• Journal of Genetic Medicine
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• v.15 no.2
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• pp.102-106
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• 2018

Aggrecan is a proteoglycan in the extracellular matrix of growth plate and cartilaginous tissues. Aggrecanopathy has been reported as a genetic cause not only for severe skeletal dysplasia but also for autosomal dominant short stature with normal to advanced bone age. We report a novel heterozygous mutation of ACAN in a Korean family with proportionate short stature identified through targeted exome sequencing. We present a girl of 4 years and 9 months with a family history of short stature over three generations. The paternal grandmother is 143 cm tall (-3.8 as a Korean standard deviation score [SDS]), the father 155 cm (-3.4 SDS), and the index case 96.2 cm (-2.9 SDS). Evaluation for short stature showed normal growth hormone (GH) peaks in the GH provocation test and a mild delayed bone age for chronological age. This subject had clinical characteristics including a triangular face, flat nasal bridge, prognathia, blue sclerae, and brittle teeth. The targeted exome sequencing was applied to detect autosomal dominant growth palate disorder. The novel variant c.910G>A (p.Asp304Asn) in ACAN was identified and this variant was found in the subject's father using Sanger sequencing. This is the first case of Korean familial short stature due to ACAN mutation. ACAN should be considered for proportionate idiopathic short stature, especially in cases of familial short stature.

• Journal of Genetic Medicine
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• v.19 no.1
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• pp.27-31
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• 2022

X-linked dominant hypophosphatemic rickets are the most common form of familial hypophosphatemic rickets resulting from hypophosphatemia caused by renal phosphate wasting, which in turn is a result of loss-of-function mutations in PHEX. Herein, we report a 39-year-old female with short stature and skeletal deformities and 12-month-old asymptomatic daughter. The female has a history of multiple surgical treatments because of lower limb deformities. Her biochemical findings revealed low serum phosphorus levels with elevated serum alkaline phosphatase activity and normal serum calcium levels, suggesting presence of hypophosphatemic rickets. To identify the molecular causes, we used a multigene testing panel and found a mutation, c.667dup (p.Asp223GlyfsTer15), in PHEX gene. To the best of our knowledge, this is a novel mutation. A heterozygous form of the same variant was detected in daughter, who showed no typical symptoms such as bow legs, frontal bossing, or waddling gate, but presented early signs of impaired mineralization in both X-ray and biochemical findings. The daughter was initiated onto early medical treatment with oral phosphate supplementation and an active vitamin D analog. Because the daughter was genetically diagnosed based on a family history before the onset of symptoms, appropriate medical management was possible from early infancy.

• Pediatric Gastroenterology, Hepatology & Nutrition
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• v.3 no.1
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• pp.68-74
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• 2000

Purpose: This study was to investigate the clinical manifestations of FTT in children. Methods: From March 1997 to July 1999, clinical observations were made on patients with FTT who had visited to Samsung Medical Center. Detailed histories and through physical examinations were taken, and when suspected organic FTT, basic laboratory studies were done. Results: Upon the review of medical records, we investigated the clinical manifestations of 74 children, aged 1 month and 13 year 1 month. The causes of FTT were composed of either physiologic (47.8%) or pathologic (52.2%) ones. Among the physiologic FTT, were there familial short stature (FSS, 14.5%), intrauterine growth retardation (IUGR, 14.5%), constitutional growth delay (CGD, 11.6%), idiosyncrasy and prematurity. Among pathologic causes, neurologic disorders (20%) are the most common causes of FTT, and then follow by GI (13.4%), allergic and infectious disorders in decreasing order. The data showed that average caloric intake in patients with FTT was 76,2% of recommended amount. FTT patients with CGD, IUGR, and idiosyncrasy had tendency to take small foods. The FTT children with prematurity, IUGR and pathologic FTT, were short and thin for their ages. However FTT children with CGD and FSS had tendency to be thin with relatively normal heights for their ages, in comparison with those of the children with prematurity, IUGR and pathologic FTT. Conclusion: The diagnosis of FTT was easily obtained with simple and through medical history, physical examination, and minimal laboratory tests. In this study, organic FTT was more prevalent than physiologic one. This results indicate that early intervention is mandatory, because children may develop significant long-term sequelae from nutritional deficiency.

• Genomics & Informatics
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• v.20 no.3
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• pp.30.1-30.9
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• 2022

Hereditary spastic paraplegia is a not common inherited neurological disorder with heterogeneous clinical expressions. ALDH18A1 (located on 10q24.1) gene-related spastic paraplegias (SPG9A and SPG9B) are rare metabolic disorders caused by dominant and recessive mutations that have been found recently. Autosomal recessive hereditary spastic paraplegia is a common and clinical type of familial spastic paraplegia linked to the SPG11 locus (locates on 15q21.1). There are different symptoms of spastic paraplegia, such as muscle atrophy, moderate mental retardation, short stature, balance problem, and lower limb weakness. Our first proband involves a 45 years old man and our second proband involves a 20 years old woman both are affected by spastic paraplegia disease. Genomic DNA was extracted from the peripheral blood of the patients, their parents, and their siblings using a filter-based methodology and quantified and used for molecular analysis and sequencing. Sequencing libraries were generated using Agilent SureSelect Human All ExonV7 kit, and the qualified libraries are fed into NovaSeq 6000 Illumina sequencers. Sanger sequencing was performed by an ABI prism 3730 sequencer. Here, for the first time, we report two cases, the first one which contains likely pathogenic NM_002860: c.475C>T: p.R159X mutation of the ALDH18A1 and the second one has likely pathogenic NM_001160227.2: c.5454dupA: p.Glu1819Argfs Ter11 mutation of the SPG11 gene and also was identified by the whole-exome sequencing and confirmed by Sanger sequencing. Our aim with this study was to confirm that these two novel variants are direct causes of spastic paraplegia.

• Journal of Genetic Medicine
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• v.19 no.1
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• pp.32-37
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• 2022

Mucopolysaccharidosis type VI (MPS VI) is an autosomal recessive lysosomal disorder caused by the deficiency of arylsulfatase B due to mutations in the ARSB gene. Here, we report the case of a Korean female with a novel variant of MPS VI. A Korean female aged 5 years and 8 months, who is the only child of a healthy non-consanguineous Korean couple, presented at our hospital for severe short stature. She had a medical history of umbilical hernia and recurrent otitis media. Her symptoms included snoring and mouth breathing. Subtle dysmorphic features, including mild coarse face, joint contracture, hepatomegaly, and limited range of joint motion, were identified. Radiography revealed deformities, suggesting skeletal dysplasia. Growth hormone (GH) provocation tests revealed complete GH deficiency. Targeted exome sequencing revealed compound heterozygous mutations in the ARSB genes c.512G>A (p.Gly171Asp; a pathogenic variant inherited from her father) and c.1157C>T (p.Ser386Phe; a novel variant inherited from her mother in familial genetic testing). Quantitative tests revealed increased urine glycosaminoglycan (GAG) levels and decreased enzyme activity of arylsulfatase B. While on enzyme replacement therapy and GH therapy, her height increased drastically; her coarse face, joint contracture, snoring, and obstructive sleep apnea improved; urine GAG decreased; and left ventricular mass index was remarkably decreased. We report a novel variant-c.1157C>T (p.Ser386Phe)-of the ARSB gene in a patient with MPS VI; these findings will expand our knowledge of its clinical spectrum and molecular mechanisms.

• Journal of the korean academy of Pediatric Dentistry
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• v.36 no.2
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• pp.298-304
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• 2009

XLH (X-linked hypophosphatemic rickets) is a form of rickets which is resistant to the usual dose of vitamin D and inherited in a X-linked dominant manner. It is also known as vitamin D-resistant rickets or familial hypophosphatemic rickets. Here we report a 6-year-and-6-month-old female patient of XLH who is diagnosed with in SNUB. She was referred from local clinic for impaction of maxillary left permanent incisor and its treatment. She presents bowing deformities of the legs, short stature, enlargement of wrist and ankles and spontaneous dental abscesses of clinically sound teeth delayed eruption, taurodontism, delayed apical closure, enlarged pulp chambers, and absent or poorly defined lamina dura. The purpose of this case is to review the literatures of XLH and report the dental and medical characteristics of this patient.

• The Journal of Korea Assosiation for Disability and Oral Health
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• v.4 no.2
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• pp.82-87
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• 2008

Cleidocranial dysplasia (CCD) is an autosomal dominant skeletal dysplasia and is caused by mutation in the CBAFA1 gene of 6p21 chromosome band. Patients with CCD express skeletal dysplasia such as hypoplastic/aplastic clavicle, brachycephalic skull, midface hypoplasia and moderate short stature. In addition to skeletal dysplasia, specific symptoms may appear in respiratory organs, auditory area, and the more distinguished, dentition. Dental findings include: delayed eruption of permanent tooth, multiple supernumerary tooth more than five, malocclusion, etc. In Patients presenting excessive SNT, complications of SNT could be prevented and will be managed through pertinently timed treatment such as tooth extraction, using space maintainer, and orthodontic management after early diagnosis. This case is about the treatment of eruption disorders in permanent teeth owing to SNT in CCD patients, who are three family members in the $3^{rd}$ generation inherited from maternal grandfather through atavism. We performed the extraction of numerous SNT and orthodontic treatment on them in this case. On evaluating panoramic and cephalometric views, some classical signs of skeletal dysplasia due to CCD were recognized in a pool of three patients, the clavicle was distinctively displayed in all patients.

• Childhood Kidney Diseases
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• v.8 no.2
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• pp.195-204
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• 2004

Purpose: Hypophosphatemic rickets is a hereditary disease, characterized by hypophosphatemia due to renal phosphate wasting, impaired renal production of 1,25-dihydroxyvitamin $D_3$, rachitic bone deformities and impaired growth. The purpose of this study is to provide clinical profiles of patients with hypophosphatemic rickets in our hospital. Methods: Between July 1983 and February 2004, 56 patients were diagnosed as having hypophosphatemic rickets. The medical records of these patients were reviewed retrospectively. Clinical manifestations, family histories, laboratory data, treatment outcomes were described. Results: Fifty six patients were enrolled in this study. The average age at symptom onset and diagnosis were 20 months and 5 years respectively. Fourteen patients had family histories. The main clinical manifestations were bow legs and short stature. There was a significant negative correlation between the ages and the height z-scores at the time of diagnosis(r=-0.47, P=0.005). Initial laboratory data showed normocalcemia, hypophosphatemia, elevated serum alkaline phosphatase, decreased tubular reabsorption of phosphate and a normal range of 1,25-dihydroxyvitamin $D_3$ Radiographic examinations of bone revealed fraying, widening and cupping of the metaphyseal ends. Treatment consisted of Joulie solution and vitamin D metabolites, and resulted in improved biochemical and radiographic findings. However, height z-scores remained essentially unchanged(P=0.224). Complications of treatment were frequently observed, including hyperparathyroidism, nephrocalcinosis, and hypercalciuria. Sixteen patients had corrective osteotomy and 4 of them underwent leg lengthening together. Conclusion: There was a gap of several years between the onset of symptoms and the diagnosis. Early treatment seems to be essential to growth. For the earlier treatment, the offsprings of affected parents should be followed up closely.