests: None

Background: Juvenile polyps (JPs) are the most common gastrointestinal polyps diagnosed in children. There is paucity of evidence differentiating polyp burden groups and the presence and significance of neoplastic changes., Methods: A retrospective chart review of patients, ages birth through 18 years with nonsyndromic JPs was performed from 2003 to 2017. Abstracted data included basic demographics, age, clinical presentation, colonoscopy findings, and pathology report. Slides of polyps with neoplasia were reviewed by a pathologist., Results: A total of 213 subjects underwent 326 procedures and 435 polypectomies. Subjects with positive family history, positive gene mutations, or numerous (>10) polyps were excluded. Groups were defined by polyp number (1, 2-4, 5-10). Polyp recurrence on repeat colonoscopy was significantly related to polyp burden (1 polyp: 1.5%/2-4 polyps 19.2%/5-10 polyps 82.6%: P < 0.001). Polyp distribution was significantly different amongst different groups with isolated polyps favoring a distal distribution. JPs harboring adenomatous foci were reported in 26 (12%) patients. JPs harboring adenomatous foci were significantly more likely to be proximally distributed but the presence of adenomatous transformation within the polyps did not correlate with polyp number or the likelihood of polyp recurrence on repeat colonoscopy., Conclusions: JP recurrence is positively and significantly related to polyp burden. JP harbored adenomatous changes independent of polyp number, underscoring a possible malignant potential in JPs. In the absence of a consistent genotype or pedigree, the presence of adenomatous transformation within JPs cannot be construed as a biomarker for syndromic juvenile polyposis.

We describe the case of a 16-year-old male patient with BMPR1A mutation and incidentally detected atrial septal defect (ASD). This patient was diagnosed with BMPR1A mutation through genetic testing and was attending for routine surveillance endoscopy when ASD was incidentally diagnosed. He was referred to cardiology outpatient clinic with plans for elective ASD closure. Through this case report we aim to discuss the pathophysiology of juvenile polyposis syndrome (JPS), highlight what we believe to be a novel presentation of comorbid BMPR1A mutation and ASD and hypothesise that patients with BMPR1A mutation and JPS may be at risk of previously unrecognised cardiovascular complications analogous to the previous association of SMAD4 JPS and cardiac abnormalities., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose of Review: Hereditary disorders affecting growth (both overgrowth and growth retardation) are frequently associated with heightened risk of neoplastic disease. This review summarizes the tumor spectra associated with these conditions and identifies disease-specific screening approaches., Recent Findings: An understanding of the molecular events underlying many of these growth disorders has evolved significantly over the past several years. Recognition of genotype-phenotype associations, in many cases, informs the cancer risk profile. Additionally, accumulating data suggest a benefit of rational presymptomatic surveillance for at-risk individuals, with a reduction in tumor-associated morbidity. Recent clinical practice recommendations have established risk-driven paradigms for tumor surveillance in the context of hereditary tumor predisposition syndromes, including those affecting growth., Summary: Clinicians caring for children with growth disorders should be aware of syndromic associations and the associated cancer risks. Knowledge of tumor spectra and recommended surveillance strategies may facilitate tumor diagnosis at an early stage and reduce morbidity of the disease and associated treatments.

Background: Infantile hemangiomas (IH) are initially warm due to increased proliferation and perfusion then involute with apoptosis and reduced perfusion. Objective quantitative evaluation of IH treatment response is essential for improving outcomes. We applied a functional imaging method, dynamic infrared (IR) thermography, to investigate IH status versus control skin and over time., Materials and Methods: A preliminary prospective observational study was conducted among 25 subjects with superficial or mixed IHs (< 19 months) over 59 clinic visits. Infrared images of IHs and control sites, standardized color images, and three-dimensional images were obtained. Tissue responses following application and removal of a cold stress were recorded with video IR thermography. Outcomes included areas under the curve during cooling (AUCcool ) and rewarming (AUCrw ) and thermal intensity distribution maps., Results: AUCcool and AUCrw were significantly higher and cooling rate slower for IHs versus uninvolved tissue indicating greater heat, presumably due to greater perfusion and metabolism for the IH. IR distribution maps showed specific areas of high and low temperature. Significant changes in IH thermal activity were reflected in the difference (AUCcool - AUCrw ), with 6.2 at 2.2 months increasing to 37.6 at 12.8 months. IH cooling rate increased with age, indicating slower recovery, and interpreted as reduced proliferation and/or involution., Conclusions: Dynamic IR thermography was a well-tolerated, quantitative functional imaging modality appropriate for the clinic, particularly when structural changes, i.e., height, volume, color, were not readily observed. It may assist in monitoring progress, individualizing treatment, and evaluating therapies., Clinical Trial Registration: www.clinicaltrials.gov (Identifier NCT02061735)., Competing Interests: The authors have no conflicts of interest in relation to this article to disclose., (© 2016 The International Society of Dermatology.)

Objectives: Hereditary biallelic mismatch repair deficiency (BMMRD) is caused by biallelic mutations in the mismatch repair (MMR) genes and manifests features of neurofibromatosis type 1, gastrointestinal (GI) polyposis, and GI, brain, and hematological cancers. This is the first study to characterize the GI phenotype in BMMRD using both retrospective and prospective surveillance data., Methods: The International BMMRD Consortium was created to collect information on BMMRD families referred from around the world. All patients had germline biallelic MMR mutations or lack of MMR protein staining in normal and tumor tissue. GI screening data were obtained through medical records with annual updates., Results: Thirty-five individuals from seven countries were identified with BMMRD. GI data were available on 24 of 33 individuals (73%) of screening age, totaling 53 person-years. The youngest age of colonic adenomas was 7, and small bowel adenoma was 11. Eight patients had 19 colorectal adenocarcinomas (CRC; median age 16.7 years, range 8-25), and 11 of 18 (61%) CRC were distal to the splenic flexure. Eleven patients had 15 colorectal surgeries (median 14 years, range 9-25). Four patients had five small bowel adenocarcinomas (SBC; median 18 years, range 11-33). Two CRC and two SBC were detected during surveillance within 6-11 months and 9-16 months, respectively, of last consecutive endoscopy. No patient undergoing surveillance died of a GI malignancy. Familial clustering of GI cancer was observed., Conclusions: The prevalence and penetrance of GI neoplasia in children with BMMRD is high, with rapid development of carcinoma. Colorectal and small bowel surveillance should commence at ages 3-5 and 8 years, respectively.

Background: Validated and reliable instruments to measure disease severity are needed to substantiate the benefit of therapies for infantile hemangioma. Two purpose-made systems have been described: the Hemangioma Activity Score (HAS) and the Hemangioma Severity Scale (HSS)., Objective: We sought to compare the HAS with the HSS in terms of ease of use, accuracy, and outcome in infants treated with oral propranolol., Methods: A prospective study of 54 infants with infantile hemangioma was conducted from October 2009 to December 2012. Propranolol was initiated at 0.5 mg/kg/d and increased to 2 mg/kg/d on day 3. The HAS and the HSS were applied independently by 2 observers., Results: Intraclass correlation coefficients of the HAS and HSS between the observers was comparable but HSS scores often remained the same upon improvement of the infantile hemangioma and therefore did not reflect disease severity. HAS decreased over time, with a dramatic drop in the first week reflecting an immediate therapeutic response., Limitations: This is a single-institution study and there may have been some selection bias in the patients who were referred for treatment., Conclusions: This study suggests that the HAS is preferable to the HSS in evaluating infantile hemangioma response to treatment., (Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: The pathogenesis of infantile haemangioma (IH) is unknown. Several mechanisms have been proposed, including hypoxia, which triggers upregulation and stabilization of hypoxia-inducible factor (HIF)1α. HIF1α stimulates downstream transcription of target genes that enhance angiogenesis., Aim: To identify possible involvement of hypoxia in the pathogenesis of IH, as hypoxia signalling constitutes a potential therapeutic target., Methods: IH tissue samples collected during the period 1991-2011 (preserved in paraffin wax) were immunohistochemically analysed for HIF1α and the known HIF1α targets: BCL2/adenovirus E1B kD-interacting protein family member 3 (BNIP3), carbon anhydrase (CA)-IX, glucose transporter (GLUT)-1, phosphorylated protein kinase B (pAKT), phosphorylated S6 protein (pS6) and vascular endothelial growth factor (VEGF). Four observers independently assessed the findings., Results: Of the 10 IH samples, 2 appeared to be in the growth phase. In all samples, GLUT-1, BNIP3, pAKT and VEGF were positive, CA-IX was weakly positive, and HIF1α was negative. pS6 was positive in 9/10 cases and negative in 1/10., Conclusions: Several factors implicated in hypoxia-induced angiogenesis may be involved in IH development. However, the small sample size and retrospective approach of the study preclude definitive conclusions. Prospective studies are needed to conclusively determine which of the factors involved in the (hypoxia) cascade are required for an IH to grow, and could thus be a possible target of drugs for IH treatment., (© 2014 British Association of Dermatologists.)

Until recently, significant advances in our understanding of the mechanisms of blood pressure regulation arose from studies of monogenic forms of hypertension and hypotension, which identified rare variants that primarily alter renal salt handling. Genome-wide association and exome sequencing studies over the past 6 years have resulted in an unparalleled burst of discovery in the genetics of blood pressure regulation and hypertension. More importantly, genome-wide association studies, while expanding the list of common genetic variants associated with blood pressure and hypertension, are also uncovering novel pathways of blood pressure regulation that augur a new era of novel drug development, repurposing, and stratification in the management of hypertension. In this review, we describe the current state of the art of the genetic and molecular basis of blood pressure and hypertension., (© 2015 American Heart Association, Inc.)

Areas of blanched skin in children may be seen as an independent finding or in association with vascular birthmarks. We performed a retrospective chart review to identify and describe infants with areas of ventral midline blanching in the presence of segmental infantile hemangiomas. We identified nine full-term infants with partial or full segmental hemangiomas and areas of midline ventral blanching. Additional ventral wall defects were seen in five patients. Six had cardiac anomalies and six had intracranial anomalies. Five were diagnosed with definite PHACE (posterior fossa, hemangioma, arterial, cardiac, and eye abnormalities) syndrome and three had possible PHACE syndrome. Eight were complicated by ulceration. Treatment varied according to the case. Ventral blanching, even in the absence of overt midline defects, can be seen in infants with segmental hemangiomas at risk for PHACE syndrome. We hypothesize that midline blanching may represent a minor manifestation of a developmental ventral defect., (© 2014 Wiley Periodicals, Inc.)

Within the last decade, there has been a tremendous progress in understanding the molecular basis of cancer. In particular, the development and the characteristic features of cancer cells are being increasingly understood. The understanding of these molecular characteristics is mandatory for the development of novel, targeted therapeutic strategies and their integration into clinical practice. In addition, tumour genetics play a critically important role for hereditary cancer syndromes, with respect to both diagnostics and clinical decision-making. The aim of this review is to highlight general principles of tumour genetics from a visceral surgeon's point of view, although a comprehensive summary of all aspects would be beyond the scope of this article due to the complexity of the topic., (Georg Thieme Verlag KG Stuttgart · New York.)

Hereditary Diffuse Gastric Cancer is an autosomal dominant inherited gastric cancer syndrome caused by germline alterations in CDH1 (E-cadherin) and CTNNA1 (alpha-E-catenin) genes. Germline CDH1 alterations encompass small frameshifts, splice-site, nonsense, and missense mutations, as well as large rearrangements. Most CDH1 truncating mutations are pathogenic, and several missense CDH1 mutations have a deleterious effect on E-cadherin function. CDH1 testing should be performed in probands. Screening of at-risk individuals is indicated from the age of consent following counselling with a multidisciplinary team. In mutation-positive individuals prophylactic gastrectomy is recommended. Endoscopic surveillance is an option for those refusing/postponing gastrectomy, those with mutations of undetermined significance, and in CDH1-negative families. Ongoing research focus on the search of genetic causes other than CDH1 or CTNNA1 germline defects; assessment of the pathogenicity and penetrance of CDH1 missense mutations and identification of somatic mechanisms behind the progression from early (indolent) lesions to invasive (lethal) carcinomas., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Constitutional mismatch repair deficiency (CMMRD) syndrome is a distinct childhood cancer predisposition syndrome that results from biallelic germline mutations in one of the four MMR genes, MLH1, MSH2, MSH6 or PMS2. The tumour spectrum is very broad, including mainly haematological, brain and intestinal tract tumours. Patients show a variety of non-malignant features that are indicative of CMMRD. However, currently no criteria that should entail diagnostic evaluation of CMMRD exist. We present a three-point scoring system for the suspected diagnosis CMMRD in a paediatric/young adult cancer patient. Tumours highly specific for CMMRD syndrome are assigned three points, malignancies overrepresented in CMMRD two points and all other malignancies one point. According to their specificity for CMMRD and their frequency in the general population, additional features are weighted with 1-2 points. They include multiple hyperpigmented and hypopigmented skin areas, brain malformations, pilomatricomas, a second childhood malignancy, a Lynch syndrome (LS)-associated tumour in a relative and parental consanguinity. According to the scoring system, CMMRD should be suspected in any cancer patient who reaches a minimum of three points by adding the points of the malignancy and the additional features. The diagnostic steps to confirm or refute the suspected diagnosis are outlined. We expect that application of the suggested strategy for CMMRD diagnosis will increase the number of patients being identified at the time when they develop their first tumour. This will allow adjustment of the treatment modalities, offering surveillance strategies for second malignancies and appropriate counselling of the entire family., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

A previously healthy 9-year-old girl presented with ataxia, headaches, and nausea of 1 month's duration. Magnetic resonance imaging demonstrated a large posterior fossa mass. Posterior segment examination revealed pigmented ocular fundus lesions (POFLs), which included cometoid dark lesions with depigmented tails and smaller, dark midperipheral lesions. The patient underwent resection for a medulloblastoma. Because of these specific retinal lesions in combination with her medullobastoma, a diagnosis of Turcot syndrome was made and subsequently confirmed by genetic testing. Turcot syndrome is one of the familial adenomatous polyposis (FAP) syndromes. This diagnosis may be life-saving because 100% of FAP patients develop colon cancer that can be cured only early with timely colectomy., (Copyright © 2014 American Association for Pediatric Ophthalmology and Strabismus. All rights reserved.)

Context: The duration of hypothalamic-pituitary-adrenal (HPA) axis suppression after glucocorticoid treatment is uncertain., Objective: We aimed to determine the duration of HPA axis suppression in prednisolone-treated infants and the age at which circadian variation in salivary cortisol is established in healthy infants., Design, Setting, and Participants: Before the adoption of propranolol treatment by the Vascular Birthmarks Clinic, 12 infants with infantile hemangioma received high-dose prednisolone for 12 to 25 weeks' duration, weaned over 4 to 6 weeks, and ceased at age 21 to 31 weeks. Parents collected serial salivary samples at two time points per day (before first and last feed) until circadian variation in salivary cortisol (measured by radioimmunoassay) was observed, when a confirmatory 1 μg Synacthen test was performed. Ten healthy control infants had serial salivary cortisol measurements to determine the age at which circadian variation is established., Main Outcome Measure: We defined circadian variation as evening salivary cortisol <50% of the early morning level on two consecutive sampling weeks., Results: Circadian variation appeared within 6 weeks (median 2.7, range 1.4-5.4) of prednisolone cessation. All confirmatory Synacthen tests were normal (peak serum cortisol >600 nmol/L) and were performed within 12 weeks of prednisolone cessation. Healthy controls developed circadian variation at median 16 weeks of age (range 8-24)., Conclusion: HPA recovery occurred within 6 to 12 weeks, shorter than empirical recommendations, to give stress cover for 6 to 12 months. Reduced duration of stress-cover precautions may reduce parental anxiety and side effects from unnecessary glucocorticoid use. Healthy control infants established circadian variation in salivary cortisol between 2 and 6 months of age.

Neuroendocrine tumours occur in some hereditary tumour syndromes, and the molecular pathophysiological mechanisms involved in these are also important in their sporadic counterparts which representing the majority of neuroendocrine tumours. These syndromes include multiple endocrine neoplasia type 1, von Hippel-Lindau syndrome, neurofibromatosis type 1 and tuberous sclerosis. All these follow an autosomal dominant inheritance. The primarily affected molecular pathways are Ras-MAPK signalling, hypoxia induced factor 1α, and mTOR signalling that are also involved in sporadic tumours and may even represent potential molecular targets of therapy. In this review, the major characteristics of hereditary tumour syndromes, their molecular genetics and the pathophysiological mechanisms involved in sporadic tumours are discussed.

The hypothesis that mitochondrial dysfunction and increased superoxide levels in thymocytes over expressing Bax (Lck-Bax1 and Lck-Bax38&1) contributes to lymphomagenesis after low-dose radiation was tested. Lck-Bax1 single-transgenic and Lck-Bax38&1 double-transgenic mice were exposed to single whole-body doses of 10 or 100 cGy of (137)Cs or iron ions (1,000 MeV/n, 150 keV/μm) or silicon ions (300 MeV/n, 67 keV/μm). A 10 cGy dose of (137)Cs significantly increased the incidence and onset of thymic lymphomas in female Lck-Bax1 mice. In Lck-Bax38&1 mice, a 100 cGy dose of high-LET iron ions caused a significant dose dependent acceleration of lymphomagenesis in both males and females that was not seen with silicon ions. To determine the contribution of mitochondrial oxidative metabolism, Lck-Bax38&1 over expressing mice were crossed with knockouts of the mitochondrial protein deacetylase, Sirtuin 3 (Sirt3), which regulates superoxide metabolism. Sirt3(-/-)/Lck-Bax38&1 mice demonstrated significant increases in thymocyte superoxide levels and acceleration of lymphomagenesis (P < 0.001). These results show that lymphomagenesis in Bax over expressing animals is enhanced by radiation exposure in both an LET and gender dependent fashion. These findings support the hypothesis that mitochondrial dysfunction leads to increased superoxide levels and accelerates lymphomagenesis in Lck-Bax transgenic mice.

Purpose: To evaluate the optical and anatomical effects of oral propranolol treatment for infantile periocular capillary haemangioma., Methods: All children diagnosed with infantile capillary haemangioma in 2008-2010 at a tertiary paediatric medical centre underwent comprehensive evaluation, including imaging, by a multidisciplinary team followed by oral propranolol treatment. Clinical follow-up was performed regularly until the lesions disappeared. Main outcome measures included changes in anatomical extraocular extension, refractive sphere and cylindrical power, and spherical equivalent in the involved eye before and after treatment and between the two eyes., Results: A total of 30 patients (8 male; mean age at diagnosis, 1.6±2.8 months) participated. The lesions affected the left eye in 53.3% and were located preseptally in 83.3%. Four patients (13.3%) received steroids before propranolol. A treatment dosage of 2 mg/kg per day was started at mean age 5.0±4.5 months, 3.3±4.3 months from disease onset. Side effects occurred in 11 patients and warranted a dose reduction (to 1 mg/kg per day) in 3 and treatment termination in 1. Findings were significant for mean reduction in involved extraocular area (P<0.0001), post-treatment reduction in mean cylindrical power in involved eyes (P=0.02), pre- and post-treatment differences in mean cylindrical power between involved and uninvolved eyes (P=0.02 and P=0.01, respectively), and post-treatment change in absolute values of mean spherical power between involved and uninvolved eyes (P=0.025)., Conclusions: Early diagnosis of infantile periocular capillary haemangioma and prompt treatment with propranolol lead to a significant reduction in the involved ocular area, in astigmatism, and prevent ocular/facial disfiguration/deformation, without rebound. Propranolol is recommended as the preferred treatment compared with other accepted therapies.

Neuroendocrine tumors (NETs) can be sporadic or they can arise in complex hereditary syndromes. Patients with hereditary NETs can be identified before the development of tumors by performing genetic screenings. The aim of the study was to evaluate the clinical and prognostic impact of a preclinical genetic screening in subjects with hereditary NET syndromes. 46 subjects referred for hereditary NET syndrome [22 MEN1, 12 MEN2, 12 Familial Paragangliomatosis (FPGL)] were enrolled and divided in 2 groups (group A, 20 subjects with clinical appearance of NET before the genetic diagnosis; group B, 26 subjects with genetic diagnosis of hereditary NET syndromes before the clinical appearance of NETs). The main outcome measures were severity of disease, prognosis, and survival. The rate of surgery for MEN1-, MEN2-, FPGL4-related tumors was 90% in group A and 35% in group B (p<0.01). Both symptoms related to tumors and symptoms related to therapies were significantly less frequent in group B than in group A (p<0.05). Tumor stage was locally advanced or metastatic in 50% of group A and in no one of group B (p<0.01). The mortality rate was 25% in group A and 0% in group B (p<0.05). An early genetic screening for hereditary NET syndromes results in an improvement in clinical presentation and morbidity. A potential impact of the genetic screening on the mortality rate of these subjects is suggested and needs to be investigated in further and more appropriate studies., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Well-differentiated thyroid cancer accounts for 95% of thyroid malignancies, and 5% of these patients will have familial disease. This compares to 25% of patients with medullary thyroid cancer (MTC) having a familial form; however, this accounts for only 1% of all patients with thyroid cancer. Most cases of familial thyroid cancer are nonmedullary (NMFTC), and have been shown to be present in familial cancer syndromes such as familial adenomatous polyposis, Cowden syndrome, Carney complex, Pendred syndrome, and Werner syndrome. This review discusses the contemporary management of the patients with familial-syndrome-associated thyroid cancer based on their individual risks for developing thyroid cancer., Summary: Most of the progress in the genetics of familial thyroid cancer has been in patients with MTC. The mutations in patients with isolated NMFTC have not been as well defined as in MTC. They are likely autosomal dominant with reduced penetrance. The patients with these familial syndromes most likely have a susceptibility gene that increases the risk of thyroid cancer. Most of the patients with a familial syndrome and NMFTC will have papillary thyroid carcinoma, suggesting that a specific gene for papillary thyroid carcinoma may also be present. In many cases, patients have a known familial syndrome that has defined risk for thyroid cancer., Conclusions: Patients with familial syndromes that are associated with thyroid cancer can be individually categorized based on syndrome risks for developing thyroid cancer. The clinician must also be knowledgeable in recognizing the possibility of an underlying familial syndrome when a patient presents with thyroid cancer.

Hereditary leiomyomatosis and renal cell cancer is a hereditary cancer syndrome in which affected individuals are at risk for cutaneous and uterine leiomyomas, and renal cancer. Previous reports have stressed the aggressiveness of the renal tumours, often with early metastasis, despite small primary tumour size. Almost all the previously reported patients were adults, and different studies showed variability in penetrance for the renal tumours. We report a patient in whom renal cancer was detected at the age of 11 years at his first routine screening imaging after he was found to carry a fumarate hydratase gene mutation (c.1189G > A) transmitted from his mother. This report serves to emphasize the need to improve guidelines for screening of at risk individuals, including the necessity for predictive genetic testing and early institution of tumour surveillance in childhood.

Wiskott-Aldrich syndrome (WAS) is a severe X-linked immunodeficiency caused by mutations in the gene encoding for WASP, a key regulator of signaling and cytoskeletal reorganization in hematopoietic cells. Mutations in WASP result in a wide spectrum of clinical manifestations ranging from the relatively mild X-linked thrombocytopenia to the classic full-blown WAS phenotype characterized by thrombocytopenia, immunodeficiency, eczema, and high susceptibility to developing tumors and autoimmune manifestations. The life expectancy of patients affected by severe WAS is reduced, unless they are successfully cured by bone marrow transplantation from related identical or matched unrelated donors. Because many patients lack a compatible bone marrow donor, the administration of WAS gene-corrected autologous hematopoietic stem cells could represent an alternative therapeutic approach. In the present review, we focus on recent progress in understanding the molecular and cellular mechanisms contributing to the pathophysiology of WAS. Although molecular and cellular studies have extensively analyzed the mechanisms leading to defects in T, B, and dendritic cells, the basis of autoimmunity and thrombocytopenia still remains poorly understood. A full understanding of these mechanisms is still needed to further implement new therapeutic strategies for this peculiar immunodeficiency.

The occurrence of cylindromas, trichoepitheliomas, and spiradenomas completes the triad for Brooke-Spiegler syndrome (BSS). This combination represents a rare genetic syndrome with tumors expressing adnexal differentiation. Malignant transformation is rare but reported, and surgical excision is warranted to prevent turban tumor formation of the scalp. Genetic testing is encouraged, with mutations present on the cylindromatosis gene, CYLD, locus. The occurrence of pegged teeth in our patient was most interesting, as it has not been reported in the literature in patients with BSS.

The genetic basis of sporadic colorectal cancer has illuminated our knowledge of human cancer genetics. This has been facilitated and catalyzed by an appreciation and deep understanding of the forms of colorectal cancer that harbor an inherited predisposition, including familial adenomatous polyposis (FAP), hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome, the hamartomatous polyposis syndromes, and certain other rare syndromes. Identification of germline mutations in pivotal genes underlying the inherited forms of colorectal cancer has yielded many dividends, including functional dissection of critical molecular pathways that have been revealed to be important in development, cellular homeostasis, and cancer; new approaches in chemoprevention, molecular diagnostics and genetic testing, and therapy; and underscoring genotypic-phenotypic relationships.

Objective: To describe a case of scalp cylindroma without features of malignancy invading through the skull and dura, and producing massive intracranial extension. Tumors of epidermis and epidermal appendages rarely show bony invasion, but invasive tendency in some tumor types has been associated with increased TP53 expression., Patient and Methods: Patient with familial cyindromatosis (Brooke-Spiegler syndrome) who had undergone numerous previous surgical excisions over the past 30 years of his scalp cylindromas. Light microscopic and immunohistochemical characterization of resected tumor, with TP53 immunostaining in the invasive tumor was compared with that seen in five other cutaneous, non-invasive cylindromas., Results: Tumor showed no increase in mitotic rate or increased immunostaining for TP53., Conclusion: Multiple previous surgeries down to pericranium may have contributed to local weakening of tissues and facilitated transcalvarial invasion. While an uncommon occurrence, both benign and malignant cylindromas have the capacity to invade bone, particularly in patients with the familial syndrome.

Hereditary central nervous tumor syndromes are a varied group of conditions that include neurofibromatosis type 1 and 2, tuberous sclerosis, Von Hippel-Lindau disease, and Cowden, Turcot, and Gorlin syndromes. The responsible genes have been identified in most of these disorders. These genes typically act as tumor suppressor genes, maintain normal cellular function and homeostasis, and regulate cell growth and differentiation. Familial central nervous system tumors are mostly inherited as autosomal dominant traits and involve germline mutations. Neoplastic development occurs when a somatic mutation inactivates the second allele. These patients also present unique challenges for their management. This review highlights the clinical manifestations, molecular genetics, pathophysiology, and current treatment options of these disorders with a focus on neuro-oncologic manifestations of the diseases.

Cancer-associated genodermatoses are a group of genetic disorders inherited in an autosomal-dominant fashion in which unique cutaneous findings are a reliable marker for the risk of developing internal malignancies. The historical, clinical and dermatopathological aspects of basal cell nevus syndrome, Muir-Torre syndrome, Cowden syndrome, Carney complex and Birt-Hogg-Dubé syndrome are reviewed in a personal and informal fashion. The latest advances in the molecular genetics of the disorders are also summarized.

Genetic cancer predisposition syndromes have been crucial to the identification of genes and pathways involved in carcinogenesis. Constitutional gene mutations segregating with distinctive cancer phenotypes provide unequivocal evidence of a gene's causal role in cancer. This type of evidence has been central in proving that oncogenes and tumor suppressor genes can cause human cancers, but has been lacking for genes implicated in generating aneuploidy. However, recently we identified mutations in the mitotic checkpoint gene BUB1B in an autosomal recessive condition characterized by mosaic aneuploidies and childhood cancers. This finding strongly suggests that aneuploidy is causally related to cancer development.

Cancer cells have aberrant patterns of DNA methylation including hypermethylation of gene promoter CpG islands and global demethylation of the genome. Genes that cause familial cancer, as well as other genes, can be silenced by promoter hypermethylation in sporadic tumors, but the methylation of these genes in tumors from kindreds with inherited cancer syndromes has not been well characterized. Here, we examine CpG island methylation of 10 genes (hMLH1, BRCA1, APC, LKB1, CDH1, p16(INK4a), p14(ARF), MGMT, GSTP1 and RARbeta2) and 5-methylcytosine DNA content, in inherited (n = 342) and non-inherited (n = 215) breast and colorectal cancers. Our results show that singly retained alleles of germline mutated genes are never hypermethylated in inherited tumors. However, this epigenetic change is a frequent second "hit", associated with the wild-type copy of these genes in inherited tumors where both alleles are retained. Global hypomethylation was similar between sporadic and hereditary cases, but distinct differences existed in patterns of methylation at non-familial genes. This study demonstrates that hereditary cancers "mimic" the DNA methylation patterns present in the sporadic tumors.