Publications by authors named "Jung-Min Ko"

105 Publications

Novel HEXA variants in Korean children with Tay-Sachs disease with regression of neurodevelopment from infancy.

Mol Genet Genomic Med 2021 Apr 3:e1677. Epub 2021 Apr 3.

Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children's Hospital, Seoul, Korea.

Background: Tay-Sachs disease (TSD) is a lysosomal storage disease caused by mutations in the HEXA gene that encodes the HexosaminidaseA (HEXA) enzyme. As HEXA normally functions to degrade the protein GM2-ganglioside in lysosomes, decreased levels of HEXAcauses an accumulation of the protein and leads to neurological toxicity. Typical clinical manifestations of TSD include neurodevelopmental regression, muscle weakness, hypotonia, hyperreflexia, ataxia, seizures, and other neurological symptoms. It is quite rare in Asian populations, wherein only two cases have been reported in Korea to date.

Methods: Clinical records, radiological assessments, and laboratory findings, such as plasma hexosaminidase assay and HEXA analysis, were extracted from the medical records of three (1 male and 2 female) independent Korean children with infantile form of Tay-Sachs disease.

Results: All three children presented with neurodevelopmental regression and strabismus at around 8 months of age. Presence of cherry-red spots in the macula led to conduction of biochemical and genetic studies for TSD confirmation. The plasma hexosaminidase assay revealed decreased HEXA activity and low to normal total hexosaminidase activity. Similarly, genetic analysis revealed 4 variants from 6 alleles, including 2 previously reported and 2 novel variants, in the HEXA gene.

Conclusion: We presented three Korean children, who were recently diagnosed with infantile-type TSDvia enzyme assay and genetic analysis. Furthermore, results showed that fundus examination can be helpful for early diagnosis of children with neurodevelopmental regression.
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http://dx.doi.org/10.1002/mgg3.1677DOI Listing
April 2021

Importance of extracutaneous organ involvement in determining the clinical severity and prognosis of incontinentia pigmenti caused by mutations in the IKBKG gene.

Exp Dermatol 2021 Mar 2. Epub 2021 Mar 2.

Department of Pediatrics, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.

Incontinentia pigmenti (IP) is a rare X-linked skin disease caused by mutations in the IKBKG gene, which is required for activation of the nuclear factor-kappa B signalling pathway. Multiple systems can be affected with highly variable phenotypic expressivity. We aimed to clarify the clinical characteristics observed in molecularly confirmed Korean IP patients. The medical records of 25 females confirmed as IP by molecular genetic analysis were retrospectively reviewed. The phenotypic score of extracutaneous manifestations was calculated to assess the disease severity. The IKBKG gene partial deletion or intragenic mutations were investigated using long-range PCR, multiplex ligation-dependent probe amplification and direct sequencing methods. Among the 25 individuals, 18 (72%) were sporadic cases. All patients showed typical skin manifestations at birth or during the neonatal period. Extracutaneous findings were noted in 17 (68%) patients; ocular manifestations (28%), neurological abnormalities (28%), hair abnormalities (20%), dental anomalies (12%), nail dystrophy (8%). The common exon 4-10 IKBKG deletion was observed in 20 (80%) patients. In addition, five intragenic sequence variants were identified, including three novel variants. The phenotype scores were highly variable, ranging from abnormal skin pigmentation only to one or more extracutaneous features, although no significant difference was observed for each clinical characteristic between the group with sequence variants and that with common large deletion. Our cohort with IP showed heterogeneity of extracutaneous manifestations and high incidence of sporadic cases. Long-term monitoring with multidisciplinary management is essential for evaluating the clinical status, providing adequate genetic counselling and understanding the genotype-phenotype correlation in IP.
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http://dx.doi.org/10.1111/exd.14313DOI Listing
March 2021

Predictors of cervical myelopathy and hydrocephalus in young children with achondroplasia.

Orphanet J Rare Dis 2021 Feb 12;16(1):81. Epub 2021 Feb 12.

Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, 03080, Seoul, Republic of Korea.

Background: Cervical myelopathy and hydrocephalus occasionally occur in young children with achondroplasia. However, these conditions are not evaluated in a timely manner in many cases. The current study presents significant predictors for cervical myelopathy and hydrocephalus in young children with achondroplasia.

Methods: A retrospective analysis of 65 patients with achondroplasia who visited Seoul National University Children's Hospital since 2012 was performed. The patients were divided into groups according to the presence of cervical myelopathy and hydrocephalus, and differences in foramen magnum parameters and ventricular parameters by magnetic resonance imaging between groups were analyzed. Predictors for cervical myelopathy and hydrocephalus were analyzed, and the cut-off points for significant ones were calculated.

Results: The group with cervical myelopathy showed foramen magnum parameters that indicated significantly lower cord thickness than in the group without cervical myelopathy, and the group with hydrocephalus showed significantly higher ventricular parameters and 'Posterior indentation' grade than the group without hydrocephalus. 'Cord constriction ratio' (OR 5199.90, p = 0.001) for cervical myelopathy and 'Frontal horn width' (OR 1.14, p = 0.001) and 'Posterior indentation' grade (grade 1: OR 9.25, p = 0.06; grade 2: OR 18.50, p = 0.01) for hydrocephalus were significant predictors. The cut-off points for cervical myelopathy were 'Cord constriction ratio' of 0.25 and 'FM AP' of 8 mm (AUC 0.821 and 0.862, respectively) and 'Frontal horn width' of 50 mm and 'Posterior indentation' grade of 0 (AUC 0.788 and 0.758, respectively) for hydrocephalus.

Conclusion: 'Cord constriction ratio' for cervical myelopathy and 'Frontal horn width' and 'Posterior indentation' grade for hydrocephalus were significant predictors and may be used as useful parameters for management. 'Posterior indentation' grade may also be used to determine the treatment method for hydrocephalus.
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http://dx.doi.org/10.1186/s13023-021-01725-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881633PMC
February 2021

Clinical Application of Sequential Epigenetic Analysis for Diagnosis of Silver-Russell Syndrome.

Ann Lab Med 2021 Jul;41(4):401-408

Division of Clinical Genetics, Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Korea.

Background: Silver-Russell syndrome (SRS) is a pre- or post-natal growth retardation disorder caused by (epi)genetic alterations. We evaluated the molecular basis and clinical value of sequential epigenetic analysis in pediatric patients with SRS.

Methods: Twenty-eight patients who met≥3 Netchine-Harbison clinical scoring system (NH-CSS) criteria for SRS were enrolled;26 (92.9%) were born small for gestational age, and 25 (89.3%) showed postnatal growth failure. Relative macrocephaly, body asymmetry, and feeding difficulty were noted in 18 (64.3%), 13 (46.4%), and 9 (32.1%) patients, respectively. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) on chromosome 11p15 was performed as the first diagnostic step. Subsequently, bisulfite pyrosequencing (BP) for imprinting center 1 and 2 (IC1 and IC2) at chromosome 11p15, on chromosome 7q32.2, and on chromosome 14q32.2 was performed.

Results: . Seventeen (60.7%) patients exhibited methylation defects, including loss of IC1 methylation (N=14; 11 detected by MS-MLPA and three detected by BP) and maternal uniparental disomy 7 (N=3). The diagnostic yield was comparable between patients who met three or four of the NH-CSS criteria (53.8% vs 50.0%). Patients with methylation defects responded better to growth hormone treatment.

Conclusions: NH-CSS is a powerful tool for SRS screening. However, in practice, genetic analysis should be considered even in patients with a low NH-CSS score. BP analysis detected additional methylation defects that were missed by MS-MLPA and might be considered as a first-line diagnostic tool for SRS.
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http://dx.doi.org/10.3343/alm.2021.41.4.401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884196PMC
July 2021

Paternal Uniparental Disomy of the Entire Chromosome 20 in a Child with Beckwith-Wiedemann Syndrome.

Genes (Basel) 2021 Jan 27;12(2). Epub 2021 Jan 27.

Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.

Epigenetic alterations at imprinted genes on different chromosomes have been linked to several imprinting disorders (IDs) such as Beckwith-Wiedemann syndrome (BWS) and pseudohypoparathyroidism type 1b (PHP1b). Here, we present a male patient with these two distinct IDs caused by two independent mechanisms-loss of methylation (LOM) at chromosome 11p15.5 associated with multi-locus imprinting disturbances (MLID and paternal uniparental disomy of chromosome 20 (patUPD20). A clinical diagnosis of BWS was made based on the clinical features of macrosomia, macroglossia, and umbilical hernia. The diagnosis of PHP1b was supported by the presence of reduced growth velocity and mild learning disability as well as hypocalcemia and hyperphosphatemia at 14 years of age. Molecular analyses, including genome-wide DNA methylation (Illumina 450k array), bisulfite pyrosequencing, single nucleotide polymorphism (SNP) array and microsatellite analysis, demonstrated loss of methylation (LOM) at IC2 on chromosome 11p15.5, and paternal isodisomy of the entire chromosome 20. In addition, imprinting disturbances were noted at the differentially methylated regions (DMRs) associated with on chromosome 1 and on chromosome 6. This is the first case report of PHP1b due to patUPD20 diagnosed in a BWS patient with LOM at IC2 demonstrating etiologic heterogeneity for multiple imprinting disorders in a single individual.
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http://dx.doi.org/10.3390/genes12020172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911624PMC
January 2021

Clinical and genetic profiling of nevoid basal cell carcinoma syndrome in Korean patients by whole-exome sequencing.

Sci Rep 2021 Jan 13;11(1):1163. Epub 2021 Jan 13.

Department of Dermatology, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, South Korea.

Nevoid basal cell carcinoma syndrome (NBCCS) is mainly characterised by multiple basal cell carcinomas (BCCs) caused by PTCH1, PTCH2, and SUFU. However, clinical and genetic data on Asian NBCCS patients are limited. We aimed to analyse the clinical phenotypes and genetic spectrum of Korean patients with NBCCS. Fifteen patients with NBCCS at Seoul National University Hospital were included, and their clinical data were analysed. Whole-exome sequencing and/or multiplex ligation-dependent probe amplification using peripheral blood were performed to identify genetic causes. Genetic analysis revealed that 73.3% (11/15) of the patients carried 9 pathogenic variants, only in the PTCH1 gene. Variants of uncertain significance (VUS) and likely benign were also detected in 2 (13.3%) and 2 (13.3%) patients, respectively. BCCs were found in the majority of the cases (93.3%) and the number of BCCs increased with age (ρ = 0.595, P = 0.019). This study revealed that PTCH1 pathogenic variants were the main cause of NBCCS in Korean patients. As BCCs are commonly detected, a periodic dermatologic examination is recommended. Finally, our results support the addition of genetic screening to the existing criteria for NBCCS diagnosis.
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http://dx.doi.org/10.1038/s41598-020-80867-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806620PMC
January 2021

Management of Osteogenesis Imperfecta: A Multidisciplinary Comprehensive Approach.

Clin Orthop Surg 2020 Dec 18;12(4):417-429. Epub 2020 Nov 18.

Division of Pediatric Orthopaedics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Korea.

Osteogenesis imperfecta (OI) is characterized by recurring fractures and limb and spine deformities. With the advent of medical therapeutics and the discovery of causative genes, as well as the introduction of a newly devised intramedullary rod, the general condition and ambulatory function of patients diagnosed with OI have been improved over the past decades. This review covers recent developments in research and management of OI.
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http://dx.doi.org/10.4055/cios20060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683189PMC
December 2020

A case of CHOPS syndrome accompanied with moyamoya disease and systemic vasculopathy.

Brain Dev 2021 Mar 26;43(3):454-458. Epub 2020 Nov 26.

Rare Diseases Center, Seoul National University Hospital, Seoul, South Korea; Division of Clinical Genetics, Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, South Korea. Electronic address:

Background: CHOPS syndrome, caused by a mutation in the AFF4 gene, is a recently established and extremely rare genetic disorder, which has moderate phenotypic overlap with Cornelia de Lange syndrome. The main phenotypes include characteristic facial features, short stature, obesity, skeletal and pulmonary involvement, and neurodevelopmental impairment.

Case Report: We report on a Korean girl with CHOPS syndrome presenting with an atypical manifestation. The patient was referred to the out-patient clinic to evaluate the underlying etiology of short stature, obesity, developmental delay, and Moyamoya disease. The patient showed characteristic facial features including a round face, thick eyebrows, and synophrys. Her developmental milestones had been delayed since infancy and a moderate degree of intellectual disability persisted. She was also diagnosed with Moyamoya disease at 6 years of age and had undergone synangiosis surgery thrice. Her renal arteries and infrarenal aorta were diffusely narrowed. A novel de novo missense variant, c.758C > T (p.Pro253Leu) in AFF4 was identified by whole exome sequencing. No additional candidate variants for her vascular manifestation were found except a susceptibility variant, c.14429G > A (p.Arg4810Lys) in RNF213, inherited from asymptomatic mother.

Conclusion: This is the first case of CHOPS syndrome accompanied by systemic vasculopathy. More clinical observations and functional studies are required to clarify this association.
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http://dx.doi.org/10.1016/j.braindev.2020.11.004DOI Listing
March 2021

The GBA p.G85E mutation in Korean patients with non-neuronopathic Gaucher disease: founder and neuroprotective effects.

Orphanet J Rare Dis 2020 11 11;15(1):318. Epub 2020 Nov 11.

Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-Gu, Seoul, 05505, Korea.

Background: Gaucher disease (GD) is caused by a deficiency of β-glucocerebrosidase, encoded by GBA. Haplotype analyses previously demonstrated founder effects for particular GBA mutations in Ashkenazi Jewish and French-Canadian populations. This study aimed to investigate the clinical characteristics and mutation spectrum of GBA in Korean GD patients and to identify founder effect of GBA p.G85E in non-neuronopathic GD patients.

Results: The study cohort included 62 GD patients from 58 unrelated families. Among them, 18 patients from 17 families harbored the p.G85E mutation. Haplotype analysis was performed for 9 probands and their parents for whom DNA samples were available. In 58 unrelated probands, the GBA mutation p.L483P was the most common (30/116 alleles, 26%), followed by p.G85E (16%), p.F252I (13%), and p.R296Q (9%). The median age at diagnosis of the 18 patients harboring the p.G85E mutation was 3.8 (range 1.2-57) years. No patients developed neurological symptoms during follow-up periods of 2.2-20.3 (median 13.9) years. The size of the shared haplotype containing GBA p.G85E was 732 kbp, leading to an estimated age of 3075 years.

Conclusion: The GBA p.G85E mutation, which appears to be neuroprotective despite producing distinctive visceromegaly and skeletal symptoms, exhibited a potential founder effect in Korean GD patients.
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http://dx.doi.org/10.1186/s13023-020-01597-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656680PMC
November 2020

Clinical and molecular spectra of BRAF-associated RASopathy.

J Hum Genet 2021 Apr 10;66(4):389-399. Epub 2020 Oct 10.

Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, South Korea.

Noonan syndrome (NS) and cardio-facio-cutaneous (CFC) syndrome are the most common subtypes of RASopathy. As an effector of Ras, BRAF is one of the molecules responsible for RASopathy. We investigated the phenotypic and genotypic features of 26 patients with BRAF-associated RASopathy. The clinical diagnoses were CFC (n = 21, 80.8%), NS (n = 3, 11.5%), NS/CFC (n = 1, 3.8%), and undefined syndromic intellectual disability (ID) (n = 1, 3.8%). The mostly shared phenotypes were ID (90.5%), cutaneous manifestations (84.6%), congenital heart defects (76.9%), short stature (76.9%), and dysmorphic features such as short neck (65.4%) and low-set ears (65.4%). Importantly, moderate to severe ID (57.1%) and epilepsy (26.9%) were noted. Eighteen different missense mutations were found, including a novel mutation, p.Phe498Tyr. p.Gln257Arg (n = 9, 34.6%) was the most common mutation, and the mutations were clustered in the cysteine-rich domain or protein kinase domain. A review of previously reported cases along with our findings revealed the existence of multiple sub-phenotypes of RASopathy within a single genotype, indicating that BRAF-associated RASopathy is not variant-specific. Our study further delineated the diverse and expanded clinical phenotypes of BRAF-associated RASopathy with their molecular genetic characteristics.
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http://dx.doi.org/10.1038/s10038-020-00852-3DOI Listing
April 2021

Clinical and Genetic Characteristics of 23 Korean Patients with Haploinsufficiency of the Short-stature Homeobox-containing Gene.

Exp Clin Endocrinol Diabetes 2020 Sep 15. Epub 2020 Sep 15.

Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children's Hospital, Seoul.

Background: The short-stature homeobox-containing gene () is one of the major growth genes in humans. The clinical spectrum of haploinsufficiency ranges from Léri-Weill dyschondrosteosis to idiopathic short stature. Herein, we describe the clinical and genetic characteristics of 23 Korean patients with deficiency disorders.

Methods: Medical records of 23 patients (19 females and 4 males) from 15 unrelated families who were genetically confirmed to have deficiency were retrospectively reviewed. gene deletions or mutations were determined by sequence analyses using multiplex ligation-dependent probe amplification, chromosomal microarray, and/or Sanger sequencing methods.

Results: In the 15 families, 9 probands were cases. All 23 patients showed mesomelia. Madelung deformity and tibia vara were observed in 13 (56.5%) and 3 (13.1%) patients, respectively. Genetically, 11 (73.3%) of the 15 families showed deletions of various sizes, and the other 4 families harboured sequence variants. Four patients had undergone orthopaedic surgeries (3 for tibia vara and 1 for Madelung deformity). Among 7 patients who had received growth hormone treatment for ≥1 year, 5 showed good responses, with a median first-year change-in-height standard deviation score of +0.6. There were no significant differences in the clinical characteristics of the deletion and point mutation groups.

Conclusions: A high index of suspicion and the genetic confirmation of deficiency are helpful for the timely management of the condition and are needed to provide genetic counselling to the family members of the patients.
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http://dx.doi.org/10.1055/a-1247-4863DOI Listing
September 2020

Hyperammonemic Encephalopathy Mimicking Ornithine Transcarbamylase Deficiency in Fibrolamellar Hepatocellular Carcinoma: Successful Treatment with Continuous Venovenous Hemofiltration and Ammonia Scavengers.

Cancer Res Treat 2021 Jan 7;53(1):283-288. Epub 2020 Sep 7.

Department of Pediatrics, Center for Pediatric Cancer, National Cancer Center, Goyang, Korea.

Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare liver cancer affecting adolescents and young adults without any pre existing liver disease. Hyperammonemic encephalopathy (HAE) is a serious paraneoplastic syndrome, and several cases of HAE have been reported in patients with FLHCC. This condition is rare; hence, there are currently no management guidelines for cancer-related HAE. Herein, we report a case of an 18-year-old man with advanced FLHCC who developed HAE during the first course of chemotherapy consisting of cisplatin, doxorubicin, 5-fluorouracil, and interferon-α. He was successfully treated with continuous venovenous hemofiltration, sodium benzoate, sodium phenylbutyrate, and amino acid supplementation for HAE. After the second course of chemotherapy, he underwent surgery, and thereafter, his ammonia levels were normal without any ammonia scavenger therapy. Treatments for HAE described here will be helpful for this rare, but serious metabolic complication of FLHCC and could partially applied to HAE related to any malignancies.
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http://dx.doi.org/10.4143/crt.2020.575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812018PMC
January 2021

Detailed analysis of phenotypes and genotypes in megalencephaly-capillary malformation-polymicrogyria syndrome caused by somatic mosaicism of PIK3CA mutations.

Orphanet J Rare Dis 2020 08 10;15(1):205. Epub 2020 Aug 10.

Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Jongnogu Daehakro 101, Seoul, 03080, Republic of Korea.

Background: Megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP) belongs to a group of conditions called the PIK3CA-related overgrowth spectrum (PROS). The varying phenotypes and low frequencies of each somatic mosaic variant make confirmative diagnosis difficult. We present 12 patients who were diagnosed clinically and genetically with MCAP. Genomic DNA was extracted mainly from the skin of affected lesions, also from peripheral blood leukocytes and buccal epithelial cells, and target panel sequencing using high-depth next-generation sequencing technology was performed.

Results: Macrocephaly was present in 11/12 patients (92%). All patients had normal body asymmetry. Cutaneous vascular malformation was found in 10/12 patients (83%). Megalencephaly or hemimegalencephaly was noted in all 11 patients who underwent brain magnetic resonance imaging. Arnold-Chiari type I malformation was also seen in 10 patients. Every patient was identified as having pathogenic or likely pathogenic variants of the PIK3CA gene. The variant allele frequency (VAF) ranged from 6.3 to 35.3%, however, there was no direct correlation between VAF and the severity of associated anomalies. c.2740G > A (p.Gly914Arg) was most commonly found, in four patients (33%). No malignancies developed during follow-up periods.

Conclusions: This is the first and largest cohort of molecularly diagnosed patients with MCAP in Korea. Targeted therapy with a PI3K-specific inhibitor, alpelisib, has shown successful outcomes in patients with PROS in a pilot clinical study, so early diagnosis for genetic counseling and timely introduction of emerging treatments might be achieved in the future through optimal genetic testing.
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http://dx.doi.org/10.1186/s13023-020-01480-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418424PMC
August 2020

Combined lung and liver transplantation for noncirrhotic portal hypertension with severe hepatopulmonary syndrome in a patient with dyskeratosis congenita.

Pediatr Transplant 2021 Mar 10;25(2):e13802. Epub 2020 Aug 10.

Department of Pediatrics, Seoul National University Hospital, Seoul, Korea.

DC is caused by defects at the level of telomere maintenance, and cells from patients with this disease have abnormally short telomeres and show premature senescence. One consequence of DC is bone marrow failure. Thus, patients with DC often require HSCT. However, HSCT does not ameliorate other DC-related manifestations. In fact, HSCT can accelerate organ dysfunction due to treatment-related complications, and solid organ transplantation is required in some patients with DC. In this report, we describe the clinical course of a 5-year-old boy who was transferred to our hospital because of progressive dyspnea, 2 years after HSCT. At admission, he had tachypnea and hypoxemia. A liver biopsy was performed for suspected HPS caused by PH, and LT was considered. Eventually, his hypoxemia worsened, and he was transferred to a PICU and started on VA ECMO. He subsequently underwent a CLLT. ECMO was stopped on post-operative day 12, extubation was achieved on post-operative day 29, and the patient recovered well from the surgery. Our results show that CLLT could be a life-saving treatment option for DC patients with very severe HPS in whom a poor outcome is expected after LT.
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http://dx.doi.org/10.1111/petr.13802DOI Listing
March 2021

A Korean child diagnosed with malonic aciduria harboring a novel start codon mutation following presentation with dilated cardiomyopathy.

Mol Genet Genomic Med 2020 09 30;8(9):e1379. Epub 2020 Jun 30.

Department of Laboratory Medicine, Kyung Hee University School of Medicine, Seoul, Korea.

Background: Malonic aciduria (MA, OMIM#248360) is an extremely rare inherited metabolic disorder caused by the deficiency of malonyl-CoA decarboxylase. The phenotype exhibited by patients with MA is variable, but may include symptoms, such as developmental delay in early childhood, seizures, vomiting, metabolic acidosis, hypoglycemia, ketosis, and cardiomyopathy. We describe the first case of a Korean child with MA who presented with dilated cardiomyopathy (DCMP) at the age of 3 months.

Methods And Results: A 3-month-old Korean boy visited our hospital for diagnosis and management of cardiomegaly. Newborn screening for inherited metabolic diseases showed a normal result; therefore, DCMP management was initiated. Biochemical and the MLYCD gene analyses subsequently confirmed diagnosis of MA. Elevated plasma C3DC level and excessive excretion of urinary malonate were observed, and two pathogenic variants, including a novel start codon mutation (c.1A>G), were identified in MLYCD. A low long-chain fat diet with middle-chain triglyceride formula and L-carnitine supplementation was initiated. The patient is now 5 years old and exhibits considerably improved cardiac function.

Conclusions: MA can be diagnosed using newborn screening; however, negative results do not exclude the possibility of disease. Metabolic screening for differential diagnosis of infantile DCMP is recommended to rule out rare, but manageable, metabolic cardiomyopathies.
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http://dx.doi.org/10.1002/mgg3.1379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507300PMC
September 2020

Lentigo maligna in a patient with xeroderma pigmentosum, variant type: A case report with dermoscopic findings and review of the literature.

Photodermatol Photoimmunol Photomed 2020 Sep 21;36(5):401-404. Epub 2020 May 21.

Department of Dermatology, Seoul National University College of Medicine, Seoul, Korea.

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http://dx.doi.org/10.1111/phpp.12568DOI Listing
September 2020

Genomic profiling of 553 uncharacterized neurodevelopment patients reveals a high proportion of recessive pathogenic variant carriers in an outbred population.

Sci Rep 2020 Jan 29;10(1):1413. Epub 2020 Jan 29.

Department of Pediatrics, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.

A substantial portion of Mendelian disease patients suffers from genetic variants that are inherited in a recessive manner. A precise understanding of pathogenic recessive variants in a population would assist in pre-screening births of such patients. However, a systematic understanding of the contribution of recessive variants to Mendelian diseases is still lacking. Therefore, genetic diagnosis and variant discovery of 553 undiagnosed Korean patients with complex neurodevelopmental problems (KND for Korean NeuroDevelopmental cohort) were performed using whole exome sequencing of patients and their parents. Disease-causing variants, including newly discovered variants, were identified in 57.5% of the probands of the KND cohort. Among the patients with the previous reported pathogenic variants, 35.1% inherited these variants in a recessive manner. Genes that cause recessive disorders in our cohort tend to be less constrained by loss-of-function variants and were enriched in lipid metabolism and mitochondrial functions. This observation was applied to an estimation that approximately 1 in 17 healthy Korean individuals carry at least one of these pathogenic variants that develop severe neurodevelopmental problems in a recessive manner. Furthermore, the feasibility of these genes for carrier screening was evaluated. Our results will serve as a foundation for recessive variant screening to reduce occurrences of rare Mendelian disease patients. Additionally, our results highlight the utility and necessity of whole exome sequencing-based diagnostics for improving patient care in a country with a centralized medical system.
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http://dx.doi.org/10.1038/s41598-020-58101-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6989631PMC
January 2020

Diagnosis and Management of Hip Dislocation in Patients with Kabuki Syndrome.

Clin Orthop Surg 2019 Dec 12;11(4):474-481. Epub 2019 Nov 12.

Division of Pediatric Orthopaedics, Seoul National University Children's Hospital, Seoul, Korea.

Background: Kabuki syndrome is a rare genetic disorder characterized by distinct dysmorphic facial features, growth deficiency, intellectual disabilities, unusual dermatoglyphic patterns, and skeletal abnormalities. The incidence of hip dislocation in Kabuki syndrome ranges from 18% to 62%. We reviewed the outcomes of management of hip dislocations in patients with Kabuki syndrome with special attention to the diagnostic processes for hip dislocation and Kabuki syndrome.

Methods: Among 30 patients with mutation-confirmed Kabuki syndrome, we selected six patients who had hip dislocations and reviewed their medical records and plain radiographs. The modes of presentation and diagnostic processes for both hip dislocations and Kabuki syndrome were investigated. The management and treatment outcomes of hip dislocations in patients with Kabuki syndrome were evaluated.

Results: The average age of patients at the time of diagnosis of hip dislocation was 7.7 months (range, 1 week to 22 months). None of the patients were diagnosed as having Kabuki syndrome at that time. Two patients were treated with a Pavlik harness; one, with closed reduction; two, with open reduction and later pelvic and/or femoral osteotomies; and one, with open reduction combined with pelvic osteotomy. The patients were followed up for 5.8 years on average (range, 2.0 to 10.5 years). The radiologic outcome was graded as Severin IA or IB for three patients who were older than 6 years at the latest follow-up (mean age, 9.9 years; range, 7.8 to 12.4 years). In the remaining three patients younger than 6 years (mean age, 3.8 years; range, 2.7 to 5.3 years), the lateral center edge angle was more than 15°. The clinical diagnosis of Kabuki syndrome was made during follow-up after hip dislocation treatment and confirmed by mutational analysis at a mean age of 4.7 years. The mean interval between the diagnosis of hip dislocation and Kabuki syndrome was 4.0 years.

Conclusions: The management of hip dislocation by conservative or surgical method showed successful results. Awareness of Kabuki syndrome could lead to an early diagnosis of this rare disease in patients with hip dislocation and allow for early detection of other underlying conditions and multidisciplinary management.
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http://dx.doi.org/10.4055/cios.2019.11.4.474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6867925PMC
December 2019

A 9-year-old Korean girl with Fontaine progeroid syndrome: a case report with further phenotypical delineation and description of clinical course during long-term follow-up.

BMC Med Genet 2019 11 27;20(1):188. Epub 2019 Nov 27.

Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children's Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, South Korea.

Background: Gorlin-Chaudhry-Moss syndrome (GCMS) and Fontaine-Farriaux syndrome (FFS) are extremely rare genetic disorders that share similar clinical manifestations. Because a de novo missense mutation of the solute carrier family 25 member 24 (SLC25A24) gene was suggested to be the common genetic basis of both syndromes, it has been proposed recently that they be integrated into a single disorder under the name of Fontaine progeroid syndrome (FPS).

Case Presentation: A 9-year-old Korean girl presented with typical clinical features of FPS. She had generalized loose skin with decreased subcutaneous fat, skin wrinkling on the forehead and limbs, skull deformities and a peculiar facial appearance with microphthalmia and midface hypoplasia, anomalies of the digits and nails, a large umbilical hernia and a nearly normal developmental outcome. She exhibited prenatal and postnatal growth retardation together with short stature, and records showed that her height and weight were invariably under - 2.0 SD from birth to the age of 10 years. SLC25A24 analysis revealed a heterozygous mutation reported previously, NM_013386:c.650G > A, p.[Arg217His]. After screening her family for the identified mutation, she was confirmed as being a de novo case of FPS caused by an SLC25A24 mutation.

Conclusion: We describe a Korean girl with typical clinical findings of FPS and a de novo mutation in SLC25A24, as well as 10 years of clinical follow-up, including growth and developmental achievements.
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http://dx.doi.org/10.1186/s12881-019-0921-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882017PMC
November 2019

Generation of a patient-specific induced pluripotent stem cell line, KSCBi006-A, for osteogenesis imperfecta type I with the COL1A1, c.3162delT mutation.

Stem Cell Res 2019 12 25;41:101622. Epub 2019 Oct 25.

Division of Intractable Diseases, National Center for Stem Cell and Regenerative Medicine, Center for Biomedical Sciences, Korea National Institute of Health, Korea Centers for Disease Control and Prevention Cheongju-si, Republic of Korea. Electronic address:

Osteogenesis imperfecta (OI) is a genetic disorder characterized by brittle bones. OI type I is the most common and usually the mildest form. We generated human induced pluripotent stem cells (hiPSCs), KSCBi006-A, from the peripheral blood mononuclear cells of a patient with OI type I using the Sendai virus delivery method. The generated hiPSCs retained the disease-causing DNA mutation (COL1A1, c.3162delT) and showed a normal karyotype. KSCBi006-A also has pluripotency and the capacity for differentiation into the three germ layers. These patient-specific iPSCs provide a valuable cellular modeling platform for OI and a resource for drug screening.
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http://dx.doi.org/10.1016/j.scr.2019.101622DOI Listing
December 2019

American consumers' perception and acceptance of an ethnic food with strong flavor: a case study of Kimchi with varying levels of red pepper and fish sauce.

J Sci Food Agric 2020 Apr 25;100(6):2348-2357. Epub 2020 Feb 25.

Department of Food and Nutrition, Research Institute of Human Ecology, Seoul National University, Seoul, Korea.

Background: A spicy ethnic food with strong flavor, such as Kimchi (Korean traditional fermented vegetable dish), may not be well-accepted by foreign consumers on the first trial, but liking can be acquired if exposed frequently. This study was conducted to understand how spiciness and fish sauce flavor impact American consumers' perception and acceptance of Kimchi. Thirteen untrained American panelists performed a flash profiling evaluating six Kimchi samples with different levels of red pepper and fish sauce. American consumers (n = 96) participated in a consumer study during which their acceptance for the same samples, along with their consumption habits, were evaluated.

Results: Ratings of perceived spiciness and liking increased as the concentration of red pepper increased, while these attributes were less affected by the level of fish sauce tested. Consumers were segmented into four clusters: general Kimchi likers (30%), spicy Kimchi likers (10%), mild Kimchi dislikers (45%), and spicy and strong-flavored Kimchi dislikers (15%). This segmentation showed a significant impact of previous experiences tasting authentic Kimchi.

Conclusion: Stronger spiciness in Kimchi is preferred by American consumers, while absence or addition of fish sauce did not influence their acceptance. Previous experience with Kimchi and a liking for spicy foods that had been already established seem to be associated with their liking for the spicier Kimchi. It is suggested that an authentic Kimchi experience further differentiated the preference pattern for Kimchi with varying levels of spiciness and fish sauce flavor. © 2019 Society of Chemical Industry.
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http://dx.doi.org/10.1002/jsfa.10106DOI Listing
April 2020

Missense Mutations in NKAP Cause a Disorder of Transcriptional Regulation Characterized by Marfanoid Habitus and Cognitive Impairment.

Am J Hum Genet 2019 11 3;105(5):987-995. Epub 2019 Oct 3.

Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Laboratory of Rare Disease Research, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo 113-8657, Japan. Electronic address:

NKAP is a ubiquitously expressed nucleoplasmic protein that is currently known as a transcriptional regulatory molecule via its interaction with HDAC3 and spliceosomal proteins. Here, we report a disorder of transcriptional regulation due to missense mutations in the X chromosome gene, NKAP. These mutations are clustered in the C-terminal region of NKAP where NKAP interacts with HDAC3 and post-catalytic spliceosomal complex proteins. Consistent with a role for the C-terminal region of NKAP in embryogenesis, nkap mutant zebrafish with a C-terminally truncated NKAP demonstrate severe developmental defects. The clinical features of affected individuals are highly conserved and include developmental delay, hypotonia, joint contractures, behavioral abnormalities, Marfanoid habitus, and scoliosis. In affected cases, transcriptome analysis revealed the presence of a unique transcriptome signature, which is characterized by the downregulation of long genes with higher exon numbers. These observations indicate the critical role of NKAP in transcriptional regulation and demonstrate that perturbations of the C-terminal region lead to developmental defects in both humans and zebrafish.
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http://dx.doi.org/10.1016/j.ajhg.2019.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848994PMC
November 2019

Clinical and Molecular Characteristics of GNAS Inactivation Disorders Observed in 18 Korean Patients.

Exp Clin Endocrinol Diabetes 2021 Feb 23;129(2):118-125. Epub 2019 Sep 23.

Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children's Hospital, Seoul, Korea.

Background: The gene on chromosome 20q13.3 is a complex, imprinted locus regulated in a tissue-specific manner. inactivation disorders are a heterogeneous group of rare disorders caused by mutations and methylation defects. These are divided into pseudohypoparathyroidism (PHP) types 1A and 1B, pseudo-pseudohypoparathyroidism (PPHP), and progressive osseous heteroplasia (POH), depending on the presence or absence of hormone resistance, Albright's hereditary osteodystrophy (AHO), and ectopic ossification.

Methods: This study analyzed the clinical characteristics and molecular genetic backgrounds of 18 Korean patients from 16 families with a genetically confirmed defect. Auxological parameters, AHO phenotypes, types of hormonal resistance, family history, and molecular genetic disturbances were reviewed retrospectively.

Results: Nine (90%) patients with PHP1A showed resistance to parathyroid hormone (PTH) and all patients showed elevated thyroid-stimulating hormone (TSH) levels at diagnosis. Eight (80%) patients were managed with levothyroxine supplementation. Three of six patients with PHP1B had elevated TSH levels, but none of whom needed levothyroxine medication. AHO features were absent in PHP1B. Patients with PPHP and POH did not show any hormone resistance, and both of them were born as small for gestational age. Among the 11 families with PHP1A, PPHP, and POH, eight different (three novel) mutations in the gene were identified. Among the six patients with PHP1B, two were sporadic cases and four showed isolated loss of methylation at A/B:TSS-DMR.

Conclusions: Clinical and molecular characteristics of Korean patients with inactivation disorders were described in this study. Also, we reaffirmed heterogeneity of PHP, contributing to further accumulation and expansion of current knowledge of this complex disease.
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http://dx.doi.org/10.1055/a-1001-3575DOI Listing
February 2021

Phenotypic and Genetic Characteristics of Five Korean Patients with Costello Syndrome.

Cytogenet Genome Res 2019 9;158(4):184-191. Epub 2019 Aug 9.

Costello syndrome (CS) is a rare genetic disorder characterized by distinctive facial appearance, cardiopulmonary complications, severe growth retardation, skin and skeletal defects, developmental delay, and tumor predisposition. CS is caused by heterozygous de novo mutations in the proto-oncogene HRAS, which is a component of the RAS/mitogen-activated protein kinase pathway. Herein, we reviewed the phenotypic and genetic features of 5 Korean patients who were genetically diagnosed with CS. Atrial tachycardia and polyhydramnios, which are important prenatal features for CS, were observed in 4 and 5 patients, respectively. The distinctive coarse facial appearances of the patients and presence of deep palmoplantar creases supported the clinical diagnosis of CS, which was confirmed by HRAS sequence analysis. Extremely poor postnatal growth was observed in all 5 patients. Further, all patients exhibited cardiac abnormalities; left ventricular hypertrophy and hypertrophic cardiomyopathy were observed in 3 patients. All 5 patients suffered from airway problems; 3 of them required intubation right after birth, and 2 of them received tracheostomy. One patient with a p.Gly12Ser mutation was diagnosed with retroperitoneal rhabdomyosarcoma alveolar type at the age of 5 years. Consistent with previous reports, both patients with p.Gly12Cys mutations died within the first year of life due to cardiopulmonary failure. Our study summarizes the characteristics of these 5 Korean patients with CS and, along with previous studies, provides clues for genotype-phenotype correlation in patients with CS.
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http://dx.doi.org/10.1159/000502045DOI Listing
September 2019

Deletion of exons 16-17b of CFTR is frequently identified in Korean patients with cystic fibrosis.

Eur J Med Genet 2019 Aug 25;62(8):103681. Epub 2019 May 25.

Dept. of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.

Cystic fibrosis (MIM #219700) is one of the most common autosomal recessively inherited diseases in Caucasians and is caused by pathogenic variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. However, this disease is much less frequent in Asian populations. Here, we performed a clinical characterization of, and genetic analysis of CFTR in, Korean patients with cystic fibrosis. Six Korean patients from five families (two females and four males; median age, 12.5 years) were enrolled. Clinical data were assessed by retrospective review of medical records. The genetic variants of CFTR were analysed by sequencing analysis and multiple ligation-dependent probe amplification (MLPA). Among the six patients, five had at least one allele with a deletion of exons 16-17 b: four had a heterozygous deletion and one had a homozygous deletion. Six of 12 alleles (50%) showed 16-17 b multi-exon deletion. All six patients had a classical cystic fibrosis phenotype and presented with chronic steatorrhea and malabsorption from infancy, resulting in growth failure and chronic recurrent respiratory symptoms, including chronic sinusitis, mucus plugging, and bronchiectasis. All patients survived with supportive care. Early diagnosis and management are important for improving the clinical outcomes of patients with cystic fibrosis. Because of the high frequency of multi- or single-exon deletions in CFTR, we suggest that molecular investigation for identifying exon deletions should be performed to establish an early confirmative diagnosis in Asian populations, including populations in Korea and Japan.
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http://dx.doi.org/10.1016/j.ejmg.2019.103681DOI Listing
August 2019

Hyperammonemia in a case of herpes simplex and anti-N-methyl-d-aspartate receptor encephalitis.

Brain Dev 2019 Aug 5;41(7):634-637. Epub 2019 Apr 5.

Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children's Hospital, Seoul, Republic of Korea. Electronic address:

Herpes simplex encephalitis (HSE) is a widely accepted risk factor for anti N-methyl-d-aspartate receptor (NMDAR) encephalitis. Association of inherited metabolic disease has never been reported in a patient with HSE and anti-NMDAR encephalitis. Herein, we report a case of pediatric HSE complicated by development of anti-NMDAR encephalitis; this patient showed subsequent recurrent, unexplained episodes of encephalopathy associated with hyperammonemia. The patient was diagnosed with lysinuric protein intolerance (LPI), a rare inborn metabolic disorder. Although it would be difficult to make conclusions regarding the casual link of HSE and anti-NMDAR encephalitis with LPI from a single case, there have been many reports that autoimmune diseases and immunologic abnormalities are frequently associated with LPI. Thus, we speculate that LPI may contribute to the development of anti-NMDAR encephalitis following HSE.
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http://dx.doi.org/10.1016/j.braindev.2019.03.013DOI Listing
August 2019

The Korean undiagnosed diseases program: lessons from a one-year pilot project.

Orphanet J Rare Dis 2019 03 20;14(1):68. Epub 2019 Mar 20.

Department of Pediatrics, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Korea.

Background: The Korean Undiagnosed Diseases Program (KUDP) was launched in January 2017 as a one-year pilot project to address the increasing global interest in patients with undiagnosed rare diseases. The purpose of this paper is to summarize the project results and emphasize the unmet research needs among patients with undiagnosed rare diseases in Korea.

Results: Patient enrollment, assessment, and diagnostic processes were determined by the KUDP clinical expert consortium. Patients followed a diagnostic workflow after being categorized into one of four groups: I) insufficient clinical information or lack of standard diagnostic processes; II) undiagnosed due to low disease awareness; III) clinically diagnosed but unconfirmed genetically due to genetic heterogeneities; or IV) unknown disease due to complex, atypical clinical presentations. After excluding two patients from group I, 97 patients were enrolled, including 10 in group II, 67 in group III, and 20 in group IV. Most of them (92 of 97, 94.8%) were pediatric patients (< 18 years old) and 59 (60.8%) were male. The primary symptoms for 80 patients (82.5%) were neurologic. During the one-year pilot study, 72 patients completed a diagnostic assessment including clinical and molecular genetic analyses; some patients also underwent pathological or biochemical analysis. Twenty-eight of these patients (28/72, 38.9%) achieved molecular genetic diagnosis. Thirteen patients were diagnosed based on traditional tests, including biochemical assay, single or targeted genetic analysis, and chromosomal microarray. We performed whole exome sequencing on 52 patients, among whom 15 (28.8%, 15/52) reached a final diagnosis. One new disorder was identified via international collaboration.

Conclusions: Using an efficient clinical diagnostic workflow, this KUDP pilot study resulted in a fair diagnostic success rate, improving the potential for additional diagnoses and new scientific discovery of complex and rare diseases. KUDP also satisfied unmet needs for rare diseases with multisystem involvement, highlighting the value of emerging genomic technologies for further research into rare and still-undiagnosed conditions.
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http://dx.doi.org/10.1186/s13023-019-1041-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6427886PMC
March 2019

Two Korean girls with complete androgen insensitivity syndrome diagnosed in infancy.

Ann Pediatr Endocrinol Metab 2018 Dec 31;23(4):220-225. Epub 2018 Dec 31.

Department of Laboratory Medicine, Seoul National University Hospital, Seoul, Korea.

Androgen insensitivity syndrome (AIS) is a rare genetic disease caused by various abnormalities in the androgen receptor (AR). The AR is an essential steroid hormone receptor that plays a critical role in male sexual differentiation and development and preservation of the male phenotype. Mutations in the AR gene on the X chromosome cause malfunction of the AR so that a 46,XY karyotype male has some physical characteristics of a woman or a full female phenotype. Depending on the phenotype, AIS can be classified as complete, partial or mild. Here, we report 2 cases of complete AIS in young children who showed complete sex reversal from male to female as a result of AR mutations. They had palpable inguinal masses and normal female external genitalia, a blind-end vagina and absent Müllerian duct derivatives. They were both 46,XY karyotype and AR gene analysis demonstrated pathologic mutations in both. Because AIS is inherited in an X-linked recessive manner, we performed genetic analysis of the female family members of each patient and found the same mutation in the mothers of both patients and in the female sibling of case 2. Gonadectomy was performed in both patients to avoid the risk of malignancy in the undescended testicles, and estrogen replacement therapy is planned for their adolescence. Individuals with complete AIS are usually raised as females and need appropriate care.
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http://dx.doi.org/10.6065/apem.2018.23.4.220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312918PMC
December 2018

A 3-Month-Old Boy With Progressive Weakness.

Brain Pathol 2018 09;28(5):773-774

Department of Pediatrics, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul, Korea.

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http://dx.doi.org/10.1111/bpa.12651DOI Listing
September 2018

Cutaneous Skeletal Hypophosphatemia Syndrome in Association with a Mosaic Mutation.

Ann Clin Lab Sci 2018 Sep;48(5):665-669

Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children's Hospital, Seoul, Korea

Recent molecular genetic studies have revealed that Schimmelpenning-Feuerstein-Mims syndrome (SFMS), which presents as sebaceous nevi, is a mosaic RASopathy caused by postzygotic somatic activating mutations in , , or Some patients with SFMS also have hypophosphatemic rickets, called cutaneous skeletal hypophosphatemia syndrome (CSHS). We here report a pediatric case of biopsy-proven CSHS with mosaic mutation in the gene. A girl who showed extensive nevus sebaceous since birth had suffered progressive lower extremity deformity since the age of 5 years. We found hypophosphatemic rickets in laboratory and radiological studies. From the molecular study with skin tissue with nevus sebaceous, we identified a heterozygous mutation, c.182A>G (p.Gln61Arg), in exon 3 of by Sanger sequencing. However, we did not find this mutation in the peripheral blood and unaffected tissue, which demonstrated mosaic distribution of the mutation throughout the body. Given the rarity of the previous genetically proven CSHS cases, accumulation of more cases is needed to establish the role of Ras activation in skeletal manifestations in CSHS, which is likely due to excessive production of fibroblast growth factor 23.
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September 2018