18q Deletion Syndrome-Associated Schizophrenia: A Case Report.

INTRODUCTION: 18q deletion syndrome is a rare genetic disorder characterized by various neurodevelopmental anomalies and medical issues. Although the occurrence of psychosis has been reported in a small number of cases, details regarding the nature of such symptoms and their response to treatment have not been described. CASE PRESENTATION: We describe a 31-year-old male with a history of speech delays, autistic features, a tethered spinal cord, bilateral vertical talus, subaortic stenosis and aortic regurgitation, recurrent otitis media, mild hearing loss, and hypospadias, who experienced a first episode of psychosis in his late 20s. His psychotic symptoms included auditory hallucinations, various delusions, and disorganization of thought. Although his presentation is atypical in certain ways (e.g., exhibiting highly fluctuant symptoms), he nonetheless meets criteria for schizophrenia. Given his overall clinical picture, chromosomal microarray analysis was completed, which revealed a 19.78 Mb deletion at 18q21.32 from nucleotide 58,226,713 to 78,015,180 (GRCh37). Despite exhibiting a somewhat idiosyncratic response to numerous antipsychotic medications, he eventually achieved partial remission of symptoms with improved insight on relatively low dose oral aripiprazole therapy. CONCLUSION: This is the first in-depth description of 18q deletion syndrome-associated schizophrenia. While our patient's atypical presentation and idiosyncratic response to treatment may be mediated by his comorbid diagnosis of autism, his unusual psychiatric phenotype may alternatively be directly related to his underlying genetic disorder. The description of additional cases in the future will hopefully help clarify matters further.

13q12.2 deletions in acute lymphoblastic leukemia lead to upregulation of FLT3 through enhancer hijacking.

Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene in 13q12.2 are among the most common driver events in acute leukemia, leading to increased cell proliferation and survival through activation of the phosphatidylinositol 3-kinase/AKT-, RAS/MAPK-, and STAT5-signaling pathways. In this study, we examine the pathogenetic impact of somatic hemizygous 13q12.2 microdeletions in B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) using 5 different patient cohorts (in total including 1418 cases). The 13q12.2 deletions occur immediately 5' of FLT3 and involve the PAN3 locus. By detailed analysis of the 13q12.2 segment, we show that the deletions lead to loss of a topologically associating domain border and an enhancer of FLT3. This results in increased cis interactions between the FLT3 promoter and another enhancer located distally to the deletion breakpoints, with subsequent allele-specific upregulation of FLT3 expression, expected to lead to ligand-independent activation of the receptor and downstream signaling. The 13q12.2 deletions are highly enriched in the high-hyperdiploid BCP ALL subtype (frequency 3.9% vs 0.5% in other BCP ALL) and in cases that subsequently relapsed. Taken together, our study describes a novel mechanism of FLT3 involvement in leukemogenesis by upregulation via chromatin remodeling and enhancer hijacking. These data further emphasize the role of FLT3 as a driver gene in BCP ALL.

Sensory processing and adaptive behavior in Phelan-McDermid syndrome: a cross-sectional study.

Phelan-McDermid syndrome (PMS) is a genetic disorder caused by a mutation or deletion of the SHANK3 gene (chromosome 22q13.3), characterized by different sensory processing anomalies. The objective of this study is to expand and provide a detailed definition of the sensory profile of patients with PMS. The secondary objective was to examine the relationship between sensory patterns and adaptive behavior. A cross-sectional study was carried out among 51 Spanish patients with a confirmed genetic diagnosis of PMS. All the participants' parents completed the Short Sensory Profile-Spanish (SSP-S) and the Adaptive Behavior Assessment System II (ABAS-II). Correlational, multiple regression and hierarchical cluster analyses were performed. An atypical sensory profile was identified in almost 75% of PMS patients. Definite differences were found among scores; nonetheless, sub-threshold values were observed in tactile sensitivity, underresponsive/seeks sensation, auditory filtering, and low energy/weak sensory categories. Conceptual, social, and practical domains, as well as the General Adaptive Composite (GAC) of the ABAS-II showed extremely low scores (i.e., <70). Significant correlations were found (p<0.005) between SSP-S scores and the conceptual, social, practical, and GAC index of the ABAS-II, whereby higher SSP-S scores were associated with better skills and higher adaptive performance. The cluster analysis indicated that the group with the largest mutation size (7.23 Mb) showed the greatest sensory processing difficulties and very low adaptive skills. CONCLUSIONS: Patients with PMS show an atypical sensory profile, which correlates with limitations in general adaptive behaviors. WHAT IS KNOWN: • PMS sensory processing difficulties were associated with a pattern of underresponsive/seeks sensation, low energy/weak, and tactile hyporeactivity. • Sensory processing difficulties have been associated with limitations in the development of appropriate adaptive communication and interaction behaviors. WHAT IS NEW: • Sensory definite differences associated with tactile hyperreactivity, as well as significant effects of underresponsiveness/seeks sensation and auditory filtering categories on the adaptive abilities were found in SHANK3deletion patients. • Cluster analysis suggests that smaller mutation sizes were related to better sensory processing and higher adaptive skills, while patients with larger deletion sizes have greater adaptive difficulties and worse sensory processing skills.

Terminal 6q deletions cause brain malformations, a phenotype mimicking heterozygous DLL1 pathogenic variants: A multicenter retrospective case series.

OBJECTIVE: Terminal 6q deletion is a rare genetic condition associated with a neurodevelopmental disorder characterized by intellectual disability and structural brain anomalies. Interestingly, a similar phenotype is observed in patients harboring pathogenic variants in the DLL1 gene. Our study aimed to further characterize the prenatal phenotype of this syndrome as well as to attempt to establish phenotype-genotype correlations. METHOD: We collected ultrasound findings from 22 fetuses diagnosed with a pure 6qter deletion. We reviewed the literature and compared our 22 cases with 14 fetuses previously reported as well as with patients with heterozygous DLL1 pathogenic variants. RESULTS: Brain structural alterations were observed in all fetuses. The most common findings (>70%) were cerebellar hypoplasia, ventriculomegaly, and corpus callosum abnormalities. Gyration abnormalities were observed in 46% of cases. Occasional findings included cerebral heterotopia, aqueductal stenosis, vertebral malformations, dysmorphic features, and kidney abnormalities. CONCLUSION: This is the first series of fetuses diagnosed with pure terminal 6q deletion. Based on our findings, we emphasize the prenatal sonographic anomalies, which may suggest the syndrome. Furthermore, this study highlights the importance of chromosomal microarray analysis to search for submicroscopic deletions of the 6q27 region involving the DLL1 gene in fetuses with these malformations.

Morbidity and mortality following noncardiac surgical procedures among children with autosomal trisomy.

BACKGROUND: Trisomy 13 (T13), trisomy 18 (T18), and trisomy 21 (T21) are the most common autosomal trisomies. One unifying feature of all trisomies is their association with major congenital malformations, which often require life-prolonging surgical procedures. Few studies, mostly among cardiac surgery patients, have examined the outcome of those who undergo surgical procedures. We examined the differences in postsurgical outcomes between the trisomy groups. METHOD: Using the National Surgical Quality Improvement Program dataset, we identified children (<18 years of age) with T13, T18, or T21 who underwent noncardiac surgery (2012-2018). We estimated the incidence of mortality and indicator of resource utilization (unplanned reoperation, unplanned tracheal reintubation, and extended length of hospital stay). RESULTS: Of the 349 158 inpatient surgical cases during the study period, we identified 4202 children with one of the autosomal trisomies of interest (T13: 152; T18: 335; and T21: 3715). The rates of postoperative mortality were substantially higher for T18 and T13 than T21 and nontrisomy children (T18 vs. T21: 11.1% vs. 1.6%, adjusted odds ratio: 5.01, 95%CI: 2.89,8.70, p < .01), (T13 vs. T21: 8.1% vs. 1.6%, adjusted odds ratio: 2.86, 95%CI: 1.25,6.54, p = .01). Children with T18 had the highest rates of extended length of stay (62.7%) and prolonged mechanical ventilation (32.5%). T18 and T13 neonates had the highest surgical mortality burden (T13: 26.5%, T18: 31.8%, and T21: 2.8%). CONCLUSION: Approximately, one-third of T18 and T13 neonates, who had surgery, died, underscoring the lethality of these trisomies and the need for a comprehensive preoperative ethical discussion with families of these children.

A Case Report of Respiratory Syncytial Virus-Infected 8p Inverted Duplication Deletion Syndrome with Low Natural Killer Cell Activity.

The 8p inverted duplication deletion [inv dup del(8p)] is a complex structural rearrangement in chromosome 8. Patients with this chromosomal abnormality exhibit developmental delay, facial dysmorphism, central nervous abnormalities, hypotonia, orthopedic abnormalities, and congenital heart defects. However, cellular immune function in inv dup del(8p) syndrome has never been reported. We present the case of a 1-month-old boy with inv dup del(8p) syndrome who had severe respiratory syncytial (RS) virus bronchiolitis. Natural killer (NK) cells are recruited to airway epithelium in the early phase of RS viral infection. A cluster of defensin genes (DEFs), which are deleted in inv dup del(8p), are located in 8p23.1. Human defensins are involved in antiviral activity through the NK cell-mediated cytotoxic pathway and envelope disruption in the normal immune response. This patient showed lower NK cell activity and α-defensin level compared with healthy controls. These results suggest that decreased NK cell activity can result from DEF haploinsufficiency. In addition to a skeletal deformity with chromosomal abnormality, NK cell-mediated immune deficiency may account for the exacerbation of RS virus bronchiolitis.

Retinoblastoma management in 13q deletion syndrome patients using super-selective chemotherapies and other cancer-directed interventions.

BACKGROUND: This study aimed to identify best practices for treating 13q deletion syndrome (13q-) patients with retinoblastoma in the era of super-selective ophthalmic artery chemosurgery (OAC) and intravitreal injection therapy (IVIT). METHODS: Retrospective study of 21 eyes from 14 patients with retinoblastoma and 13q- who were treated at Memorial Sloan Kettering Cancer Center (MSKCC) between May 2006 and May 2020, with a mean follow up of 3.7 years. Ocular survival, patient survival, and treatment toxicities were assessed. RESULTS: Nine of the 12 eyes that underwent OAC/IVIT at MSKCC have been progression free for at least 1 year since their last treatments. Fifteen out of 26 OAC cycles resulted in grade 3-4 hematologic toxicity. There was one death from sepsis in the setting of intravenous chemotherapy (IVC) for metastatic disease that occurred after OAC/IVIT therapy. The 2-year Kaplan-Meier ocular survival estimate for the whole cohort was 75% and for the eyes that received OAC or IVIT at MSKCC 83%. For OAC hematologic toxicities, one platelet transfusion and two filgrastim doses were administered, and one patient was hospitalized for neutropenic fevers. CONCLUSIONS: The majority of 13q- eyes treated with OAC/IVIT-based regimens can be cured, and there were no deaths related to complications from OAC or IVIT. 13q- Patients did have increased risk of systemic treatment complications, even from super-selective chemotherapies. Despite these toxicities, only one patient developed febrile neutropenia, one patient required a blood product transfusion, and two patients received filgrastim for both OAC and IVC complications. PRÉCIS: Children with 13q deletion syndrome with retinoblastoma managed with intra-arterial and intravitreal chemotherapy have excellent patient and ocular survival with acceptable toxicity.

Chromosomal mosaicism: Origins and clinical implications in preimplantation and prenatal diagnosis.

The diagnosis of chromosomal mosaicism in the preimplantation and prenatal stage is fraught with uncertainty and multiple factors need to be considered in order to gauge the likely impact. The clinical effects of chromosomal mosaicism are directly linked to the type of the imbalance (size, gene content, and copy number), the timing of the initial event leading to mosaicism during embryogenesis/fetal development, the distribution of the abnormal cells throughout the various tissues within the body as well as the ratio of normal/abnormal cells within each of those tissues. Additional factors such as assay noise and culture artifacts also have an impact on the significance and management of mosaic cases. Genetic counseling is an important part of educating patients about the likelihood of having a liveborn with a chromosome abnormality and these risks differ according to the time of ascertainment and the tissue where the mosaic cells were initially discovered. Each situation needs to be assessed on a case-by-case basis and counseled accordingly. This review will discuss the clinical impact of finding mosaicism through: embryo biopsy, chorionic villus sampling, amniocentesis, and noninvasive prenatal testing using cell-free DNA.

Case report: Spinal anesthesia for cesarean section in a parturient with Potocki-Lupski syndrome.

BACKGROUND: Potocki -Lupski syndrome is an uncommon disorder caused by a micro-duplication in chromosome 17p11.2. Variable clinical manifestations bring troubles to the general and neuraxial anesthesia, including mental retardation, facial dysmorphisms, structural cardiovascular anomalies, scoliosis, and malignant hyperthermia. Until now, the anesthesia management for cesarean section in these patients has not been reported yet. CASE PRESENTATION: Here we present a 23-year-old Chinese parturient with Potocki -Lupski syndrome who underwent elective cesarean section under spinal anesthesia. She was transferred to our hospital in her 40th week of gestation. She had a history of IgA nephropathy for more than three years and was diagnosed with Potocki -Lupski syndrome (17p12p11.2 segment 3.1 Mb repeat) in the 29th week of pregnancy. Amniocentesis showed the fetus had no abnormal autosomes. Preoperative multidisciplinary consultation suggested that she should terminate the pregnancy as soon as possible. She was ASA II. Her BMI was 26.43 kg/m2. Her airway evaluation was normal. Her spine could bend well and her spinal interspace could be touched clearly. We did the single spinal anesthesia at L2-3 interspace and gave 0.5% bupivacaine 1.7 ml. The absolute anesthesia level reached T8. The Apgar score for the newborn infant was 10 for 1st minute, 5th minute, and 10th minute. The vital signs were steady without using any vasoactive drugs. The patient had a good prognosis, and was subsequently discharged from hospital. CONCLUSION: To date, the case may be the first reported spinal anesthesia for the parturient with Potocki -Lupski syndrome. Although its manifestations are variable, the spinal anesthesia is feasible under careful and comprehensive preoperative evaluation.

Phelan McDermid Syndrome: Multiple Sclerosis as a Rare but Treatable Cause for Regression-A Case Report.

Phelan McDermid syndrome (PMcD) is a neurogenetic disease associated with haploinsufficiency of the SHANK3 gene due to a spectrum of anomalies in the terminal region of the long arm of chromosome 22. SHANK3 is the abbreviation for SH3 domain and ankyrin repeat-containing protein, a gene that encodes for proteins of the postsynaptic density (PSD) of excitatory synapses. This PSD is relevant for the induction and plasticity of spine and synapse formation as a basis for learning processes and long-term potentiation. Individuals with PMcD present with intellectual disability, muscular hypotonia, and severely delayed or absent speech. Further neuropsychiatric manifestations cover symptoms of the autism spectrum, epilepsy, bipolar disorders, schizophrenia, and regression. Regression is one of the most feared syndromes by relatives of PMcD patients. Current scientific evidence indicates that the onset of regression is variable and affects language, motor skills, activities of daily living and cognition. In the case of regression, patients normally undergo further diagnostics to exclude treatable reasons such as complex-focal seizures or psychiatric comorbidities. Here, we report, for the first time, the case of a young female who developed progressive symptoms of regression and a dystonic-spastic hemiparesis that could be traced back to a comorbid multiple sclerosis and that improved after treatment with methylprednisolone.

Congenital heart defects associated with aneuploidy syndromes: New insights into familiar associations.

The frequent occurrence of congenital heart defects (CHDs) in chromosome abnormality syndromes is well-known, and among aneuploidy syndromes, distinctive patterns have been delineated. We update the type and frequency of CHDs in the aneuploidy syndromes involving trisomy 13, 18, 21, and 22, and in several sex chromosome abnormalities (Turner syndrome, trisomy X, Klinefelter syndrome, 47,XYY, and 48,XXYY). We also discuss the impact of noninvasive prenatal screening (mainly, cell-free DNA analysis), critical CHD screening, and the growth of parental advocacy on their surgical management and natural history. We encourage clinicians to view the cardiac diagnosis as a "phenotype" which supplements the external dysmorphology examination. When detected prenatally, severe CHDs may influence decision-making, and postnatally, they are often the major determinants of survival. This review should be useful to geneticists, cardiologists, neonatologists, perinatal specialists, other pediatric specialists, and general pediatricians. As patients survive (and thrive) into adulthood, internists and related adult specialists will also need to be informed about their natural history and management.

Incontinence and psychological symptoms in Phelan-McDermid syndrome.

AIMS: Phelan-McDermid syndrome (PMD) is a congenital syndrome caused by a deletion on chromosome 22q13.3. About 600 cases have been identified worldwide. PMD is characterized by neonatal hypotonia, moderate/severe intellectual impairment, impaired expressive language, and typical dysmorphic features. Psychological symptoms as hyperactivity, attention problems, restlessness, and stereotyped-repetitive behavior were reported. The aim of the study was to assess incontinence and associated psychological problems in PMD. METHODS: Forty-one individuals with PMD were recruited through a German support group (48.8% male; mean age 13.4 years; range, 4-55 years). Parents or caregivers completed the developmental behavior checklist (DBC), as well as the parental questionnaire: enuresis/urinary incontinence, including six questions on adaptive toileting skills. RESULTS: Rates of nocturnal enuresis (NE), daytime urinary incontinence, and fecal incontinence were 86%, 73%, and 79%. Rates were similar in all age groups (children, teens, adults). Constipation was present in 19%. Forty-two percent of the sample had a clinically relevant DBC score, with adults more affected than teens. Persons with NE had significantly higher "anxiety/depression" subscale scores. Toileting skills were more developed in adults than in children. Sixty-eight percent had further physical disabilities. CONCLUSIONS: Incontinence rates in PMD are high in all age groups. However, persons with PMD can improve their toilet skills. Therefore, the assessment and treatment of incontinence in persons with PMD is recommended. Constipation does not seem to be a major problem in PMD. Due to the high prevalence rates of somatic conditions, an assessment for organic and functional incontinence is recommended.

Pediatric waitlist and heart transplant outcomes in patients with syndromic anomalies.

PURPOSE: We sought to determine whether the presence of a systemic SA with potential complicating factors affects waitlist and post-HT outcomes in pediatric patients. METHODS: This is a single-center retrospective review of pediatric patients listed for HT between January 1, 2009, and July 1, 2018. Patients were selected based on the presence of any underlying syndromes, which included chromosomal anomalies, skeletal myopathies, connective tissue disorders, mitochondrial disease,and other systemic disorders. Waitlist and post-HT outcomes were compared to those without SA. RESULTS: A total of 243 patients were listed for HT, of which 21 (9%) patients had associated SA. Of those, 16 (76%) survived to transplant, 3 (14%) died while on the waitlist, 1 (5%) improved and was removed from the waitlist, and 1 (5%) patient is currently listed. Waitlist survival was not different between those with/without an associated syndrome (P = 1.0). Among those who survived to HT, there was no difference in listing days (70 vs 90, P = .8), survival to hospital discharge [14 (93%) vs 150 (95%), P = .6], post-HT intubation days (2 vs 2 days, P = .6), or post-HT hospital length of stay (18 vs 18 days, P = .8). Overall survival during the study period post-HT was not different between groups (P = .8). CONCLUSION: A SA was present in 9% of pediatric patients wait-listed for HT, but was not associated with an increased waitlist mortality or post-HT hospital morbidity or long-term survival. For several anomalies, HT is safe and feasible.

Utility of chromosomal microarray for diagnosis in cases of nonimmune hydrops fetalis.

PURPOSE: Chromosomal microarray (CMA) is recommended in the diagnostic evaluation of cases with fetal structural anomalies when invasive testing is pursued. However, the utility of CMA for nonimmune hydrops fetalis (NIHF) specifically is not well known. Our objective was to describe the overall yield of CMA in the diagnostic evaluation of NIHF, comparing isolated cases to those with concurrent structural anomalies. METHODS: This was a retrospective cohort study of all prenatally diagnosed NIHF cases evaluated at the University of California, San Francisco from 2008 to 2018. NIHF due to twin-twin transfusion syndrome was excluded. RESULTS: There were 131 cases of prenatally diagnosed NIHF. In 43/44 cases with a CMA performed, results were categorized as normal or likely benign. One case was found on CMA to have a large pathogenic duplication of 21p11.2q22.3, which could have been detected by karyotype and was consistent with a diagnosis of Down syndrome. There was no incremental yield demonstrated for CMA over karyotype. CONCLUSIONS: Among a cohort of prenatally diagnosed NIHF cases, CMA did not identify any copy number variants beyond those detectable by karyotype, and the vast majority of CMAs were normal. These results suggest that CMA has low diagnostic utility for NIHF.

Acute Orbital Compromise after Intra-Arterial Chemotherapy in a Complex Retinoblastoma Associated with 13q Deletion Syndrome.

INTRODUCTION: The intra-arterial chemotherapy (IAC) is increasingly used as a first-line therapy for retinoblastoma. The IAC has proved to be relatively safe. However, many local side effects of IAC have been described. CASE PRESENTATION: This case report describes a local side effect presenting as proptosis and myositis with vascular access difficulty of the middle meningeal artery, in a 2-year-old male with left eye diffuse multifocal stage Vb retinoblastoma complicated with retinal detachment. DISCUSSION/CONCLUSION: IAC is assured to provide as efficient results in eliminating the tumor as the systemic chemotherapy, without causing the systemic side effects. It has become an alternative to systemic chemotherapy. A better understanding of the local side effects is required.

Atypical Prader-Willi and 15q13.3 Microdeletion Syndromes in a Patient with an Unbalanced Translocation.

Prader-Willi syndrome (PWS) and recurrent 15q13.3 microdeletion syndrome can be caused by genomic rearrangements in the complex 15q11q13 chromosomal region. Here, we describe the first female child with PWS and 15q13.3 microdeletion syndrome resulting from an unusual 10.7-Mb deletion from 15pter to 15q13.3 due to an unbalanced de novo 15;19 translocation. The patient presents with hypotonia, microcephaly, developmental delay with lack of speech, intellectual disability, happy demeanor, clinodactyly of the 4th and 5th fingers, and dysmorphic facial features discordant for PWS and consistent with an atypical phenotype.

Objective measures of sleep disturbances in children with Potocki-Lupski syndrome.

Potocki-Lupski syndrome (PTLS; MIM 610883) is a neurodevelopmental disorder caused by a microduplication, a 3.7 Mb copy number variant, mapping within chromosome 17p11.2, encompassing the dosage-sensitive RAI1 gene. Whereas RAI1 triplosensitivity causes PTLS, haploinsufficiency of RAI1 due to 17p11.2 microdeletion causes the clinically distinct Smith-Magenis syndrome (SMS; MIM 182290). Most individuals with SMS have an inversion of the melatonin cycle. Subjects with PTLS have mild sleep disturbances such as sleep apnea with no melatonin abnormalities described. Sleep patterns and potential disturbances in subjects with PTLS have not been objectively characterized. We delineated sleep characteristics in 23 subjects with PTLS who underwent a polysomnogram at Texas Children's Hospital. Eleven of these subjects (58%) completed the Child's Sleep Habits Questionnaire (CSHQ). Urinary melatonin was measured in one patient and published previously. While the circadian rhythm of melatonin in PTLS appears not to be disrupted, we identified significant differences in sleep efficiency, percentage of rapid eye movement sleep, oxygen nadir, obstructive apnea hypopnea index, and periodic limb movements between prepubertal subjects with PTLS and previously published normative data. Data from the CSHQ indicate that 64% (7/11) of parents do not identify a sleep disturbance in their children. Our data indicate that younger individuals, <10 years, with PTLS have statistically significant abnormalities in five components of sleep despite lack of recognition of substantial sleep disturbances by parents. Our data support the contention that patients with PTLS should undergo clinical evaluations for sleep disordered breathing and periodic limb movement disorder, both of which are treatable conditions.

Long-term remission of bilateral Wilms tumors that developed from premature separation of chromatids/mosaic variegated aneuploidy syndrome due to bilateral nephrectomy and peritoneal dialysis.

We report a 38-month-old Japanese male with premature chromatid separation/mosaic variegated aneuploidy syndrome bearing biallelic BUB1B germline mutations who suffered from bilateral Wilms tumor. After right nephrectomy, dactinomycin monotherapy was administered for the left Wilms tumor; however, severe adverse reaction prevented the patient from receiving further chemotherapy. Left nephrectomy was then performed without postoperative chemotherapy. The patient survived for 15 months after bilateral nephrectomy without peritoneal relapse, metastasis of Wilms tumor, or the occurrence of rhabdomyosarcoma and maintained a good quality of life while receiving peritoneal dialysis at home.

Focal Cortical Anomalies and Language Impairment in 16p11.2 Deletion and Duplication Syndrome.

Individuals with copy number variants (CNV) in the 16p11.2 chromosomal region are at high risk for language disorders. We investigate whether the extent and location of focal cortical anomalies are associated with language impairment in individuals with 16p11.2 CNVs. High-resolution T1-weighted MRI scans from 30 16p11.2 deletion (16p-del), 25 16p11.2 duplication (16p-dup), and 90 noncarrier controls (NCC) were analyzed to derive personalized cortical anomaly maps through single-case cortical thickness (CT) comparison to age-matched normative samples. Focal cortical anomalies were elevated in both 16p-del and 16p-dup and their total extent was inversely correlated with Full-Scale IQ. Clusters of abnormally thick cortex were more extensive in the 16p-del group and clusters of abnormally thin cortex were more extensive in the 16p-dup group. Abnormally thick clusters were more extensive in left lateral temporal and bilateral postcentral and mesial occipital regions in 16p-del. Focal cortical anomalies in the left middle temporal region and pars opercularis (Broca's region) of children with 16-del were associated with lower scores on a comprehensive language evaluation. Results extend neuroanatomical findings in 16p11.2 syndrome to include spatially heterogenous focal cortical anomalies that appear to disrupt language ability in accordance with the functional specialization of left frontotemporal regions.

Mosaic trisomy 22 in a 4-year-old boy with congenital heart disease and general hypotrophy: A case report.

BACKGROUND: Trisomy 22 mosaicism is a rare autosomal anomaly with survival compatibility. Recognition of the complete trisomy 22 which is incompatible with life from the mosaic form is critical for genetic counseling. Affected mosaic cases have prevalent clinical presentations such as webbed neck, developmental delay, abnormal ears, cardiac disorders, and microcephaly. Phenotype of these patients is milder than full chromosomal aneuploidy, and the severity of the phenotype depends on the count of trisomic cells. We describe a 4-year-old boy with mosaic trisomy 22 from healthy parents and no family history of any genetic disorders in the pedigree. METHOD AND RESULTS: The patient had determined dysmorphic clinical features including facial asymmetry, cleft palate, gastroenteritis, hydronephrosis, developmental delay, genital anomalies, dysplastic toenails, flattened nasal bridge, congenital heart defect, hearing loss, cryptorchidism, and hypotonic muscle. He is the first reported with hypothyroidism and larynx wall thickness in worldwide and the first with atrial septal defect (ASD) from Iran. Chromosomal analyses using G-banding indicated a de novo Mos 47,XY,+22(6)/46,XY(44) karyotype with no other chromosomal structural changes. CONCLUSIONS: Our observations confirm the importance of cytogenetic analyses for determining the cause of congenital anomalies and provide a useful genetic counseling. In addition, due to the fact that some of mosaic trisomy 22 features are unavoidable such as CHD and general hypotrophy, we suggest including echocardiography test for early diagnosis during the clinical assessment.