Genetic evaluation using next-generation sequencing of children with short stature: a single tertiary-center experience.

PURPOSE: We used next-generation sequencing (NGS) to investigate the genetic causes of suspected genetic short stature in 37 patients, and we describe their phenotypes and various genetic spectra. METHODS: We reviewed the medical records of 50 patients who underwent genetic testing using NGS for suspected genetic short stature from June 2019 to December 2022. Patients with short stature caused by nongenetic factors or common chromosomal abnormalities were excluded. Thirty-seven patients from 35 families were enrolled in this study. We administered one of three genetic tests (2 targeted panel tests or whole exome sequencing) to patients according to their phenotypes. RESULTS: Clinical and molecular diagnoses were confirmed in 15 of the 37 patients, for an overall diagnostic yield of 40.5%. Fifteen pathogenic/likely pathogenic variants were identified in 13 genes (ACAN, ANKRD11, ARID1B, CEP152, COL10A1, COL1A2, EXT1, FGFR3, NIPBL, NRAS, PTPN11, SHOX, SLC16A2). The diagnostic rate was highest in patients who were small for their gestational age (7 of 11, 63.6%). CONCLUSION: Genetic evaluation using NGS can be helpful in patients with suspected genetic short stature who have clinical and genetic heterogeneity. Further studies are needed to develop patient selection algorithms and panels containing growth-related genes.

Novel In-Frame Deletion CNOT3 Variant in a Family With Intellectual Developmental Disorder With Speech Delay and Dysmorphic Facies.

Objectives: Intellectual developmental disorder with speech delay, autism, and dysmorphic facies (IDDSADF) is caused by heterozygous CNOT3 (MIM# 604910) variants on chromosome 19q13. This study aimed to identify and describe the clinical features of a Korean family with maternally inherited speech delay and intellectual and developmental disability to elucidate the underlying genetic mechanism. Methods: We conducted whole-exome sequencing and confirmatory Sanger sequencing on the proband, the mother, and unaffected grandparents with wild-type genotypes. Results: The phenotypes of the mother and 2 daughters presented muscular hypotonia, global developmental delay, speech delay, intellectual disability, macrocephaly, facial dysmorphic features, and focal corpus callosum hypoplasia. Whole-exome sequencing identified a novel in-frame deletion, c.2017_2019del (p.Phe673del) in CNOT3, located in the C-terminal negative on the TATA-less-box domain. Discussion: This report presents a new possible mechanism underlying IDDSADF caused by CNOT3 variants-an in-frame deletion. The findings enhance our understanding of early-life neurodevelopment and the genotype-phenotype relationships of IDDSADF caused by CNOT3 variants. In addition, this report could assist in early diagnosis and facilitate genetic counseling.

Abdominal closure with different oblique planes in island TRAM flaps: a method for achieving a better scar and contour of the donor site

Background@#An autologous abdominal flap can provide an aesthetically pleasing breast with a natural feel. However, contracted scars and hourglass contour deformities at the abdominal donor site can sometimes occur. These complications can reduce patient satisfaction and quality of life. Therefore, we performed different oblique plane closure of the abdominal donor site and evaluated the aesthetic scores in comparison with the conventional vertical single plane closure. @*Methods@#The procedures begin with a beveled incision down to the fascia level during transverse rectus abdominis muscle flap elevation. At the time of donor site closure, Scarpa’s fascia and the subcutaneous layers are sutured while being pulled downward. Sixty patients were divided into two groups: group A (single vertical plane closure) and group B (different oblique plane closure). Abdominal scars were scored by five reviewers using the scar scale. @*Results@#There were no significant differences in scores for vascularization, dog-ear presence, and umbilical shape of the scar between the two groups. However, group B showed marked improvements in flatness, contracture, and thickness of the scar surface. Notably, the different oblique plane closure in group B achieved much higher scores for the abdominal contour than group A. @*Conclusions@#The vertical single plane suture of the abdominal donor site may result in depressive contracture with poor cosmetic outcomes. The different oblique plane closure technique markedly improved the appearance of scars on the abdomen. This technique is likely to enhance patient satisfaction with both the breast and abdominal outcomes of breast reconstruction using an abdominal flap.

Effectiveness of a postoperative continuous irrigation system via a catheter following implant-based breast reconstruction

Background@#Implant-based breast reconstruction is a technique frequently used for breast reconstruction. Infection and inflammation are considered to be the most troublesome complications of implant-based breast reconstruction and can lead to capsular contracture or implant failure. To date, however, only a few methods have been proposed to prevent these complications. Therefore, the authors introduce a simple irrigation system using indwelling drain catheters to decrease postoperative inflammation. @*Methods@#Continuous saline irrigation was performed once per day for 3 days immediately after prosthesis-based breast reconstruction. Normal saline (500 mL) was inserted into the implant pocket through a superomedial-oriented drain catheter and drained through an inferolateral-oriented drain catheter using a suction device. Inflammatory indicators, including C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), white blood cell count (WBC), and postoperative complications were compared between the non-irrigation and irrigation groups. @*Results@#This study included 37 patients divided into two groups (20 non-irrigation and 17 irrigation). An analysis of inflammatory indicators revealed that the peak CRP level in the irrigation group was significantly lower than that in the non-irrigation group, while no statistically significant differences were found for the other mediators (ESR and WBC). In the immediate postoperative period, continuous irrigation effectively washed out tissue debris and blood clots within the implant pocket, which helped maintain the function of the drain catheter and decrease pro-inflammatory mediators. @*Conclusions@#This irrigation method was simple and cost-effective for decreasing inflammation within the breast pocket. Furthermore, it can also be applied to infected breast pockets in combination with antibiotics.

Does the dominant hand’s use affect the complication rates in prosthetic breast reconstruction?

Background@#Numerous studies have investigated risk factors for unfavorable outcomes in prosthetic breast reconstruction, such as obesity, perioperative radiotherapy, and acellular dermal matrix use. However, no reports have explored whether the use of the dominant hand influences complications in breast reconstruction. To address this gap in the literature, analyzed complication rates between the dominant and non-dominant sides after reconstruction. @*Methods@#We retrospectively reviewed the charts of 160 patients (170 breasts) who underwent breast reconstruction from February 2017 to March 2022. We analyzed the complications between beasts on the dominant and non-dominant sides according to the reconstruction method. @*Results@#During prosthetic breast reconstruction, the drainage volume and duration on the dominant side exceeded those on the non-dominant side after reconstruction (duration: 9.79 days on the dominant side vs. 9.12 days on the non-dominant side, P=0.196; volume: 771.1 mL on the dominant side vs. 654.3 mL on the non-dominant side, P=0.027). The incidence of complications such as wound dehiscence, mastectomy flap necrosis, and infection was significantly higher in the dominant hand group (infection: 6 vs. 0, P=0.014; dehiscence: 15 vs. 4, P=0.009; flap necrosis: 13 vs. 4, P=0.024). @*Conclusions@#Complications including seroma, infection, and mastectomy skin flap necrosis following prosthetic reconstruction were common in breasts on the dominant-hand side. Therefore, meticulous management and restriction of shoulder movement can aid in preventing seroma-related complications in prosthetic breast reconstruction, especially on the side of the dominant hand.

Clinical application of prenatal chromosomal microarray

A prenatal chromosomal microarray (CMA) is generally recommended when a major anomaly is suspected on prenatal ultrasonography. As it can overcome the limitations of conventional karyotyping, it is expected that the number of prenatal CMA test requests will gradually increase. However, given the specificity of prenatal diagnosis, there are practical considerations compared to postnatal testing, such as the validation of prenatal specimens, maternal cell contamination, precautions when reporting variants of uncertain significance, and the need for comprehensive genetic counseling considering secondary findings. The purpose of this article is to provide necessary information to health care providers in consideration of these issues and to provide appropriate genetic counseling to patients.

Genetic Profile and Associated Characteristics of 150 Korean Patients with Retinitis Pigmentosa.

PURPOSE: Retinitis pigmentosa (RP) shows great diversity between genotypes and phenotypes, and it is important to identify the causative genes. This study aimed to analyze the molecular profiles, associated ocular characteristics, and progression of RP in Korean patients. METHODS: All the genetic variants in patients with RP, identified using targeted next-generation sequencing (NGS) with a panel of 88 RP-related genes between November 2018 and November 2019, were retrospectively reviewed. All the patients underwent comprehensive ophthalmological evaluations, and their clinical and family histories were recorded. The best-corrected visual acuity (BCVA) deterioration and photoreceptor disruption progression rates were determined based on the major causative mutational genes using nonlinear mixed models, and the differences among them were investigated using the interaction effect. RESULTS: Among the 144 probands, 82 variants in 24 causative genes were identified in 77 families (53.5%). Most of the RP cases were associated with autosomal recessive variants (N = 64 (44.4%)), followed by autosomal dominant (N = 10 (6.9%)) and X-linked variants (N = 3 (2.1%)). The four most frequently affected genes were EYS (N = 15 (10.4%)), USH2A (N = 12 (8.3%)), PDE6B (N = 9 (6.3%)), and RP1 (N = 8 (5.6%)). Epiretinal membranes and cystoid macular edema were frequently noted in the patients with USH2A (75.0%) and PDE6B (50.0%) variants, respectively. During the follow-up period, the BCVA and photoreceptor disruption changes were significantly different among the patients carrying the four common causative genes (P=0.014 and 0.034, resp.). Patients with PDE6B variants showed faster BCVA changes (0.2 LogMAR/10 years), and those with USH2A variants showed the fastest ellipsoid zone disruptions (-170.4 µm/year). CONCLUSION: In conclusion, our genetic analysis using targeted NGS provides information about the prevalence of RP-associated mutations in Korean patients. Delineating clinical characteristics according to genetic variations may help clinicians identify subtype features and predict the clinical course of RP.

Facial reanimation using the hypoglossal nerve and ansa cervicalis: a short-term retrospective analysis of surgical outcomes

Background@#Transferring the hypoglossal nerve to the facial nerve using an end-to-end method is very effective for improving facial motor function. However, this technique may result in hemitongue atrophy. The ansa cervicalis, which arises from the cervical plexus, is also used for facial reanimation. We retrospectively reviewed cases where facial reanimation was performed using the ansa cervicalis to overcome the shortcomings of existing techniques of hypoglossal nerve transfer. @*Methods@#The records of 15 patients who underwent hypoglossal nerve transfer were retrospectively reviewed. Three methods were used: facial reanimation with hypoglossal nerve transfer (group 1), facial nerve reanimation using the ansa cervicalis (group 2), and sural nerve interposition grafting between the hypoglossal nerve and facial nerve (group 3). In group 1, the ansa cervicalis was coapted to neurotize the distal stump of the hypoglossal nerve in a subset of patients. Clinical outcomes were evaluated using the House-Brackmann (H-B) grading system and Emotrics software. @*Results@#All patients in group 1 (n = 4) achieved H-B grade IV facial function and showed improvements in the oral commissure angle at rest (preoperative vs. postoperative difference, 6.48° ± 0.77°) and while smiling (13.88° ± 2.00°). In groups 2 and 3, the oral commissure angle slightly improved at rest (group 2: 0.95° ± 0.53°, group 3: 1.35° ± 1.02°) and while smiling (group 2: 2.06° ± 0.67°, group 3: 1.23° ± 0.56°). In group 1, reduced tongue morbidity was found in patients who underwent ansa cervicalis transfer. @*Conclusion@#Facial reanimation with hypoglossal nerve transfer, in combination with hypoglossal nerve neurotization using the ansa cervicalis for complete facial palsy patients, might enable favorable facial reanimation outcomes and reduce tongue morbidity. Facial reanimation using the ansa cervicalis or sural nerve for incomplete facial palsy patients did not lead to remarkable improvements, but it warrants further investigation.

Reconstructive methods to resolve intractable fistulas that develop after radiation therapy in patients with head and neck cancer

Background@#Radiation therapy (RT) is frequently used for supportive treatment and management of advanced head and neck cancers. This study performed a retrospective review of the treatment methods that were used for intractable draining fistulas in seven patients who had received RT for head and neck cancers. Treatment methods used for two of the seven patients are presented in detail. @*Methods@#From 2009 to 2020, seven patients underwent reconstructive surgery for intractable fistulas which occurred after RT for head and neck cancers. Patient characteristics, medical history, treatment method, and treatment outcome were reviewed for each case. The type of surgery performed, failure rate, and treatment period were also analyzed. Results: In this study, a total of seven patients received additional management for radiation-induced fistulas. Patients underwent a mean of 3.3± 1.4 surgeries (maximum: six surgeries) to resolve their fistulas. The mean time interval from the first surgery to the last surgery for the patients to achieve resolution of the fistula was 8.7 months. Loco-regional flaps have performed an average of 1.9± 1.5 times. However, all loco-regional flaps failed. Instead, the patients’ intractable fistulas were resolved with the use of distant flaps or free tissue transfers. Conclusion: Fistulas that develop after head and neck cancer treatment following RT are difficult to treat with simple loco-regional flap procedures. Therefore, more aggressive treatment techniques, such as distant flap or free tissue transfer, may be needed to shorten patients’ treatment periods and avoid unnecessary surgeries.

Clinical characteristics and disease progression of retinitis pigmentosa associated with PDE6B mutations in Korean patients.

Due to the genotype-phenotype heterogeneity in retinitis pigmentosa (RP), molecular diagnoses and prediction of disease progression is difficult. This study aimed to report ocular and genetic data from Korean patients with PDE6B-associated RP (PDE6B-RP), and establish genotype-phenotype correlations to predict the clinical course. We retrospectively reviewed targeted next-generation sequencing or whole exome sequencing data for 305 patients with RP, and identified PDE6B-RP in 15 patients (median age, 40.0 years). Amongst these patients, ten previously reported PDE6B variants (c.1280G > A, c.1488del, c.1547T > C, c.1604T > A, c.1669C > T, c.1712C > T, c.2395C > T, c.2492C > T, c.592G > A, and c.815G > A) and one novel variant (c.712del) were identified. Thirteen patients (86.7%) experienced night blindness as the first symptom at a median age of 10.0 years. Median age at diagnosis was 21.0 years and median visual acuity (VA) was 0.20 LogMAR at the time of genetic analysis. Nonlinear mixed models were developed and analysis revealed that VA exponentially decreased over time, while optical coherence tomography parameters linearly decreased, and this was related with visual field constriction. A high proportion of patients with the c.1669C > T variant (7/9, 77.8%) had cystoid macular edema; despite this, patients with this variant did not show a higher rate of functional or structural progression. This study will help clinicians predict functional and structural progression in patients with PDE6B-RP.

E-TUBE: dielectric waveguide cable for high-speed communication.

The demand for advanced interconnects to satisfy market requirements on bandwidth, cost, and power is ever increasing with the expansion of data centers. An interconnect called E-TUBE is presented as a cost-and-power-efficient all-electrical-domain wideband waveguide solution for high-speed high-volume short-reach communication links. The E-TUBE achieves an unprecedented level of throughput-distance product, bending radius, and channel density without requiring complex manufacturing process. The E-TUBE link demonstrates nearly 25 GHz bandwidth at a carrier frequency of 70 GHz and exhibits a frequency-independent insertion loss of 5 dB/m with a frequency-independent group delay of 4 ns/m. Such loss and delay characteristics independent of frequency enabled broadband data transmission over extended reach compared to conventional waveguide links. The E-TUBE link transmits 25 Gbps NRZ data over 3 m distance using a 70 GHz RF CMOS transceiver IC, which is the state-of-the-art throughput-reach product. This new interconnect is expected to overcome the limitations of existing electrical and optical interconnects and to replace them in high throughput links, including but not limited to, 100/400 Gbps board-to-board communications.

The first familial case of inherited intellectual developmental disorder with dysmorphic facies and behavioral abnormalities (IDDFBA) with a novel FBXO11 variant.

Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities (IDDFBA) caused by germline de novo variants in FBXO11 was recently recognized as a novel intellectual disability (ID) syndrome through reverse phenotyping after whole-exome sequencing (WES). Fewer than 50 disease-causing de novo FBXO11 variants in IDDFBA are reported thus far. Here, we present the first report of a family showing autosomal dominantly inherited IDDFBA, harboring a novel heterozygous variant in FBXO11 (c.2401_2405dup;p. Gly803Leufs*6) identified by WES. In this family, the mother and two daughters showed mild ID and mild facial dysmorphism. This finding is expected to increase our understanding of the genotype-phenotype of IDDFBA and to facilitate genetic counseling for the disorder caused by FBXO11.

Differences in PD-1 expression on CD8+ T-cells in chronic myeloid leukemia patients according to disease phase and TKI medication.

Malignant cells can increase in number using immune escape mechanisms such as immune checkpoints. In this study, we evaluated the expression of an immune checkpoint programmed death 1 (PD-1) on T-cell subsets in chronic myeloid leukemia (CML). We obtained bone marrow aspirate samples from CML patients and from individuals without evidence of hematologic malignancies (controls). PD-1 expression on T-cell subsets was measured using flow cytometric analysis. PD-1 expression levels on CD8+ T-cells were significantly lower in complete hematologic response (CHR) than in controls, chronic phase, and blast phase (BP). In CML patients receiving imatinib and dasatinib, PD-1 expression levels on CD8+ T-cells were lower than that at diagnosis. PD-1 expression levels on CD8+ T-cells were positively correlated with quantitative levels of the BCR/ABL fusion gene. PD-1 expression levels on CD4+ T-cells were higher in BP than in CHR. PD-1 expression levels on CD4+ T-cells did not differ significantly according to different medications or quantitative BCR/ABL1 fusion gene levels. Low PD-1 expression on CD8+ T-cells might play a role in maintaining CHR in CML patients. Immune monitoring of PD-1 expression on CD8+ T-cells may predict the disease course. In cases of refractory disease or resistance to imatinib or dasatinib, the use of PD-1 inhibitors would be helpful.

First Case of Double T-Cell Receptor Alpha/Delta Rearrangements of t(11;14) and inv(14) and Subsequent JAK2 Rearrangement in a Patient With T-cell Acute Lymphoblastic Leukemia

No abstract available.

Reconstruction of a completely obstructed rectosigmoid vaginal introitus in a transgender woman

Rectosigmoid vaginoplasty is a frequently used surgical method in male-to-female sex reassignment surgery. However, severe side effects, such as sepsis, may occur owing to stricture, mucorrhea, and rectovaginal fistula. Herein, we present the case of a 29-yearold patient who underwent complete reconstruction of an obstructed rectosigmoid vaginal orifice. The patient had undergone male-to-female sex reassignment surgery with rectosigmoid vaginoplasty 8 years previously. The vaginal introitus was completely obstructed, and mucous secretions of the rectum remained in the blind pouch. Therefore, she developed several complications, including panperitonitis, sepsis, and repeated obstruction. We performed complete resection of the scar and reconstructed the orifice of the neovagina using a pudendal thigh island flap. The patient’s lifethreatening condition subsided with the successful release of the vaginal orifice. Vaginal orifice stricture is a frequent complication of rectosigmoid vaginoplasty. A pudendal thigh flap can be used to effectively and safely release this stricture and reconstruct the neo-orifice of the rectosigmoid vagina without recurrence.

POEMS Syndrome: Bone Marrow, Laboratory, and Clinical Findings in 24 Korean Patients.

POEMS syndrome is a rare paraneoplastic syndrome, which includes polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes due to plasma cell (PC) neoplasm. Diagnosis of this disease is challenging because of its rarity and complex clinical manifestations. We attempted to identify the key clinical features and characteristic bone marrow (BM) findings of POEMS syndrome, by reviewing the medical records and BM analyses of 24 Korean patients. Frequent clinical manifestations included polyneuropathy (100%), monoclonal gammopathy (100%), organomegaly (92%), extravascular volume overload (79%), and endocrinopathy (63%). The BM analyses revealed mild PC hyperplasia (median PCs: 5.5%) and frequent megakaryocytic hyperplasia (88%), megakaryocyte clusters (88%), and hyperlobation (100%). Flow cytometry of BM aspirates using CD138/CD38/CD45/CD19/CD56 showed normal (67%, 4/6) or neoplastic PC immunophenotypes (33%, 2/6). A diagnosis of POEMS syndrome must be considered when a patient suspected of having PC dyscrasia shows the above clinical presentation and BM findings.

POEMS Syndrome: Bone Marrow, Laboratory, and Clinical Findings in 24 Korean Patients

POEMS syndrome is a rare paraneoplastic syndrome, which includes polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes due to plasma cell (PC) neoplasm. Diagnosis of this disease is challenging because of its rarity and complex clinical manifestations. We attempted to identify the key clinical features and characteristic bone marrow (BM) findings of POEMS syndrome, by reviewing the medical records and BM analyses of 24 Korean patients. Frequent clinical manifestations included polyneuropathy (100%), monoclonal gammopathy (100%), organomegaly (92%), extravascular volume overload (79%), and endocrinopathy (63%). The BM analyses revealed mild PC hyperplasia (median PCs: 5.5%) and frequent megakaryocytic hyperplasia (88%), megakaryocyte clusters (88%), and hyperlobation (100%). Flow cytometry of BM aspirates using CD138/CD38/CD45/CD19/CD56 showed normal (67%, 4/6) or neoplastic PC immunophenotypes (33%, 2/6). A diagnosis of POEMS syndrome must be considered when a patient suspected of having PC dyscrasia shows the above clinical presentation and BM findings.

Branchial cleft cyst in the parotid gland in a human immunodeficiency virus-negative patient

In branchial lymphoepithelial cyst (BLEC), which is also known as branchial cleft cyst, the remnants of a branchial arch develop into a cyst, causing swelling. The first case of BLEC in the parotid gland was reported by Hildebrant in 1895. Since then, BLEC in the parotid gland has continued to be reported, but in rare cases. A 45-year-old man presented to our hospital with a swelling of the left cheek of approximately 6 months’ duration. The patient underwent a superficial parotidectomy and was pathologically diagnosed with BLEC. Of note, this was the first case of non-human immunodeficiency virus (HIV)-related BLEC of the parotid gland in South Korea. BLEC is a benign condition, but its treatment depends on the presence of HIV infection. In HIV-negative patients, BLEC does not require a further work-up to evaluate metastasis. Our case report describes the diagnosis and treatment of BLEC in a patient without HIV.

Exclusive tongue tip reconstruction of hemiglossectomy defects using the underrated lateral arm free flap with bilobed design

BACKGROUND: Tongue reconstruction is challenging with the unique function and anatomy. Goals for reconstruction differ depending on the extent of reconstruction. Thin and pliable flaps are useful for tongue tip reconstruction, for appearance and mobility. This study reports lateral arm free flap (LAFF) as a safe and optimal option for hemi-tongue reconstruction, especially for tongue tip after hemiglossectomy. METHODS: Thirteen LAFFs were performed for hemi-tongue reconstruction after hemiglossectomy from 1995 to 2018. Of the 13 patients, seven were male and six were female, age varying from 24 to 64 years. RESULTS: All flaps healed uneventfully without complications. Donor sites were closed primarily. The recipient vessels for microvascular anastomosis were mainly superior thyroidal artery, external jugular vein. All patients returned to normal diet, with no complaints regarding reconstructed tongue and donor site. CONCLUSION: The LAFF is hairless, thin (especially with lateral epicondyle approach), and potentially sensate. They are advantageous features for tongue tip and hemi-tongue reconstruction. Donor site sacrifices the inessential posterior radial collateral artery, and the scar is hidden under short sleeve shirts. We believe that LAFF can be considered as the first choice flap for hemitongue reconstruction, over radial forearm free flaps.