Medulloblastoma Associated with Down Syndrome: From a Rare Event Leading to a Pathogenic Hypothesis

Down syndrome (DS) is the most common chromosome abnormality with a unique cancer predisposition syndrome pattern: a higher risk to develop acute leukemia and a lower incidence of solid tumors. In particular, brain tumors are rarely reported in the DS population, and biological behavior and natural history are not well described and identified. We report a case of a 10-year-old child with DS who presented with a medulloblastoma (MB). Histological examination revealed a classic MB with focal anaplasia and the molecular profile showed the presence of a CTNNB1 variant associated with the wingless (WNT) molecular subgroup with a good prognosis in contrast to our case report that has shown an early metastatic relapse. The nearly seven-fold decreased risk of MB in children with DS suggests the presence of protective biological mechanisms. The cerebellum hypoplasia and the reduced volume of cerebellar granule neuron progenitor cells seem to be a possible favorable condition to prevent MB development via inhibition of neuroectodermal differentiation. Moreover, the NOTCH/WNT dysregulation in DS, which is probably associated with an increased risk of leukemia, suggests a pivotal role of this pathway alteration in the pathogenesis of MB; therefore, this condition should be further investigated in future studies by molecular characterizations.

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Epilepsy in Down Syndrome: A Highly Prevalent Comorbidity

Journal of Clinical Medicine ◽

10.3390/jcm10132776 ◽

2021 ◽

Vol 10 (13) ◽

pp. 2776

Author(s):

Miren Altuna ◽

Sandra Giménez ◽

Juan Fortea

Keyword(s):

Down Syndrome ◽

Functional Outcomes ◽

Clinical Presentation ◽

Late Onset ◽

Current Knowledge ◽

Epileptic Seizures ◽

Myoclonic Epilepsy ◽

Increased Risk ◽

Number Of Individuals

Individuals with Down syndrome (DS) have an increased risk for epilepsy during the whole lifespan, but especially after age 40 years. The increase in the number of individuals with DS living into late middle age due to improved health care is resulting in an increase in epilepsy prevalence in this population. However, these epileptic seizures are probably underdiagnosed and inadequately treated. This late onset epilepsy is linked to the development of symptomatic Alzheimer’s disease (AD), which is the main comorbidity in adults with DS with a cumulative incidence of more than 90% of adults by the seventh decade. More than 50% of patients with DS and AD dementia will most likely develop epilepsy, which in this context has a specific clinical presentation in the form of generalized myoclonic epilepsy. This epilepsy, named late onset myoclonic epilepsy (LOMEDS) affects the quality of life, might be associated with worse cognitive and functional outcomes in patients with AD dementia and has an impact on mortality. This review aims to summarize the current knowledge about the clinical and electrophysiological characteristics, diagnosis and treatment of epileptic seizures in the DS population, with a special emphasis on LOMEDS. Raised awareness and a better understanding of epilepsy in DS from families, caregivers and clinicians could enable earlier diagnoses and better treatments for individuals with DS.

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Adaptation of the Clinical Dementia Rating Scale for adults with Down syndrome

Journal of Neurodevelopmental Disorders ◽

10.1186/s11689-019-9300-2 ◽

2019 ◽

Vol 11 (1) ◽

Author(s):

Christina N. Lessov-Schlaggar ◽

Olga L. del Rosario ◽

John C. Morris ◽

Beau M. Ances ◽

Bradley L. Schlaggar ◽

...

Keyword(s):

Down Syndrome ◽

Alzheimer Disease ◽

Rating Scale ◽

Assessment Instruments ◽

Clinical Dementia Rating ◽

Data Set ◽

Cognitive Domains ◽

Increased Risk ◽

Caregiver Questionnaire ◽

Raven's Progressive Matrices

Abstract Background Adults with Down syndrome (DS) are at increased risk for Alzheimer disease dementia, and there is a pressing need for the development of assessment instruments that differentiate chronic cognitive impairment, acute neuropsychiatric symptomatology, and dementia in this population of patients. Methods We adapted a widely used instrument, the Clinical Dementia Rating (CDR) Scale, which is a component of the Uniform Data Set used by all federally funded Alzheimer Disease Centers for use in adults with DS, and tested the instrument among 34 DS patients recruited from the community. The participants were assessed using two versions of the modified CDR—a caregiver questionnaire and an in-person interview involving both the caregiver and the DS adult. Assessment also included the Dementia Scale for Down Syndrome (DSDS) and the Raven’s Progressive Matrices to estimate IQ. Results Both modified questionnaire and interview instruments captured a range of cognitive impairments, a majority of which were found to be chronic when accounting for premorbid function. Two individuals in the sample were strongly suspected to have early dementia, both of whom had elevated scores on the modified CDR instruments. Among individuals rated as having no dementia based on the DSDS, about half showed subthreshold impairments on the modified CDR instruments; there was substantial agreement between caregiver questionnaire screening and in-person interview of caregivers and DS adults. Conclusions The modified questionnaire and interview instruments capture a range of impairment in DS adults, including subthreshold symptomatology, and the instruments provide complementary information relevant to the ascertainment of dementia in DS. Decline was seen across all cognitive domains and was generally positively related to age and negatively related to IQ. Most importantly, adjusting instrument scores for chronic, premorbid impairment drastically shifted the distribution toward lower (no impairment) scores.

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Mismatch Repair Deficiency as a Predictive and Prognostic Biomarker in Molecularly Classified Endometrial Carcinoma

Cancers ◽

10.3390/cancers13133124 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3124

Author(s):

Mikko Loukovaara ◽

Annukka Pasanen ◽

Ralf Bützow

Keyword(s):

Risk Factors ◽

Mismatch Repair ◽

Molecular Classification ◽

The Cancer Genome Atlas ◽

Molecular Profile ◽

New Therapeutic Approaches ◽

Increased Risk ◽

Mmr Deficiency ◽

Endometrial Carcinomas ◽

Risk Of Cancer

The aggressiveness of mismatch repair (MMR) deficient endometrial carcinomas was examined in a single institution retrospective study. Outcomes were similar for MMR proficient (n = 508) and deficient (n = 287) carcinomas, identified by immunohistochemistry. In accordance with molecular classification based on The Cancer Genome Atlas (TCGA), tumors with abnormal p53 staining or polymerase-ϵ exonuclease domain mutation were excluded from the MMR proficient subgroup, termed as “no specific molecular profile” (NSMP). Compared with NSMP (n = 218), MMR deficiency (n = 191) was associated with poor disease-specific survival (p = 0.001). MMR deficiency was associated with an increased risk of cancer-related death when controlling for confounders (hazard ratio 2.0). In the absence of established clinicopathologic risk factors, MMR deficiency was invariably associated with an increased risk of cancer-related death in univariable analyses (hazard ratios ≥ 2.0). In contrast, outcomes for MMR deficient and NSMP subgroups did not differ when risk factors were present. Lymphatic dissemination was more common (p = 0.008) and the proportion of pelvic relapses was higher (p = 0.029) in the MMR deficient subgroup. Our findings emphasize the need for improved triage to adjuvant therapy and new therapeutic approaches in MMR deficient endometrial carcinomas.

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Association between Inflammatory Conditions and Alzheimer’s Disease Age of Onset in Down Syndrome

Journal of Clinical Medicine ◽

10.3390/jcm10143116 ◽

2021 ◽

Vol 10 (14) ◽

pp. 3116

Author(s):

Florence Lai ◽

Nathaniel Mercaldo ◽

Cassandra M. Wang ◽

Giovi G. Hersch ◽

Herminia Diana Rosas

Keyword(s):

Down Syndrome ◽

Age Of Onset ◽

Vitamin B12 Deficiency ◽

Inflammatory Conditions ◽

Increased Risk ◽

Wide Range ◽

High Prevalence ◽

Autoimmune Conditions ◽

B12 Deficiency ◽

The Relationship

Adults with Down syndrome (DS) have an exceptionally high prevalence of Alzheimer disease (AD), with an earlier age of onset compared with the neurotypical population. In addition to beta amyloid, immunological processes involved in neuroinflammation and in peripheral inflammatory/autoimmune conditions are thought to play important roles in the pathophysiology of AD. Individuals with DS also have a high prevalence of autoimmune/inflammatory conditions which may contribute to an increased risk of early AD onset, but this has not been studied. Given the wide range in the age of AD onset in those with DS, we sought to evaluate the relationship between the presence of inflammatory conditions and the age of AD onset. We performed a retrospective study on 339 adults with DS, 125 who were cognitively stable (CS) and 214 with a diagnosis of AD. Data were available for six autoimmune conditions (alopecia, celiac disease, hypothyroidism, psoriasis, diabetes and vitamin B12 deficiency) and for one inflammatory condition, gout. Gout was associated with a significant delay in the age of AD onset by more than 2.5 years. Our data suggests that inflammatory conditions may play a role in the age of AD onset in DS. Further studies are warranted.

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Intracerebral haemorrhage in Down syndrome: protected or predisposed?

F1000Research ◽

10.12688/f1000research.7819.1 ◽

2016 ◽

Vol 5 ◽

pp. 876 ◽

Cited By ~ 18

Author(s):

Lewis Buss ◽

Elizabeth Fisher ◽

John Hardy ◽

Dean Nizetic ◽

Jurgen Groet ◽

...

Keyword(s):

Down Syndrome ◽

Intracerebral Haemorrhage ◽

Early Onset ◽

Epidemiological Data ◽

Haemorrhagic Stroke ◽

Brain Parenchyma ◽

Chromosome 21 ◽

Clinical Consequence ◽

Increased Risk ◽

The Central Nervous System

Down syndrome (DS), which arises from trisomy of chromosome 21, is associated with deposition of large amounts of amyloid within the central nervous system. Amyloid accumulates in two compartments: as plaques within the brain parenchyma and in vessel walls of the cerebral microvasculature. The parenchymal plaque amyloid is thought to result in an early onsetAlzheimer’s disease (AD) dementia, a phenomenon so common amongst people with DS that it could be considered a defining feature of the condition. The amyloid precursor protein (APP) gene lies on chromosome 21 and its presence in three copies in DS is thought to largely drive the early onset AD. In contrast, intracerebral haemorrhage (ICH), the main clinical consequence of vascular amyloidosis, is a more poorly defined feature of DS. We review recent epidemiological data on stroke (including haemorrhagic stroke) in order to make comparisons with a rare form of familial AD due to duplication (i.e. having three copies) of the APP region on chromosome 21, here called ‘dup-APP’, which is associated with more frequent and severe ICH. We conclude that although people with DS are at increased risk of ICH, this is less common than in dup-APP, suggesting the presence of mechanisms that act protectively. We review these mechanisms and consider comparative research into DS and dup-APP that may yield further pathophysiological insight.

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An Increased Risk of Second Malignant Neoplasms After Rhabdomyosarcoma: Population-Based Evidence for a Cancer Predisposition Syndrome?

Pediatric Blood & Cancer ◽

10.1002/pbc.25678 ◽

2015 ◽

Vol 63 (2) ◽

pp. 196-201 ◽

Cited By ~ 17

Author(s):

Natasha M. Archer ◽

Renata Parada Amorim ◽

Rafaela Naves ◽

Simone Hettmer ◽

Lisa R. Diller ◽

...

Keyword(s):

Population Based ◽

Cancer Predisposition ◽

Malignant Neoplasms ◽

Cancer Predisposition Syndrome ◽

Increased Risk ◽

Second Malignant Neoplasms

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Practice Tips for Measuring the Nuchal Translucency

Ultrasound ◽

10.1179/174313408x353819 ◽

2008 ◽

Vol 16 (4) ◽

pp. 220-225 ◽

Cited By ~ 1

Author(s):

Debbie Nisbet

Keyword(s):

Down Syndrome ◽

Nasal Bone ◽

Nuchal Translucency ◽

Operator Technique ◽

Increased Risk ◽

Fetal Nasal Bone ◽

Form Part ◽

The Uk ◽

Bone Assessment ◽

Down Syndrome Screening

In some countries, measurement of nuchal translucency (NT) is incorporated into national antenatal screening programmes to help detect pregnancies at increased risk of Down syndrome. Accurate measurement of the NT requires a specific technique. This article is an illustrated practical guide outlining the steps required for measuring the NT; it provides useful tips for improving operator technique and advises how to avoid common pitfalls. Although fetal nasal bone assessment does not currently form part of official Down syndrome screening programmes (in Australia or the UK), it is included here as debate about its usefulness continues.

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Polymorphisms inHSD17B1: Early Onset and Increased Risk of Alzheimer’s Disease in Women with Down Syndrome

Current Gerontology and Geriatrics Research ◽

10.1155/2012/361218 ◽

2012 ◽

Vol 2012 ◽

pp. 1-8 ◽

Cited By ~ 8

Author(s):

Joseph H. Lee ◽

Susan Gurney ◽

Deborah Pang ◽

Alexis Temkin ◽

Naeun Park ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Down Syndrome ◽

Age At Onset ◽

Nucleotide Polymorphisms ◽

Risk Alleles ◽

Increased Risk ◽

Estrogen Activity ◽

Intron 4

Background/Aims. Genetic variants that affect estrogen activity may influence the risk of Alzheimer's disease (AD). In women with Down syndrome, we examined the relation of polymorphisms in hydroxysteroid-17beta-dehydrogenase (HSD17B1) to age at onset and risk of AD.HSD17B1encodes the enzyme 17β-hydroxysteroid dehydrogenase (HSD1), which catalyzes the conversion of estrone to estradiol.Methods. Two hundred and thirty-eight women with DS, nondemented at baseline, 31–78 years of age, were followed at 14–18-month intervals for 4.5 years. Women were genotyped for 5 haplotype-tagging single-nucleotide polymorphisms (SNPs) in theHSD17B1gene region, and their association with incident AD was examined.Results. Age at onset was earlier, and risk of AD was elevated from two- to threefold among women homozygous for the minor allele at 3 SNPs in intron 4 (rs676387), exon 6 (rs605059), and exon 4 inCOASY(rs598126). Carriers of the haplotype TCC, based on the risk alleles for these three SNPs, had an almost twofold increased risk of developing AD (hazard ratio = 1.8, 95% CI, 1.1–3.1).Conclusion. These findings support experimental and clinical studies of the neuroprotective role of estrogen.

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Investigating the Link Between Trisomy 21 and Acquired Mutations in the GATA1 Gene

The Physician ◽

10.38192/1.6.1.c9 ◽

2019 ◽

Vol 6 (1) ◽

pp. c9

Author(s):

Triya Chakravorty ◽

Irene Roberts

Keyword(s):

Down Syndrome ◽

Acute Myeloid Leukaemia ◽

Myeloid Leukaemia ◽

Trisomy 21 ◽

Children With Down Syndrome ◽

Transient Abnormal Myelopoiesis ◽

Increased Risk ◽

Leukaemic Cells ◽

Acute Myeloid

Children with Down syndrome (DS) due to trisomy 21 (T21) are at an increased risk of developing the neonatal preleukaemic disorder transient abnormal myelopoiesis (TAM), which may transform into childhood acute myeloid leukaemia (ML-DS). Leukaemic cells in TAM and ML-DS have acquired mutations in the GATA1 gene. Although it is clear that acquired mutations in GATA1 are necessary for the development of TAM and ML-DS, questions remain concerning the mechanisms of disease.

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Investigating the clinical, pathological and molecular profile of oncocytic adrenocortical neoplasms

Endocrine Oncology ◽

10.1530/eo-21-0011 ◽

2021 ◽

Author(s):

Eleanor Fewings ◽

Serena Khoo Sert Kim ◽

Alexey Larionov ◽

Alison Marker ◽

Olivier Giger ◽

...

Keyword(s):

Treatment Strategies ◽

Case Series ◽

Missense Variant ◽

Molecular Profiling ◽

The Cancer Genome Atlas ◽

Biological Behavior ◽

Molecular Profile ◽

Mutation Burden ◽

Rare Tumours ◽

Paired Tumour

Background: Malignant oncocytic adrenocortical neoplasms (OANs) are rare tumours with a distinctive biological behavior compared to conventional adrenocortical carcinoma (ACC). The current prognostic systems overestimate the malignant potential of these tumours and guidance for surveillance and treatment strategies are lacking. Aim: To evaluate the utility of clinical, pathological and molecular markers in predicting the biological behavior and outcomes of malignant OANs. Methods: A retrospective clinicopathological review of ten histologically confirmed OANs was carried out. Whole exome sequencing (WES) of germline and paired tumour samples was performed for four of the ten OAN cases and compared to WES data from five cases of conventional ACC and data from The Cancer Genome Atlas (TCGA). We reviewed all cases of malignant OAN reported in the literature and compared to our case series. Results: Eight (80%) tumours were classified as malignant, one borderline and one benign (Lin-Weiss-Bisceglia criteria: LWB). The malignant OAN were larger tumours and had higher MIB index and Helsinki scores. Molecular profiling identified a pathogenic germline variant in MSH6 in an individual in the OAN group. The OAN samples had a lower mutation burden compared to the ACC samples. Somatic driver variants were identified in OAN and ACC samples including a pathogenic missense variant in CTNNB1. Conclusion: In this study, the LWB classification demonstrated sensitivity for the differentiation of benign from malignant OAN. Molecular profiling identified dysregulation in DNA repair and Wnt signaling pathways in both OAN and ACC samples, suggesting a molecular overlap between OAN and conventional ACC.

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