Prevalence of respiratory epithelial adenomatoid hamartomas (REAH) associated with nasal polyposis: an epidemiological study - how to diagnose.

OBJECTIVES: To highlight the prevalence of respiratory epithelial adenomatoid hamartomas in the olfactory cleft of patients with nasal polyposis. To demonstrate characteristics indicative of hamartoma on the CT scans of paranasal sinuses during surgery and in histopathological exams. METHODS: Cross-sectional study carried out in Hospital das Clínicas da UFMG and Núcleo de Otorrino BH. We performed 114 nasal endoscopic surgeries for polyposis, between February 2015 and November 2019. We assessed the olfactory cleft width in all preoperative CT scans. Upon seeing an indication of hamartoma on the CT scan, we took a tissue sample from the olfactory cleft during the surgery and sent for histopathological exam. We referred the samples to a pathologist experienced in the anatomopathological diagnosis of respiratory epithelial adenomatoid hamartomas. RESULTS: Of the 114 patients with polyposis, 54 (47.4%) had olfactory cleft enlargement and, 100% of them had tissue with a dense and hardened polypoid aspect, with a slight cerebriform appearance in this region during the surgery. Histology confirmed a respiratory epithelial adenomatoid hamartoma. CONCLUSION: This observation suggests that the presence of hamartomas in polyposis is common, but underdiagnosed. LEVEL OF EVIDENCE: Step 3 (Level 3).

Gelastic seizures: a retrospective study in five tertiary hospital centres.

This study aimed to characterize, clinically and neurophysiologically, a series of patients with gelastic seizures (GS), including both adults and children. We retrospectively collected patients with GS from epilepsy clinics of five tertiary hospital centres within a single country. Patients were selected through relatives'/caregivers' descriptions, home video and/or video-EEG monitoring. GS were identified through ictal semiology. Thirty-five patients were enrolled; 62.9% had initial GS in infancy, 14.3% in adolescence and 22.8% at adult age. Twenty-six had abnormal MRI: eight presented with hypothalamic hamartoma (HH) and 16 non-HH lesions that included different structural aetiologies and genetic, metabolic and immune aetiologies. All patients with HH had their first GS in infancy or adolescence. For the remaining aetiologies, GS started in infancy in 59.3%, in adolescence in 11.1% and at adult age in 29.6%. Video-EEG data was available for analysis in 11 patients, including seven patients with a non-HH MRI lesion. The ictal onset topography on scalp video-EEG was usually concordant with the MRI lesion (in 6/7 patients) and the most frequent ictal onset was fronto-temporal. In two patients, both video-EEG and MRI suggested a parietal and occipital epileptogenic zone. Aetiologies and patterns of affected topography unrelated to HH are common in patients with GS, and all age groups may manifest with this type of ictal semiology. This ictal manifestation has no lateralizing value and, despite a clear preponderance for hypothalamic, frontal and temporal lobe origins, other brain areas, namely the parietal and occipital lobes, should be considered.

Hypothalamic hamartomas in adulthood: Clinical spectrum and treatment outcome-A unicenter experience.

INTRODUCTION: Clinical manifestations of the hypothalamic hamartoma-epilepsy syndrome (HH-ES) in adulthood are variable. Efficacy of therapeutic options and outcome are diverse. METHODS: Retrospective study of adult patients diagnosed with a HH in magnetic resonance imaging and epilepsy who attended our tertiary Epilepsy Unit between 2003 and 2018. We report the clinical and electroencephalographic features of a series of adult patients with HH and related epilepsy seen in our center together with the treatments and seizure outcome. RESULTS: We describe a series of eight patients. Five males (62.5%), median age at evaluation was 28.5 years (IQR: 15.5). Clinical manifestations included focal with preserved and impaired awareness emotional seizures (gelastic seizures [GS]) in six patients (75%), focal tonic, atonic with impaired awareness and focal to bilateral tonic-clonic seizures. Mild GS were the only symptom in one patient. Three patients (37.5%) had endocrinological disturbances such as obesity and hypothyroidism. Fifty percent of the patients showed psychiatric comorbidity such as anxiety disorder and aggressiveness, and two patients had psychomotor delay. Seven patients (87.7%) had drug-resistant seizures and three of them were treated with radiosurgery. Out of the treated group, only one (33.3%) became seizure-free 2 years after surgery but developed psychiatric problems. The other two patients had an Engel IV outcome and received a vagal nerve stimulation (VNS) implant. VNS did not lead to changes either in intensity nor in seizure frequency. CONCLUSIONS: Hypothalamic hamartoma-epilepsy syndrome clinical manifestations in adult patients are as variable as at pediatric age. Outcome of therapeutic options such as radiosurgery or VNS may be poorer at this stage.

Neuropsychiatric profile of paediatric hypothalamic hamartoma: systematic review and case series.

AIM: To evaluate neuropsychiatric comorbidities in children and adolescents with hypothalamic hamartoma. METHOD: We retrospectively analysed case notes for all individuals with hypothalamic hamartoma referred to Great Ormond Street Hospital, London, between 2000 and 2016. In addition, a systematic review aiming to identify all previous paediatric case series was performed. Psychiatric symptoms, demographics, physical comorbidities, and cognitive functioning were recorded for all cases where possible. Analyses were performed to determine which factors were associated with psychopathology and potential mechanisms investigated. RESULTS: Forty-six cases were included in the case series (28 males, 18 females; mean age at assessment 11y 8mo [1y 11mo-16y 11mo, SD 4y 0mo]). Twenty-nine papers representing data from 264 cases met inclusion criteria for the systematic review. Overall, at least 50% of cases presented with psychopathology. Epilepsy, intellectual disability, and male sex were associated with externalizing disorders (attention-deficit/hyperactivity disorder, conduct and oppositional defiance disorders, and rage attacks). Intellectual disability mediated the effects of epilepsy on externalizing psychopathology. No factors were associated with internalizing disorders (anxiety and depressive disorders), although these were not well reported. INTERPRETATION: Psychiatric comorbidities are highly prevalent in the presentation of paediatric hypothalamic hamartoma. The aetiology of psychopathology comprises a range of interacting biological and psychosocial factors with particular influence from epilepsy. Further research is required to achieve an evidence base for treatment. WHAT THIS PAPER ADDS: Over half of children with hypothalamic hamartoma present with psychiatric comorbidity. Externalizing and internalizing disorders are present in approximately 60% and 30% of children with hypothalamic hamartomas respectively. Epilepsy and male sex are associated with externalizing psychopathology. Intellectual disability mediates the association between epilepsy and externalizing symptoms. No clear associations are evident for internalizing disorders or precocious puberty.

PERFIL NEUROPSIQUIÁTRICO DEL HAMARTOMA HIPOTALÁMICO EN PEDIATRÍA: REVISIÓN SISTEMÁTICA Y SERIE DE CASOS: OBJETIVO: Evaluar las comorbilidades neuropsiquiátricas en niños y adolescentes con hamartoma hipotalámico. MÉTODO: En este estudio analizamos retrospectivamente las notas de los casos de todos los individuos con hamartoma hipotalámicos referidos al Great Ormond Street Hospital, London, entre el 2000 y 2016. Además, realizamos una revisión bibliográfica sistemática dirigida a identificar la serie de casos pediátricos. Síntomas psiquiátricos, demográfico, comorbilidades físicas y funcionamiento cognitivo fueron recolectados en todos los casos posibles.Se efectuaron análisis para determinar qué factores se asociaron con psicopatología y se investigaron mecanismos potenciales. RESULTADOS: En total 46 casos fueron incluidos en la serie de casos (28 masculinos, 18 femeninos, media de edad a la evaluación 11 años y 8 meses, DS 4 años y 0 mes). La revisión bibliográfica identifico 29 artículos describiendo 264 casos que reunieron criterios de inclusión para la extracción de datos. En total, al menos 50% de casos presentaban psicopatología. Epilepsia, discapacidad intelectual, y sexo masculino fueron asociados con desórdenes externos (déficit de atención con hiperactividad, desórdenes conductuales y oposicional desafiante, ataques de furia). Ningún factor fue asociado con la internalización de desórdenes neuropsiquiátricos (desórdenes de ansiedad y depresión), aunque éstos no fueron bien reportados. INTERPRETACIÓN: Las comorbilidades psiquiátricas son altamente prevalentes en la presentación del hamartoma hipotalámico pediátrico. La etiología de la psicopatología comprende un rango de interacciones biológicas y factores psicosociales con particular influencia de la epilepsia. Se requiere más información de investigación para reunir evidencia científica que guie el tratamiento.

PERFIL NEUROPSIQUIÁTRICO DO HAMARTOMA HIPOTALÂMICO PEDIÁTRICO: REVISÃO SISTEMÁTICA E SÉRIE DE CASOS: OBJETIVO: Avaliar comorbidades neuropsiquiátricas em crianças e adolescentes com hamartoma hipotalâmico. MÉTODO: Nós analisamos retrospectivamente os registros de casos de todos os indivíduos encaminhados para o Hospital Great Ormond Street, Londres, entre 2000 e 2016. Além disso, uma revisão sistemática visando identificar todos os casos pediátricos prévios foi realizada. Sintomas psiquiátricos, dados demográficos, comorbidades físicas, e funcionamento cognitivo foram registrados para todos os casos em que foi possível. Análises foram realizadas para determinar quais fatores se associavam com psicopatologia e potenciais mecanismos foram investigados. RESULTADOS: Quarenta e seis casos foram incluídos na série de casos (28 do sexo masculino, 18 do sexo feminino; média de idade na avaliação 11a 8m (1a 11m-16a 11m, DP 4a 0m). Vinte e nove artigos representando dados de 264 casos atenderam aos critérios de inclusão para a revisão sistemática. No total, pelo menos 50% dos casos apresentaram psicopatologia. Epilepsia, deficiência intelectual, e sexo masculino eram associados com desordens externalizantes (transtorno de déficit de atenção e hiperatividade, transtornos de conduta e de desafio oposicional, e ataques de raiva). A deficiência intelectual mediou os efeitos da epilepsia e da psicopatologia externalizante. Nenhum fator foi associado com transtornos internalizantes (ansiedade e transtornos depressivos), embora estes não tenham sido bem reportados. INTERPRETAÇÃO: Comorbidades psiquiátricas são altamente prevalentes na apresentação do hamartoma hipotalâmico pediátrico. A etiologia da psicopatologia envolve uma variedade de fatores biológicos e psicossociais que interagem, com particular influência da epilepsia. Mais pesquisas são necessárias para se atingir uma base de evidências para o tratamento.

Syringocystadenoma papilliferum arising in a naevus sebaceous.

Naevus sebaceus is a cutaneous hamartoma with the potential of developing into benign or malignant neoplasms. Syringocystadenoma papilliferum (SCAP) have been reported to originate from naevus sebaceus. SCAP is a rare, benign adnexal skin tumour of apocrine or eccrine type of differentiation which typically presents as a nodule or a plaque on the scalp or face. We report a case of syringocystadenoma papilliferum arising in an undiagnosed pre-existing naevus sebaceus in a 56-year-old female.

Syndromic sebaceous nevus: current findings.

BACKGROUND: Sebaceous nevus is a congenital malformation of the skin that usually occurs on the scalp or face. Syndromic forms do rarely exist with associated cerebral and ocular malformations. The skin lesions are pale at birth and become irregular by puberty. In the adult patient, tumors (usually benign) develop from sebaceous nevus. Their surgical excision during childhood can give a better result in terms of the definitive scar. OBJECTIVES: The aim of this study is to analyze our cases of syndromic sebaceous hamartoma, perform a review of the existing literature, and propose guidelines for the therapeutic plan. METHODS: This is a retrospective study reviewing the cases of syndromic sebaceous nevus treated in the Department of Orthopedic Plastic Pediatric Surgery in Montpellier, France, and the Department of Pediatric Surgery in Lausanne, Switzerland, between 1994 and 2016. RESULTS: The files of six patients with syndromic sebaceous nevus were analyzed. The average age at the first consultation was 4 months. The location was craniofacial in all cases. Cerebral radiological imaging was performed on all patients; two showed abnormal findings. Four patients underwent ophthalmic examination, which all revealed abnormalities. Three patients had other associated malformations. Three patients presented with epilepsy or learning difficulties in the course of follow-up. CONCLUSION: All patients presenting with extensive sebaceous nevus of the craniofacial region should benefit from cerebral imagery and ophthalmic examination since there is a very high probability of associated abnormalities. The developmental problems encountered could not be definitively associated with the skin malformations.

Psychiatric comorbidity with hypothalamic hamartoma: Systematic review for predictive clinical features.

OBJECTIVE: We conducted a systematic review of the English-language literature to identify clinical features associated with a higher risk of psychiatric symptoms (aggression and rage behaviors) in patients with hypothalamic hamartoma (HH) and epilepsy. METHODS: Two publicly-accessible databases (PubMed and Cochrane Library) were searched for Hypothalamic Hamartoma AND Epilepsy. We identified peer-reviewed original research publications (case reports or clinical series; N=19) in which clinical data was provided on an individual basis. Subjects were cohorted into those with (N=51) and without (N=68) behavioral aggression. Multiple clinical features were collated and subjected to univariate analysis to determine possible differences between these two cohorts. RESULTS: The presence of aggression significantly correlated with 1) male gender, 2) younger age at time of first seizure onset, 3) the presence of intellectual disability, and 4) the presence of multiple seizure types (versus gelastic seizures only). For those patients undergoing surgical treatment, aggression also correlated with younger age at the time of surgical intervention. CONCLUSION: Possible predictive clinical features for the presence of aggression and rage behaviors in patients with hypothalamic hamartoma and epilepsy are identified. These results may contribute to the complex treatment decisions that are unique to this population.

Chronic Obstructive Pulmonary Disease Mismatch: A Case of Tracheal Hamartoma.

OBJECTIVE: To demonstrate the diagnostic challenge of tracheal hamartoma in a patient with chronic obstructive pulmonary disease (COPD). CLINICAL PRESENTATION AND INTERVENTION: A 65-year-old man with COPD was admitted with sudden onset of asphyxia attacks related to the position of his body. Computerized tomography (CT) of the neck showed a soft tissue mass with calcification, which occluded more than two-thirds of the proximal part of the trachea. The tumor was completely removed, and histopathology confirmed hamartoma. CONCLUSION: This case report showed the detection of a primary tracheal tumor on CT. This finding enabled the correct diagnosis and led to appropriate treatment in the form of surgery.

Hair and Scalp Disorders in a Tuscan Pediatric Dermatological Outpatient Clinic: A Clinical and Epidemiological Evaluation.

OBJECTIVES: The aim of this study was to evaluate the clinical and epidemiological profile of hair and scalp disorders in children referred to the Pediatric Dermatology Outpatient Clinic. MATERIALS AND METHODS: We performed a retrospective study of children with hair loss problems or scalp diseases who turned to the Pediatric Dermatology Service, Anna Meyer Pediatric Hospital, Florence, Italy, from January 1, 2009, to December 31, 2009. Demographics, personal and familial medical history, laboratory tests, clinical examination, final diagnosis and therapeutic interventions were obtained from the manual chart review. RESULTS: Of the 2,640 children who had access to the Pediatric Dermatology Service, 190 (7.19%) had a hair or scalp disorder. Among the 190 children, 60 (31.57%) presented with nonscarring alopecia, 56 (29.47%) had benign neoplasias, hamartomas or vascular malformations of the scalp, 51 (26.84%) had scalp inflammatory diseases, 14 (7.36%) had scarring alopecia, 5 (2.63%) had infections and 2 (1.05%) had infestation of the scalp. A case of constitutional hypertrichosis (0.52%) and also a case (0.52%) of lamellar ichthyosis were diagnosed. CONCLUSIONS: Our results underline that hair and scalp diseases represent an important percentage of admittances to a dermatological pediatric outpatient clinic. The variety and complexity of the diseases observed in this study included diseases commonly found also in adulthood.

[Head and neck hamartomas: 10 years of experience at the Charité--University Medical Center Berlin]. / Hamartome im Kopf-Hals-Bereich: 10 Jahre Erfahrung an der Charité--Universitätsmedizin Berlin.

BACKGROUND: Head and neck tumors are rare entities in neonates. Hamartomas are benign congenital neoplasms. To date, there is a lack of sufficient epidemiological data concerning hamartomas in the field of otorhinolaryngology. MATERIALS AND METHODS: We retrospectively analyzed experiences at the Charité over the past 10 years in an ICD-10-based manner. Our otorhinolaryngology department maintains close cooperation with the level 1 perinatal center on our campus. RESULTS: The authors identified 3 patients suffering from fibrous hamartomas. This corresponds to an incidence of 2-3/30,000 newborns. The clinical aspects and courses are described in detail. Experiences with the management of hamartomas obstructing the upper aerodigestive tract are described. CONCLUSION: Head and neck hamartomas are very rare malformations. They possess the ability to cause otorhinolaryngological emergencies in newborns. Interdisciplinary management and histological assessment are mandatory. Anmerkung.

[Evolution of ideas and techniques, and future prospects in epilepsy surgery]. / Évolution des idées et des techniques, et perspectives d'avenir en chirurgie de l'épilepsie.

INTRODUCTION: The aim of this article was to review and evaluate the published literature related to the outcome of epilepsy surgery, while placing it in an historical perspective, and to describe the future prospects in this field. STATE OF ART: Temporal lobe surgery achieves seizure freedom in about 70% of cases. Seizure outcome is similar in the pediatric population. Extratemporal resections impart good results to 40% to 60% of patients, with a better prognosis in the case of frontal lobe surgery. Pediatric hemispherotomy leads to seizure control in about 80% of children. Radiosurgery used as a treatment for temporal mesial epilepsy has an outcome quite similar to that obtained with surgical resection, but provides a neuropsychological advantage. Radiosurgery is also effective in 60% of children treated for seizures related to hypothalamic hamartoma. Regarding palliative surgery, callosotomy and multiple subpial transections show satisfactory outcomes in over 60% of cases. Neuromodulation techniques (vagus nerve stimulation and bilateral stimulation of the anterior nucleus of the thalamus) allow a 50% reduction of seizures in half of patients. PERSPECTIVES: Transcranial magnetic stimulation combined with electroencephalography seems a promising technique because of its diagnostic, prognostic and therapeutic applications. Transcranial ultrasound stimulation, which can reversibly control neuronal activity, is also under consideration. Concerning neuromodulation, trigeminal nerve stimulation may become an alternative to vagus nerve stimulation; while other targets of deep brain stimulation are being evaluated. Also, the possibility of coupling SEEG seizure focus detection with concomitant laser or radiofrequency focus destruction is under development. CONCLUSIONS: Constant evolution of epilepsy surgery has improved patient outcomes over time. Current research and development axes suggest the continuation of this trend and a reduction of the invasiveness of surgical procedures.

Predictors of respiratory epithelial adenomatoid hamartomas of the olfactory clefts in patients with nasal polyposis.

OBJECTIVES/HYPOTHESIS: To look for predictors of respiratory epithelial adenomatoid hamartomas (REAH) development in patients operated for nasal polyposis (NP) by adjusting on confounding factors. STUDY DESIGN: Prospective study. METHODS: One hundred and six patients with NP, endoscopically operated between September 2009 and March 2012 on the ethmoidal labyrinths and olfactory clefts, were enrolled in this study. Clinical data was collected 1 day prior to surgery by using a standard grid without knowledge of any histological features. Patients were then divided into two groups based on operative and pathological reports: with and without REAH in the olfactory cleft (REAH-OC). The multivariate logistic regression model was used to assess independent factors linked to the presence of REAH-OC in patients with NP. RESULTS: The mean duration of NP disease in patients with REAH-OC was about 13.95 ± 10.8 years versus 5.7 ± 5.6 years in patients without REAH-OC (P < 0.0001). Seventy-four percent of patients with REAH-OC had undergone one or more NP-related surgeries in their lifetime, in contrast with 49.21% of patients without REAH-OC (P = 0.009). According to the multivariate logistic regression analysis, those patients experiencing NP ≥ 10 years (OR 4.0, 95% CI 1.304-12.062, P = 0.015) and those with asthma (OR 2.5, 95% CI 1.004-6.29, P < 0.05) were at an increased risk of developing REAH-OC. CONCLUSION: The development of REAH in patients with NP appears as a specific disease of the mucosa of the OC, induced by a long-lasting and/or severe inflammation of the olfactory clefts. LEVEL OF EVIDENCE: 4.

Clinicopathological and EBV analysis of respiratory epithelial adenomatoid hamartoma.

BACKGROUND: To investigate the clinicopathological characteristics of respiratory epithelial adenomatoid hamartoma (REAH) in residents of Southern China and to study the correlation between REAH and Epstein-Barr virus (EBV). METHODS: Clinicopathological data of 53 cases of REAH were retrospectively analyzed. The immunoreactivity for CK 7, CK20, CEA, p53, and Ki-67, Alcian blue-periodic acid-Schiff (AB-PAS) staining and in situ hybridization for EBV-encoded RNA (EBER) were carried out. RESULTS: REAH lesions were covered with ciliated columnar epithelium and proliferation of subepithelial glands, which were positive for CK7, and negative for CK20, CEA, and p53. Goblet cell metaplasia was stained blue by AB-PAS. The frequency of EBER positive cases in REAH located in nasopharynx was 27.78%, compared with that in the nasal cavity (15.79%) and paranasal sinuses (12.50%), there were no statistical differences. CONCLUSIONS: REAH is an uncommon entity with distinctive morphologic features and EBV may have nothing to do with REAH. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here:http://www.diagnosticpathology.diagnomx.eu/vs/5875687401178748.

Lennox-Gastaut syndrome symptomatic to hypothalamic hamartoma: evolution and long-term outcome following surgery.

BACKGROUND: Lennox-Gastaut syndrome is a catastrophic childhood cryptogenic or symptomatic epilepsy. Hypothalamic hamartomas cause refractory epilepsy often consistent with Lennox-Gastaut syndrome. METHODS: Children with Lennox-Gastaut syndrome were defined by a triad of multiple generalized seizure types, slow spike-and-wave on EEG, and mental retardation. RESULTS: Twenty-one of 159 hypothalamic hamartoma patients (14%) met the diagnostic criteria of Lennox-Gastaut syndrome. The median age of patients at epilepsy onset was 0.9 years (range, birth to 9 years). Six of the 21 patients (28%) had preceding infantile spasms. All patients underwent different surgical approaches, including endoscopic, transcallosal, orbitozygomatic resections, and radiosurgery treatment. Five of the 21 (24%) were seizure free with an additional 9 (42%) having at least >90% seizure reduction. Only 1 patient was not effectively treated (<50% seizure reduction). Eighty-eight percent of parents reported improvement in behavioral functioning. Shorter duration of epilepsy prior to surgery was a significant predictor of surgical outcome. CONCLUSIONS: Patients with Lennox-Gastaut syndrome symptomatic to hypothalamic hamartomas have better postsurgical outcome due to other etiologies compared with cryptogenic and symptomatic Lennox-Gastaut syndrome patients. However, compared with overall hypothalamic hamartomas postsurgical outcomes, this cohort was less favorable. Earlier surgery may lead to better outcomes.

A study of multiple biliary hamartomas based on 1697 liver biopsies.

OBJECTIVE: Multiple biliary hamartomas (MBHs) are rare benign malformations of the intrahepatic bile ducts. There are only a handful of clinical studies based on large populations on the incidence of MBHs. MATERIALS AND METHODS: A series of 1697 consecutive liver needle biopsies was examined for the occurrence of MBHs. RESULTS: A total of six patients (0.35%, four men and two women, a 2 : 1 ratio) were confirmed by histology to have MBHs. Of the total of 1697 patients, 59 (3.5%) patients were younger than 18 years of age, 828 patients (48.8%) were between 18 and 38 years of age, and 810 patients (47.7%) were older than 38 years of age. Of the six MBHs patients, one was 17 years of age and the other five patients were older than 39 years of age. The median (range) age of the patients was 42 (17-63) years. Although nearly half (48.8%) of the biopsied patients were between 18 and 38 years of age, no MBH was found in this group. All MBHs patients were diagnosed with fibrosis/cirrhosis by initial ultrasound scanning; however, only two patients were confirmed to have cirrhosis by histological examination. Of those two patients with cirrhosis, one had concomitant congenital hepatic fibrosis and the other had concomitant cirrhotic hepatitis B. The latter patient developed hepatocellular carcinoma 1 year after biopsy. No kidney cysts were found in any of the six MBHs patients. MRI scanning was performed in four patients and the results were consistent with the histological diagnosis. CONCLUSION: MBHs are not common in patients who undergo liver biopsy and, in this study, the occurrence was higher in the older age group.

Multiple congenital melanocytic nevi and neurocutaneous melanosis are caused by postzygotic mutations in codon 61 of NRAS.

Congenital melanocytic nevi (CMN) can be associated with neurological abnormalities and an increased risk of melanoma. Mutations in NRAS, BRAF, and Tp53 have been described in individual CMN samples; however, their role in the pathogenesis of multiple CMN within the same subject and development of associated features has not been clear. We hypothesized that a single postzygotic mutation in NRAS could be responsible for multiple CMN in the same individual, as well as for melanocytic and nonmelanocytic central nervous system (CNS) lesions. From 15 patients, 55 samples with multiple CMN were sequenced after site-directed mutagenesis and enzymatic digestion of the wild-type allele. Oncogenic missense mutations in codon 61 of NRAS were found in affected neurological and cutaneous tissues of 12 out of 15 patients, but were absent from unaffected tissues and blood, consistent with NRAS mutation mosaicism. In 10 patients, the mutation was consistently c.181C>A, p.Q61K, and in 2 patients c.182A>G, p.Q61R. All 11 non-melanocytic and melanocytic CNS samples from 5 patients were mutation positive, despite NRAS rarely being reported as mutated in CNS tumors. Loss of heterozygosity was associated with the onset of melanoma in two cases, implying a multistep progression to malignancy. These results suggest that single postzygotic NRAS mutations are responsible for multiple CMN and associated neurological lesions in the majority of cases.

The presentation and clinical significance of sinonasal respiratory epithelial adenomatoid hamartoma (REAH).

BACKGROUND: Sinonasal respiratory epithelial adenomatoid hamartoma (REAH) is a benign glandular proliferation with ciliated epithelium. Little is known about REAH, with only a few published case reports appearing since its original description in 1995. Classically described as an isolated polypoid lesion arising from the nasal septum, more recent descriptions also suggest that REAH can occur among nasal polyps. We report the largest experience with REAH to date, and aim to better understand and characterize this unique entity. METHODS: In this case series, all cases of REAH diagnosed between 2006 and 2011 were reviewed. Clinical presentation, histologic and radiographic features, and operative findings were examined. RESULTS: There were 45 patients 19 females and 26 males, with a mean age of 55.9 years (range, 23-83). Most cases of REAH (33/45, 73%) were found in association with another pathologic process (sinonasal polyposis, adenoiditis, hereditary hemorrhagic telangiectasia [HHT], inverted papilloma [IP], or malignancy). Of these, REAH occurring among diffuse polyposis (79% of cases) represented the large majority. The average Harvard computed tomography (CT) stage for this cohort was 3.1. The other presentation of REAH (12/45, 27%) was an isolated sinonasal mass. In cases of isolated REAH, the majority of lesions (75%) were noted to be originating in the olfactory clefts. CONCLUSION: Isolated REAH, which may mimic a neoplasm, appears to be a different clinical entity than the more common form encountered in association with nasal polyps and inflammation. Further investigation into the etiology and clinical significance is needed.