RESUMO
We report a series of four unrelated adults with Smith-Magenis syndrome (SMS) and concomitant features of Birt-Hogg-Dubé (BHD) syndrome based upon haploinsufficiency for FLCN and characteristic renal cell carcinomas and/or evidence of cutaneous fibrofolliculomas. Three of the cases constitute the first known association of histopathologically verified characteristic BHD-associated renal tumors in adults with SMS; the fourth was identified to have histologically confirmed skin fibrofolliculomas. Molecular analysis documented second-hit FLCN mutations in two of the three cases with confirmed BHD renal pathology. These cases suggest the need to expand management recommendations for SMS to include kidney cancer surveillance starting at 20 years of age, as per the screening recommendations for BHD syndrome.
Assuntos
Síndrome de Birt-Hogg-Dubé , Carcinoma de Células Renais , Neoplasias Renais , Neoplasias Cutâneas , Síndrome de Smith-Magenis , Adulto , Humanos , Síndrome de Birt-Hogg-Dubé/complicações , Síndrome de Birt-Hogg-Dubé/diagnóstico , Síndrome de Birt-Hogg-Dubé/genética , Síndrome de Smith-Magenis/complicações , Detecção Precoce de Câncer , Proteínas Proto-Oncogênicas/genética , Proteínas Supressoras de Tumor/genética , Neoplasias Renais/genética , Carcinoma de Células Renais/genética , Neoplasias Cutâneas/genéticaRESUMO
Von Hippel-Lindau (VHL) is a hereditary multisystem disorder caused by germline alterations in the VHL gene. VHL patients are at risk for benign as well as malignant lesions in multiple organs including kidney, adrenal, pancreas, the central nervous system, retina, endolymphatic sac of the ear, epididymis, and broad ligament. An estimated 30%-35% of all families with VHL inherit a germline deletion of one, two, or all three exons. In this study, we have extensively characterized germline deletions identified in patients from 71 VHL families managed at the National Cancer Institute, including 59 partial (PD) and 12 complete VHL deletions (CD). Deletions that ranged in size from 1.09 to 355 kb. Fifty-eight deletions (55 PD and 3 CD) have been mapped to the exact breakpoints. Ninety-five percent (55 of 58) of mapped deletions involve Alu repeats at both breakpoints. Several novel classes of deletions were identified in this cohort, including two cases that have complex rearrangements involving both deletion and inversion, two cases with inserted extra Alu-like sequences, six cases that involve breakpoints in Alu repeats situated in opposite orientations, and a "hotspot" PD of Exon 3 observed in 12 families that involves the same pair of Alu repeats.
Assuntos
Doença de von Hippel-Lindau , Feminino , Deleção de Genes , Células Germinativas , Mutação em Linhagem Germinativa , Humanos , Masculino , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Doença de von Hippel-Lindau/genéticaRESUMO
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a familial cancer syndrome associated with the development of cutaneous and uterine leiomyomas, and an aggressive form of type 2 papillary kidney cancer. HLRCC is characterized by germline mutation of the FH gene. This study evaluated the prevalence and clinical phenotype of FH deletions in HLRCC patients. Patients with phenotypic manifestations consistent with HLRCC who lacked detectable germline FH intragenic mutations were investigated for FH deletion. A series of 28 patients from 13 families were evaluated using a combination of a comparative genomic hybridization (CGH) array and/or CLIA-approved FH deletion/duplication analyses. Thirteen distinct germline deletions were identified in the 13 UOB families, including 11 complete FH gene deletions and 2 partial FH gene deletions. The size of eight evaluated complete FH deletions varied from â¼4.74 Mb to 249 kb, with all deletions resulting in additional gene losses. Two partial FH gene deletions were identified, with one resulting in loss of exon 1 and the upstream region of the FH gene only. Kidney cancer was diagnosed in 9 (32%) of 28 patients and 7 (54%) of 13 families possessing either complete or partial FH deletions. Cutaneous and uterine leiomyomas were observed at similar rates to those in FH point mutation families. Complete or partial FH gene alterations in HLRCC families are associated with all of the canonical HLRCC manifestations, including type 2 papillary kidney cancer and should be screened for in any patient at-risk for this disorder.
Assuntos
Carcinoma de Células Renais/genética , Fumarato Hidratase/genética , Deleção de Genes , Genoma , Mutação em Linhagem Germinativa , Neoplasias Renais/genética , Leiomiomatose/genética , Fenótipo , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , LinhagemRESUMO
PURPOSE: Cowden syndrome is a hereditary cancer syndrome associated with a germline mutation in PTEN. Patients are predisposed to multiple malignancies including renal cell carcinoma. MATERIALS AND METHODS: Patients with Cowden syndrome were evaluated as part of a clinical protocol. Those with a history of renal cell carcinoma underwent review of clinical features, tumor characteristics and family history. Renal tumors were evaluated for loss of heterozygosity. RESULTS: Among 24 patients with Cowden syndrome 4 were identified with renal cell carcinoma (16.7%). Three patients had solitary tumors, 2 with papillary type I histology and 1 with clear cell histology. The fourth patient had bilateral, synchronous chromophobe tumors. No patients had a prior family history of renal cell carcinoma. All patients with renal cell carcinoma had dermatologic manifestations of Cowden syndrome and had macrocephaly. Loss of heterozygosity at the PTEN mutation was identified in 4 tumors (80%). No genotype-phenotype association was found, as the same mutation was identified in different renal cell carcinoma histologies. CONCLUSIONS: Renal cell carcinoma is an underappreciated feature of Cowden syndrome. As most patients lack a prior family history or a distinctive renal cell carcinoma histology, recognition of the associated nonrenal features should target referral for genetic counseling. PTEN loss of heterozygosity is common in Cowden syndrome renal tumors. Because loss of PTEN can activate mTOR and mTOR inhibitors are Food and Drug Administration approved to treat renal cell carcinoma, these agents have clinical potential in renal cell carcinoma associated with Cowden syndrome.
Assuntos
Carcinoma de Células Renais/genética , Síndrome do Hamartoma Múltiplo/genética , Neoplasias Renais/genética , Mutação , PTEN Fosfo-Hidrolase/genética , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , LinhagemRESUMO
OBJECTIVE: To describe a family in which 3 members presented with mixed epithelial tumor of the kidney (MEST) and were found to possess a germline mutation in CDC73, a gene which is associated with hyperparathyroidism-jaw tumor syndrome (HPT-JT). MATERIALS AND METHODS: Blood and tumor DNA from three family members who presented with a primary diagnosis of MEST was subjected to targeted gene sequencing to identify potential genetic components. RESULTS: A germline start codon mutation (p.M1I) in CDC73 was identified in all 3 family members who presented with MEST and 2 tumors from 1 patient demonstrated somatic copy-neutral loss of heterozygosity. Patients presented with no evidence of hyperparathyroidism or jaw tumors, but both female patients had hysterectomies at an early age due to excessive bleeding and numerous fibroids, which is common in HPT-JT. A germline p.M1I mutation has been previously reported in a family with clinical features of HPT-JT. CONCLUSION: Patients with MEST may be at risk for HPT-JT and CDC73 germline mutation testing of MEST patients should be considered.
Assuntos
Mutação em Linhagem Germinativa , Neoplasias Renais/genética , Tumor Misto Maligno/genética , Proteínas Supressoras de Tumor/genética , Adenoma/genética , Idoso , Feminino , Fibroma/genética , Humanos , Hiperparatireoidismo/genética , Neoplasias Maxilomandibulares/genética , Masculino , Pessoa de Meia-Idade , LinhagemRESUMO
IMPORTANCE: Cutaneous leiomyomas can be associated with severe paroxysmal pain in which nerve conduction may have a key role. Medical management of painful cutaneous leiomyomas is generally unsatisfactory. OBJECTIVE: To assess the efficacy of intralesional botulinum toxin A in the management of pain associated with cutaneous leiomyomas. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled pilot study conducted from January 5, 2009, to March 27, 2014. The setting was a single-center study at the National Institutes of Health among participants 18 years or older with cutaneous leiomyomas characterized by pain at least once weekly and pain of at least 4 on a pain scale ranging from 0 to 10. INTERVENTIONS: Eighteen participants were randomized to receive intralesional botulinum toxin A (5 U per 1 cm2) or equivalent volumes of intralesional saline placebo. MAIN OUTCOMES AND MEASURES: The primary outcomes were the differences in average lesional pain assessed by the Brief Pain Inventory and visual analog scale before and after ice provocation over a 4-week period. RESULTS: No significant difference in average lesional pain was observed between the study arms. Decreased pain was reported in the botulinum toxin vs placebo arms by visual analog scale scores before ice provocation (median, 0.00; range, -3.30 to 0.70 for botulinum toxin and median, 0.40; range, -1.30 to 1.50 for placebo; P = .06); however, this finding was nonsignificant. No significant difference was observed in change in pain after ice provocation. A significant difference was seen between the arms in skin-related quality of life by total Dermatology Life Quality Index (median, -4.00; range, -8.00 to 2.00 for botulinum toxin and median, 0.00; range, -1.00 to 4.00 for placebo; P = .007) and with the specific skin pain-related question on the Dermatology Life Quality Index (median, -1.00; range, -2.00 to 1.00 for botulinum toxin and median, 0.00; range, -1.00 to 0.00 for placebo; P = .048). No significant difference was found in pain as ascertained by Patient Global Impression of Change at week 4. No serious adverse events related to botulinum toxin use were observed. CONCLUSIONS AND RELEVANCE: The use of botulinum toxin to treat painful cutaneous leiomyomas was associated with improved quality of life and with a trend toward improved pain at rest. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00971620.
Assuntos
Toxinas Botulínicas Tipo A/administração & dosagem , Leiomioma/complicações , Fármacos Neuromusculares/administração & dosagem , Dor/tratamento farmacológico , Neoplasias Cutâneas/complicações , Adulto , Idoso , Toxinas Botulínicas Tipo A/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Injeções Intralesionais , Leiomioma/patologia , Masculino , Pessoa de Meia-Idade , Fármacos Neuromusculares/efeitos adversos , Dor/etiologia , Medição da Dor , Projetos Piloto , Qualidade de Vida , Neoplasias Cutâneas/patologia , Resultado do Tratamento , Adulto JovemRESUMO
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant condition in which susceptible individuals are at risk for the development of cutaneous leiomyomas, early onset multiple uterine leiomyomas and an aggressive form of type 2 papillary renal cell cancer. HLRCC is caused by germline mutations in the fumarate hydratase (FH) gene which inactivate the enzyme and alters the function of the tricarboxylic acid (Krebs) cycle. Issues surrounding surveillance and treatment for HLRCC-associated renal cell cancer were considered as part of a recent international symposium on HLRCC. The management protocol proposed in this article is based on a literature review and a consensus meeting. The lifetime renal cancer risk for FH mutation carriers is estimated to be 15 %. In view of the potential for early onset of RCC in HLRCC, periodic renal imaging and, when available, predictive testing for a FH mutation is recommended from 8 to 10 years of age. However, the small risk of renal cell cancer in the 10-20 years age range and the potential drawbacks of screening should be carefully discussed on an individual basis. Surveillance preferably consists of annual abdominal MRI. Treatment of renal tumours should be prompt and generally consist of wide-margin surgical excision and consideration of retroperitoneal lymph node dissection. The choice for systemic 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 of families.
Assuntos
Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/genética , Detecção Precoce de Câncer/métodos , Neoplasias Renais/diagnóstico , Neoplasias Renais/genética , Feminino , Humanos , Leiomiomatose/complicações , Masculino , Pessoa de Meia-Idade , Síndromes Neoplásicas Hereditárias , Neoplasias Cutâneas/complicações , Neoplasias Uterinas/complicaçõesRESUMO
Clinicians and scientists understand the medical implications of BHD; however, what may not be apparent to clinicians and scientists are the psycho-social aspects of living with BHD. Although medical reality differs among people who have Birt-Hogg-Dubé, they often share multiple non-medical ramifications ranging from economic and physical insecurity to interruptions in familial communication patterns and relationships. Physicians cognizant of the psycho-social aspects of having BHD are in a position to offer enhanced and meaningful non-medical interventions and care to their patient with BHD.
Assuntos
Síndrome de Birt-Hogg-Dubé/psicologia , Pacientes/psicologia , Qualidade de Vida/psicologia , Síndrome de Birt-Hogg-Dubé/complicações , Humanos , MédicosRESUMO
In addition to the associated cutaneous and pulmonary manifestations, individuals with the Birt-Hogg-Dubé (BHD) syndrome have an increased risk of developing kidney cancer, which is often bilateral and multifocal. The risk of developing a renal tumor in this population does not decrease with age and therefore warrants a lifelong screening approach. We recommend abdominal imaging every 36 months in individuals without renal lesions at initial screening. Once renal tumors are identified, they should be followed with interval imaging studies until the largest tumor reaches 3 cm in maximal diameter, at which point nephron-sparing surgery should be ideally pursued. While the histology of renal tumors can vary in the BHD syndrome, most tumors possess a relatively indolent natural history and do not require adjuvant therapy if resected when localized to the kidney. With this approach, the vast majority of patients will achieve a curative oncologic outcome and avoid the medical sequelae of chronic renal insufficiency that could otherwise result from total nephrectomy.