Complex lymphatic anomalies: Molecular landscape and medical management.

The lymphatic system is one of the most essential and complex systems in the human body. Disorders that affect the development or function of the lymphatic system can lead to multi-system complications and life-long morbidity. The past two decades have seen remarkable progress in our knowledge of the basic biology and function of the lymphatic system, the molecular regulators of lymphatic development, and description of disorders associated with disrupted lymphangiogensis. In this chapter we will touch on the clinical features of complex lymphatic anomalies, new molecular knowledge of the drivers of these disorders, and novel developmental therapeutics for lymphatic disease.

A Retrospective Analysis of Early 20th Century Asylum Records of Patients with Dementia Praecox.

Mental illness definitions and classifications are to a certain extent intrinsically tied to social factors. To empirically examine the impact of sociodemographic factors on patients institutionalized with dementia praecox in the early 20th century, we examined records from Dorothea Dix Hospital (DDH), an asylum in Southeastern United States. Data was extracted from digitally archived handwritten admission ledgers and general casebooks. Of those institutionalized at DDH between 1896-1917, 190 patients were diagnosed with dementia praecox. Clinical characteristics of patients are described using descriptive text analysis. We used regression models to examine the influence of sociodemographic factors on length of stay and release condition from the asylum. Race was not recorded for any patient and presumed White since DDH was not racially integrated until 1960s. Women had a significantly increased odds (OR = 3.8, p = 0.016) of dying in the facility than getting discharged; being single significantly increased the odds of dying in the facility (OR = 6.8, p = 0.002). Marital status predicted length of stay-being single increased the length of stay (b = 5.97, t (159) = 2.43, p = 0.016) adjusting for the effects of gender, age, and education. We report the impact of gender and marital status on patient release condition and length of stay in an asylum in the early 20th century. Results from the historical data we empirically examined are relevant today as women continue to experience disparities in mental health care. Family support was crucial to better outcomes then, as it is today.

Microcystic lymphatic malformations in Turner syndrome are due to somatic mosaicism of PIK3CA.

Turner syndrome (45,X) is caused by a complete or partial absence of a single X chromosome. Vascular malformations occur due to abnormal development of blood and/or lymphatic vessels. They arise from either somatic or germline pathogenic variants in the genes regulating growth and apoptosis of vascular channels. Aortic abnormalities are a common, known vascular anomaly of Turner syndrome. However, previous studies have described other vascular malformations as a rare feature of Turner syndrome and suggested that vascular abnormalities in individuals with Turner syndrome may be more generalized. In this study, we describe two individuals with co-occurrence of Turner syndrome and vascular malformations with a lymphatic component. In these individuals, genetic testing of the lesional tissue revealed a somatic pathogenic variant in PIK3CA-a known and common cause of lymphatic malformations. Based on this finding, we conclude that the vascular malformations presented here and likely those previously in the literature are not a rare part of the clinical spectrum of Turner syndrome, but rather a separate clinical entity that may or may not co-occur in individuals with Turner syndrome.

Updates in Genetic Testing for Head and Neck Vascular Anomalies.

Vascular anomalies include benign or malignant tumors or benign malformations of the arteries, veins, capillaries, or lymphatic vasculature. The genetic etiology of the lesion is essential to define the lesion and can help navigate choice of therapy. . In the United States, about 1.2% of the population has a vascular anomaly, which may be underestimating the true prevalence as genetic testing for these conditions continues to evolve.

Genomic profiling informs diagnoses and treatment in vascular anomalies.

Vascular anomalies are malformations or tumors of the blood or lymphatic vasculature and can be life-threatening. Although molecularly targeted therapies can be life-saving, identification of the molecular etiology is often impeded by lack of accessibility to affected tissue samples, mosaicism or insufficient sequencing depth. In a cohort of 356 participants with vascular anomalies, including 104 with primary complex lymphatic anomalies (pCLAs), DNA from CD31+ cells isolated from lymphatic fluid or cell-free DNA from lymphatic fluid or plasma underwent ultra-deep sequencing thereby uncovering pathogenic somatic variants down to a variant allele fraction of 0.15%. A molecular diagnosis, including previously undescribed genetic causes, was obtained in 41% of participants with pCLAs and 72% of participants with other vascular malformations, leading to a new medical therapy for 63% (43/69) of participants and resulting in improvement in 63% (35/55) of participants on therapy. Taken together, these data support the development of liquid biopsy-based diagnostic techniques to identify previously undescribed genotype-phenotype associations and guide medical therapy in individuals with vascular anomalies.

Mosaic pathogenic variants in AKT3 cause capillary malformation and undergrowth.

Capillary malformations are slow-flow vascular malformations that affect the microcirculation including capillaries and post capillary venules and can be associated with growth differences. Specifically, the association of capillary malformations with undergrowth is a vastly understudied vascular syndrome with few reports of genetic causes including PIK3CA, GNAQ, and GNA11. Recently, a somatic pathogenic variant in AKT3 was identified in one child with a cutaneous vascular syndrome similar to cutis marmorata telangiectatica congenita, undergrowth, and no neurodevelopmental features. Here, we present a male patient with a capillary malformation and undergrowth due to a somatic pathogenic variant in AKT3 to confirm this association. It is essential to consider that mosaic pathogenic variants in AKT3 can cause a wide spectrum of disease. There is a need for future studies focusing on capillary malformations with undergrowth to understand the underlying mechanism.

Increased Prevalence of Rare Copy Number Variants in Treatment-Resistant Psychosis.

BACKGROUND: It remains unknown why ~30% of patients with psychotic disorders fail to respond to treatment. Previous genomic investigations of treatment-resistant psychosis have been inconclusive, but some evidence suggests a possible link between rare disease-associated copy number variants (CNVs) and worse clinical outcomes in schizophrenia. Here, we identified schizophrenia-associated CNVs in patients with treatment-resistant psychotic symptoms and then compared the prevalence of these CNVs to previously published schizophrenia cases not selected for treatment resistance. METHODS: CNVs were identified using chromosomal microarray (CMA) and whole exome sequencing (WES) in 509 patients with treatment-resistant psychosis (a lack of clinical response to ≥3 adequate antipsychotic medication trials over at least 5 years of psychiatric hospitalization). Prevalence of schizophrenia-associated CNVs in this sample was compared to that in a previously published large schizophrenia cohort study. RESULTS: Integrating CMA and WES data, we identified 47 cases (9.2%) with at least one CNV of known or possible neuropsychiatric risk. 4.7% (n = 24) carried a known neurodevelopmental risk CNV. The prevalence of well-replicated schizophrenia-associated CNVs was 4.1%, with duplications of the 16p11.2 and 15q11.2-q13.1 regions, and deletions of the 22q11.2 chromosomal region as the most frequent CNVs. Pairwise loci-based analysis identified duplications of 15q11.2-q13.1 to be independently associated with treatment resistance. CONCLUSIONS: These findings suggest that CNVs may uniquely impact clinical phenotypes beyond increasing risk for schizophrenia and may potentially serve as biological entry points for studying treatment resistance. Further investigation will be necessary to elucidate the spectrum of phenotypic characteristics observed in adult psychiatric patients with disease-associated CNVs.

Double aneuploidy mosaicism involving chromosomes 18 and 21 in a neonate.

BACKGROUND: Double aneuploidy is common, especially in products of conception, frequently involving a combination of a sex chromosome and an acrocentric chromosome. Double autosomal trisomies are rare with only five cases reported. Double aneuploidy mosaicism involving two different cell lines is rarer with only three cases reported. CASE PRESENTATION: We report a fourth case of double aneuploidy mosaicism on a baby. Results of a 24-h preliminary chromosome analysis at birth showed a mosaic karyotype, 47,XX,+18[15]/47,XX,+21[8]/48,XX,+21,+mar[7]. Reflex testing to SNP microarray with the same sample collected at birth showed gain of a 77.9 Mb region on chromosome 18 and gain of a 32.5 Mb region on chromosome 21. Microarray did not show any other copy number variants indicating that the marker chromosome may not contain any euchromatic material. A repeat chromosome analysis at 1-year of age showed a mosaic karyotype, 47,XX,+18[76]/47,XX,+21[4] with loss of the marker cell line. CONCLUSION: Based on our results, we propose that the mosaic double autosomal trisomy in our case was due to two independent non-disjunction events in a normal zygote very early during embryogenesis.

Genotypic and phenotypic variability of 22q11.2 microdeletions - an institutional experience.

Patients with chromosome 22q11.2 deletion syndromes classically present with variable cardiac defects, parathyroid and thyroid gland hypoplasia, immunodeficiency and velopharyngeal insufficiency, developmental delay, intellectual disability, cognitive impairment, and psychiatric disorders. New technologies including chromosome microarray have identified smaller deletions in the 22q11.2 region. An increasing number of studies have reported patients presenting with various features harboring smaller 22q11.2 deletions, suggesting a need to better elucidate 22q11.2 deletions and their phenotypic contributions so that clinicians may better guide prognosis for families. We identified 16 pediatric patients at our institution harboring various 22q11.2 deletions detected by chromosomal microarray and report their clinical presentations. Findings include various neurodevelopmental delays with the most common one being attention deficit hyperactivity disorder (ADHD), one reported case of infant lethality, four cases of preterm birth, one case with dual diagnoses of 22q11.2 microdeletion and Down syndrome. We examined potential genotypic contributions of the deleted regions.

Copy neutral absence of heterozygosity on chromosome 15 distal long arm: A surrogate marker for Prader-Willi/Angelman syndromes?

BACKGROUND: Copy-neutral absence of heterozygosity (CN-AOH) observed on a single chromosome or part of a chromosome may be indicative of uniparental disomy (UPD) and may require additional testing when such chromosomes or chromosome regions are known to harbor imprinted genes. CASE PRESENTATION: Here we report 2 cases of neonates that presented to clinic with hypotonia, poor oral skills including inability to feed by mouth, weak cry, no response to noxious stimulation and vertical plantar creases (case 1) and hypotonia and respiratory distress (case 2). A preliminary chromosome analysis showed normal karyotypes in both cases while the high-resolution single nucleotide polymorphism (SNP) microarray showed copy neutral absence of heterozygosity involving chromosome 15 distal long arm. In case 1, the CN-AOH involved a 28.7 Mb block from genomic coordinates 73703619_102429049. In case 2, the CN-AOH involved a 15.3 Mb block from genomic coordinates 54729197_70057534. In both cases, methylation-specific PCR did not detect an unmethylated allele for the SNRPN gene suggesting either a deletion of paternal allele or maternal UPD for chromosome 15. Since microarray analysis did not show any copy number alterations on chromosome 15, a microdeletion was ruled out. CONCLUSIONS: Based on our cases, we suggest that CN-AOH on chromosome 15, even if it does not involve the critical region of 15q12q13, should warrant additional studies for diagnosis of Prader-Willi/Angelman syndromes.

Phenotypes Associated with 16p11.2 Copy Number Gains and Losses at a Single Institution.

Chromosome 16p11.2 is one of the susceptible sites for recurrent copy number variations (CNVs) due to flanking near-identical segmental duplications. Five segmental duplications, named breakpoints 1 to 5 (BP1-BP5), have been defined as recombination hotspots within 16p11.2. Common CNVs on 16p11.2 include a proximal ~593 kb between BP4 and BP5, and a distal ~220 kb between BP2 and BP3. We performed a search for patients carrying 16p11.2 CNVs, as detected using chromosome microarray (CMA), in the Molecular Diagnostic Laboratory at the University of Texas Medical Branch (UTMB), in Galveston. From March 2013 through April 2018, a total of 1200 CMA results were generated for germline testing, and 14 patients tested positive for 16p11.2 CNVs, of whom 7 had proximal deletion, 2 had distal deletion, 4 had proximal duplication, and 1 had distal duplication. Herein, we provide detailed phenotype data for these patients. Our study results show that developmental delay, abnormal body weight, behavioral problems, and hypotonia are common phenotypes associated with 16p11.2 CNVs.

Genotypic and phenotypic variability of 22q11.2 microduplications: An institutional experience.

Duplications in the 22q11.2 region can cause 22q11.2 duplication syndrome and encompass a variety of phenotypes including developmental delays, facial abnormalities, cardiovascular defects, central nervous system delays, and other congenital abnormalities. However, the contribution of these contiguous duplicated regions to the clinical phenotypes has not been fully elucidated. In this study, we identified nine patients carrying different 22q11.2 microduplications detected by chromosomal microarray. Of these patients, seven pediatric patients presented with various clinical features including two neonate cases died shortly after birth, and two healthy adults. We examined region specific genotype-phenotype associations and found unpredictability associated with 22q11.2 duplications in these nine patients.

A De novo HDAC2 variant in a patient with features consistent with Cornelia de Lange syndrome phenotype.

Cornelia de Lange syndrome (CdLS) is an autosomal dominant genetic disorder caused by pathogenic variants in NIPBL, RAD21, SMC3, HDAC8, or SMC1A; all of which code for proteins that are components of, or interact with, the cohesin complex. Despite the identification of multiple genes associated with CdLS, over 25% of individuals strongly suspected to have CdLS have negative genetic testing, indicating that there are additional genes associated with the condition. HDAC2 codes for histone deacetylase 2 (HDAC2) and, like HDAC8, is a Class 1 histone deacetylase. We present a patient with a novel de novo variant in HDAC2 with many clinical features consistent with CdLS including severe developmental delay, limb abnormalities, congenital heart defect, cryptorchidism and hypoplastic genitalia, growth retardation, and characteristic craniofacial features. Although variants in HDAC2 are not currently associated with human disease, the variant identified in this patient is within a highly conserved amino acid residue and has not been observed in healthy populations. This information, along with the patient's clinical presentation and the functional similarity between the HDAC2 and HDAC8 proteins, suggests that HDAC2 should be further investigated as a candidate gene for CdLS or a CdLS-like syndrome.

Natural history and genotype-phenotype correlations in 72 individuals with SATB2-associated syndrome.

SATB2-associated syndrome (SAS) is an autosomal dominant disorder characterized by significant neurodevelopmental disabilities with limited to absent speech, behavioral issues, and craniofacial anomalies. Previous studies have largely been restricted to case reports and small series without in-depth phenotypic characterization or genotype-phenotype correlations. Seventy two study participants were identified as part of the SAS clinical registry. Individuals with a molecularly confirmed diagnosis of SAS were referred after clinical diagnostic testing. In this series we present the most comprehensive phenotypic and genotypic characterization of SAS to date, including prevalence of each clinical feature, neurodevelopmental milestones, and when available, patient management. We confirm that the most distinctive features are neurodevelopmental delay with invariably severely limited speech, abnormalities of the palate (cleft or high-arched), dental anomalies (crowding, macrodontia, abnormal shape), and behavioral issues with or without bone or brain anomalies. This comprehensive clinical characterization will help clinicians with the diagnosis, counseling and management of SAS and help provide families with anticipatory guidance.

Taxonomic and thematic semantic systems.

Object concepts are critical for nearly all aspects of human cognition, from perception tasks like object recognition, to understanding and producing language, to making meaningful actions. Concepts can have 2 very different kinds of relations: similarity relations based on shared features (e.g., dog-bear), which are called "taxonomic" relations, and contiguity relations based on co-occurrence in events or scenarios (e.g., dog-leash), which are called "thematic" relations. Here, we report a systematic review of experimental psychology and cognitive neuroscience evidence of this distinction in the structure of semantic memory. We propose 2 principles that may drive the development of distinct taxonomic and thematic semantic systems: differences between which features determine taxonomic versus thematic relations, and differences in the processing required to extract taxonomic versus thematic relations. This review brings together distinct threads of behavioral, computational, and neuroscience research on semantic memory in support of a functional and neural dissociation, and defines a framework for future studies of semantic memory. (PsycINFO Database Record

Distinct Effects of Lexical and Semantic Competition during Picture Naming in Younger Adults, Older Adults, and People with Aphasia.

Producing a word requires selecting among a set of similar alternatives. When many semantically related items become activated, the difficulty of the selection process is increased. Experiment 1 tested naming of items with either multiple synonymous labels ("Alternate Names," e.g., gift/present) or closely semantically related but non-equivalent responses ("Near Semantic Neighbors," e.g., jam/jelly). Picture naming was fastest and most accurate for pictures with only one label ("High Name Agreement"), slower and less accurate in the Alternate Names condition, and slowest and least accurate in the Near Semantic Neighbors condition. These results suggest that selection mechanisms in picture naming operate at two distinct levels of processing: selecting between similar but non-equivalent names requires two selection processes (semantic and lexical), whereas selecting among equivalent names only requires one selection at the lexical level. Experiment 2 examined how these selection mechanisms are affected by normal aging and found that older adults had significantly more difficulty in the Near Semantic Neighbors condition, but not in the Alternate Names condition. This suggests that aging affects semantic processing and selection more strongly than it affects lexical selection. Experiment 3 examined the role of the left inferior frontal gyrus (LIFG) in these selection processes by testing individuals with aphasia secondary to stroke lesions that either affected the LIFG or spared it. Surprisingly, there was no interaction between condition and lesion group: the presence of LIFG damage was not associated with substantively worse naming performance for pictures with multiple acceptable labels. These results are not consistent with a simple view of LIFG as the locus of lexical selection and suggest a more nuanced view of the neural basis of lexical and semantic selection.

What we talk about when we talk about access deficits.

Semantic impairments have been divided into storage deficits, in which the semantic representations themselves are damaged, and access deficits, in which the representations are intact but access to them is impaired. The behavioural phenomena that have been associated with access deficits include sensitivity to cueing, sensitivity to presentation rate, performance inconsistency, negative serial position effects, sensitivity to number and strength of competitors, semantic blocking effects, disordered selection between strong and weak competitors, correlation between semantic deficits and executive function deficits and reduced word frequency effects. Four general accounts have been proposed for different subsets of these phenomena: abnormal refractoriness, too much activation, impaired competitive selection and deficits of semantic control. A combination of abnormal refractoriness and impaired competitive selection can account for most of the behavioural phenomena, but there remain several open questions. In particular, it remains unclear whether access deficits represent a single syndrome, a syndrome with multiple subtypes or a variable collection of phenomena, whether the underlying deficit is domain-general or domain-specific, whether it is owing to disorders of inhibition, activation or selection, and the nature of the connection (if any) between access phenomena in aphasia and in neurologically intact controls. Computational models offer a promising approach to answering these questions.

Effect of repetition proportion on language-driven anticipatory eye movements.

Previous masked priming research in word recognition has demonstrated that repetition priming is influenced by experiment-wise information structure, such as proportion of target repetition. Research using naturalistic tasks and eye-tracking has shown that people use linguistic knowledge to anticipate upcoming words. We examined whether the proportion of target repetition within an experiment can have a similar effect on anticipatory eye movements. We used a word-to-picture matching task (i.e., the visual world paradigm) with target repetition proportion carefully controlled. Participants' eye movements were tracked starting when the pictures appeared, one second prior to the onset of the target word. Targets repeated from the previous trial were fixated more than other items during this preview period when target repetition proportion was high and less than other items when target repetition proportion was low. These results indicate that linguistic anticipation can be driven by short-term within-experiment trial structure, with implications for the generalization of priming effects, the bases of anticipatory eye movements, and experiment design.

Effects of phonological and semantic deficits on facilitative and inhibitory consequences of item repetition in spoken word comprehension.

Repeating a word can have both facilitative and inhibitory effects on subsequent processing. The present study investigated these dynamics by examining the facilitative and inhibitory consequences of different kinds of item repetition in two individuals with aphasia and a group of neurologically intact control participants. The two individuals with aphasia were matched on overall aphasia severity, but had deficits at different levels of processing: one with a phonological deficit and spared semantic processing, the other with a semantic deficit and spared phonological processing. Participants completed a spoken word-to-picture matching task in which they had to pick which of four object images matched the spoken word. The trials were grouped into pairs such that exactly two objects from the first trial in a pair were present on screen during the second trial in the pair. When the second trial's target was the same as the first trial's target, compared to control participants, both participants with aphasia exhibited equally larger repetition priming effects. When the second trial's target was one of the new items, the participant with a phonological deficit exhibited a significantly more negative effect (i.e., second trial response slower than first trial response) than the control participants and the participant with a semantic deficit. Simulations of a computational model confirmed that this pattern of results could arise from (1) normal residual activation being functionally more significant when overall lexical processing is slower and (2) residual phonological activation of the previous trial's target having a particularly strong inhibitory effect specifically when phonological processing is impaired because the task was phonologically-driven (the spoken input specified the target). These results provide new insights into perseveration errors and lexical access deficits in aphasia.