Birt-Hogg-Dubé (BHD) syndrome is a rare autosomal dominant disorder that is characterized by skin fibrofolliculomas, pulmonary cysts, and renal tumors. The objective of this study was to describe the features of Korean patients with BHD syndrome. Clinical data were retrospectively reviewed in 12 patients (10 confirmed by direct sequencing of the folliculin (FLCN) gene and two confirmed by clinical diagnosis) diagnosed from 2004 to 2016 at Asan Medical Center, Seoul, South Korea. Criteria proposed by the European BHD consortium were used for diagnosis. The median follow-up was 52 months. The mean age was 41.3 years and 66.7% were female. Eight patients (66.7%) had a history of pneumothorax, which was recurrent in 75%. Skin lesions were detected in 25.0% and renal cancer in 25.0%. Among mutations of the FLCN gene, the duplication of cytosine in the C8 tract of exon 11 (c.1285dupC) was the most common (40%); however, a novel heterozygous sequence variant of c.31T>C (p.C11R) in exon 4 was detected in one patient. All patients had multiple and bilateral pulmonary cysts, distributed in predominantly lower, peripheral and subpleural regions of the lungs. Most patients showed preserved lung function that remained unchanged during follow-up, and two (16.7%) developed cancers (renal cancer in one and breast cancer in one). Our data suggest that Korean patients with BHD syndrome may have a higher risk of pneumothorax, less frequent skin lesions, and a novel FLCN mutation compared to previous reports. Multiple bilateral and basal-predominant cysts were the most common radiologic features.

Fatty acid oxidation disorders (FAODs) include more than 15 distinct disorders with variable clinical manifestations. After the introduction of newborn screening using tandem mass spectrometry, early identification of FAODs became feasible. This study describes the clinical, biochemical and molecular characteristics of FAODs patients detected by newborn screening (NBS) compared with those of 9 patients with symptomatic presentations. Clinical and genetic features of FAODs patients diagnosed by NBS and by symptomatic presentations were reviewed. Fourteen patients were diagnosed with FAODs by NBS at the age of 54.8 ± 4.8 days: 5 with very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, 5 with medium chain acyl-CoA dehydrogenase (MCAD) deficiency, 1 with primary carnitine deficiency, 1 with carnitine palmitoyltransferase 1A (CPT1A) deficiency, 1 with long-chain 3-hydroxyacyl-CoA dehydrogenase or mitochondrial trifunctional protein (LCAHD/MTP) deficiency, and 1 with short chain acyl-CoA dehydrogenase (SCAD) deficiency. Three patients with VLCAD or LCHAD/MTP deficiency developed recurrent rhabdomyolysis or cardiomyopathy, and one patient died of cardiomyopathy. The other 10 patients remained neurodevelopmentally normal and asymptomatic during the follow-up. In 8 patients with symptomatic presentation, FAODs manifested as LCHAD/MTP deficiencies by recurrent rhabdomyolysis or cadiomyopathy (6 patients), and VLCAD deficiency by cardiomyopathy (1 patient), and CPT1A deficiency by hepatic failure (1 patient). Two patients with LCHAD/MTP deficiencies died due to severe cardiomyopathy in the neonatal period, and developmental disability was noted in CPT1A deficiency (1 patient). NBS helped to identify the broad spectrum of FAODs and introduce early intervention to improve the clinical outcome of each patient. However, severe clinical manifestations developed in some patients, indicating that careful, life-long observation is warranted in all FAODs patients.

Background Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is classified either as Kallmann syndrome (KS) with anosmia or normosmic idiopathic hypogonadotropic hypogonadism (nIHH) and caused by mutations in more than 30 different genes. Recent advances in next-generation sequencing technologies have revolutionized the identification of causative genes by using massively parallel sequencing of multiple samples. This study was performed to establish the genetic etiology of IGD using a targeted gene panel sequencing of 69 known human IGD genes. Methods This study included 28 patients with IGD from 27 independent families. Exomes were captured using customized SureSelect kit (Agilent Technologies) and sequenced on the Miseq platform (Illumina, Inc.), which includes a 163,269 bp region spanning 69 genes. Results Four pathogenic and six likely pathogenic sequence variants were identified in 11 patients from 10 of the 27 families (37%) included in the study. We identified two known pathogenic mutations in CHD7 and PROKR2 from two male patients (7.4%). Novel sequence variants were also identified in 10 probands (37%) in CHD7, SOX3, ANOS1, FGFR1, and TACR3. Of these, while eight variants (29.6%) were presumed to be pathogenic or likely pathogenic, the remaining two were classified as variants of uncertain significance. Of the two pre-pubertal males with anosmia, one harbored a novel heterozygous splice site variant in FGFR1. Conclusions The overall diagnostic yield was 37% of the patients who had undergone targeted gene panel sequencing. This approach enables rapid, cost-effective, and comprehensive genetic screening in patients with KS and nIHH.

Adrenal hypoplasia is a rare congenital disorder, which can be classified into a non-syndromic form, without extra-adrenal features, and a syndromic form, with such features. Despite biochemical and molecular genetic evaluation, etiologic diagnosis cannot be performed in many patients with adrenal hypoplasia. The patient in this case was a boy born at 31 weeks of gestation with a weight of 882 g (< 3rd percentile) to non-consanguineous parents. Genital examination showed micropenis and bilateral cryptorchidism. On the third day of life, he manifested hypotension with high urine output, hyponatremia, hyperkalemia, hypernatriuria, high plasma adrenocorticotropic hormone level, and high plasma renin activity, suggesting acute adrenal insufficiency. The serum 17α-hydroxyprogesterone level was normal. Adrenal insufficiency improved following administration of hydrocortisone and 9α-fludrocortisone, but the patient died of recurrent infection at 4 months of age. He was suspected as IMAGE (Intrauterine growth restriction, Metaphyseal dysplasia, Adrenal hypoplasia congenita, and Genital anomalies) syndrome. However, no mutation in CDKN1C was identified. Targeted exome sequencing using the TruSight One Sequencing Panel (Illumina) identified a heterozygous mutation of c.2944C > T (p.R982C) in exon 3 in SAMD9. This report describes the first Korean case of MIRAGE syndrome. The patient presented with severe primary adrenal insufficiency, intrauterine growth retardation, and recurrent infection. SAMD9 mutation should be considered in patients who present with adrenal hypoplasia and extra-adrenal phenotypes.

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.