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Background/Aims: Syndromes of reduced sensitivity to thyroid hormone can be caused by innate resistance to thyroid hormone (RTH), thyroid hormone cell transporter defects, or thyroid hormone metabolism defects. This study was performed to describe clinical, endocrinological, and molecular characteristics of patients with disorders associated with impaired sensitivity to thyroid hormone due to THRB or SLC16A2 mutations. Methods: This study included 5 probands (1 male and 4 females) with RTH and 6 patients with Allan-Herndon-Dudley syndrome (AHDS). Clinical features and endocrine findings were reviewed retrospectively. Molecular analysis of two candidate genes, THRB or SLC16A2, confirmed the diagnosis. Results: Among RTH patients, median age at diagnosis was 5.6 years. Three patients were classified as having generalized RTH, whereas the other 2 patients were regarded as having isolated pituitary RTH. Three novel heterozygous mutations and 2 known mutations in THRB were identified from 5 independent pedigrees. All mutations were located in the major ligand-binding domain. In AHDS patients, delayed development was apparent between 3 and 6 months of age. Direct sequencing of SLC16A2 identified 6 hemizygous missense mutations in each patient: p.I188N, p.G221R, p.A224V, p.G276R, p.W398R, and p.G401R. Conclusions: This study identified 3 novel mutations in THRB in RTH patients and 1 novel mutation in SLC16A2 in AHDS patients. Routine neonatal screening based on the TSH assay has a limited role in detecting RTH or AHDS. Therefore, genetic testing of the candidate genes THRB and SLC16A2 should be performed for diagnosis of RTH and AHDS in patients with the suggestive clinical phenotype.

Background/Aims: Heterozygous mutations of NR5A1, which encodes steroidogenic factor 1 (SF1), were identified in patients with 46,XY disorders of sex development (DSD) with normal adrenal function. This study was aimed to identify and functionally characterize mutations of NR5A1 in patients with 46,XY DSD. Methods: This study included 51 patients from 49 unrelated families with 46,XY DSD. Genomic DNA was extracted from peripheral blood leukocytes, and direct sequencing of all coding exons and their flanking introns of NR5A1 was performed. Transient transfections and dual-luciferase® reporter assays were performed to evaluate the effect of NR5A1 variants on transcriptional activity. Results: Four of 49 patients (8.2%) harbored a novel heterozygous sequence variant of NR5A1: c.80G>C (p.G26A), c.847T>C (p.C283R), c.1151del (p.L384Rfs*7), and c.1333G>T (p.E445*). They presented with female external genitalia with clitoromegaly in infancy or childhood, or primary amenorrhea in adolescence. In vitro functional studies of SF1 activity determined that each variant, except p.E445*, led to a reduced expression of downstream target genes and disturbed the regulation of gonadal development. Conclusions: Loss-of-function mutations of NR5A1 are a relatively common cause of 46,XY DSD. Therefore, genetic defects of NR5A1 should be considered as an etiology in subjects with 46,XY DSD without adrenal insufficiency.

Background/Aims: Donohue syndrome is an extremely rare autosomal recessive disorder caused by mutations in INSR. This study describes the clinical course of a patient with Donohue syndrome, and we also evaluated the molecular and functional characteristics of 2 novel INSR mutations. Methods: Our patient was a male newborn with acanthosis nigricans, lack of subcutaneous fat, hirsutism, thick lips, and high serum insulin levels, all of which are characteristic of Donohue syndrome. INSR mutation analysis was performed, and Western blot analysis was used to verify the effects of the novel mutations on INSR protein expression. Results: Direct INSR sequencing identified the following 2 novel compound heterozygous mutations in the β-subunit of INSR: p.Arg1066* and p.Gln1232*. Western blot analysis of skin fibroblasts revealed a comparable expression of the α-subunit of INSR in mutant and control samples, but reduced levels of mature INSR β-subunit protein were found in mutant INSR-expressing cells in comparison to the controls. Conclusions: This study describes the clinical course of a male patient with Donohue syndrome and the molecular characteristics of 2 novel compound heterozygous mutations in INSR. These novel nonsense mutations are associated with reduced expression of the mature INSR β-subunit, which was most likely due to impaired proreceptor processing.