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Fabry disease (FD), a rare X-linked lysosomal storage disorder, is caused by mutations in the α-galactosidase A gene gene encoding α-galactosidase A (α-Gal A). The functional deficiency of α-Gal A results in progressive accumulation of neutral glycosphingolipids, causing multi-organ damages including cardiac, renal, cerebrovascular systems. The current treatment is comprised of enzyme replacement therapy (ERT), oral pharmacological chaperone therapy and adjunctive supportive therapy. ERT has been introduced 20 years ago, changing the outcome of FD patients with proven effectiveness. However, FD patients have many unmet needs. ERT needs a life-long intravenous therapy, inefficient bio-distribution, and generation of anti-drug antibodies. Migalastat, a pharmacological chaperone, augmenting α-Gal A enzyme activity only in patients with mutations amenable to the therapy, is now available for clinical practice. Furthermore, these therapies should be initiated before the organ damage becomes irreversible. Development of novel drugs aim at improving the clinical effectiveness and convenience of therapy. Clinical trial of next generation ERT is underway. Polyethylene glycolylated enzyme has a longer halflife and potentially reduced antigenicity, compared with standard preparations with longer dosing interval. Moss-derived enzyme has a higher affinity for mannose receptors, and seems to have more efficient access to podocytes of kidney which is relatively resistant to reach by conventional ERT. Substrate reduction therapy is currently under clinical trial. Gene therapy has now been started in several clinical trials using in vivo and ex vivo technologies. Early results are emerging. Other strategic approaches at preclinical research level are stem cell-based therapy with genome editing and systemic mRNA therapy.
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Congenital adrenal hyperplasia (CAH) is a group of autosomally recessive disorders that result from impaired synthesis of glucocorticoid and mineralocorticoid. Most cases (~95%) are caused by mutations in the CYP21A2 gene, which encodes steroid 21-hydroxylase. CAH patients manifest a wide phenotypic spectrum according to their degree of residual enzyme activity. CYP21A2 and its pseudogene (CYP21A1P) are located 30 kb apart in the 6q21.3 region and share approximately 98% of their sequences in the coding region. Both genes are aligned in tandem with the C4, SKT19, and TNX genes, forming 2 segments of the RCCX modules that are arranged as STK19-C4A-CYP21A1P-TNXA-STK19B-C4B-CYP21A2-TNXB. The high sequence homology between the active gene and pseudogene leads to frequent microconversions and large rearrangements through intergenic recombination. The TNXB gene encodes an extracellular matrix glycoprotein, tenascin-X (TNX), and defects in TNXB cause Ehlers-Danlos syndrome. Deletions affecting both CYP21A2 and TNXB result in a contiguous gene deletion syndrome known as CAH-X syndrome. Because of the high homology between CYP21A2 and CYP21A1P, genetic testing for CAH should include an evaluation of copy number variations, as well as Sanger sequencing. Although it poses challenges for genetic testing, a large number of mutations and their associated phenotypes have been identified, which has helped to establish genotype-phenotype correlations. The genotype is helpful for guiding early treatment, predicting the clinical phenotype and prognosis, and providing genetic counseling. In particular, it can help ensure proper management of the potential complications of CAH-X syndrome, such as musculoskeletal and cardiac defects. This review focuses on the molecular pathophysiology and genetic diagnosis of 21-hydroxylase deficiency and highlights genetic testing strategies for CAH-X syndrome.
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Purpose@#Androgen insensitivity syndrome (AIS) is a rare X-linked recessive disorder caused by unresponsiveness to androgens because of mutations in the AR gene. Here, we investigated the clinical outcomes and molecular spectrum of AR variants in patients with AIS attending a single academic center. @*Methods@#This study included 19 patients with AIS who were confirmed by molecular analysis of AR. Clinical features and endocrinological findings were retrospectively collected, including presenting features, external genitalia, sex of rearing, timing of gonadectomy, pubertal outcomes, and sex hormone levels. Molecular analysis of AR was performed using Sanger, targeted gene panel, or whole-exome sequencing. @*Results@#Among all 19 patients, 14 (74%) were classified as having complete AIS (CAIS), whereas 5 (26%) had partial AIS (PAIS). All patients with CAIS, and 3 patients with PAIS were reared as female. One patient with CAIS manifested a mixed germ cell tumor at the age of 30 years. Molecular analysis of AR identified 19 sequence variants; 12 (63%) were previously reported, and the remaining 7 (37%) were novel. Missense mutations were the most common type (12 of 19, 63%), followed by small deletions, nonsense mutations, an insertion, and a splice site mutation. @*Conclusion@#Here, we describe the clinical outcomes and molecular characteristics of 19 Korean patients with AIS. Patients with PAIS manifested various degrees of masculinization of the external genitalia. Nonsense and frameshift mutations were frequent in patients with CAIS, whereas patients with PAIS harbored exclusively missense mutations.
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Primary hyperparathyroidism (PHPT) is a hypercalcemia disorder with inappropriately normal or increased serum parathyroid hormone (PTH) levels resulting from excessive secretion of PTH from one or more of the parathyroid glands. PHPT is uncommon in infants and children, with an estimated incidence of 2–5 cases per 100,000 persons. Patients with PHPT usually present with bone pain, urolithiasis, or nephrolithiasis, as well as nonspecific symptoms such as fatigue and weakness. Asymptomatic hypercalcemia may also be detected incidentally. Only a few cases of pediatric PHPT have been reported in Korea. We present three patients (a 9-year-old girl, a 14-year-old boy, and a 14-year-old girl) with PHPT who manifested variable clinical features of hypercalcemia. The first and second patients each had a parathyroid adenoma and presented with abdominal pain caused by pancreatitis and a ureter stone, respectively. The third patient had an ectopic mediastinal parathyroid adenoma and presented with gait disturbance and weakness of the lower extremities. All of the patients underwent surgical resection of parathyroid adenoma, and their serum calcium levels subsequently normalized without medication.
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Background@#Discontinuing growth hormone (GH) treatment during the transition to adulthood has been associated with adverse health outcomes in patients with childhood-onset growth hormone deficiency (CO-GHD). This study investigated the metabolic changes associated with interrupting GH treatment in adolescents with CO-GHD during the transition period. @*Methods@#This study included 187 patients with CO-GHD who were confirmed to have adult GHD and were treated at six academic centers in Korea. Data on clinical parameters, including anthropometric measurements, metabolic profiles, and bone mineral density (BMD) at the end of childhood GH treatment, were collected at the time of re-evaluation for GHD and 1 year after treatment resumption. @*Results@#Most patients (n=182, 97.3%) had organic GHD. The median age at treatment discontinuation and re-evaluation was 15.6 and 18.7 years, respectively. The median duration of treatment interruption was 2.8 years. During treatment discontinuation, body mass index Z-scores and total cholesterol, low-density lipoprotein, and non-high-density lipoprotein (HDL) cholesterol levels increased, whereas fasting glucose levels decreased. One year after GH treatment resumption, fasting glucose levels, HDL cholesterol levels, and femoral neck BMD increased significantly. Longer GH interruption (>2 years, 60.4%) resulted in worse lipid profiles at re-evaluation. The duration of interruption was positively correlated with fasting glucose and non-HDL cholesterol levels after adjusting for covariates. @*Conclusion@#GH treatment interruption during the transition period resulted in worse metabolic parameters, and a longer interruption period was correlated with poorer outcomes. GH treatment should be resumed early in patients with CO-GHD during the transition period.
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Purpose@#Osteogenesis imperfecta (OI) is a rare bone fragility disorder caused by defects in type 1 collagen biosynthesis. This study investigated the genotype-phenotype correlations and the efficacy of pamidronate therapy in patients with OI in a single academic center. @*Methods@#This study included 24 patients with OI. A clinical scoring system was used to evaluate disorder severity. COL1A1 and COL1A2 genes were analyzed in 13 patients using Sanger sequencing. Genotype-phenotype correlations and the efficacy of pamidronate therapy were analyzed through a retrospective medical chart review. @*Results@#Of the 24 patients, 18 (75%) were classified as type I (12 with type Ia and 6 with type Ib), 2 as type III (8.4%), and 4 as type IV (16.7%). Type Ia patients showed relatively higher lumbar bone mineral density (BMD) standard deviation scores (SDS) and lower clinical scores than those with other types. Seven patients with qualitative mutations had lower lumbar BMD-SDS (P=0.015) and higher clinical scores (P=0.008) than 6 patients with quantitative mutations. The annual fracture frequency and lumbar BMD-SDS improved in patients with qualitative mutations after pamidronate treatment. @*Conclusion@#This study demonstrated that OI patients with qualitative mutations in COL1A1/2 had a more severe phenotype than those with quantitative mutations. Patients with qualitative mutations showed a significant reduction in fracture frequency and an increase in lumbar BMD-SDS after pamidronate treatment. Clinical score and genotype might be helpful for predicting phenotype and response to pamidronate therapy in OI patients.
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Purpose@#Despite aggressive medical and nutritional management, patients with methylmalonic acidemia (MMA) often suffer from multi-organ damage. Early deceased donor liver transplantation (DDLT) has emerged as an intervention to prevent disease progression. We investigated the efficacy of living donor LT (LDLT) with a potential carrier of MMA and a small volume of graft in patients with MMA as an alternative to DDLT. @*Methods@#Of five patients (three male, two female; median age 5.7 years; range, 1.3–13.7 years), four underwent carrier LDLT, while one underwent non-carrier auxiliary LDLT. All patients received pre- and post-LT continuous renal replacement therapy and were provided with minimal restriction diet according to serum MMA level after LT. MMA levels in the serum and urine, the incidence of metabolic crisis, and clinical findings before and after LT were compared. @*Results@#The survival rate was 100% during 2.2 years of follow up period after LT. In all five cases, MMA titer in the serum after transplantation decreased with less restrictive diet. Metabolic crisis was not observed during the follow-up period. In addition, no patient showed progression of severe renal impairment requiring hemodialysis. Progression of delayed cognitive development was not observed. Social functioning with improved neuropsychiatric development was observed. @*Conclusion@#This study showed that LDLT achieved improved quality of life with less restrictive diet, therefore it could be a feasible alternative option to DDLT for the treatment of patients with MMA, even with an auxiliary LT.
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Mitochondrial fatty acid β-oxidation (mFAO), which is the major pathway for the degradation of fatty acids and is critical for maintaining energy homeostasis in the human body, consists of carnitine transport, the carnitine shuttle, and fatty acid β-oxidation. Inherited metabolic defects of mFAO result in more than 15 distinct mFAO disorders (mFAODs) with varying clinical manifestations. The common elements of the clinical presentation of mFAODs are hypoketotic hypoglycemia, (cardio)myopathy, arrhythmia, and rhabdomyolysis, indicating the importance of FAO during fasting or stressful situations. The management of all mFAODs includes avoidance of fasting, aggressive treatment during illness, and supplementation of carnitine or appropriate nutritional support, if necessary. Through the introduction of newborn screening using tandem mass spectrometry, early identification of mFAODs became feasible, leading to an early initiation of treatment with improved outcomes. However, many unmet needs remain with regard to the long-term management of patients with mFAODs.
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Purpose@#Despite aggressive medical and nutritional management, patients with methylmalonic acidemia (MMA) often suffer from multi-organ damage. Early deceased donor liver transplantation (DDLT) has emerged as an intervention to prevent disease progression. We investigated the efficacy of living donor LT (LDLT) with a potential carrier of MMA and a small volume of graft in patients with MMA as an alternative to DDLT. @*Methods@#Of five patients (three male, two female; median age 5.7 years; range, 1.3–13.7 years), four underwent carrier LDLT, while one underwent non-carrier auxiliary LDLT. All patients received pre- and post-LT continuous renal replacement therapy and were provided with minimal restriction diet according to serum MMA level after LT. MMA levels in the serum and urine, the incidence of metabolic crisis, and clinical findings before and after LT were compared. @*Results@#The survival rate was 100% during 2.2 years of follow up period after LT. In all five cases, MMA titer in the serum after transplantation decreased with less restrictive diet. Metabolic crisis was not observed during the follow-up period. In addition, no patient showed progression of severe renal impairment requiring hemodialysis. Progression of delayed cognitive development was not observed. Social functioning with improved neuropsychiatric development was observed. @*Conclusion@#This study showed that LDLT achieved improved quality of life with less restrictive diet, therefore it could be a feasible alternative option to DDLT for the treatment of patients with MMA, even with an auxiliary LT.
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Purpose@#Osteoporosis is a skeletal disorder characterized by reduced bone mass that results in increased risk of fractures. Pediatric osteoporosis can be caused by monogenic diseases, chronic diseases, and/or their treatment. This study was performed to investigate the effect of pamidronate infusion on osteoporosis in children and adolescents. @*Methods@#This study included 13 unrelated pediatric patients (10 males and 3 females) whose bone mineral density (BMD) z-score was <-2.0. Pamidronate was administered intravenously at a dosage of 1 mg/kg for 3 consecutive days every 4 months. Clinical and biochemical findings were reviewed retrospectively. The BMD values of the lumbar spine and femoral neck were assessed by dual energy x-ray absorptiometry at baseline and annually. @*Results@#The underlying diseases were immobilization (62%), inflammatory bowel disease (23%), protein-losing enteropathy (8%), and idiopathic juvenile osteoporosis (8%). The mean age at the start of treatment was 12.7±4.3 years. Duration of treatment ranged from 12–50 months. The baseline height-standard deviation score (SDS) and weight-SDS were -2.01±2.08 and -2.60±1.62, respectively. The lumbar spine BMD z-scores improved significantly after 1 year of pamidronate treatment, but the femoral neck BMD z-scores did not. However, both z-scores had significantly increased by the end of treatment. @*Conclusion@#This study demonstrated that pamidronate treatment increased BMD in pediatric patients with osteoporosis with no significant adverse events. Further studies are required to better define the long-term efficacy and safety of pamidronate therapy in a large number of pediatric patients.
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Primary adrenal insufficiency (PAI) in pediatric age is a rare, but potentially fatal condition caused by diverse etiologies including biochemical defects of steroid biosynthesis, developmental abnormalities of the adrenal gland, or reduced responsiveness to adrenocorticotropic hormone. Compared to adult PAI, pediatric PAI is more often the result of genetic (monogenic, syndromic disorders) than acquired conditions. During the past decade, rare monogenic disorders associated with PAI have helped unravel the underlying novel molecular genetic mechanism. The diagnosis of adrenal insufficiency in children and young infancy is often challenging, usually based on clinical suspicion and endocrine laboratory findings. Pediatric endocrinologists sometimes encounter therapeutic difficulty in finding the balance between undertreatment and overtreatment, determining how to optimize the dose over the patient’s lifetime, and maximizing mimicry of normal cortisol secretion with glucocorticoid replacement therapy.
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Purpose@#Osteoporosis is a skeletal disorder characterized by reduced bone mass that results in increased risk of fractures. Pediatric osteoporosis can be caused by monogenic diseases, chronic diseases, and/or their treatment. This study was performed to investigate the effect of pamidronate infusion on osteoporosis in children and adolescents. @*Methods@#This study included 13 unrelated pediatric patients (10 males and 3 females) whose bone mineral density (BMD) z-score was <-2.0. Pamidronate was administered intravenously at a dosage of 1 mg/kg for 3 consecutive days every 4 months. Clinical and biochemical findings were reviewed retrospectively. The BMD values of the lumbar spine and femoral neck were assessed by dual energy x-ray absorptiometry at baseline and annually. @*Results@#The underlying diseases were immobilization (62%), inflammatory bowel disease (23%), protein-losing enteropathy (8%), and idiopathic juvenile osteoporosis (8%). The mean age at the start of treatment was 12.7±4.3 years. Duration of treatment ranged from 12–50 months. The baseline height-standard deviation score (SDS) and weight-SDS were -2.01±2.08 and -2.60±1.62, respectively. The lumbar spine BMD z-scores improved significantly after 1 year of pamidronate treatment, but the femoral neck BMD z-scores did not. However, both z-scores had significantly increased by the end of treatment. @*Conclusion@#This study demonstrated that pamidronate treatment increased BMD in pediatric patients with osteoporosis with no significant adverse events. Further studies are required to better define the long-term efficacy and safety of pamidronate therapy in a large number of pediatric patients.
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Primary adrenal insufficiency (PAI) in pediatric age is a rare, but potentially fatal condition caused by diverse etiologies including biochemical defects of steroid biosynthesis, developmental abnormalities of the adrenal gland, or reduced responsiveness to adrenocorticotropic hormone. Compared to adult PAI, pediatric PAI is more often the result of genetic (monogenic, syndromic disorders) than acquired conditions. During the past decade, rare monogenic disorders associated with PAI have helped unravel the underlying novel molecular genetic mechanism. The diagnosis of adrenal insufficiency in children and young infancy is often challenging, usually based on clinical suspicion and endocrine laboratory findings. Pediatric endocrinologists sometimes encounter therapeutic difficulty in finding the balance between undertreatment and overtreatment, determining how to optimize the dose over the patient’s lifetime, and maximizing mimicry of normal cortisol secretion with glucocorticoid replacement therapy.
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Purpose@#Oral supplementation of vitamin D can be inefficient in patients with vitamin D deficiency caused by intestinal malabsorption. This study investigated the efficacy and safety of parenteral vitamin D supplementation in infants and children with vitamin D deficiency caused by intestinal malabsorption. @*Methods@#This study included 11 patients with vitamin D deficiency who were unresponsive to oral vitamin D or were unable to try oral vitamin D therapy due to underlying conditions. All patients were treated with weekly intramuscular injection of cholecalciferol 50,000 IU. Radiological findings and biochemical parameters including serum calcium, phosphorus, alkaline phosphatase, 25-hydroxyvitamin D3 (25(OH)D3), and parathyroid hormone levels were reviewed retrospectively. @*Results@#Underlying diseases included small bowel atresia (n=3), necrotizing enterocolitis (n=3), congenital megacolon (n=2), chronic intestinal pseudoobstruction (n=1), congenital mesenteric band (n=1), and Crohn disease (n=1). Three patients exhibited rickets on X-ray findings. The mean duration of treatment was 4.8±2.9 weeks. The alkaline phosphatase levels were decreased from 710±650 IU/L to 442±284 IU/L (P=0.143). The 25(OH)D3 level was increased from 6.0±3.4 ng/mL to 50.4±28.8 ng/mL (P=0.008) after 3 months. Two patients with rickets showed improved radiologic findings after parenteral treatment. @*Conclusion@#Parenteral vitamin D therapy was effective and safe in patients with vitamin D deficiency caused by intestinal malabsorption. Long-term follow-up is needed to establish the efficacy of parenteral vitamin D therapy in a large number of patients.
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Purpose@#Cytochrome P450 oxidoreductase (POR) deficiency is a rare autosomal recessive disorder caused by mutations in the POR gene encoding an electron donor for all microsomal P450 enzymes. It is characterized by adrenal insufficiency, ambiguous genitalia, maternal virilization during pregnancy, and skeletal dysplasia. In this study, we investigated the clinical, hormonal, and molecular characteristics of patients with POR deficiency in Korea. @*Methods@#This study included four patients with POR deficiency confirmed by biochemical and molecular analysis of POR. Clinical and biochemical findings were reviewed retrospectively. Mutation analysis of POR was performed by Sanger sequencing after polymerase chain reaction amplification of all coding exons and the exon-intron boundaries. @*Results@#All patients presented with adrenal insufficiency and ambiguous genitalia regardless of their genetic sex. Two patients harbored homozygous p.R457H mutations in POR and presented with adrenal insufficiency and genital ambiguity without skeletal phenotypes. The other two patients with compound heterozygous mutations of c.[1329_1330insC];[1370G>A] (p.[I444Hfs*6];[R457H]) manifested skeletal abnormalities, such as craniosynostosis and radiohumeral synostosis, suggesting Antley-Bixler syndrome. They also had multiple congenital anomalies involving heart, kidney, and hearing ability. All patients were treated with physiologic doses of oral hydrocortisone. @*Conclusion@#We report the cases of 4 patients with POR deficiency identified by mutation analysis of POR. Although the study involved a small number of patients, the POR p.R457H mutation was the most common, suggesting founder effect in Korea. POR deficiency is rare and can be misdiagnosed as 21-hydroxylase or 17α-hydroxylase/17,20-lyase deficiency. Therefore, molecular analysis is critical for confirmatory diagnosis.
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PURPOSE: Patients with ovotesticular disorder of sex development (DSD) and mixed gonadal dysgenesis (MGD) usually present with asymmetric gonads and have wide phenotypic variations in internal and external genitalia. The differential diagnosis of these conditions is based on karyotype and pathological findings of the gonads. This study investigated the clinical features at presentation, karyotype, sex of rearing, and pubertal outcomes of patients with ovotesticular DSD and MGD.METHODS: The study comprised 23 patients with DSD who presented with asymmetric gonads. The presenting features, karyotype, sex of rearing, and pubertal outcomes were reviewed retrospectively.RESULTS: All 23 patients presented with ambiguous genitalia at a median age of 1 month (range, 1 day–1.6 years). Müllerian duct remnants were identified in 15 of 23 patients (65.2%). Fourteen patients were diagnosed with ovotesticular DSD, whereas the other 9 were diagnosed with MGD. Eight of 14 patients (57.1%) with ovotesticular DSD were raised as males, while 7 of 9 patients with MGD (77.8%) were assigned as males. One male-assigned patient with ovotesticular DSD changed to female sex at age 20 years.CONCLUSION: Patients with ovotesticular DSD and MGD manifest overlapping clinical presentations and hormonal profiles. It is difficult to determine the sex of rearing and predict long-term pubertal outcomes. Therefore, long-term follow-up is required to monitor spontaneous puberty, sex outcome, and urological and gynecological complications.
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Adolescente , Femenino , Humanos , Masculino , Diagnóstico Diferencial , Trastornos del Desarrollo Sexual , Estudios de Seguimiento , Genitales , Disgenesia Gonadal , Disgenesia Gonadal Mixta , Gónadas , Cariotipo , Trastornos Ovotesticulares del Desarrollo Sexual , Pubertad , Estudios RetrospectivosRESUMEN
KBG syndrome is an autosomal dominant syndrome presenting with macrodontia, distinctive facial features, skeletal anomalies, and neurological problems caused by mutations in the ankyrin repeat domain 11 (ANKRD11) gene. The diagnosis of KBG is difficult in very young infants as the characteristic macrodontia and typical facial features are not obvious. The youngest patient diagnosed to date was almost one year of age. We here describe a 2-month-old Korean boy with distinctive craniofacial features but without any evidence of macrodontia due to his very early age. He also had a congenital megacolon without ganglion cells in the rectum. A de novo deletion of exons 5–9 of the ANKRD11 gene was identified in this patient by exome sequencing and real-time genomic polymerase chain reaction. As ANKRD11 is involved in the development of myenteric plexus, a bowel movement disorder including a congenital megacolon is not surprising in a patient with KBG syndrome and has possibly been overlooked in past cases.
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Humanos , Lactante , Masculino , Repetición de Anquirina , Diagnóstico , Exoma , Exones , Ganglión , Enfermedad de Hirschsprung , Trastornos del Movimiento , Plexo Mientérico , Reacción en Cadena de la Polimerasa , RectoRESUMEN
Noonan syndrome (NS) and NS-related disorders (cardio-facio-cutaneous syndrome, Costello syndrome, NS with multiple lentigines, or LEOPARD [lentigines, ECG conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth and sensory neural deafness] syndrome) are collectively named as RASopathies. Clinical presentations are similar, featured with typical facial features, short stature, intellectual disability, ectodermal abnormalities, congenital heart diseases, chest & skeletal deformity and delayed puberty. During past decades, molecular etiologies of RASopathies have been growingly discovered. The functional perturbations of the RAS-mitogen-activated protein kinase pathway are resulted from the mutation of more than 20 genes (PTPN11, SOS1, RAF1, SHOC2, BRAF, KRAS, NRAS, HRAS, MEK1, MEK2, CBL, SOS2, RIT, RRAS, RASA2, SPRY1, LZTR1, MAP3K8, MYST4, A2ML1, RRAS2). The PTPN11 (40–50%), SOS1 (10–20%), RAF1 (3–17%), and RIT1 (5–9%) mutations are common in NS patients. In this review, the constellation of overlapping clinical features of RASopathies will be described based on genotype as well as their differential diagnostic points and management.
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Humanos , Anomalías Congénitas , Síndrome de Costello , Diagnóstico , Ectodermo , Electrocardiografía , Genitales , Genotipo , Cardiopatías , Hipertelorismo , Discapacidad Intelectual , Lentigo , Síndrome de Noonan , Panthera , Proteínas Quinasas , Pubertad Tardía , Estenosis de la Válvula Pulmonar , TóraxRESUMEN
BACKGROUND: Fabry disease is an X-linked recessive disorder caused by deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A). Previous studies identified many cases of Fabry disease among men with left ventricular hypertrophy (LVH). The purpose of this study was to define the frequency of Fabry disease among Korean men with LVH. METHODS: In this national prospective multicenter study, we screened Fabry disease in men with LVH on echocardiography. The criterion for LVH diagnosis was a maximum LV wall thickness 13 mm or greater. We screened 988 men with LVH for plasma α-Gal A activity. In patients with low α-Gal A activity (< 3 nmol/hr/mL), we searched for mutations in the α-galactosidase gene. RESULTS: In seven men, α-Gal A activity was low. Three had previously identified mutations; Gly328Arg, Arg301Gln, and His46Arg. Two unrelated men had the E66Q variant associated with functional polymorphism. In two patients, we did not detect GLA mutations, although α-Gal A activity was low on repeated assessment. CONCLUSION: We identified three patients (0.3%) with Fabry disease among unselected Korean men with LVH. Although the prevalence of Fabry disease was low in our study, early treatment of Fabry disease can result in a good prognosis. Therefore, in men with unexplained LVH, differential diagnosis of Fabry disease should be considered.
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Humanos , Masculino , Diagnóstico , Diagnóstico Diferencial , Ecocardiografía , Enfermedad de Fabry , Hipertrofia Ventricular Izquierda , Plasma , Prevalencia , Pronóstico , Estudios ProspectivosRESUMEN
BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of autosomal recessive liver diseases that present as neonatal cholestasis. Little is known of this disease in Korea. METHODS: The records of five patients histologically diagnosed with PFIC, one with PFIC1 and four with PFIC2, by liver biopsy or transplant were reviewed, and ATP8B1 and ABCB11 mutation status was analyzed by direct DNA sequencing. Clinicopathological characteristics were correlated with genetic mutations. RESULTS: The first symptom in all patients was jaundice. Histologically, lobular cholestasis with bile plugs was the main finding in all patients, whereas diffuse or periportal cholestasis was identified only in patients with PFIC2. Giant cells and ballooning of hepatocytes were observed in three and three patients with PFIC2, respectively, but not in the patient with PFIC1. Immunostaining showed total loss of bile salt export pump in two patients with PFIC2 and focal loss in two. Lobular and portal based fibrosis were more advanced in PFIC2 than in PFIC1. ATP8B1 and ABCB11 mutations were identified in one PFIC1 and two PFIC2 patients, respectively. One PFIC1 and three PFIC2 patients underwent liver transplantation (LT). At age 7 months, one PFIC2 patient was diagnosed with concurrent hepatocellular carcinoma and infantile hemangioma in an explanted liver. The patient with PFIC1 developed steatohepatitis after LT. One patient showed recurrence of PFIC2 after 10 years and underwent LT. CONCLUSIONS: PFIC is not rare in patients with neonatal cholestasis of unknown origin. Proper clinicopathologic correlation and genetic testing can enable early detection and management.