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A Novel Mutation of IGSF1 in a Japanese Patient of Congenital Central Hypothyroidism Without Macroorchidism

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A Novel Mutation of IGSF1 in a Japanese Patient of Congenital Central Hypothyroidism Without Macroorchidism Endocrine Journal 2013, 60 (2), 245-249 RAPID COMMUNI C ATION A novel mutation of IGSF1 in a Japanese patient of congenital central hypothyroidism without macroorchidism Toshihiro Tajima, Akie Nakamura and Katsura Ishizu Department of Pediatrics, Hokkaido University School of Medicine, Sapporo 060-8635, Japan Abstract. Congenital central hypothyroidism (C-CH) is a rare disease known to be caused by mutations of the genes encoding TSH β or the TRH receptor gene, although the cause of the disease in a number of patients has not yet been clarified. Recently, mutations and deletions of the immunoglobulin superfamily member 1 (IGSF1) gene have been reported to be the cause of C-CH. Here we report a Japanese male patient with C-CH due to a novel IGSF1 mutation. He was detected by neonatal mass screening of simultaneous TSH and free T4 measurements and levothyroxine was initiated. At 6 years of age he underwent 123 I scintigraphy after levothyroxine treatment had been discontinued for one month and his thyroid and pituitary function were evaluated. Since TSH and PRL responses after TRH stimulation were low, his diagnosis of C-CH was confirmed. During follow up, whereas onset of his puberty was delayed, his secondary sex characterization completed at 17 years old. In this patient we analyzed IGSF1 and TRHR. As results, we identified a novel insertion mutation in IGSF1 (c.3528-3529insC), resulting in a premature stop codon (p.Pro1082Trpfs39X). In conclusion, we identified a novel mutation of IGSF1 in a Japanese male patient with C-CH. Key words: Immunoglobulin superfamily gene 1 (IGSF1), Central hypothyroidism, Mutation, Thyroid stimulating hormone (TSH), Prolactin (PRL) CONGENITAL CENTRAL HYPOTHYROIDISM lar C terminal domain [11-13]. It has been shown that (C-CH) is an unusual condition characterized by low human IGSF1 and mouse Igsf1 are highly expressed in levels of both thyroid hormones and of thyroid-stimu- Rathke’s pouch and adult pituitary gland and testis [10, lating hormone (TSH) [1, 2]. Patients with this disorder 12]. In addition, Igsf1 protein is expressed in mouse are not detected by neonatal screening programs based thyrotropes, somatotropes and lactotropes, but not in on TSH measurements, which is frequently in the low to gonadotropes [10]. normal range. However, this type of CH has been iden- In this study, we report a Japanese male patient with tified by neonatal screening for CH on the basis of thy- C-CH, who was identified by a neonatal mass screen- roxine (T4) or free T4 and TSH concentrations [1-3]. ing and a novel IGSF1 mutation in this patient. Isolated C-CH remains a rare disease and is due mainly to genetic deficit of the β-subunit of TSH Methods (OMIM 188540) or the thyrotropin-releasing hor- mone (TRH) receptor (OMIM 188545) mutations Neonatal CH screening [4-9]. Most recently, mutations and deletions of human The neonatal CH screening program in Sapporo was immunoglobulin superfamily gene 1 (IGSF1) have based on simultaneous TSH and free T4 measurement been reported in X-linked C-CH [10]. IGSF1 encodes in dried blood on filter paper specimens [3, 14]. Dried a plasma membrane immunoglobulin super family gly- blood samples on filter paper are collected from neo- coprotein , containing twelve C2 type immunoglobulin natal infants born in Sapporo City at 4-6 days of age loops, a transmembrane domain, and a short intracellu- from maternity and parturition clinics to Sapporo City Institute of Health. TSH and free T4 were measured Submitted Jan. 5, 2013; Accepted Jan. 21, 2013 as EJ13-0009 simultaneously on blood spots on filter paper. TSH and Released online in J-STAGE as advance publication Jan. 30, 2013 Correspondence to: Toshihiro Tajima, Department of Pediatrics, free T4 were measured by ELISA kits (Bayer Medical Hokkaido University School of Medicine, N15, W7, Sapporo 060- Enzaplate Neo-TSH and Enzplate N-FT4 kits, Japan). 8635, Japan. E-mail: [email protected] To detect the severe CH, children with TSH con- ©The Japan Endocrine Society 246 Tajima et al. centrations more than or equal to 50 mU/L and/or free T4 less than < 0.5 ng/dL were directly referred to the expert hospital. Second heel puncture was requested if one of the following criteria for recall testing was met: (1) free T4 < 1.0 ng/dL, (2) high TSH concen- tration (>10 mU/L). Infants whose TSH or free T4 in the second testing were successively out of the normal range were sent to the expert hospital. We previously reported the frequency of C-CH in Sapporo [3]. Pituitary hormone stimulation test Serum levels of TSH and prolactin (PRL) were deter- mined in response to TRH (5µg/kg). GH provocative tests were performed using insulin (0.1 IU/kg). Serum levels of LH and FSH were determined in response to GnRH (2µg/kg). Genetic studies Our institutional ethics committee approved the study, and the patients’ parents provided written Fig. 1 Growth chart of our patient informed consent. Sequence analysis of IGSF1 Genomic DNA was extracted from peripheral blood Table 1 Endocrinological findings of the patient leukocytes. Exon and exon-intron boundaries of IGSF1 Symptoms No were amplified by polymerase chain reaction (PCR) Blood Free T4 (ng/dL) at mass screening 0.76 (5 days) using primers as reported previously [10]. After ampli- Blood TSH (mU/L) at mass screening 1.7 (5 days) fication, PCR products were purified and sequenced Free T4 at referral 0.76 (18 days) directly with an ABI PRISM Dye Terminator Cycle Free T3 (pg/mL)at referral 2.71 (18 days) Kit and an ABI 373A automated fluorescent sequencer TSH at referral 1.76 (18 days) (PE Applied Biosystems, Foster City, CA). In addi- tion to IGSF1, TRHR was also sequenced according to a reported study [9]. to have C-CH, he was referred to our hospital at 18 days Case Report of age for further evaluation. At that time, he showed no symptoms and bilateral femoral epiphyses were 5x3 Patient, now a 21-year old Japanese boy, was born mm by X-ray examination. His serum thyroid function after 39 weeks of gestation by normal vaginal deliv- was as follows, TSH = 1.76 mU/L, FT4 = 0.76 ng/dL, ery in Sapporo city and was the third child of noncon- FT3=2.71pg/mL (normal range for this age, TSH 0.3- sanguineous parents. His parents were healthy. His 3.50 mU/L, FT4 1.40-1.88 ng/dL and FT3 2.42-4.80 growth is shown in Fig. 1. There was no family history pg/mL, respectively) (Table 1). He was thought to have of thyroid disease. His birth weight was 3,528 g and C-CH and levothyroxine was initiated. Thereafter, the his length was 50 cm. Neonatal mass screening for CH dose of levothyroxine was gradually increased and 70 showed blood TSH = 1.7 mU/L, and FT4 = 0.75 ng/dL µg/day was required to maintain serum FT4 within the at 5 days of age. Because of this result, he was reque- normal range at 6 years of age. At 6 years of age he tsed for the second sample of blood filter paper and the underwent 123 I scintigraphy after levothyroxine treat- second smaple was taken at 16 days of age. The results ment had been discontinued for one month and his thy- of the second sample were as follows; TSH=0.6 mU/L roid and pituitary function were evaluated. The scin- and FT4=0.51 ng/dL (Table 1). Since he was suspected tigraph was a normal size of thyroid gland and uptake IGSF1 gene and hypothyroidism 247 Table 2 Results of TRH, Insulin and GnRH stimulation at 6 years of age Minutes 0 15 30 60 90 120 TSH (mU/L) 2.45 4.90 5.17 4.28 3.10 2.55 PRL (ng/mL) 0,25 0.77 1.18 0.67 0.62 0.40 GH (ng/mL) 1.0 3.2 6.0 5.8 2.5 2.0 LH (IU/L) <0.1 0.70 1.17 1.14 0.63 0.49 FSH (IU/L) 0.30 1.78 2.98 3.89 4.10 3.89 Fig. 2 Sequence of exon 16 of patient and wild type (A) Sequence of exon 16 of the patient. A C base is inserted (c.3528-3529insC) (arrow). This insertion changes an open read- ing frame, resulting in a premature codon 39 bases downstream (p.Pro1082Trpfs39X). (B) Wild type sequence was 31% at 24 hr. Results of stimulation test are sum- lar sizes are 15 mL and 12 mL by prader orchidometer, marized in Table 2. Serum TSH exhibited low values resepctively. His serum LH and FSH levels are 1.5 and in response to TRH stimulation. TSH was 2.45 mU/L 3.5 mU/L, respectively. His serum teststerone level is before, 5.17 mU/L at 60 min. Basal FT4 and FT3 were 780 ng/dL. 0.35 ng/dL and 1.52 pg/mL, respectively (normal range for this age, FT4, 1.11-1.58 ng/dL and FT3, 5.1-3.90 Results pg/mL, respectively). Serum PRL also showed a low response to TRH stimulation (from 0.25 to 1.18 ng/ Sequence analysis of IGSF1 demonstrated one mL). GH increased from 1.0 to 6.3 ng/mL after insulin base insertion mutation in exon 16 (c.3528-3529insC) tolerance test. GnRH test showed a normal response (Fig. 2A). Neither one hundred normal Japanese sub- of LH and FSH for his age (LH, <0.1 to 1.17IU/L, and jects had this base insertion.
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