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1.
Neuropathol Appl Neurobiol ; 50(2): e12970, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38504418

RESUMO

PTEN hamartoma tumour syndrome (PHTS) comprises different hereditary conditions caused by germline PTEN mutations, predisposing to the development of multiple hamartomas in many body tissues and also increasing the risk of some types of cancer. Cerebellar involvement in PHTS patients has been long known due to the development of a pathognomonic cerebellar hamartoma (known as dysplastic gangliocytoma of the cerebellum or Lhermitte-Duclos disease). Recently, a crucial role of the cerebellum has been highlighted in the pathogenesis of autism spectrum disorders, now recognised as a phenotype expressed in a variable percentage of PHTS children. In addition, rare PTEN variants are indeed identified in medulloblastoma as well, even if they are less frequent than other germline gene mutations. The importance of PTEN and its downstream signalling enzymatic pathways, PI3K/AKT/mTOR, has been studied at different levels in both human clinical settings and animal models, not only leading to a better understanding of the pathogenesis of different disorders but, most importantly, to identify potential targets for specific therapies. In particular, PTEN integrity makes an important contribution to the normal development of tissue architecture in the nervous system, including the cerebellum. Thus, in patients with PTEN germline mutations, the cerebellum is an affected organ that is increasingly recognised in different disorders, whereas, in animal models, cerebellar Pten loss causes a variety of functional and histological alterations. In this review, we summarise the range of cerebellar involvement observed in PHTS and its relationships with germline PTEN mutations, along with the phenotypes expressed by murine models with PTEN deficiency in cerebellar tissue.


Assuntos
Neoplasias Cerebelares , Síndrome do Hamartoma Múltiplo , Criança , Humanos , Animais , Camundongos , Mutação em Linhagem Germinativa , Fosfatidilinositol 3-Quinases , PTEN Fosfo-Hidrolase/genética , Cerebelo/patologia , Síndrome do Hamartoma Múltiplo/genética , Síndrome do Hamartoma Múltiplo/patologia , Fenótipo , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/patologia , Células Germinativas/patologia , Mutação
2.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 41(2): 230-233, 2024 Feb 10.
Artigo em Chinês | MEDLINE | ID: mdl-38311565

RESUMO

OBJECTIVE: To explore the genetic etiology of a child with Cowden syndrome 1 (CS1). METHODS: A child who had visited the Ningbo Women and Children's Hospital on August 26, 2022 was selected as the study subject. Clinical information of the child was collected. Genomic DNA was extracted from peripheral blood samples of the child and his family members and subjected to whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing. RESULTS: The child, a 13-year-old boy, had manifested with severe mental retardation, hyperactivity, autistic behavior, sparse and prominent teeth, macrocephaly, and skin freckles on the penis. His mother had presented with multiple papules, hamartomatous polyps, thyroid adenoma and macrocephaly. WES results revealed that the child has harbored a nonsense c.781C>T (p.Q261*) variant of the PTEN gene, which was inherited from his mother. Based on the guidelines from the American College of Medical Genetics and Genomics, the c.781C>T variant was classified as likely pathogenic (PVS1+PM2_Supporting). CONCLUSION: The c.781C>T variant of the PTEN gene probably underlay the pathogenesis in the child and his mother. Above finding has facilitated genetic counseling for this family.


Assuntos
Transtorno do Espectro Autista , Síndrome do Hamartoma Múltiplo , Megalencefalia , Adolescente , Humanos , Masculino , Síndrome do Hamartoma Múltiplo/genética , Mães , Mutação , Pele
3.
Medicine (Baltimore) ; 103(1): e36212, 2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-38181272

RESUMO

RATIONALE: Lhermitte-Duclos disease (LDD), or dysplastic cerebellar gangliocytoma (DCG), is a rare tumor originating from the cerebellar cortex. LDD is a benign neuroglial tumor with uncertain prognosis. Over 200 cases have been reported in the literature mostly in the form of case reports. Thus, we present a spectacular case of LDD with excessive calcification in a female septuagenarian. PATIENT CONCERNS: A 72-year-old female presented with progressive dizziness for 8 months and suffered a head and sacrococcygeal region injury 20 days prior to her admission in our neurosurgery department. DIAGNOSIS: Computed tomography scan showed a right nonspecific cerebellar mass with striated calcification. Magnetic resonance imaging revealed a right "tiger-striped" alteration of the cerebellar cortex. H&E staining revealed a low grade glial neural tumor which was consistent with the diagnosis of LDD or DCG. INTERVENTION: The lesion was total resected. OUTCOMES: The patient recovered well and the cerebellar dysfunctional symptoms subsided 3 months after the operation and 2 years follow-up revealed no recurrence of the lesion and no neurological deficits. LESION: We postulate that the calcification of LDD is age-related and the pathogenesis of disease often observed in young adulthood.


Assuntos
Neoplasias Encefálicas , Calcinose , Glioma , Síndrome do Hamartoma Múltiplo , Feminino , Humanos , Adulto Jovem , Adulto , Idoso , Síndrome do Hamartoma Múltiplo/complicações , Síndrome do Hamartoma Múltiplo/diagnóstico , Síndrome do Hamartoma Múltiplo/cirurgia , Calcinose/diagnóstico por imagem , Calcinose/cirurgia , Calcificação Fisiológica , Cerebelo
4.
Cell Rep Med ; 5(2): 101384, 2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38242121

RESUMO

Individuals with PTEN hamartoma tumor syndrome (PHTS) harbor pathogenic germline PTEN variants that confer a significantly increased lifetime risk of various organ-specific cancers including second primary malignant neoplasms (SMNs). Currently, there are no reliable biomarkers that can predict individual-level cancer risk. Despite the highly promising value of cell-free DNA (cfDNA) as a biomarker for underlying sporadic cancers, the utility of cfDNA in individuals with known cancer-associated germline variants and subclinical cancers remains poorly understood. We perform ultra-low-pass whole-genome sequencing (ULP-WGS) of cfDNA from plasma samples from patients with PHTS and cancer as well as those without cancer. Analysis of cfDNA reveals that patients with PHTS and SMNs have distinct cfDNA size distribution, aberrant genome-wide fragmentation, and differential fragment end motif frequencies. Our work provides evidence that cfDNA profiles may be used as a marker for SMN risk in patients with PHTS.


Assuntos
Ácidos Nucleicos Livres , Síndrome do Hamartoma Múltiplo , Neoplasias , Humanos , Síndrome do Hamartoma Múltiplo/diagnóstico , Síndrome do Hamartoma Múltiplo/genética , Síndrome do Hamartoma Múltiplo/complicações , PTEN Fosfo-Hidrolase/genética , Mutação em Linhagem Germinativa , Ácidos Nucleicos Livres/genética
5.
Am J Surg Pathol ; 48(2): 150-156, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-37899509

RESUMO

Storiform collagenoma is a rare mesenchymal skin tumor that is composed of thickened collagen bundles arranged in a characteristic storiform pattern with a relatively hypocellular CD34-positive spindle cell component. Storiform collagenoma is most often sporadic, but multiple lesions can occur in Cowden syndrome, which is characterized by germline alterations in PTEN (phosphatase and tensin homolog) on chromosome 10. Here, we investigated the molecular pathogenesis of storiform collagenoma using a targeted next-generation DNA sequencing platform, including 5 sporadic cases and one case associated with Cowden syndrome. Recurrent PTEN alterations were identified in all cases, with biallelic PTEN inactivation observed in the case associated with Cowden syndrome and one sporadic case. Unexpectedly, we also identified recurrent activating mutations in the platelet-derived growth factor receptor beta ( PDGFRB ) gene. This included a missense substitution in the D5 Ig-like domain of PDGFRB in the Cowden syndrome-associated case. In addition, we report missense alterations in the juxtamembrane domain of PDGFRB in 4 of 5 (80%) sporadic cases, including mutations that have been previously described in sporadic myofibroma and myopericytoma. Therefore, we confirm the neoplastic nature of storiform collagenoma, we expand the spectrum of reported PDGFRB alterations in mesenchymal tumors and we suggest a possible collaborative role for PTEN and PDGFRB in the pathogenesis of storiform collagenoma.


Assuntos
Fibroma , Síndrome do Hamartoma Múltiplo , Neoplasias Cutâneas , Humanos , Síndrome do Hamartoma Múltiplo/genética , Síndrome do Hamartoma Múltiplo/patologia , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Fibroma/patologia , Neoplasias Cutâneas/patologia , PTEN Fosfo-Hidrolase/genética , Mutação
6.
Oral Oncol ; 148: 106630, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37979468

RESUMO

Cowden Syndrome (CS) is a rare genetic disease caused by mutations in the PTEN tumor suppressor gene, often presenting a challenging diagnosis due to its diverse clinical manifestations. Although extensively linked to several types of cancer, the precise association between CS and oral malignancies, particularly squamous cell carcinoma (SCC), remains poorly understood. This report describes a unique case of late diagnosis of CS in a 53-year-old female patient who later developed SCC in the inferior alveolar ridge, even without exposure to classic risk factors. The need to increase awareness in the medical and dental communities about CS and its manifestations in the oral cavity is highlighted. Early recognition and management of conditions associated with CS have a significant impact on patients' quality of life. Encouraging the publication of similar cases is recommended to encourage detailed analyzes and investigations in order to better understand the possible association between the syndrome and the development of malignancies in the oral cavity.


Assuntos
Carcinoma de Células Escamosas , Síndrome do Hamartoma Múltiplo , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Feminino , Humanos , Pessoa de Meia-Idade , Síndrome do Hamartoma Múltiplo/complicações , Síndrome do Hamartoma Múltiplo/diagnóstico , Síndrome do Hamartoma Múltiplo/genética , Carcinoma de Células Escamosas/complicações , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/complicações , Qualidade de Vida , Neoplasias Bucais/complicações , Neoplasias Bucais/diagnóstico , PTEN Fosfo-Hidrolase/genética , Neoplasias de Cabeça e Pescoço/complicações
8.
J Cutan Pathol ; 51(4): 267-271, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38140907

RESUMO

Sclerotic fibroma (SF) is a rare subset of dermal fibromas that occurs sporadically or in association with Cowden syndrome (CS). We report a case of a patient with known CS and a solitary lesion on the scalp. Histologic examination demonstrated a well-circumscribed lesion with sclerotic dermis and a whorled collagen pattern, multinucleated giant cells, and dendritic spindle cells. Nuclear atypia or mitotic figures were not noted. The giant cells were negative for Melan-A, SOX-10, EMA, SOX-10, and factor XIIIa. These findings are consistent with a giant cell collagenoma (GCC). Despite possible overlap with SF, GCC has not been associated with CS. This makes our case unique and suggests that GCC should be included in the spectrum of CS-associated cutaneous lesions. The diagnosis of SF may lead to the identification of previously undiagnosed CS; accordingly, GCC, even when present as a solitary lesion, may indicate the need for further work-up and screening for CS.


Assuntos
Fibroma , Síndrome do Hamartoma Múltiplo , Nevo , Dermatopatias , Neoplasias Cutâneas , Humanos , Síndrome do Hamartoma Múltiplo/diagnóstico , Neoplasias Cutâneas/patologia , Fibroma/complicações , Fibroma/patologia , Dermatopatias/patologia , Células Gigantes/patologia
9.
Oncogene ; 42(50): 3698-3707, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37907589

RESUMO

Individuals with a PTEN germline mutation receive the molecular diagnosis of PTEN hamartoma tumor syndrome (PHTS). PHTS displays a complex spectrum of clinical phenotypes including harmartomas, predisposition to cancers, and autism spectrum disorder (ASD). Clear-cut genotype-phenotype correlations are yet to be established due to insufficient information on the PTEN function being impacted by mutations. To fill this knowledge gap, we compared functional impacts of two selected missense PTEN mutant alleles, G132D and M134R, each respectively being associated with distinct clinical phenotype, ASD or thyroid cancer without ASD using gene-edited human induced pluripotent stem cells (hiPSCs). In homozygous hiPSCs, PTEN expression was severely reduced by M134R mutation due to shortened protein half-life. G132D suppressed PTEN expression to a lesser extent than Μ134R mutation without altering protein half-life. When challenged with γ-irradiation, G132D heterozygous cells exited radiation-induced G2 arrest earlier than wildtype and M134R heterozygous hiPSCs despite the similar DNA damage levels as the latter two. Immunoblotting analyses suggested that γ-irradiation induced apoptosis in G132D heterozygous cells to lesser degrees than in the hiPSCs of other genotypes. These data suggest that ASD-associated G132D allele promotes genome instability by premature cell cycle reentry with incomplete DNA repair.


Assuntos
Transtorno do Espectro Autista , Síndrome do Hamartoma Múltiplo , Células-Tronco Pluripotentes Induzidas , Neoplasias da Glândula Tireoide , Humanos , Transtorno do Espectro Autista/genética , Mutação em Linhagem Germinativa , Células-Tronco Pluripotentes Induzidas/metabolismo , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fenótipo , Pontos de Checagem do Ciclo Celular
10.
Genes (Basel) ; 14(10)2023 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-37895258

RESUMO

Cowden syndrome (CS) is a rare disease that was first described in 1963 and later included in the large group of genodermatoses. It is the most common syndrome among the PTEN-associated hamartomatous tumor syndromes (PHTS). CS has an autosomal dominant inheritance pattern, with increased penetrance and variable expressivity, making early diagnosis difficult. Mutations in the PTEN gene (phosphatase and TENsin homolog) are involved in its pathogenesis, involving many organs and systems originating in the three embryonic layers (ectodermum, endodermum, and mesodermum). The consequence is the development of hamartomatous lesions in various organs (brain, intestines, thyroid, oropharyngeal cavity, colon, rectum, etc.). Multiple intestinal polyps are common in patients with CS, being identified in over 95% of patients undergoing colonoscopy. The authors describe the case of a patient who presented the first signs of the disease at 3 ½ years (tonsil polyp) but was diagnosed only at the age of 20 following a colonoscopy that revealed hundreds of intestinal polyps, suggesting further molecular testing. A heterozygous frameshift mutation was identified in the PTEN gene, classified as a potentially pathogenic variant (c.762del.p(Val255*)). The authors present this case to highlight the path taken by the patient from the first symptoms to the diagnosis and to emphasize the clinical aspects of this mutational variant that have still not been identified in other patients with this syndrome.


Assuntos
Síndrome do Hamartoma Múltiplo , Humanos , Síndrome do Hamartoma Múltiplo/diagnóstico , Síndrome do Hamartoma Múltiplo/genética , Mutação da Fase de Leitura , PTEN Fosfo-Hidrolase/genética , Mutação , Pólipos Intestinais/complicações
11.
Head Neck Pathol ; 17(4): 1071-1074, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37735289

RESUMO

A 56-year-old Brazilian woman sought dental care, presenting with multiple asymptomatic papillomatous lesions with a coalescent pattern and intermingled cobblestone-like clefts along the alveolar ridge and marginal and attached gingivae. Multiple whitish papules were also observed on the face, neck, and limbs. Incisional biopsies of these lesions were performed. Microscopically, the skin lesion revealed epithelial clear cells and intraepithelial keratinization with areas of orthokeratosis, while the gingival lesions showed a parakeratinized stratified squamous epithelium with collagenous connective tissue. These features were consistent with those of a trichilemmoma and fibroepithelial hyperplasia, respectively. This article illustrates a case of Cowden syndrome (CS), a rare multisystem genetic condition in which both cutaneous and mucosal tissues were affected. Fewer than 40 cases of CS with oral involvement affecting middle-aged adults have been documented hitherto.


Assuntos
Síndrome do Hamartoma Múltiplo , Papiloma , Dermatopatias , Neoplasias Cutâneas , Adulto , Pessoa de Meia-Idade , Feminino , Humanos , Síndrome do Hamartoma Múltiplo/complicações , Síndrome do Hamartoma Múltiplo/patologia , Neoplasias Cutâneas/patologia , Gengiva/patologia , PTEN Fosfo-Hidrolase/genética
13.
BMC Med Genomics ; 16(1): 166, 2023 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-37442961

RESUMO

BACKGROUND: PTEN hamartoma syndrome (PHTS) is an autosomal dominant disorder characterized by pathogenic variants in the tumor suppressor gene phosphatase and tensin homolog (PTEN). It is associated with an increased risk of muco-cutaneous features, hamartomatous tumors, and cancers. Mosaicism has been found in a few cases of patients with de novo PHTS, identified from blood samples. We report a PHTS patient with no variant identified from blood sample. Constitutional PTEN mosaicism was detected through sequencing of DNA from different tumoral and non-tumoral samples. CASE PRESENTATION: Our patient presented clinical Cowden syndrome at 56 years of age, with three major criteria (macrocephaly, Lhermitte Duclos disease, oral papillomatosis), and two minor criteria (structural thyroid lesions, esophageal glycogenic acanthosis). Deep sequencing of PTEN of blood leukocytes did not reveal any pathogenic variants. Exploration of tumoral (colonic ganglioneuroma, esophageal papilloma, diapneusia fibroids) and non-tumoral stomach tissues found the same PTEN pathogenic variant (NM_000314.4 c.389G > A; p.(Arg130Gln)), with an allelic frequency of 12 to 59%, confirming genomic mosaicism for Cowden syndrome. CONCLUSIONS: This case report, and review of the literature, suggests that systematic tumor analysis is essential for patients presenting PTEN hamartoma syndrome in the absence of any causal variant identified in blood leukocytes, despite deep sequencing. In 65 to 70% of cases of clinical Cowden syndrome, no pathogenic variant in the PTEN is observed in blood samples: mosaicism may explain a significant number of these patients. Tumor analysis would improve our knowledge of the frequency of de novo variations in this syndrome. Finally, patients with mosaicism for PTEN may not have a mild phenotype; medical care identical to that of heterozygous carriers should be offered.


Assuntos
Síndrome do Hamartoma Múltiplo , Humanos , Síndrome do Hamartoma Múltiplo/diagnóstico , Síndrome do Hamartoma Múltiplo/genética , Síndrome do Hamartoma Múltiplo/patologia , Mosaicismo , Pele/patologia , DNA , Análise de Sequência de DNA , PTEN Fosfo-Hidrolase/genética
14.
Endocr Relat Cancer ; 30(10)2023 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-37451289

RESUMO

Thyroid cancer surveillance (TCS) with ultrasound (US) is advised for PTEN hamartoma tumour syndrome (PHTS) patients due to increased thyroid cancer (TC) risk. However, data supporting TCS guidelines are scarce. We aimed to assess the detection and yield of annual TCS with US in adult PHTS patients without a TC history and to evaluate the impact of a reduced US interval on the TCS yield. A retrospective cohort study was conducted, including adult PHTS patients and medical record data between 2005 and 2021. The yield from annual TCS was compared with hypothetical biennial and triennial TCS after two initial US with annual interval by counting delayed detection of nodular growth, thyroid adenoma, and TC. During 279 follow-up years, 84 patients (median age 40 years) underwent 349 US. Thyroidectomy was performed in 6/84 (7%) patients, revealing a minimally invasive follicular TC in one patient aged 22 and a thyroid adenoma in two patients aged 21 and 53. Multiple thyroid nodules were diagnosed in 73/84 (87%) patients (median age 36 years). Nodular growth was detected in 9/56 (16%) patients, and its detection would have been delayed in 4-7% US rounds with biennial TCS, and in 2-6% US rounds with triennial TCS. US-based thyroiditis and indeterminate non-malignant lymph nodes were found in 8/74 (11%) and 7/72 (10%) patients, respectively. Following our findings combined with the literature, we propose starting TCS before age 18 and reducing the follow-up frequency after the initial two US from annual to biennial if no suspicious findings are detected.


Assuntos
Síndrome do Hamartoma Múltiplo , Neoplasias da Glândula Tireoide , Nódulo da Glândula Tireoide , Humanos , Adulto , Síndrome do Hamartoma Múltiplo/diagnóstico , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/patologia , Tireoidectomia , Nódulo da Glândula Tireoide/patologia , Ultrassonografia , PTEN Fosfo-Hidrolase/genética
15.
A A Pract ; 17(7): e01690, 2023 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-37409736

RESUMO

Anesthetic considerations for adults with Bannayan-Riley-Ruvalcaba syndrome, part of the PTEN (phosphatase and tensin homolog) hamartoma tumor syndrome, are not well described. As patients may require surgical intervention for associated musculoskeletal, intestinal, oncologic, or soft tissue masses, knowledge of implications of anesthesia is necessary. Airway management may be challenging given macrocephaly and accumulation of lymphangiomatous tissue in the oro/hypopharynx. This report describes a patient with typical features, nonreassuring external airway anatomy, and developmental delay, which precluded an awake airway management technique. The airway was secured with the use of high-flow nasal oxygen and videolaryngoscopy.


Assuntos
Anestésicos , Síndrome do Hamartoma Múltiplo , Hamartoma , Humanos , Adulto , Síndrome do Hamartoma Múltiplo/cirurgia , Síndrome do Hamartoma Múltiplo/patologia , Mutação
16.
Childs Nerv Syst ; 39(11): 3295-3299, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37368068

RESUMO

Lhermitte-Duclos disease (LDD) refers to cerebellar dysplastic gangliocytoma, a slow-growing tumor. Pathogenic variants of voltage-gated potassium channels have been associated with epilepsy of variable severity. These include the sodium-activated potassium channel subfamily T member 2 (KCNT2) gene, which encodes for pore-forming alpha subunits. KCNT2 gene mutations have been recently described to cause developmental and epileptic encephalopathies (DEEs). The purpose of the present article is to describe an extremely rare case of a young child who has both LDD and KCNT2 mutation. Our patient is an 11-year-old boy who presented with an absence episode, and his investigations revealed electroencephalography (EEG) abnormalities, LDD, and a heterozygous KCNT2 mutation. Regarding LDD patients, epileptic seizures have been reported in very few cases. Reports of patients with mutated KCNT2 variants are also extremely rare. It is for sure that LDD and KCNT2 mutation is an extremely rare combination. Although further follow-up is mandatory in order to draw safe conclusions for our case, the available data support that our patient is either the first reported case of a subclinical KCNT2 mutation or the first case of its clinical expression in late childhood so far.


Assuntos
Neoplasias Cerebelares , Epilepsia , Síndrome do Hamartoma Múltiplo , Masculino , Humanos , Criança , Síndrome do Hamartoma Múltiplo/complicações , Síndrome do Hamartoma Múltiplo/genética , Síndrome do Hamartoma Múltiplo/patologia , Neoplasias Cerebelares/cirurgia , Mutação/genética , Epilepsia/genética , Epilepsia/complicações , Sódio , Imageamento por Ressonância Magnética , Canais de Potássio Ativados por Sódio/genética
17.
J Hum Genet ; 68(10): 721-724, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37336910

RESUMO

Colorectal, hamartomatous juvenile polyps occur as part of different hereditary syndromes, including Juvenile polyposis syndrome and PTEN-hamartoma tumour syndrome. However, based on clinical manifestations alone, it is difficult to differentiate between the syndromes, and genetic analysis with an NGS-panel is often used to aid diagnostics. We report a 59-year-old male with colorectal juvenile polyps, who had been referred to genetic testing but had normal genetic analysis. He did not fulfil the clinical criteria of PTEN- hamartoma tumour syndrome, but the clinical criteria of Juvenile polyposis syndrome. With Whole Genome Sequencing we detected a novel intronic variant of unknown significance in PTEN (NC_000010.11:g.89687361 A > G(chr10, hg19), NM_000314.8:c.209 + 2047 A > G). RNA analysis classified the variant as likely pathogenic as it results in a pseudoexon inclusion introducing a frameshift and a premature stop codon. The patient was then diagnosed with PTEN-hamartoma Tumour syndrome. To our knowledge this is the first report of a variant resulting in pseudoexon inclusion in PTEN.


Assuntos
Síndrome do Hamartoma Múltiplo , Hamartoma , Síndromes Neoplásicas Hereditárias , Neoplasias Retais , Masculino , Humanos , Pessoa de Meia-Idade , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndrome do Hamartoma Múltiplo/diagnóstico , Síndrome do Hamartoma Múltiplo/genética , Síndrome do Hamartoma Múltiplo/patologia , PTEN Fosfo-Hidrolase/genética
18.
Front Endocrinol (Lausanne) ; 14: 1205785, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37361526

RESUMO

We report the case of a paediatric female patient affected by Bannayan-Riley-Ruvalcaba syndrome (BRRS) and congenital hypothyroidism (CH) with homozygous mutation of the TPO gene. She underwent total thyroidectomy at the age of seven years because of the development of a multinodular goiter. BRRS patients present an increased risk of benign and malignant thyroid disease since childhood because of inactivating mutation of PTEN, an onco-suppressor gene. Instead, homozygous mutations in the TPO gene can be associated with severe forms of hypothyroidism with goiter; previous studies have described cases of follicular and papillary thyroid cancer in CH patients with TPO mutation despite a perfectly controlled thyroid function with Levothyroxine therapy. To our knowledge, this is the first case that describes the possible synergic role of coexisting mutation of both TPO and PTEN in the development of multinodular goiter underlining the importance of a tailored surveillance program in these patients, especially during childhood.


Assuntos
Hipotireoidismo Congênito , Bócio , Síndrome do Hamartoma Múltiplo , Neoplasias da Glândula Tireoide , Humanos , Criança , Feminino , Síndrome do Hamartoma Múltiplo/complicações , Síndrome do Hamartoma Múltiplo/genética , Síndrome do Hamartoma Múltiplo/patologia , Hipotireoidismo Congênito/complicações , Hipotireoidismo Congênito/genética , Mutação , Bócio/complicações , Bócio/genética , Bócio/cirurgia , PTEN Fosfo-Hidrolase/genética
19.
Am J Surg Pathol ; 47(9): 1001-1010, 2023 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-37357918

RESUMO

The aim of this study was to assess the histopathologic spectrum of renal tumors in patients with PTEN hamartoma tumor syndrome (PHTS), with a specific focus on potential features predictive of the underlying syndrome. A multi-institutional study was conducted to obtain clinical and pathologic data on renal tumors arising in patients with PHTS, either diagnosed by germline mutational analysis or clinical criteria for Cowden syndrome. Histologic sections of the renal tumors were re-reviewed for classification. Twelve renal epithelial tumors from 9 patients were identified (4 males and 5 females, with a mean age of 41.8 y), 7 of whom carried germline PTEN mutations. All 12 renal epithelial tumors were renal cell carcinomas (RCCs): 5 were chromophobe RCCs, 4 papillary RCCs, and 3 RCC not otherwise specified. Pathologic stage distribution was: 7 (59%) pT1a, 2 (17%) pT1b, 1 (8%) pT2a, 1 (8%) pT2b, and 1 (8%) pT3a. World Health Organization/International Society of Urological Pathology (WHO/ISUP) histologic grade was applicable in 7 (54%) nonchromophobe tumors: 4 (57%) G2, 2 (29%) G3, and 1 (14%) G4. An unexpected histologic finding was the presence of 2 patients with incidental microscopic collections of intrarenal adipocytes that had no features of angiomyolipoma (and were negative with 2 sensitive PEComa markers: cathepsin-K and GPNMB); both were classified as lipoma/"lipomatous hamartomas." The average follow-up interval was 67.8 months (13 to 172 mo): 5 patients had no evidence of disease, 2 were lost to follow-up, 1 died of other (non-PHTS) causes (ie, prostate cancer), and 1 was alive with metastatic RCC to the lung (RCC not otherwise specified with rhabdoid differentiation). All tumors showed loss of nuclear PTEN staining by immunohistochemistry. Fumarate hydratase was retained and 2SC was negative in all papillary RCCs. CK7 was moderate-strong/diffuse positive in 4 of 5 chromophobe RCCs and in 3 of 4 papillary RCCs. Renal epithelial tumors associated with PHTS represent a heterogeneous group of RCCs, but classic chromophobe and papillary RCC are most common. The majority have a favorable clinical behavior as would be predicted by subtype. In contrast to other hereditary renal neoplasia syndromes, morphologic features of the RCCs do not allow identification of PHTS-associated neoplasia with any degree of specificity in the absence of clinical setting and/or prior history, but the presence of microscopic "lipomas" within the kidney may provide a clue in rare cases. Therefore, clinical suspicion and genetic counseling with germline testing remain necessary for identifying PHTS-associated RCC.


Assuntos
Carcinoma de Células Renais , Síndrome do Hamartoma Múltiplo , Neoplasias Renais , Lipoma , Síndromes Neoplásicas Hereditárias , Masculino , Feminino , Humanos , Adulto , Carcinoma de Células Renais/patologia , Síndrome do Hamartoma Múltiplo/complicações , Síndrome do Hamartoma Múltiplo/genética , Neoplasias Renais/patologia , Síndromes Neoplásicas Hereditárias/complicações , PTEN Fosfo-Hidrolase/genética , Glicoproteínas de Membrana
20.
Eur J Med Genet ; 66(8): 104798, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37307869

RESUMO

PTEN hamartoma tumor syndromes (PHTS) comprise hamartomatous overgrowth syndromes associated with PTEN germline mutations. In this case report, we describe a variant identified by next generation sequencing causing peculiar dermatological and skeletal features not yet described in the literature. Being cognizant of such unique disease presentations in PHTS, that manifest at a very young age, could help facilitate a timely diagnosis by clinicians and thus the early education of families on active cancer surveillance. This specific case also strengthens the concept of variable presentation of PHTS and the need for genetic testing early on, even if not all criteria for PHTS are met for a formal clinical diagnosis.


Assuntos
Síndrome do Hamartoma Múltiplo , Humanos , Síndrome do Hamartoma Múltiplo/diagnóstico , Síndrome do Hamartoma Múltiplo/genética , Síndrome do Hamartoma Múltiplo/patologia , PTEN Fosfo-Hidrolase/genética , Testes Genéticos , Mutação em Linhagem Germinativa
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