Clinical and molecular characteristics of hemophilia A affected individuals and carriers: A 24 years experience from three centers.

Hemophilia A is a rare bleeding disorder with variable expressivity and allelic heterogeneity. Despite the advancement of prenatal diagnostics and molecular studies, the number of studies reviewing the reproductive choices of hemophilia A carriers and affected individuals remains limited. Through this retrospective review, we hope to gain a deeper understanding of hemophilia A-affected individuals' clinical and molecular characteristics, as well as the reproductive choices of the at-risk couples. A total of 122 individuals harboring likely causative F8 gene alterations from 64 apparently unrelated families attending three centers between 3/2000 and 3/2023 were included in this study. Their clinical and molecular findings as well as reproductive choices were gathered in a clinical setting and verified through the electronic medical record database of the public health system. Forty-seven affected males and 75 female heterozygous carriers were included in the analysis. Among 64 apparently unrelated families, 36 distinct pathogenic/likely pathogenic variants were identified, of which 30.6% (11/36) of variants were novel. While the majority of clinical findings and genotype-phenotype correlations appear to be in accordance with existing literature, female carriers who had no fertility intention were significantly more likely to have affected sons than those who had fertility intention (5/19 vs. 4/5; p = 0.047). Through this retrospective review, we summarized the clinical and molecular characteristics of 122 individuals harboring pathogenic/likely pathogenic F8 variants, as well as their fertility intentions and reproductive outcomes. Further studies are required to look into the considerations involved in reproductive decision-making.

Gastric adenocarcinoma location and postoperative complication rates in Asian patients: A 2014-2019 NSQIP analysis.

BACKGROUND: Asian gastric cancer patients have higher long-term survival rates post-gastrectomy. This study compares 30-day post-gastrectomy outcomes between Asians and non-Asians. METHODS: Gastric cancer patients undergoing elective gastrectomies were identified in 2014-2019 NSQIP datasets (n â€‹= â€‹1,438). Demographics, comorbidities, and postoperative outcomes were analyzed. RESULTS: Asians had lower odds of total gastrectomy (AOR â€‹= â€‹0.52, p â€‹= â€‹0.003), age ≥65 (AOR â€‹= â€‹0.60, p â€‹= â€‹0.006), smoking history (AOR â€‹= â€‹0.35, p â€‹< â€‹0.001), dyspnea (AOR â€‹= â€‹0.25, p â€‹= â€‹0.01), and hypoalbuminemia (AOR â€‹= â€‹0.62, p â€‹= â€‹0.025); they also had lower BMI (p â€‹< â€‹0.001). Postoperative outcomes were not significantly different aside from a shorter median length of hospital stay in days (LOS) (Asians: 7 (6, 11); non-Asians: 8 (6, 11); p â€‹< â€‹0.001). CONCLUSIONS: Asian gastric cancer patients have significantly lower odds of having select preoperative comorbidities and have shorter hospital LOS.

Disparities in the Prevalence of Psychiatric Illness in Hawaii's Houseless Population: A Retrospective Chart Review.

In the State of Hawaii, previous research has suggested that minority groups such as Native Hawaiians and Other Pacific Islanders are disproportionately affected by mental health disorders and have less access to mental health services. The purpose of this study was to determine if similar disparities in the prevalence of psychiatric disorders among different ethnic groups are also present among Hawaii's houseless population. A retrospective chart review of records from one of Oahu's major houseless outreach clinics was performed to gather patient demographics and reported histories of psychiatric diagnoses. Reported disease prevalence rates were compared between larger ethnic categories as well as ethnic sub-groups. Results demonstrated higher rates of certain serious mental illnesses among the houseless; however, several other psychiatric diagnoses were unexpectedly found to be less prevalent than in the general population. Additionally, houseless Pacific Islander groups were unexpectedly found to often have disproportionally lower rates of psychiatric diagnoses despite being identified as high risk by other studies. Overall, our findings may indicate unique ethnic trends in the prevalence of mental health disorders among the houseless in Hawaii or may suggest increased social and/or cultural barriers to diagnosis among certain groups that will require more diligent screening and culturally competent care from providers.

Intellectual Functioning of Children With Isolated PRS, PRS-Plus, and Syndromic PRS.

OBJECTIVE: Describe the intelligence quotient (IQ) of children with Pierre Robin sequence (PRS). DESIGN: Prospective cohort study. SETTING: Neurodevelopmental follow-up clinic within a hospital. PATIENTS: Children with PRS (n = 45) who had been in the Neonatal Intensive Care Unit (NICU) were classified by a geneticist into 3 subgroups of isolated PRS (n = 20), PRS-plus additional medical features (n = 8), and syndromic PRS (n = 17) based on medical record review and genetic testing. MAIN OUTCOME MEASURE: Children with PRS completed IQ testing at 5 or 8 years of age with the Wechsler Preschool and Primary Scale of Intelligence, Third Edition (WPPSI-III) or Fourth Edition (WPPSI-IV) or the Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV) or Fifth Edition (WISC-V). RESULTS: IQ scores were more than 1 to 2 standard deviations below the mean for 36% of the overall sample, which was significantly greater compared to test norms (binomial test P = .001). There was a significant association between PRS subtype and IQ (Fisher's exact P = .026). While only 20% of children with isolated PRS were within 1 standard deviation below average and 35% of children with syndromic PRS were below 1 to 2 standard deviations, 75% of PRS-plus children scored lower than 1 to 2 standard deviations below the mean. CONCLUSION: PRS subgroups can help identify children at risk for cognitive delay. The majority of children with PRS-plus had low intellectual functioning, in contrast to the third of children with syndromic PRS who had low IQ and the majority of children with isolated PRS who had average or higher IQ.

Breast nodular fasciitis in a postmenopausal woman: A case report and review of recent literature.

Nodular fasciitis (NF) is a benign soft tissue lesion that can occur anywhere in the body. Its occurrence in the breast is a rare phenomenon, but is clinically important to distinguish from a malignant tumor as they both present as lesions of the breast. In this report, we discuss a case of NF of the breast in an postmenopausal woman who presented with an asymmetry of the breast on an annual screening mammogram followed by diagnostic imaging and a core biopsy. Ultimately, excision of the lesion (1.2 cm) was the definitive treatment for this patient and histological evaluation confirmed the diagnosis of NF. Additionally, we review the most recent literature on this topic discussing the significance to better understand the characteristics and best treatment course for breast NF. Results from a review of 11 breast NF cases demonstrated that the average age at diagnosis is 49, the mean diameter of lesions was 1.33 cm, and lesions were more frequently identified in the right upper breast. The clinical features of breast NF may present similarly to that of a malignant tumor. Accurate diagnosis with immunohistochemistry staining or USP6 FISH analysis is critical to prevent misdiagnosis and overtreatment. Clinician awareness, surgical treatment, and patient education are important for best management of breast NF.

Patient Understanding of Oncologic Radiology Reports: Is Access to Electronic Medical Records Helpful?

Access to electronic medical record (EMR) patient portals made it easier for patients to quickly acquire the results of their radiology studies. However, there is little research on how well oncology patients understand the findings of radiology reports presented in the online portal without patient-physician discussion. This study assessed oncology patients' confidence and accuracy in interpreting radiology reports either with or without layman translations. A survey based on a radiology report was administered to oncology patients and caregivers. Two versions of the radiological report were randomly distributed, either a standard report or one with layman translations to evaluate participant understanding and accuracy of interpreting radiological results. Among 85 participants, a majority (67.8%) reported wanting patient portal access to radiological reports, yet less than a quarter (21.2%) felt confident in reading and interpreting radiological reports. Univariate binary logistic regression models showed that participants who read the lay report were 8 times more likely to find the radiology report easy to read. This research demonstrated that the inclusion of layman translation of standard radiology reports improves oncology patients' and caregivers' understanding of such reports with statistically significant and clinically meaningful increases in readability.

Genomic Landscape of Circulating-Tumor DNA in a Diverse Cohort of Metastatic Breast Cancer Patients.

INTRODUCTION: Breast cancer is the most prevalent cancer and the second leading cause of cancer death among women in the United States. Liquid biopsy is becoming a more commonly accepted method in clinical practice. Thus, there is a need to investigate ways to utilize circulating-tumor DNA (ctDNA) in metastatic breast cancer (mBC). The primary objective of this study was to characterize the genomic landscape of ctDNA in a diverse patient population and across different subtypes of mBC. METHODS: We analyzed the ctDNA profile in patients (n = 45) with mBC who received a Guardant360 liquid biopsy test. Patient demographics, age at diagnosis, race, subtype, and mutations were included in the analysis. RESULTS: The majority of patients (n = 39, 86.7%) had at least one gene alteration detected in their liquid biopsy. We found no statistically significant differences in genomic landscape according to race. However, there were differences seen in tumor genomics according to age and subtype. Postmenopausal patients were more likely to have detectable disease on liquid biopsy compared to premenopausal patients (p = 0.001). Mutations in ESR1 (n = 10) and PIK3CA (n = 8) were more commonly seen in hormone positive (HR+) mBC, where known tailored treatment options are available (i.e., fulvestrant and alpelisib respectively). The most common alterations detected include TP53 (n = 22) followed by PIK3CA (n = 15), ESR1 (n = 11), CCND1 (n = 7), and ERBB2 (n = 7). CONCLUSION: Liquid biopsies are effective tools that can reveal clinically relevant information including mutational status and therapeutic options.

Concurrent PANK2 and OCA2 variants in a patient with retinal dystrophy, hypopigmented irides and neurodegeneration.

PURPOSE: To report a case of concurrent pantothenate kinase-associated neurodegeneration (PKAN) and oculocutaneous albinism (OCA) with dual PANK2 and OCA2 variants in a Chinese patient who presented with early-onset reduced vision, nyctalopia, and neurological symptoms. MATERIALS AND METHODS: Based on the ocular phenotype and provisional diagnosis of rod-cone dystrophy, genetic testing was pursued. Peripheral blood DNA extraction was carried out with the next-generation sequencing technique, which involved a population-specific medical exome virtual panel. Pre- and post-test counseling were carried out by clinical geneticists. RESULT: Homozygous missense variants in PANK2 {NM_153638.3}:c.655 G>A (p.(Gly219Ser)) and OCA2{NM_025160.6}:c.1327 G>A(p.(Val443Ile)) were identified. The molecular diagnoses of pantothenate kinase associated neurodegeneration (OMIM#234200) and albinism, oculocutaneous, type II (OMIM#203200) were supported by clinical findings. CONCLUSION: Two rare autosomal recessive diseases, pantothenate kinase-associated neurodegeneration (PKAN) and oculocutaneous albinism (OCA) were detected in our patient. Ocular and systemic manifestations, as well as neuroimaging findings were compatible with the diseases identified. Genetic analysis is imperative in making an accurate molecular diagnosis in these rare conditions to allow timely counseling, disease prognostication and management.

Genotype/phenotype correlation in 123 Chinese patients with Tuberous Sclerosis Complex.

Tuberous Sclerosis Complex (TSC) is a multisystemic neurocutaneous disorder with autosomal dominant inheritance. We performed mutation analyses on 123 Chinese patients with "definite TSC" according to the latest diagnostic criteria. Pathogenic / likely-pathogenic variants were identified in 72.2% of all index patients (70/97), in which 35.7% (25/70) had TSC1 variants and 64.3% (45/70) had TSC2 variants. 84.5% (82/97) cases were sporadic and 15.5% (15/97) cases were familial. 62 unique variants were reported, in which 41.9% (26/62) were novel. Male patients had significantly more subependymal nodules (p=0.029) than females, whereas renal angiomyolipoma (p=0.032) occurred predominantly in females. Sporadic cases also had more renal angiomyolipoma (p=0.004), cortical tubers (p=0.008), hypopigmented macules (p=0.018) and fibrous cephalic plaques (p=0.028) than cases with known inheritance. Patients with TSC2 pathogenic variants were more likely to have mental retardation (p<0.001), cardiac rhabdomyoma (p=0.004), renal angiomyolipoma (p=0.006) and facial angiofibromas (p=0.026) than those with TSC1 pathogenic variants, while mutation-negative cases showed a mixed phenotype between those with TSC1 and TSC2 variants. There were no significant phenotypic differences between patients with and without TSC1/TSC2 variants, but TSC2 missense and in-frame variants were associated with higher frequencies of mental retardation (P<0.001), renal angiomyolipoma (p=0.001), cardiac rhabdomyoma (p=0.012) and facial angiofibroma (p=0.021) than those with TSC1 frameshift and splice site variants. Furthermore, a higher frequency of mental retardation (p=0.013) was observed in patients with TSC2 missense and in-frame variants than those with frameshift and splice site variants. All 14 antenatal-onset patients had cardiac rhabdomyoma. They had fewer seizures (p=0.028) than patients with paediatric-onset, but were more likely to have mental retardation (p=0.035) than individuals with adult-onset disease. Generally, paediatric-onset patients had more neurological manifestations, while initial presentations of adult-onset TSC were more diverse.

Investigation of Chromosomal Structural Abnormalities in Patients With Undiagnosed Neurodevelopmental Disorders.

Background: Structural variations (SVs) are various types of the genomic rearrangements encompassing at least 50 nucleotides. These include unbalanced gains or losses of DNA segments (copy number changes, CNVs), balanced rearrangements (such as inversion or translocations), and complex combinations of several distinct rearrangements. SVs are known to play a significant role in contributing to human genomic disorders by disrupting the protein-coding genes or the interaction(s) with cis-regulatory elements. Recently, different types of genome sequencing-based tests have been introduced in detecting various types of SVs other than CNVs and regions with absence of heterozygosity (AOH) with clinical significance. Method: In this study, we applied the mate-pair low pass (∼4X) genome sequencing with large DNA-insert (∼5 kb) in a cohort of 100 patients with neurodevelopmental disorders who did not receive informative results from a routine CNV investigation. Read-depth-based CNV analysis and chimeric-read-pairs analysis were used for CNV and SV analyses. The region of AOH was indicated by a simultaneous decrease in the rate of heterozygous SNVs and increase in the rate of homozygous SNVs. Results: First, we reexamined the 25 previously reported CNVs among 24 cases in this cohort. The boundaries of these twenty-five CNVs including 15 duplications and 10 deletions detected were consistent with the ones indicated by the chimeric-read-pairs analysis, while the location and orientation were determined in 80% of duplications (12/15). Particularly, one duplication was involved in complex rearrangements. In addition, among all the 100 cases, 10% of them were detected with rare or complex SVs (>10 Kb), and 3% were with multiple AOH (≥5 Mb) locating in imprinting chromosomes identified. In particular, one patient with an overall value of 214.5 Mb of AOH identified on 13 autosomal chromosomes suspected parental consanguinity. Conclusion: In this study, mate-pair low-pass GS resolved a significant proportion of CNVs with inconclusive significance, and detected additional SVs and regions of AOH in patients with undiagnostic neurodevelopmental disorders. This approach complements the first-tier CNV analysis for NDDs, not only by increasing the resolution of CNV detection but also by enhancing the characterization of SVs and the discovery of potential causative regions (or genes) contributory to could be complex in composition NDDs.

Old and new perspectives on Neurofibromatosis type 1: Clinical and molecular characterization of 832 patients from a single centre over 16 years.

Neurofibromatosis type 1 (NF1; OMIM #162200) is the commonest multi-systemic neurocutaneous tumour-predisposition disorder. It has an age-related complete penetrance but a highly variable inter- and intra-familial expressivity. This article summarizes the clinical features and molecular characteristics of 832 clinically or molecularly confirmed NF1 patients from 697 unrelated families recruited from a single centre in Hong Kong diagnosed during the 16 years period from Jan 2005 to Jan 2021. In this study, we have estimated the incidences of clinical features, reported on the molecular findings and explored new genotype-phenotype correlations.

Utilizing Liquid Biopsy for Treatment Management in Bone-Dominant Metastatic Breast Cancer: A Case Report.

Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer death among women in the United States. In clinical practice, the standard method to confirm metastatic disease and tailor treatment is to biopsy a metastatic site. Bone is the most common metastatic site, occurring in up to 70% of patients with advanced breast cancer. Standard-of-care management includes a needle biopsy with histopathological analysis to confirm tumor status and to evaluate for mutations. However, bone biopsies can be technically challenging and are oftentimes painful for patients. Given the challenges in acquisition and analysis of bone samples in metastatic breast cancer (mBC), a liquid biopsy is a less invasive alternative that can reveal clinically relevant alterations. Here, we report two cases of bone-dominant hormone-positive (HR+) mBC, in which circulating tumor DNA (ctDNA) was extracted from blood samples using two different next-generation sequencing (NGS) platforms to identify molecular targets for FDA approved treatment. In both patients, PIK3CA mutations were detected and subsequently started on alpelisib along with aromatase inhibitor or fulvestrant treatment. These cases demonstrate a feasible real-world clinical application to liquid biopsies.

CTNNB1-related neurodevelopmental disorder in a Chinese population: A case series.

CTNNB1-related disorder is an autosomal dominant neurodevelopmental disorder characterized by a variable degree of cognitive impairment, microcephaly, truncal hypotonia, peripheral spasticity, visual defects, and dysmorphic features. In this case series, we report the clinical and molecular findings of nine Chinese patients affected by CTNNB1-related disorders. The facial features of these affected individuals appear to resemble what had been previously described, with thin upper lip (77.8%) and hypoplastic alae nasi (77.8%) being the most common. Frequently reported clinical characteristics in our cohort include developmental delay (100%), peripheral spasticity (88.9%), truncal hypotonia (66.7%), microcephaly (66.7%), and dystonia (44.4%). While various eye manifestations were reported, two affected individuals (22.2%) in our cohort had familial exudative vitreoretinopathy. One of the affected individuals had craniosynostosis, a feature not reported in the literature before. To our knowledge, this is the first reported Chinese case series of CTNNB1-related neurodevelopmental disorders. Further studies are required to look into whether ethnic differences play a role in phenotypic variations.

Prenatal phenotype of Kabuki syndrome: A case series and literature review.

OBJECTIVES: Kabuki syndrome (KS) is a genetic disorder characterized by intellectual disability, facial dysmorphism and congenital anomalies. We aim to investigate the prenatal features of fetuses with KS and to provide a comprehensive review of the literature on prenatal sonographic abnormalities associated with KS. METHODS: We retrospectively reviewed the prenatal ultrasound findings of all mothers of children with molecularly confirmed KS in Hong Kong, between 1991 and 2019. We also performed systematic review of the literature to identify studies on the prenatal findings in KS. RESULTS: We identified 11 cases with KS with detectable fetal ultrasound findings ranging from no detectable abnormalities to a variety of non-specific findings including increased nuchal translucency, pleural effusion, cardiac anomalies, renal anomalies, intrauterine growth restriction, polyhydramnios, oligohydramnios and single umbilical artery. In combining our cases with the 77 cases published, 42 (50.6%) of them had more than one abnormal antenatal ultrasound finding. The most frequent ultrasound features observed were cardiac anomalies (49.4%), followed by polyhydramnios (28.9%), genitourinary anomalies (26.5%), single umbilical artery (15.7%), intrauterine growth restriction (14.5%) and hydrops fetalis/pleural effusion/ascites (12.0%). CONCLUSIONS: These cases demonstrate the prenatal phenotypic heterogeneity associated with KS. Although the ultrasound abnormalities are non-specific, KS should be considered in the differential diagnosis when these fetal findings following normal microarray analysis/karyotyping.

First Case Report of Maternal Mosaic Tetrasomy 9p Incidentally Detected on Non-Invasive Prenatal Testing.

Tetrasomy 9p (ORPHA:3390) is a rare syndrome, hallmarked by growth retardation; psychomotor delay; mild to moderate intellectual disability; and a spectrum of skeletal, cardiac, renal and urogenital defects. Here we present a Chinese female with good past health who conceived her pregnancy naturally. Non-invasive prenatal testing (NIPT) showed multiple chromosomal aberrations were consistently detected in two sampling times, which included elevation in DNA from chromosome 9p. Amniocentesis was performed and sent for chromosomal microarray, which was normal. Maternal karyotype revealed that mos 47,XX,+dic(9;9)(q21.1;q21.1)(24)/46,XX(9) presents mosaic tetrasomy for the short arm of chromosome 9p and is related to the NIPT results showing elevation in DNA from chromosome 9p. The pregnancy was uneventful, and the patient was delivered at term. Maternal samples were obtained at two different time points after delivery showed the same multiple chromosomal aberrations detected during pregnancy. This is a first report on an unusual case of mosaic isodicentric tetrasomy 9p in a healthy adult with normal intellect. With widespread adoption of NIPT for screening fetal aneuploidy and genome-wide copy number changes, a rise in incidental detection of maternal rare genetic syndrome will bring challenges in our current approach to genetic counselling and prenatal diagnosis.

Genotype and phenotype in 18 Chinese patients with Coffin-Siris syndrome.

Coffin-Siris syndrome (CSS, MIM# 1359200) is a multisystem congenital disorder characterized by coarse facial features, hypoplasia of the fifth digits and nails, and intellectual disability. It is a genetically heterogeneous condition caused by pathogenic variants in genes encoding proteins of the BAF (BRG1-associated factors) chromatin modeling complex and its downstream transcriptional factor. To date over 220 CSS individuals with pathogenic variants found have been described in the literature. This case series reported 18 molecularly confirmed Chinese individuals (17 with ARIDIB (OMIM*614556) variants and one with SMARCB1 (OMIM*601607) variant) from 17 unrelated families in Hong Kong. The clinical features of these 18 Chinese CSS patients together with two previously reported Chinese patients with ARID1B variants were reviewed. Among the 19 Chinese patients with ARID1B variants, our data suggested a lower prevalence of feeding problem, autistic features, agenesis of corpus callosum (ACC) or partial/hypoplasia of corpus callosum, and sparse hair when compared with previous reports. There was appearing higher prevalence of digital hypoplasia. Digital hypoplasia was observed to become less noticeable with time in some patients. This report highlighted the age-dependent phenotypic presentation of CSS and ethnicity-related effect on ARID1B-CSS phenotype. Moreover, this series included the first family with molecularly confirmed maternal somatic mosaicism of ARID1B variant leading to familial CSS recurrence.

An adult Chinese patient with developmental delay with short stature, dysmorphic features, and sparse hair (Loucks-Innes syndrome).

Variants of the diphthamide biosynthesis I (DPH1, OMIM*603527) are associated with developmental delay, short stature, and sparse hair syndrome (DEDSSH/DPH1 syndrome) (OMIM# 616901). Another name is Loucks-Innes syndrome. DPH1 syndrome is an ultrarare and severe neurodevelopmental disorder. Less than 20 patients were reported from different ethnicities. Here, we described the first Chinese adult with genetically confirmed DPH1 syndrome. We summarized previously reported patients in the literature and found that developmental delay, unusual skull shape, sparse hair, and facial dysmorphism were consistently present in all DPH1 syndrome patients. Dysplastic toenails and dental abnormalities are age-dependent characteristics of DPH1 syndrome. Our patient was the first reported patient with documented growth hormone deficiency. Dental and endocrine checkup should be considered in the routine follow-up of DPH1 syndrome patients.

Clinical and molecular characterization study of Chinese Kabuki syndrome in Hong Kong.

Kabuki syndrome (OMIM #147920 and 300867) is a rare genetic disorder characterized by a distinctive facial gestalt, intellectual disability and multiple congenital anomalies. We summarized the clinical features and molecular findings of the Kabuki syndrome (KS) patients diagnosed in Hong Kong between January 1991 and December 2019. There were 21 molecularly confirmed KS. Twenty of them were due to pathogenic KMT2D variants and one patient had KDM6A deletion. Nine KMT2D variants were novel. The clinical phenotype of our Chinese KS patients was largely comparable with that reported in patients of other ethnicities. This study expands the mutation spectrum but also provide important natural history information of Chinese KS in literature.