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Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterized by severe glucocorticoid deficiency associated with failure of adrenal responsiveness to ACTH but no mineralocorticoid deficiency. We report a 2 month-old boy of nonconsanguineous parents, presented with hyperpigmentation. Physical examination showed diffuse dark skin of body including, oral mucosa, gum, hands, nails and scrotum. Laboratory evaluation revealed low serum cortisol (0.3 microg/dL), with very high plasma ACTH level (18,000 pg/mL), and serum cortisol level did not increase after ACTH stimulation test. Serum sodium, potassium, plasma renin activity, aldosterone and 17-hydroxyprogesterone were normal. Sequence analysis of the ACTH receptor (MC2R) gene showed a homozygous mutation of D103N. Diagnosis of FGD was made and treatment started with oral hydrocortisone.

Wilson's disease (WD) is characterized by excessive accumulation of intracellular copper in liver and extrahepatic tissues, leading to significant oxidative stress and tissue damage. To date, several diagnostic biomarkers for WD such as serum ceruloplasmin, serum or urine copper levels and copper content in liver have been identified. However, these biomarkers may not be convincing for the diagnosis in some WD patients. To identify additional novel diagnostic biomarkers, we compared the serum protein profiles of asymptomatic childhood WD patients (n=20), without neurologic manifestation or liver cirrhosis, with normal controls (n=13). Fourteen spots, five up-regulated and nine down-regulated (>2-fold), were differentially expressed in WD patients in comparison to normal control on 2-DE. Among them, three spots were down-regulated in both male and female WD. MS/MS analysis revealed that the three spots were complement component C3, complement factor B and alpha-2 macroglobulin. By comparative proteome analysis, complement component C3, complement factor B and alpha-2 macroglobulin, which are related to oxidative stress and inflammation, turned out to be good candidates for novel diagnostic biomarkers for early stages of WD.

In the absence of hypertension, hypertrophic cardiomyopathy is the most common cause of left ventricular hypertrophy (LVH). However, it has been reported that up to 3% of males with unexplained LVH have Fabry disease, an X-linked disorder of glycophospholipid metabolism that is due to a deficiency in the lysosomal enzyme alpha-galactosidase A (alpha-Gal A). A 44-year-old man was admitted to our hospital with palpitations. He had a history of chronic renal failure diagnosed at age 33 followed by kidney transplantation performed at our institution 2 years later, as well as long-standing hypohidrosis. His medications included prednisolone (5 mg daily), mycophenolate mofetil (1,000 mg, bid), and cyclosporine (150 mg, bid). On hospital day two, an echocardiogram demonstrated increased left ventricular wall thickness (septal wall thickness of 28 mm, posterior wall thickness of 20 mm). Diastolic dysfunction was noted on transmitral flow patterns and tissue Doppler imaging. The patient was found to have low plasma alpha-Gal A activity. A previously reported H46R missense mutation was detected in his alpha-Gal A gene and the patient was subsequently diagnosed with Fabry disease.

Antley-Bixler syndrome (ABS) is a skeletal malformation syndrome primarily affecting the skull and limbs. Although causal mutations in the FGFR2 gene have been found in some patients, mutations in the electron donor enzyme P450 oxidoreductase gene (POR) have recently been found to cause ABS in other patients. In addition to skeletal malformations, POR deficiency also causes glucocorticoid deficiency and congenital adrenal hyperplasia with ambiguous genitalia in both sexes. Here, we report on a 7-month-old Korean girl with ABS and ambiguous genitalia who was confirmed by POR gene analysis. Our patient showed typical skeletal findings with brachycephaly, mid-face hypoplasia, and radiohumeral synostosis. She also had partial labial fusion and a single urogenital orifice, as well as increased 17alpha-hydroxyprogesterone levels, suggesting a 21-hydroxylase deficiency. Cortisol and DHEA-sulfate response to rapid adrenocorticotropic hormone (ACTH) stimulation was inadequate. Direct sequencing of the POR gene revealed compound heterozygous mutations (I444fsX449 and R457H). This is the first report of a Korean patient with ABS caused by POR gene mutations.

Niemann-Pick disease (NPD) is an inherited metabolic disorder caused by a deficiency of the enzyme acid sphingomyelinase coded by SMPD1 gene. In contrast with type A NPD, a severe neurodegenerative disease of infancy, type B NPD patients have little or no neurodegeneration, and frequently survive into adulthood. Although over 100 mutations have been found within the SMPD1 gene causing NPD, there was only one report about SMPD1 mutation status of a Korean NPD patient. We report a case of a 32-yr-old female, who presented with thrombocytopenia without any neurologic involvement. Hepatosplenomegaly was detected by both physical examination and imaging studies, and a thoracic radiograph examination showed a pattern of interstitial lung disease. Biochemical tests revealed increased liver enzymes, cholesterol, triglyceride, and LDL-cholesterol, and decreased HDL-cholesterol. Sea-blue or foamy vacuolated histiocytes occurred in bone marrow and liver. Sequencing analysis of SMPD1 using genomic DNA from peripheral leukocytes identified a compound heterozygote of two mutations at exon 2: p.E246K and p.A357V. The former is a known mutation in an Italian patient, and the latter has not been reported yet. She has received oral rosuvastatin to treat hyperlipidemia at a dose of 10 mg per day for 4 months. This is the second report in which the mutation of SMPD1 gene was detected in a Korean NPD patient. The active genetic analysis of SMPD1 gene in patients with typical findings of type B NPD would enable us to facilitate diagnosis as well as to accumulate data on molecular characteristics of Korean NPD patients.

Objectives: ARC (arthrogryposis, renal dysfunction, and cholestasis) syndrome is a rare, fatal cause of neonatal intrahepatic cholestasis without known treatment modalities and has recently been ascribed to a mutation in the VPS33B gene. We assessed the clinical characteristics and investigated the VPS33B mutations in Korean patients with ARC syndrome., Patients and Methods: We reviewed the medical records of 6 patients with ARC syndrome among 90 patients with neonatal cholestasis from 2000 to 2005 and assessed the relative incidence rate ratio, clinical symptoms, laboratory findings, and pathological findings. DNA samples from 5 patients, 4 parents, and 2 fetuses were analyzed for VPS33B mutations., Results: The relative incidence rate ratio was 1/7 that of biliary atresia (95% CI 0.33-0.06). All 6 patients presented with ichthyosis and recurrent infection, and failed to thrive with the 3 main symptoms. All of the patients died within the age of 12 months. They had various severities of cholestasis, metabolic acidosis, nephrogenic diabetes insipidus, chronic diarrhea, platelet abnormalities, and central nervous system anomalies. We identified 1 novel c.403+2T>A splice-site mutation, 2 frame-shift mutations (c.1509_1510insG, c.790_791del), 1 nonsense mutation (c.661C>A), and 1 known nonsense mutation (c.1518C>T) in the VPS33B gene. Prenatal diagnosis was performed in 2 different families., Conclusions: This study indicates that the incidence of ARC syndrome is not as rare as has been thought. We found 4 novel and 1 known mutations in ARC syndrome patients and performed prenatal diagnosis in 2 families, which will facilitate genetic diagnosis and counseling for affected families.

Objectives: PRSS1 and SPINK1 are 2 important genes in the defense mechanism guarding against the development of pancreatitis. This study aimed to evaluate the prevalence of PRSS1 and SPINK1 mutations and to explore the presence of any ethnic specificity in Korean patients., Methods: A total of 47 patients from 40 families including 37 patients with idiopathic pancreatitis and 10 patients with familial pancreatitis were prospectively enrolled. Fifty healthy controls were included for analysis of SPINK1 IVS3+2T site., Results: PRSS1 mutations were observed in 6 patients from 2 families and SPINK1 mutations in 13 patients from 11 families, respectively. In case of SPINK1 mutations, N34S and IVS3+2T>C were identified in 3 and 11 patients, respectively, including one with compound N34S/IVS3+2T>C heterozygote. The prevalence of SPINK1 IVS3+2T>C mutations was 26.8% among 41 patients without PRSS1 mutations, whereas the prevalence among 50 healthy controls was 0%. Only PRSS1 R122H was identified. Late onset of symptoms at the age of 36 years and absence of symptoms at the age of 47 years were observed in 2 patients with PRSS1 mutations., Conclusions: PRSS1 and SPINK1 mutations were not rare in Korean patients with idiopathic and familial pancreatitis. SPINK1 IVS3+2T>C was a prevalent mutation in this population.

Objective: A human GH receptor (GHR) gene exon 3 polymorphism (d3-GHR) has been reported to be associated with responsiveness to GH therapy. We assessed the frequencies of this polymorphism in Korean control and idiopathic short stature (ISS) populations, and analysed short-term growth response to GH therapy according to GHR-exon 3 genotypes in Korean children with ISS., Design and Patients: This was a retrospective study in 158 ISS children. Auxological and endocrine parameters were measured, and the GHR-exon 3 genotype was analysed. Allelic frequencies of GHR-exon 3 genotype were compared between the ISS group and a control group. GH had been administered for 62 patients, 52 of whom remained prepubertal after the first follow-up year. Changes in height velocity (HV) and IGF-1 and IGFBP-3 concentrations following GH therapy were compared in patients with these genotypes., Results: There was no difference in GHR-exon 3 genotype frequency between ISS and control groups of Koreans. However, the fl/fl genotype was more frequent in Koreans than in Caucasians. ISS children with d3-GHR showed a significantly higher increment in HV (P = 0.002) and a marginally significant increment in IGF-1 concentration (P = 0.064) at the first year of GH therapy., Conclusion: fl-GHR was more frequently detected in a Korean population than in Caucasians. The growth promotion efficacy of GH therapy differed significantly between ISS patients with and without the d3-GHR allele. These findings indicate that the GHR-exon 3 polymorphism can affect the growth promoting efficacy of short-term GH therapy in Korean children with ISS.

Background: Kawasaki disease (KD) is an acute vasculitis syndrome of unknown etiology that frequently affects small to medium size arteries. C-C chemokine receptor 5 (CCR5) is a chemokine receptor that binds C-C chemokines. This study investigated the association of the CCR5 (-2135C/T) polymorphism with KD in Korean children., Methods: The study population consisted 189 Korean children with KD and 194 Korean children with congenital heart disease (CHD). CCR5 (-2135C/T) polymorphism genotypes were determined using the single-base extension method., Results: The allele frequencies of the CCR5 (-2135C/T) polymorphism differed significantly between CHD children and KD children (-2135T/T, 16.75% vs. 30.05%, aOR 2.14, 95% CI 1.31-3.51). The tested laboratory parameters differed significantly between the KD and CHD groups. The development of coronary artery aneurysm in KD patients was not associated with the CCR5 polymorphism., Conclusions: Our findings suggest that the T allele at the CCR5 (-2135C/T) polymorphism might be associated with the development of KD in Korean children but does not appear to be associated with the development of coronary artery aneurysm.

Thyroid hormone resistance syndrome (RTH) is a rare disorder and is characterized by elevated levels of circulating free thyroid hormones, inappropriate secretion of thyroid stimulating hormone (TSH), and reduced peripheral tissue response to thyroid hormone. 90% of RTH subjects, when studied at the level of the gene, have been found to harbor mutations in the thyroid hormone receptor-beta(THRB) gene. These affected individuals have been shown to possess a variety of missense mutations, resulting from changes in a single nucleotide in the THRB gene that corresponds to amino acid alternation. However, insertion or deletion mutations in the THRB gene sequence are quite rare, and have been observed in only a very few cases. In this study, we describe two such cases, in which two members of the same family were determined to harbor an insertion mutation in exon 10, and had also been diagnosed with generalized RTH. This insertion mutation, specifically the insertion of a cytosine at nucleotide 1358 of the THRB gene, is, to the best of our knowledge, the first such mutation reported among RTH patients in Korea.

Achondroplasia (ACH) and hypochondroplasia (HCH) share clinical features characterized by disproportionate short stature with rhizomelic shortening of the limbs. In an attempt to clarify genotype-phenotype correlation in ACH and HCH, we investigated the presence of the previously identified mutations of FGFR3 in 26 patients with ACH- or HCH-mimicking features and compared clinical and radiographic findings between the two groups. Using genomic DNA sequencing and RFLP analysis, G380R, an ACH-specific mutation, and N540K, an HCH-specific mutation, were detected in 13 patients (50%) and five patients (19%), respectively. No mutations of FGFR3 were detected in eight patients (31%). No remarkable clinical or radiological differences were evident among the ACH infants and children with G380R, the HCH patients with N540K, and the patients without verified mutations. These results suggest that genotype-based diagnosis needs to precede proper genetic counseling for patients with ACH or HCH, which show very similar clinical and radiological features.

Background/aims: Many genes encoding pituitary transcription factors involved in the formation of the pituitary gland are identified. Different mutations in these genes have been reported in patients with familial combined pituitary hormone deficiency (CPHD). This study was undertaken to analyze PIT1, PROP1, LHX3, and HESX1 in 12 CPHD patients with abnormal pituitary magnetic resonance imaging (MRI). Since embryonic development of the pituitary requires the coordinated expression of specific transcription factors, we postulated the presence of mutations in PIT1, PROP1, LHX3, and HESX1 genes., Methods: Anterior pituitary function was evaluated. Each gene was PCR amplified exon by exon, and subsequently sequenced., Results: In all cases, MRI examination showed abnormal pituitary gland development featuring ectopic neurohypophysis, hypoplastic anterior lobe, empty sella, and septo-optic dysplasia. Endocrinologically, all patients revealed multiple pituitary hormone deficiency including growth hormone, thyroid stimulating hormone, luteinizing hormone, follicular stimulating hormone and adrenocorticotropin. They were all sporadic cases without a positive family history. None of disease-causing specific mutations were identified in PIT1, PROP1, LHX3, and HESX1 genes of 12 sporadic CPHD patients with abnormal pituitary imaging. However, 2 novel polymorphisms were found in PROP1 gene: IVS1+3 A-->G and 27 T-->C (Ala9Ala) in exon 1. Their allele frequencies in patients and normal controls were not statistically different. Overall, allele frequencies of these polymorphisms were as follows: for the IVS1+3 A-->G polymorphism, the allele frequency of A was 54%, and 46% for G, with 58% of an A/G heterozygosity. For the 27 T-->C (Ala9Ala) polymorphism, the allele frequency of T was 46%, and 54% for G, with 42% of a T/C heterozygosity., Conclusions: Mutations of PIT1, PROP1, LHX3, and HESX1 genes are very rare in sporadic CPHD patients with abnormal pituitary MRI., (Copyright 2003 S. Karger AG, Basel)