Identification of a Cowden syndrome patient with a novel PTEN mutation and establishment of patient-derived induced pluripotent stem cells

Cowden syndrome (CS) is an autosomal dominant inherited disorder characterized by multiple hamartomas in various organs such as the mucosa, skin, and gastrointestinal tract. Patients with CS are at high risk for breast and thyroid cancers. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor gene that negatively regulates the AKT pathway, and PTEN mutations are known to be the major causes of this syndrome. However, the pathogenesis of this syndrome has not been clarified. Here, we present a case of a Japanese woman with multiple oral polyps, breast cancer, and thyroid cancer who was clinically diagnosed with CS. We obtained DNA and RNA samples from the patient’s peripheral blood mononuclear cells (PBMCs) and buccal mucosa tumor. Next-generation sequencing revealed novel germline mutations (c.1020delT and c.1026G > A) in exon 8 of PTEN. Sanger sequencing identified no PTEN transcript from the mutant allele. Furthermore, CS-specific induced pluripotent stem cells (CS-iPSCs) were established from PBMCs of the patient under feeder- and serum-free culture. Compared with healthy PBMCs and iPSCs, both of the CS-derived PBMCs and CS-iPSCs exhibited significantly reduced expression of the PTEN transcript. The transcriptional variant, PTENδ, was increased in CS-iPSCs, suggesting that it may be the cause of the disease.

Impaired social cognition and fine dexterity in patients with Cowden syndrome associated with germline PTEN variants

PurposeCowden syndrome (CS) is an autosomal dominant disease related to germline PTEN variants and is characterised by multiple hamartomas, increased risk of cancers and frequent brain alteration. Since the behaviour of patients with CS sometimes appears to be inappropriate, we analysed their neuropsychological functioning.MethodsThis monocentric study was conducted between July 2018 and February 2020. A standardised neuropsychological assessment, including an evaluation of social cognition, executive functions, language and dexterity, as well as a cerebral MRI were systematically proposed to all patients with CS. Moreover, PTEN variants were identified.ResultsFifteen patients from 13 families were included, with six non-sense (40%), three missense (20%), five frameshift (33.3%) and one splice site (6.6%) variant types. Twelve patients (80%) had altered social cognition: 10 patients had an abnormal modified Faux-Pas score and 5 had Ekman’s facial emotions recognition impairment. Nearly all patients (93%) had impaired dexterity. Cerebral MRI showed various cerebellar anomalies in seven patients (46.7%).ConclusionAltered social cognition and impaired fine dexterity are frequently associated with CS. Further studies are needed to confirm these results and to determine whether dexterity impairment is due to the effect of germline PTEN variants in the cerebellum.

Lhermitte duclos disease: what to expect during surgery?

Lhermitte and Duclos first described the dysplastic gangliocytoma of the cerebellum in 1920. In the last 100 years, its clinical presentation, radiological features, pathological characteristics, and association with Cowden syndrome have been well described. However, documentation of surgical experiences is lagging. We here describe intraoperative experience during the removal of the tumor, which could help the operating surgeon plan and mental makeup.

Inherited endocrine syndromes and MEN

This chapter begins with genetic testing for monogenic endocrine disorders, and then goes on to define the diagnosis, treatment, and management of McCune-Albright syndrome, neurofibromatosis, von Hippel-Lindau disease, Carney complex, Cowden syndrome, and POEMS syndrome. It then goes on to the clinical features and management of MEN type 1 and MEN type 2, and MEN type 4. Inherited primary hyperparathyroidism, phaeochromocytoma-paraganglioma syndromes, and renal calculi.

The surgical resection of dysplastic cerebellar gangliocytoma assisted by intraoperative sonography: illustrative case

BACKGROUND Dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease) is an extremely rare, slow-growing hereditary mass lesion that is mainly characterized by both specific neuroradiological features and secondary hydrocephalus. Patients may present with symptoms of cerebellar mass lesion and increased intracranial pressure. As an important part of Cowden syndrome, Lhermitte-Duclos disease in adults is typically marked by PTEN gene mutation. OBSERVATIONS The clinical management of a 31-year-old woman who suffered Lhermitte-Duclos disease was introduced in this case report. Subtotal resection was performed with the assistance of intraoperative sonography to relieve obstructive hydrocephalus, and prophylactic C1 laminectomy was performed to prevent possible postoperative progression of the residual lesion. Perioperative care and surgical process were clearly revealed in an accompanying video. Intraoperative sonography of Lhermitte-Duclos disease presents hyperechoic distorted thickening cortices surrounded by hypoechoic edema belt. The patient did not report any significant neurological complications or sequelae after the lesion resection. LESSONS The authors first reported the use of intraoperative sonography in resection of adult-onset Lhermitte-Duclos disease. Hopefully, the educative case report can provide a feasible experience in the diagnosis and treatment of Lhermitte-Duclos disease.

Cowden syndrome and Lhermitte - Duclos disease: A case report and review of the literature

Cowden syndrome (CS) is a rare, autosomal dominant, multisystem disease related to the mutation of Phosphatase and tensin homolog (PTEN) tumour suppressor gene. It is characterized by the occurrence of multiple hamartomas, mucocutaneous lesions, and is associated with a high risk of malignancies. Lhermitte–Duclos Disease (LDD), or dysplastic cerebellar gangliocytoma, is a rare hamartomatous lesion of the cerebellar cortex with a unique “Tiger Stripe” appearance on Magnetic Resonance Imaging (MRI). Since 1991, LDD has been considered pathognomonic and part of CS. In addition, as almost all adult onset LDD cases were associated with PTEN gene mutations, LDD and CS are both included in PTEN Harmartoma Tumour Syndrome (PHTS). In this article, we report a 48-year-old female patient, who presented with a right cerebellar lesion resulting in hydrocephalus. The histology of the cerebellar lesion confirmed the diagnosis of LDD, and her clinical history is highly suggestive of CS. Due to the high incidence of multisystemic malignancies and other disease, it is important for clinicians to be aware of the association between LDD and CS. Affected patients should be evaluated carefully and screened for cancers accordingly, so as to allow early diagnosis and treatment.