Brain morphological analysis in PTEN hamartoma tumor syndrome.

PTEN hamartoma tumor syndrome (PHTS) is a spectrum of hereditary cancer syndromes caused by germline mutations in PTEN. PHTS is of high interest, because of its high rate of neurological comorbidities including macrocephaly, autism spectrum disorder, and intellectual dysfunction. Since detailed brain morphology and connectivity of PHTS remain unclear, we quantitatively evaluated brain magnetic resonance imaging (MRI) in PHTS. Sixteen structural T1-weighted and 9 diffusion-weighted MR images from 12 PHTS patients and neurotypical controls were used for structural and high-angular resolution diffusion MRI (HARDI) tractography analyses. Mega-corpus callosum was observed in 75%, polymicrogyria in 33%, periventricular white matter lesions in 83%, and heterotopia in 17% of the PHTS participants. While gyrification index and hemispheric cortical thickness showed no significant differences between the two groups, significantly increased global and regional brain volumes, and regionally thicker cortices in PHTS participants were observed. HARDI tractography showed increased volume and length of callosal pathways, increased volume of the arcuate fasciculi (AF), and increased length of the bilateral inferior longitudinal fasciculi (ILF), bilateral inferior fronto-occipital fasciculi (IFOF), and bilateral uncinate fasciculus. A decrease in fractional anisotropy and an increased in apparent diffusion coefficient values of the AF, left ILF, and left IFOF in PHTS.

PTEN Hamartoma tumor syndrome in childhood: A review of the clinical literature.

PTEN hamartoma tumor syndrome (PHTS) is a highly variable autosomal dominant condition associated with intellectual disability, overgrowth, and tumor predisposition phenotypes, which often overlap. PHTS incorporates a number of historical clinical presentations including Bannayan-Riley-Ruvalcaba syndrome, Cowden syndrome, and a macrocephaly-autism/developmental delay syndrome. Many reviews in the literature focus on PHTS as an adult hamartoma and malignancy predisposition condition. Here, we review the current literature with a focus on pediatric presentations. The review starts with a summary of the main conditions encompassed within PHTS. We then discuss PHTS diagnostic criteria, and clinical features. We briefly address rarer PTEN associations, and the possible role of mTOR inhibitors in treatment. We acknowledge the limited understanding of the natural history of childhood-onset PHTS as a cancer predisposition syndrome and present a summary of important management considerations.

Broad spectrum of neuropsychiatric phenotypes associated with white matter disease in PTEN hamartoma tumor syndrome.

White matter lesions have been described in patients with PTEN hamartoma tumor syndrome (PHTS). How these lesions correlate with the neurocognitive features associated with PTEN mutations, such as autism spectrum disorder (ASD) or developmental delay, has not been well established. We report nine patients with PTEN mutations and white matter changes on brain magnetic resonance imaging (MRI), eight of whom were referred for reasons other than developmental delay or ASD. Their clinical presentations ranged from asymptomatic macrocephaly with normal development/intellect, to obsessive compulsive disorder, and debilitating neurological disease. To our knowledge, this report constitutes the first detailed description of PTEN-related white matter changes in adult patients and in children with normal development and intelligence. We present a detailed assessment of the neuropsychological phenotype of our patients and discuss the relationship between the wide array of neuropsychiatric features and observed white matter findings in the context of these individuals.

Characterization of cryptic splicing in germline PTEN intronic variants in Cowden syndrome.

Germline mutations in the tumor-suppressor gene PTEN predispose to subsets of Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome, and autism. Evidence-based classification of PTEN variants as either deleterious or benign is urgently needed for accurate molecular diagnosis and gene-informed genetic counseling. We studied 34 different germline PTEN intronic variants from 61 CS patients, characterized their PTEN mRNA processing, and analyzed PTEN expression and downstream readouts of P-AKT and P-ERK1/2. While we found that many mutations near splice junctions result in exon skipping, we also identified the presence of cryptic splicing that resulted in premature termination or a shift in isoform usage. PTEN protein expression is significantly lower in the group with splicing changes while P-AKT, but not P-ERK1/2, is significantly increased. Our observations of these PTEN intronic variants should contribute to the determination of pathogenicity of PTEN intronic variants and aid in genetic counseling.

Cutaneous reflex modulation and self-induced reflex attenuation in cerebellar patients.

Modulation of cutaneous reflexes is important in the neural control of walking, yet knowledge about underlying neural pathways is still incomplete. Recent studies have suggested that the cerebellum is involved. Here we evaluated the possible roles of the cerebellum in cutaneous reflex modulation and in attenuation of self-induced reflexes. First we checked whether leg muscle activity during walking was similar in patients with focal cerebellar lesions and in healthy control subjects. We then recorded cutaneous reflex activity in leg muscles during walking. Additionally, we compared reflexes after standard (computer triggered) stimuli with reflexes after self-induced stimuli for both groups. Biceps femoris and gastrocnemius medialis muscle activity was increased in the patient group compared with the control subjects, suggesting a coactivation strategy to reduce instability of gait. Cutaneous reflex modulation was similar between healthy control subjects and cerebellar patients, but the latter appeared less able to attenuate reflexes to self-induced stimuli. This suggests that the cerebellum is not primarily involved in cutaneous reflex modulation but that it could act in attenuation of self-induced reflex responses. The latter role in locomotion would be consistent with the common view that the cerebellum predicts sensory consequences of movement.

Cognitive characteristics of PTEN hamartoma tumor syndromes.

PURPOSE: We sought to characterize cognition in individuals with germline PTEN mutations (n = 23) as well as in PTEN mutation-negative individuals with classic Cowden syndrome or Bannayan-Riley-Ruvalcaba syndrome (n = 2). METHODS: Twenty-five individuals completed a comprehensive neuropsychological evaluation. One sample t-tests and effect sizes were used to examine differences in participant test scores compared with normal controls. Composite scores were created for each patient within each of the cognitive domains assessed and classified as above average, average, or below average according to normative standards. χ(2) analyses compared these classifications to expected proportions in normal control samples. RESULTS: The mean intelligence quotient was in the average range, and the range of intellectual functioning was very wide (from extremely low to very superior). However, in a large subset of patients, scores were lower than expected on measures of motor functioning, executive functioning, and memory recall, suggesting disruption of frontal circuits in these participants. CONCLUSION: This is the first study to characterize cognition in individuals with PTEN mutations and associated syndromes using a comprehensive neuropsychological battery. Contrary to previous reports suggesting an association with intellectual disability, the mean intelligence quotient was average, and there was a broad range of intellectual abilities. Specific evidence of disruption of frontal circuits may have implications for treatment compliance and cancer surveillance, and further investigation is warranted.

Endometrial cancer in a 14-year-old girl with Cowden syndrome: a case report.

The appearance of endometrial cancer in adolescence is uncommon and warrants investigation for an hereditary cancer syndrome. Cowden syndrome is an autosomal dominant cancer syndrome associated with a germline PTEN mutation and increased risk of breast, thyroid, endometrial and colon cancer. In this report we present a case of a 14-year-old nulligravid female diagnosed with grade 1 endometrial adenocarcinoma. She subsequently developed fibrocystic breast disease and colon polyps and was diagnosed with Cowden syndrome at age 20. We therefore recommend formal evaluation for Cowden syndrome to be considered when endometrial cancer is diagnosed in adolescence.

Bilateral Lhermitte-Duclos disease.

Lhermitte-Duclos disease (LDD) is a pathologic entity with progrediating, diffuse hypertrophy chiefly of the stratum granulosum of the cerebellum. Typically LDD is a unilateral lesion of the cerebellum or in vermis. Here we report a case of LDD with bilateral lesions of cerebellar hemispheres managed surgically. A 28-year-old woman presented with one-year history of progressive headache, nausea, vomiting, and blurred vision. Neurologic examination revealed a bilateral mild papilledema, mild dysmetria, and dysdiadochokinesia. The cerebellar lesions caused moderate mass effect in posterior fossa with hydrocephalus, and Chiari type I malformation. We performed the suboccipital-retrosigmoid approach, and removed completely the left intracerebellar mass. Symptoms related to elevated intracranial pressure disappeared in a short period postoperatively.

Lhermitte-Duclos disease with atypical vascularization--case report and review of the literature.

OBJECTIVE: A case of Lhermitte-Duclos disease (LDD, dysplastic gangliocytoma) with atypical vascularization is reported. LDD is a rare cerebellar mass lesion which may be associated with Cowden's syndrome and the PTEN germline mutation. CASE MATERIAL: A 61-year-old male presented 15 years before with a transient episode of unspecific gait disturbance. Initial magnetic resonance (MR) imaging revealed a right-sided, diffuse, nonenhancing cerebellar mass lesion. No definitive diagnosis was made at that time, and the symptoms resolved spontaneously. 15 years later, the patient presented with acute onset of vomiting associated with headache and ataxic gait. MR imaging showed a progression of the lesion with occlusive hydrocephalus. The lesion depicted a striated pattern characteristic for LDD with T1-hypointense and T2-hyperintense bands, nonenhancing with contrast. After resection of the mass lesion, the cerebellar and hydrocephalic symptoms improved rapidly. The pathological examination confirmed the diagnosis of dysplastic gangliocytoma (WHO Grade I) with enlarged granular and molecular cell layers, reactive gliosis and dysplastic blood vessels. No other clinical features associated with Cowden's syndrome were present. CONCLUSIONS: This case illustrates that LDD with atypical vascularization is a slow-growing posterior fossa mass lesion which may remain asymptomatic for many years. Timing of surgical treatment and extent of resection in patients with LDD is controversial. The typical features on standard T1-/T2-weighted MR imaging allow a diagnosis without surgery in most cases. The authors believe that the decision to treat in these cases should be based on clinical deterioration.

Pten loss in the mouse thyroid causes goiter and follicular adenomas: insights into thyroid function and Cowden disease pathogenesis.

Inactivation and silencing of the tumor suppressor PTEN are found in many different epithelial tumors, including thyroid neoplasia. Cowden Disease patients, who harbor germ-line PTEN mutations, often display thyroid abnormalities, including multinodular goiter and follicular adenomas, and are at increased risk of thyroid cancer. To gain insights into the role PTEN plays in thyroid function and disease, we have generated a mouse strain, in which Cre-mediated recombination is used to specifically delete Pten in the thyrocytes. We found that Pten mutant mice develop diffuse goiter characterized by extremely enlarged follicles, in the presence of normal thyroid-stimulating hormone and T4 hormone levels. Loss of Pten resulted in a significant increase in the thyrocyte proliferative index, which was more prominent in the female mice, and in increased cell density in the female thyroid glands. Surprisingly, goitrogen treatment did not cause a substantial increase of the mutant thyroid size and increased only to some extent the proliferation index of the female thyrocytes, suggesting that a relevant part of the thyroid-stimulating hormone-induced proliferation signals are funneled through the phosphatidylinositol-3-kinase (PI3K)/Akt cascade. Although complete loss of Pten was not sufficient to cause invasive tumors, over two thirds of the mutant females developed follicular adenomas by 10 months of age, showing that loss of Pten renders the thyroid highly susceptible to neoplastic transformation through mechanisms that include increased thyrocyte proliferation. Our findings show that constitutive activation of the PI3K/Akt cascade is sufficient to stimulate continuous autonomous growth and provide novel clues to the pathogenesis of Cowden Disease and sporadic nontoxic goiter.

Hemimegalencephaly with Bannayan-Riley-Ruvalcaba syndrome.

Hemimegalencephaly is known to occur in Proteus syndrome, but has not been reported, to our knowledge, in the other PTEN mutation-related syndrome of Bannayan-Riley-Ruvalcaba. Here, we report a patient with Bannayan-Riley-Ruvalcaba syndrome who also had hemimegalencephaly and in whom the hemimegalencephaly was evident well before presentation of the characteristic manifestations of Bannayan-Riley-Ruvalcaba syndrome. An 11-year-old boy developed drug-resistant focal seizures on the fifth day of life. MRI revealed left hemimegalencephaly. He later showed macrocephaly, developmental delay, athetotic quadriplegic cerebral palsy, and neuromuscular scoliosis. Freckling of the penis, which is characteristic of Bannayan-Riley-Ruvalcaba syndrome, was not present at birth but was observed at 9 years of age. Gene analysis revealed a c.510 T>G PTEN mutation. This patient and his other affected family members, his father and two siblings, were started on the tumour screening procedures recommended for patients with PTEN mutations. This case highlights the importance of early screening for PTEN mutations in cases of hemimegalencephaly not otherwise explained by another disorder, even in the absence of signs of Proteus syndrome or the full manifestations of Bannayan-Riley Ruvalcaba syndrome.

A family with PTEN mutations with malignancy and an unusually high number of offspring with autism spectrum disorder: a case report.

BACKGROUND: Cowden's syndrome (OMIM:158350), a rare genetic disorder (incidence ~ 1:250,000), is caused by mutations of the tumor suppressor gene PTEN. In this report, we describe clinical manifestations of a 56-year-old patient diagnosed with Cowden's syndrome and his family with PTEN mutations. The family has an unusually high number of offspring with autism spectrum disorder. CASE PRESENTATION: Except for his 80-year-old Caucasian father, all of our index case's living Caucasian kindred (three children, brother, and nephew) had PTEN mutations and macrocephaly. Prior to genetic testing, his mother and sister died of breast cancer at 42 and 38 years old, respectively. After PTEN mutation was identified, our patient underwent complete thyroidectomy (histology showing micropapillary carcinoma) and right nephrectomy for renal cell carcinoma. All of his three children (13-year-old son, 11- and 8-year-old daughters) have been diagnosed with autism spectrum disorder. His son and brother underwent total thyroidectomy. His nephew had thyroid nodules. Management of Cowden's syndrome requires clinical examinations and investigations every 6 to 12 months from 18 years old or 5 years before the family's earliest age of cancer diagnosis and should focus on all clinical manifestations associated with PTEN mutations to identify early abnormal changes in skin, breasts, thyroid, endometrium, gut, and kidneys. Input from specialists across different disciplines is necessary. CONCLUSIONS: We describe a man and his family with PTEN mutations who have increased risk of cancers and an unusually high number of offspring with autism spectrum disorder. Early recognition and close surveillance are vital in order to provide treatment and early screening for asymptomatic at-risk relatives.

Childhood Lhermitte-Duclos Disease Progressing to Medulloblastoma in Bilateral Cerebellar Hemispheres: Report of Unusual Case.

BACKGROUND: Lhermitte-Duclos disease is an extremely rare pathologic entity characterized by a cerebellar mass composed of enlarged cerebellar folia containing abnormal ganglion cells. This entity usually presents in young and middle-aged adults and rarely in children. There is no study in the literature analyzing the long-term clinical course of this disease to assess the behavior primarily because of its rarity. CASE DESCRIPTION: We present our experience with a 7-year-old patient of Lhermitte-Duclos disease who was followed up for 5 years and found to have progressed to bilateral World Health Organization grade IV medulloblastoma. This case denotes the malignant potential of this rare disorder. CONCLUSIONS: LDD is seen rarely and demands a high degree of suspicion in patients presenting with cerebellar mass and/or imaging characteristics. It is prudent to keep these patients in close follow-up for early detection of malignant transformation.

Frequent vomiting attacks in a patient with Lhermitte-Duclos disease: a rare pathophysiology of cerebellar lesions?

Lhermitte-Duclos disease (LDD) is a neurological disease caused by a hamartomatous lesion in the cerebellum. Clinically, LDD is commonly associated with progressive space-occupying lesion effects in the posterior fossa, increasing intracranial pressure, occlusive hydrocephalus, and focal neurological deficits of adjacent structures. The authors report the case of a 10-year-old boy with LDD who had been suffering from vomiting attacks (VAs). These VAs had been brief in duration but extremely frequent, and they had been resistant to antiemetic drugs since the early postnatal period. Magnetic resonance imaging at 8 months of age revealed a right cerebellar lesion with very little space-occupying lesion effect, but the causal relationship with VAs was not evident at that point, because no clinical symptoms or signs other than vomiting were suggestive of increased intracranial pressure. The VAs were initially diagnosed as autonomic ataxia and had been treated with antiemetic drugs for approximately 10 years, but the patient's symptoms were not improved at all in frequency or duration. He developed convulsive seizures at 9 years of age and was referred to the authors' epilepsy center. The VAs were initially speculated to represent an aspect of seizures, but antiepileptic agents proved ineffective against this symptom despite remission of convulsive seizures. Video-electroencephalography monitoring did not show any evolving ictal patterns associated with the vomiting. Careful reevaluation of MRI studies revealed that the cerebellar lesion was fused with the cerebellum, middle and inferior cerebellar peduncles, and dorsolateral medulla oblongata with some distortion. FDG-PET identified hypermetabolism in the cerebellar lesion. After establishing the diagnosis of LDD, the authors performed subtotal resection of the lesion based on the likelihood of a causal relationship between the cerebellar lesion and the vomiting center of the medulla oblongata. Postoperatively and for 2 years, VAs have remained completely suppressed. The authors hypothesize that the pathophysiology of VAs in LDD includes a tumor-like space-occupying effect on the vomiting center of the medulla oblongata, and even partial resection of the lesion may prove effective.

Hitting the mark in hamartoma syndromes.

The missed mark or hamartia underlying each hamartoma syndrome is a mutation in a tumor suppressor gene. This sets the stage for the development of frequent and early tumors in multiple organs. Loss of function of the tumor suppressor in neoplastic cells leads to dysregulation of signaling pathways and tumor growth. The convergence of these signaling pathways to the mTOR pathway suggests that rapamycin or rapamycin-like drugs have potential for treatment, perhaps in combination with drugs targeting other signaling pathways. Haploinsufficient cells also play significant roles in tumor formation. Disrupting interactions between neoplastic cells and surrounding haploinsufficient cells using antiangiogenesis therapies represent an additional approach for treatment. It is hoped that the debilitating effects of these syndromes soon will be alleviated or even reversed though targeted therapies.