Clinical characteristics of HNF1B-related disorders in a Japanese population

doi:10.1007/s10157-019-01747-0

. 2019 Sep;23(9):1119-1129.

doi: 10.1007/s10157-019-01747-0. Epub 2019 May 27.

Clinical characteristics of HNF1B-related disorders in a Japanese population

China Nagano¹, Naoya Morisada^{2

3}, Kandai Nozu¹, Koichi Kamei⁴, Ryojiro Tanaka⁵, Shoichiro Kanda⁶, Shinichi Shiona⁷, Yoshinori Araki⁸, Shinichiro Ohara⁹, Chieko Matsumura¹⁰, Katsuaki Kasahara¹¹, Yukiko Mori¹², Akane Seo¹³, Kenichiro Miura¹⁴, Miki Washiyama¹⁵, Keisuke Sugimoto¹⁶, Ryoko Harada¹⁷, Satoshi Tazoe¹⁸, Hiroyo Kourakata¹⁹, Mayumi Enseki²⁰, Daisuke Aotani²¹, Takeshi Yamada²², Nana Sakakibara¹, Tomohiko Yamamura¹, Shogo Minamikawa¹, Kenji Ishikura^{4

23}, Shuichi Ito²⁴, Motoshi Hattori¹⁴, Kazumoto Iijima¹

Affiliations

¹ Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan.
² Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan. [email protected].
³ Department of Clinical Genetics, Hyogo Prefectural Kobe Children's Hospital, 1-6-7, Minatojimaminami-machi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan. [email protected].
⁴ Division of Nephrology and Rheumatology, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan.
⁵ Department of Nephrology, Hyogo Prefectural Kobe Children's Hospital, 1-6-7 Minatojima Minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan.
⁶ Department of Pediatrics, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
⁷ Department of Pediatrics, Oita Prefectural Hospital, 476, Oaza-Bujyo, Oita, Oita, 870-8511, Japan.
⁸ Department of Pediatrics, Hokkaido Medical Center, 5-7-1-1 Yamanote Nishi-ku, Sapporo, Hokkaido, 063-0005, Japan.
⁹ Department of Pediatrics, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima-shi, Fukushima, 960-1295, Japan.
¹⁰ Department of Pediatrics, National Hospital Organization Chibahigashi National Hospital, 673 Nitonacho, Chuo-ku, Chiba, Chiba, 260-8712, Japan.
¹¹ Department of Pediatric Nephrology, Japanese Red Cross Nagoya Daini Hospital, 2-9 Myokencho, Syowa-ku, Nagoya, 4668-650, Japan.
¹² Department of Pediatrics, Japanese Red Cross Fukui Hospital, 2-4-1, Tsukimi, Fukui, 918-8501, Japan.
¹³ Department of Diabetes and Endocrinology, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
¹⁴ Department of Pediatric Nephrology, Tokyo Women's Medical University, School of Medicine, 8-1, Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan.
¹⁵ Department of Diabetes and Endocrinology, Kusatsu General Hospital, 1660 Yabase-cho, Kusatsu, Siga, 525-8585, Japan.
¹⁶ Department of Pediatrics, Faculty of Medicine, Kindai University, 377-2, Ohno-Higashi, Osakasayama, Osaka, 589-8511, Japan.
¹⁷ Department of Nephrology, Tokyo Metropolitan Children's Medical Center, 2-8-29, Musashidai, Fuchu, Tokyo, 183-8561, Japan.
¹⁸ Department of Metabolism, Osaka City General Hospital, 2-13-22 Miyakojimahondori, Miyakojima-ku, Osaka, 534-0021, Japan.
¹⁹ Department of Respiratory Medicine, Niigata Saiseikai Sanjo Hospital, 6-18 Oonohata, Sanjyo-shi, Niigata, 955-8511, Japan.
²⁰ Department of Pediatrics, Tokai University Hospital, 143, Shimokasuya, Isehara-shi, Tokyo, 259-1193, Japan.
²¹ Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences and Medical School, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan.
²² Department of Pediatrics, Niigata University School of Medicine, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan.
²³ Department of Pediatrics, Kitasato University School of Medicine, 1-15-1, Kitasato, Minami-ku, Sagamihara, 252-0375, Japan.
²⁴ Department of Pediatrics, Yokohama City University, 3-9, Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.

PMID: 31131422
DOI: 10.1007/s10157-019-01747-0

Clinical characteristics of HNF1B-related disorders in a Japanese population

China Nagano et al. Clin Exp Nephrol. 2019 Sep.

. 2019 Sep;23(9):1119-1129.

doi: 10.1007/s10157-019-01747-0. Epub 2019 May 27.

Authors

Affiliations

¹ Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan.
² Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan. [email protected].
³ Department of Clinical Genetics, Hyogo Prefectural Kobe Children's Hospital, 1-6-7, Minatojimaminami-machi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan. [email protected].
⁴ Division of Nephrology and Rheumatology, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan.
⁵ Department of Nephrology, Hyogo Prefectural Kobe Children's Hospital, 1-6-7 Minatojima Minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan.
⁶ Department of Pediatrics, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
⁷ Department of Pediatrics, Oita Prefectural Hospital, 476, Oaza-Bujyo, Oita, Oita, 870-8511, Japan.
⁸ Department of Pediatrics, Hokkaido Medical Center, 5-7-1-1 Yamanote Nishi-ku, Sapporo, Hokkaido, 063-0005, Japan.
⁹ Department of Pediatrics, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima-shi, Fukushima, 960-1295, Japan.
¹⁰ Department of Pediatrics, National Hospital Organization Chibahigashi National Hospital, 673 Nitonacho, Chuo-ku, Chiba, Chiba, 260-8712, Japan.
¹¹ Department of Pediatric Nephrology, Japanese Red Cross Nagoya Daini Hospital, 2-9 Myokencho, Syowa-ku, Nagoya, 4668-650, Japan.
¹² Department of Pediatrics, Japanese Red Cross Fukui Hospital, 2-4-1, Tsukimi, Fukui, 918-8501, Japan.
¹³ Department of Diabetes and Endocrinology, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
¹⁴ Department of Pediatric Nephrology, Tokyo Women's Medical University, School of Medicine, 8-1, Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan.
¹⁵ Department of Diabetes and Endocrinology, Kusatsu General Hospital, 1660 Yabase-cho, Kusatsu, Siga, 525-8585, Japan.
¹⁶ Department of Pediatrics, Faculty of Medicine, Kindai University, 377-2, Ohno-Higashi, Osakasayama, Osaka, 589-8511, Japan.
¹⁷ Department of Nephrology, Tokyo Metropolitan Children's Medical Center, 2-8-29, Musashidai, Fuchu, Tokyo, 183-8561, Japan.
¹⁸ Department of Metabolism, Osaka City General Hospital, 2-13-22 Miyakojimahondori, Miyakojima-ku, Osaka, 534-0021, Japan.
¹⁹ Department of Respiratory Medicine, Niigata Saiseikai Sanjo Hospital, 6-18 Oonohata, Sanjyo-shi, Niigata, 955-8511, Japan.
²⁰ Department of Pediatrics, Tokai University Hospital, 143, Shimokasuya, Isehara-shi, Tokyo, 259-1193, Japan.
²¹ Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences and Medical School, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan.
²² Department of Pediatrics, Niigata University School of Medicine, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan.
²³ Department of Pediatrics, Kitasato University School of Medicine, 1-15-1, Kitasato, Minami-ku, Sagamihara, 252-0375, Japan.
²⁴ Department of Pediatrics, Yokohama City University, 3-9, Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.

PMID: 31131422
DOI: 10.1007/s10157-019-01747-0

Abstract

Background: Hepatocyte nuclear factor 1β (HNF1B), located on chromosome 17q12, causes renal cysts and diabetes syndrome (RCAD). Moreover, various phenotypes related to congenital anomalies of the kidney and urinary tract (CAKUT) or Bartter-like electrolyte abnormalities can be caused by HNF1B variants. In addition, 17q12 deletion syndrome presents with multi-system disorders, as well as RCAD. As HNF1B mutations are associated with different phenotypes and genotype-phenotype relationships remain unclear, here, we extensively studied these mutations in Japan.

Methods: We performed genetic screening of RCAD, CAKUT, and Bartter-like syndrome cases. Heterozygous variants or whole-gene deletions in HNF1B were detected in 33 cases (19 and 14, respectively). All deletion cases were diagnosed as 17q12 deletion syndrome, confirmed by multiplex ligation probe amplification and/or array comparative genomic hybridization. A retrospective review of clinical data was also conducted.

Results: Most cases had morphological abnormalities in the renal-urinary tract system. Diabetes developed in 12 cases (38.7%). Hyperuricemia and hypomagnesemia were associated with six (19.3%) and 13 cases (41.9%), respectively. Pancreatic malformations were detected in seven cases (22.6%). Ten patients (32.3%) had liver abnormalities. Estimated glomerular filtration rates were significantly lower in the patients with heterozygous variants compared to those in patients harboring the deletion (median 37.6 vs 58.8 ml/min/1.73 m²; p = 0.0091).

Conclusion: We present the clinical characteristics of HNF1B-related disorders. To predict renal prognosis and complications, accurate genetic diagnosis is important. Genetic testing for HNF1B mutations should be considered for patients with renal malformations, especially when associated with other organ involvement.

Keywords: Diabetes; Gout; HNF1B; Hypomagnesaemia; Liver abnormality; Renal malformations.

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References

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[1] J Mol Endocrinol. 2001 Aug;27(1):11-29 - PubMed

[2] J Mol Endocrinol. 2001 Aug;27(1):11-29 - PubMed

[3] J Am Soc Nephrol. 2003 Aug;14(8):2033-41 - PubMed

[4] J Am Soc Nephrol. 2003 Aug;14(8):2033-41 - PubMed

[5] EMBO J. 2004 Apr 7;23(7):1657-68 - PubMed

[6] EMBO J. 2004 Apr 7;23(7):1657-68 - PubMed

[7] Ann Intern Med. 2004 Apr 6;140(7):510-7 - PubMed

[8] Ann Intern Med. 2004 Apr 6;140(7):510-7 - PubMed

[9] J Med Genet. 2006 Jan;43(1):84-90 - PubMed

[10] J Med Genet. 2006 Jan;43(1):84-90 - PubMed

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Clinical characteristics of HNF1B-related disorders in a Japanese population

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Clinical characteristics of HNF1B-related disorders in a Japanese population

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