Automatic speech recognition (ASR) for the diagnosis of pronunciation of speech sound disorders in Korean children.

This study presents a model of automatic speech recognition (ASR) that is designed to diagnose pronunciation issues in children with speech sound disorders (SSDs) to replace manual transcriptions in clinical procedures. Because ASR models trained for general purposes mainly predict input speech into standard spelling words, well-known high-performance ASR models are not suitable for evaluating pronunciation in children with SSDs. We fine-tuned the wav2vec2.0 XLS-R model to recognise words as they are pronounced by children, rather than converting the speech into their standard spelling words. The model was fine-tuned with a speech dataset of 137 children with SSDs pronouncing 73 Korean words that are selected for actual clinical diagnosis. The model's Phoneme Error Rate (PER) was only 10% when its predictions of children's pronunciations were compared to human annotations of pronunciations as heard. In contrast, despite its robust performance on general tasks, the state-of-the-art ASR model Whisper showed limitations in recognising the speech of children with SSDs, with a PER of approximately 50%. While the model still requires improvement in terms of the recognition of unclear pronunciation, this study demonstrates that ASR models can streamline complex pronunciation error diagnostic procedures in clinical fields.

Comparison of Clinical Findings of Congenital Muscular Torticollis Between Patients With and Without Sternocleidomastoid Lesions as Determined by Ultrasonography.

AIM: To compare clinical findings for patients with congenital muscular torticollis (CMT) between those with and without a sternocleidomastoid (SCM) lesion. METHODS: Medical records of 182 patients with CMT were retrospectively reviewed and the patients were divided into SCM lesion and nonlesion groups by ultrasonographic results. Intrauterine position, age, duration of therapy, rotation/tilting side, and the passive range of motion and angle of the neck were compared. RESULTS: There were 74 SCM lesion and 108 nonlesion cases. The mean age at the first visit was 55.3 days in the SCM lesion group and 146.6 days in the nonlesion group. The mean therapy time in the nonlesion group was 66.5 days, significantly shorter than for the SCM lesion group (117.5 d). Tilting and rotation of the head in the same direction was observed only in the nonlesion group (n=9, 8.3%). Rotational limitation of the affected muscle side was 22.6 degree in the SCM lesion and 3.6 degree in the nonlesion group, and the tilting limitation was 19.2 degree in the SCM lesion and 10.4 degree in the nonlesion group. CONCLUSIONS: The nonlesion group had a better prognosis with shorter treatment duration. This group was more limited in head tilting than in head rotation, and the pattern of head rotation/tilting in the same direction was observed only in this group. These findings suggest that pathophysiological mechanisms and clinical characteristics may differ between CMT patients with and without SCM lesions. LEVEL OF EVIDENCE: Level II-prognostic studies, retrospective study.

Relationship between starting age of cranial-remolding-orthosis therapy and effectiveness of treatment in children with deformational plagiocephaly.

PURPOSE: The aim of this study was to investigate the optimal age for starting cranial-remolding-orthosis therapy in children with deformational plagiocephaly. METHODS: Medical records of 310 patients with deformational plagiocephaly were retrospectively reviewed and the initial and final cranial vault asymmetry index (CVAI), age when starting therapy, duration of therapy, mean change of CVAI, improvement rate, and treatment success were analyzed. We compared outcomes according to the groups divided by ages starting therapy. RESULTS: There were no significant differences in improvement rate and duration of cranial-remolding-orthosis therapy among patients starting therapy at the age of 3, 4, and 5 months. However, when starting therapy after the age of 6 months, the rates of CVAI improvement were significantly lower and the duration of therapy was significantly increased. CONCLUSION: Considering the spontaneous resolution effect according to the head growth nature, the age 5 month is the optimal period to start cranial-remolding-orthosis therapy for deformational plagiocephaly.

Anti-inflammatory and lymphangiogenetic effects of low-level laser therapy on lymphedema in an experimental mouse tail model.

The aim of the present study was to investigate the therapeutic mechanism of low-level laser therapy (LLLT) in the mouse tail lymphedema model. Six-week-old female mice were classified into the laser treatment group, sham treatment group, and surgical control group (10 mice per group). LLLT was administered daily for 10 min from the surgical day to 11 days (12 times). Macrophage activation and lymphatic vessel regeneration were evaluated through immunohistochemical staining with anti-F4/80 and anti-LYVE-1 antibodies, respectively, at 12 days post-procedure. Quantitative real-time polymerase chain reaction (qPCR) was performed to measure messenger RNA (mRNA) expression of vascular endothelial growth factor A, B, C, R1, R2, and R3 (VEGF-A, VEGF-B, VEGF-C, VEGFR1, VEGFR2, and VEGFR3) at 12 days post-procedure. Student's t and one-way ANOVA tests were performed for statistical analyses. Significance was defined as p < 0.05. The thickness of the tail rapidly increased until 6 days in the laser and sham groups. The mice in the laser group showed a significantly decreased thickness compared with the sham group at 10 and 12 days. Immunohistochemistry assay revealed that LLLT reduced inflammation and induced new lymphatic vessel growth. qPCR showed that expressions of VEGFR3 were (p = 0.002) increased in the laser group. These results suggest that LLLT has anti-inflammatory and lymphangiogenetic effects for the management of lymphedema.

Autistic and Rett-like features associated with 2q33.3-q34 interstitial deletion.

We describe the fourth reported case of a de novo 2q33.3-q34 interstitial deletion and review the literature in attempt to identify relevant candidate genes. A 15-month-old female patient presented for evaluation with poor eye contact and developmental delay. She had microcephaly and mild dysmorphic features, such as downslanting palpebral fissures, high forehead, small mouth, high palate, and general hypotonia. At 30 months of age, she was referred to the genetic clinic for an evaluation of persistent developmental delay, autistic traits, and Rett-like features, including bruxism and repetitive movement of the left hand. Chromosome analysis revealed 46,XX at the 550 band level. No abnormalities were found on analysis of MECP2 gene for Rett syndrome and a DNA methylation test for Prader-Willi syndrome. An array comparative genomic hybridization analysis revealed a de novo 2q33.3-q34 heterozygous deletion (206,048,173-211,980,867). The deletion was estimated to be 5.9 Mb in size and contained 34 known genes. Candidate genes were identified as NRP2, ADAM23, KLF7, CREB1, MAP2, UNC80, and LANCL1 for the 2q33.3-q34 interstitial deletion.

Language-specific dysgraphia in Korean patients with right brain stroke: influence of unilateral spatial neglect.

The purpose of the present study was to investigate the relationship between Korean language-specific dysgraphia and unilateral spatial neglect in 31 right brain stroke patients. All patients were tested for writing errors in spontaneous writing, dictation, and copying tests. The dysgraphia was classified into visuospatial omission, visuospatial destruction, syllabic tilting, stroke omission, stroke addition, and stroke tilting. Twenty-three (77.4%) of the 31 patients made dysgraphia and 18 (58.1%) demonstrated unilateral spatial neglect. The visuospatial omission was the most common dysgraphia followed by stroke addition and omission errors. The highest number of errors was made in the copying and the least was in the spontaneous writing test. Patients with unilateral spatial neglect made a significantly higher number of dysgraphia in the copying test than those without. We identified specific dysgraphia features such as a right side space omission and a vertical stroke addition in Korean right brain stroke patients. In conclusion, unilateral spatial neglect influences copy writing system of Korean language in patients with right brain stroke.

Diagnostic Yield of Trio Whole-Genome Sequencing in Children with Undiagnosed Developmental Delay or Congenital Anomaly: A Prospective Cohort Study.

Developmental delays (DD) and congenital anomalies (CA) are prevalent yet often remain undiagnosed despite comprehensive genetic testing. This study aims to investigate the diagnostic yield of trio whole-genome sequencing (WGS) in children presenting with DD or CA who remained undiagnosed after previous genetic testing. A prospective cohort study was conducted on children with undiagnosed DD or CA at a single tertiary hospital. All participants suspected of genetic conditions had undergone chromosome analysis, chromosome microarray analysis (CMA), and clinical exome sequencing (CES); however, a subset remained undiagnosed. The WGS test was administered to both the affected children and their parents. A total of 52 children were included, and 10 (19.2%) had undergone a genetic diagnosis through WGS. Eight of these cases were associated with autosomal dominant and de novo variants. WGS led to successful diagnosis due to several factors, including small structural variants, genes not covered in the CES panel, the discovery of newly implicated genes, issues related to coverage depth, low variant allele frequency, challenges in variant interpretation, and differences in the interpretation of variants of unknown significance among clinicians. This study highlights the clinical value of trio WGS testing in undiagnosed children with DD or CA. Notably, an additional 19.2% of affected children were diagnosed through this method.

Increased Upper Extremity Muscle Mass in Ambulatory Children with Cerebral Palsy.

AIM: To compare muscle mass in the upper and lower extremities between ambulatory children with cerebral palsy (CP) and typically developing (TD) children. MATERIALS AND METHODS: A total of 21 children aged 2 to 12 years with CP and a Gross Motor Function Classification System (GMFCS) level of I, II, or III were matched with 21 TD children for age, sex, and body mass index. The lean body mass (LBM) of each extremity was calculated from whole-body dual-energy X-ray absorptiometry. RESULTS: The LBM of the upper extremities was greater in children with CP compared to TD children, and the difference was significant in the GMFCS level II group (1340.6 g vs. 1004.2 g, p = 0.027). There was no significant difference in the LBM of the lower extremities between the CP and TD groups (p = 0.190). The ratio of lower extremity LBM to total extremity LBM was lower in children with CP, while the ratio of upper extremity LBM to total extremity LBM was higher in children with CP (73.2% vs. 78.5% [p < 0.001] and 26.7% vs. 21.5% [p < 0.001], respectively). CONCLUSIONS: Ambulatory children with CP, especially in the GMFCS level II group, exhibit greater muscle mass in the upper extremities compared to TD children.

CTNNB1-related neurodevelopmental disorder mimics cerebral palsy: case report.

While somatic gain-of-function mutations in the CTNNB1 gene cause diverse malignancies, germline loss-of-function mutations cause neurodevelopmental disorders or familial exudative vitreoretinopathy. In particular, CTNNB1-related neurodevelopmental disorders have various phenotypes, and a genotype-phenotype relationship has not been established. We report two patients with CTNNB1-related neurodevelopmental disorder whose clinical features were similar to those of cerebral palsy, hindering diagnosis.

Combining chromosomal microarray and clinical exome sequencing for genetic diagnosis of intellectual disability.

Despite the current widespread use of chromosomal microarray analysis (CMA) and exome/genome sequencing for the genetic diagnosis of unexplained intellectual disability (ID) in children, gaining improved diagnostic yields and defined guidelines remains a significant challenge. This is a cohort study of children with unexplained ID. We analyzed the diagnostic yield and its correlation to clinical phenotypes in children with ID who underwent concurrent CMA and clinical exome sequencing (CES). A total of 154 children were included (110 [71.4%] male; mean [SD] age, 51.9 [23.1] months). The overall diagnosis yield was 26.0-33.8%, with CMA contributing 12.3-14.3% and CES contributing 13.6-19.4%, showing no significant difference. The diagnostic rate was significantly higher when gross motor delay (odds ratio, 6.69; 95% CI, 3.20-14.00; P < 0.001), facial dysmorphism (odds ratio, 9.34; 95% CI 4.29-20.30; P < 0.001), congenital structural anomaly (odds ratio 3.62; 95% CI 1.63-8.04; P = 0.001), and microcephaly or macrocephaly (odds ratio 4.87; 95% CI 2.05-11.60; P < 0.001) were presented. Patients with only ID without any other concomitant phenotype (63/154, 40.9%) exhibited a 6.3-11.1% diagnostic rate.

Syringomyelia: A New Phenotype of SPG11-Related Hereditary Spastic Paraplegia?

Hereditary spastic paraplegia (HSP) refers to a group of neurodegenerative disorders affecting motor neurons in the central nervous system. HSP type 11 is the most frequent subtype of autosomal recessive HSPs. Caused by pathogenic variants in SPG11, HSP type 11 has a heterogeneous clinical presentation, including various degrees of cognitive dysfunction, spasticity and weakness predominantly in the lower extremities among other features. An 8-year-old boy visited our rehabilitation clinic with a chief complaint of intellectual impairment. Motor weakness was not apparent, but he exhibited a mild limping gait with physical signs of upper motor neuron involvement. Next generation sequencing revealed biallelic pathogenic variants, c.2163dupT and c.5866+1G>A in SPG11, inherited biparentally which was confirmed by Sanger sequencing. Brain imaging study showed thinning of corpus callosum, consistent with previous reports, however whole spine imaging study revealed extensive syringomyelia in his spinal cord, a rare finding in HSP type 11. Further studies are needed to determine whether this finding is a true phenotype associated with HSP type 11.

A novel pathogenic variant of DNMT3A associated with craniosynostosis: a case report of Heyn-Sproul-Jackson syndrome.

Pathogenic variants of DNMT3A have been implicated in Tatton-Brown-Rahman syndrome, an overgrowth disorder with macrocephaly and intellectual disability. However, there are recent reports of variants in the same gene giving rise to an opposing clinical phenotype presenting with microcephaly, growth failure, and impaired development-named Heyn-Sproul-Jackson syndrome (HESJAS). Here, we present a case of HESJAS caused by a novel pathogenic variant of DNMT3A. A five-year-old girl presented with severe developmental delay. Perinatal and family history were non-contributory. Physical exam showed microcephaly and facial dysmorphic features, and neurodevelopmental assessments revealed profound global developmental delay. Brain magnetic resonance imaging findings were normal; however, brain 3D computed tomography revealed craniosynostosis. Next generation sequencing revealed a novel heterozygous variant in DNMT3A (NM_175629.2: c.1012_1014 + 3del). The patient's parents did not carry the variant. In this report, a novel feature associated with HESJAS (craniosynostosis) is described, along with a more detailed account of clinical manifestations than those in the original report.

NDUFAF6-Related Leigh Syndrome Caused by Rare Pathogenic Variants: A Case Report and the Focused Review of Literature.

Leigh syndrome is a neurodegenerative disorder that presents with fluctuation and stepwise deterioration, such as neurodevelopmental delay and regression, dysarthria, dysphagia, hypotonia, dystonia, tremor, spasticity, epilepsy, and respiratory problems. The syndrome characteristically presents symmetric necrotizing lesions in the basal ganglia, brainstem, cerebellum, thalamus, and spinal cord on cranial magnetic resonance imaging. To date, more than 85 genes are known to be associated with Leigh syndrome. Here, we present a rare case of a child who developed Leigh syndrome due to pathogenic variants of NDUFAF6, which encodes an assembly factor of complex I, a respiratory chain subunit. A targeted next-generation sequencing analysis related to mitochondrial disease revealed a missense variant (NM_152416.4:c.371T > C; p.Ile124Thr) and a frameshift variant (NM_152416.4:c.233_242del; p.Leu78GInfs*10) inherited biparentally. The proband underwent physical therapy and nutrient cocktail therapy, but his physical impairment gradually worsened.

Case Report: The success of face analysis technology in extremely rare genetic diseases in Korea: Tatton-Brown-Rahman syndrome and Say-Barber -Biesecker-Young-Simpson variant of ohdo syndrome.

Tatton-Brown-Rahman syndrome (TBRS) and Say-Barber-Biesecker- Young-Simpson variant of Ohdo syndrome (SBBYSS) are extremely rare genetic disorders with less than 100 reported cases. Patients with these disorders exhibit a characteristic facial dysmorphism: TBRS is characterized by a round face, a straight and thick eyebrow, and prominent maxillary incisors, whereas SBBYSS is characterized by mask-like facies, blepharophimosis, and ptosis. The usefulness of Face2Gene as a tool for the identification of dysmorphology syndromes is discussed, because, in these patients, it suggested TBRS and SBBYSS within the top five candidate disorders. Face2Gene is useful for the diagnosis of extremely rare diseases in Korean patients, suggesting the possibility of expanding its clinical applications.

Case Report: Pansynostosis, Chiari I Malformation and Syringomyelia in a Child With Frontometaphyseal Dysplasia 1.

Frontometaphyseal dysplasia 1 (FMD1) is a rare otopalatodigital spectrum disorder (OPDSD) that is inherited as an X-linked trait and it is caused by gain-of-function mutations in the FLNA. It is characterized by generalized skeletal dysplasia, and craniofacial abnormalities including facial dysmorphism (supraorbital hyperostosis, hypertelorism, and down-slanting palpebral fissures). The involvement of the central nervous system in patients with OPDSD is rare. Herein, we present the case of a 12-year-old boy with facial dysmorphism, multiple joint contractures, sensorineural hearing loss, scoliosis, craniosynostosis, and irregular sclerosis with hyperostosis of the skull. Brain and whole-spine magnetic resonance imaging revealed Chiari I malformation with extensive hydrosyringomyelia from the C1 to T12 levels. Targeted next-generation sequencing identified a hemizygous pathologic variant (c.3557C>T/p.Ser1186Leu) in the FLNA, confirming the diagnosis of FMD1. This is the first report of a rare case of OPDSD with pansynostosis and Chiari I malformation accompanied by extensive syringomyelia.

Prominent Asymmetric Muscle Weakness and Atrophy in Seronegative Immune-Mediated Necrotizing Myopathy.

Immune-mediated necrotizing myopathy, a new subgroup of inflammatory myopathies, usually begins with subacute onset of symmetrical proximal muscle weakness. A 35-year-old male presented with severe asymmetric iliopsoas atrophy and low back pain with a previous history of left lower extremity weakness. Although his first left lower extremity weakness occurred 12 years ago, he did not receive a clear diagnosis. Magnetic resonance imaging of both thigh muscles showed muscle edema and contrast enhancement in patch patterns, and the left buttock and thigh muscles were more atrophied compared to the right side. Serum creatine kinase levels were elevated, and serologic testings were all negative. Genetic testing using a targeted gene-sequencing panel for neuromuscular disease including myopathy identified no pathogenic variants. Muscle biopsy on the right vastus lateralis showed scattered myofiber necrosis with phagocytosis and an absence of prominent inflammatory cells, consistent with seronegative necrotizing myopathy. Thus, unusual asymmetric muscle weakness and atrophy can be a manifestation of inflammatory myopathy.

Transient Neonatal Diabetes Mellitus in SHORT Syndrome: A Case Report.

SHORT syndrome is a rare autosomal dominant disorder characterized by multiple congenital defects and is historically defined by its acronym: short stature, hyperextensibility of joints and/or inguinal hernia, ocular depression, Rieger anomaly, and teething delay. Herein, we report a male infant with SHORT syndrome who presented with transient neonatal diabetes mellitus (TNDM) with insulin resistance. The proband was born at 38 weeks of gestation but displayed facial dysmorphic features. Intrauterine growth restriction (IUGR) was detected on a prenatal ultrasonography test. His birth weight was 1.8 kg (<3rd percentile), length 44 cm (<3rd percentile), and head circumference 31 cm (<3rd percentile). The patient's blood glucose level started to increase at 5 days of age (218-263 mg/dl) and remained high at 20 days of age (205-260 mg/dl). He was treated with subcutaneous insulin and the blood glucose level gradually stabilized. Blood glucose level was stabilized over time without insulin treatment at 6 weeks of age. Clinical exome sequencing showed a heterozygous pathogenic variant, NM_181523.3:c.1945C>T (p.Arg649Trp) in exon 15 of the phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) known as the causative gene for SHORT syndrome. Examination of the patient at 10 months of age revealed no hyperglycemic episode and glycated hemoglobin level was 5.2%. To the best of our knowledge, this is the first case of TNDM in SHORT syndrome due to a pathogenic variant of PIK3R1. We believe that our case can aid in expanding the phenotypes of SHORT syndrome.

Case Report: Co-occurrence of Duchenne Muscular Dystrophy and Frontometaphyseal Dysplasia 1.

Herein, we present a rare case of co-occurring Duchenne muscular dystrophy (DMD) and frontometaphyseal dysplasia 1 (FMD1), two different X-linked diseases, in a 7-year-old boy. He presented with proximal muscle weakness and elevated creatine phosphokinase levels. A multiplex ligation-dependent probe amplification study of DMD revealed the de novo duplications of exons 2-37, thereby confirming the diagnosis of DMD. Initial evaluation revealed atypical features, such as facial dysmorphism, multiple joint contractures, and severe scoliosis, at an early age. However, these were overlooked and were assumed to be atypical manifestations of DMD. Then, the patient's maternal cousin was diagnosed with FMD1 with pathogenic missense variant in FLNA (NM_001110556.2: c.3557C>T/p.Ser1186Leu). A family genetic test revealed that the patient and his mother had the same pathogenic variant in FLNA. The patient's atypical manifestations were considered symptoms of FMD1. Therefore, if one disease does not fully explain the patient's clinical features, an expanded genetic study is needed to detect coincidental disease.

Compound heterozygous variants including a novel copy number variation in a child with atypical ataxia-telangiectasia: a case report.

BACKGROUND: Ataxia-telangiectasia is a rare autosomal recessive, neurodegenerative disorder caused by alterations in the ATM gene. The majority of ATM pathogenic variants are frameshift or nonsense variants which are predicted to truncate the whole ATM protein. Herein, we report on an ataxia telangiectasia child with atypical phenotype who was identified as compound heterozygous for two ATM variants involving a previously described pathogenic single nucleotide variation (SNV) and a novel copy number variation (CNV). CASE PRESENTATION: A 6-year-old boy presented with delayed development and oculomotor apraxia. Brain magnetic resonance imaging showed interval development of mild atrophy in the cerebellum. Serum alpha fetoprotein level was in normal range. Next-generation sequencing and single-nucleotide polymorphism array tests were performed. Next-generation sequencing revealed a heterozygous nonsense pathogenic variant in ATM, c.742C > T (p.Arg248Ter) inherited from the father. Single-nucleotide polymorphism array revealed a compound heterozygous CNV, arr[GRCh37] 11q22.3(10851766-108183226) × 1, 31460 bp (exons 24-40 deletion of ATM) inherited from the mother, which was validated by reverse transcription-polymerase chain reaction analysis (RT-PCR). We demonstrated that this variant (NM_000051.4:c.3403_6006del) generated a product of in-frame deletion of exon 24-40 of ATM (p.Ser1135_Gln2002del). CONCLUSIONS: The compound heterozygosity for ATM variants involving a previously described pathogenic SNV and a novel CNV may be associated with the atypical clinical manifestations. This clinical report extends the genetic and phenotypic spectrum of ATM pathogenic variants in atypical ataxia-telangiectasia, thus making implementation of advanced analysis beyond the routine next-generation sequencing an important consideration in diagnosis and rehabilitation services for children with ataxia-telangiectasia.