MIRAGE syndrome is a rare cause of 46,XY DSD born SGA without adrenal insufficiency

Hirohito Shima, Mie Hayashi, Takashi Tachibana, Makoto Oshiro, Naoko Amano, Tomohiro Ishii, Hidenori Haruna, Maki Igarashi, Masafumi Kon, Ryuji Fukuzawa, Yukichi Tanaka, Maki Fukami, Tomonobu Hasegawa, Satoshi Narumi

Research output: Contribution to journalArticle

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Abstract

Background MIRAGE syndrome, a congenital multisystem disorder due to pathogenic SAMD9 variants, describes a constellation of clinical features including 46,XY disorders of sex development (DSD), small for gestational age (SGA) and adrenal insufficiency (AI). It is poorly understood whether SAMD9 variants underlie 46,XY DSD patients born SGA (46,XY DSD SGA) without AI. This study aimed to define the frequency and phenotype of SAMD9 variants in 46,XY DSD SGA without AI. Methods Forty-nine Japanese patients with 46,XY DSD SGA (Quigley scale, 2 to 6; gestational agematched birth weight percentile, <10) without history of AI were enrolled. The single coding exon of SAMD9 was PCR-amplified and sequenced for each patient. Pathogenicity of an identified variant was verified in vitro. Placenta tissues were obtained from the variant-carrying patient, as well as from another previously described patient, and were analyzed histologically. Results In one 46,XY DSD SGA patient, a novel heterozygous SAMD9 variant, p.Phe1017Val, was identified. Pathogenicity of the mutant was experimentally confirmed. In addition to DSD and SGA, the patient had neonatal thrombocytopenia, severe postnatal grow restriction, chronic diarrhea and susceptibility to infection, all features consistent with MIRAGE, leading to premature death at age 14 months. The patient did not have any manifestations or laboratory findings suggesting AI. Placenta tissues of the two variant-carrying patients were characterized by maldevelopment of distal villi without other findings of maternal underperfusion. Conclusions MIRAGE syndrome is a rare cause of 46,XY DSD SGA without AI. This study exemplifies that AI is a common feature of MIRAGE syndrome but that the absence of AI should not rule out a diagnosis of the syndrome.

Original languageEnglish
Article numbere0206184
JournalPLoS One
Volume13
Issue number11
DOIs
Publication statusPublished - 2018 Nov 1

Fingerprint

XY Disorders of Sex Development 46
small for gestational age
Adrenal Insufficiency
Gestational Age
Tissue
gender
Exons
placenta
Placenta
Virulence
pathogenicity
Neonatal Alloimmune Thrombocytopenia
Disorders of Sex Development
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Premature Mortality
thrombocytopenia
villi
Birth Weight
birth weight
exons

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Shima, H., Hayashi, M., Tachibana, T., Oshiro, M., Amano, N., Ishii, T., ... Narumi, S. (2018). MIRAGE syndrome is a rare cause of 46,XY DSD born SGA without adrenal insufficiency. PLoS One, 13(11), [e0206184]. https://doi.org/10.1371/journal.pone.0206184

MIRAGE syndrome is a rare cause of 46,XY DSD born SGA without adrenal insufficiency. / Shima, Hirohito; Hayashi, Mie; Tachibana, Takashi; Oshiro, Makoto; Amano, Naoko; Ishii, Tomohiro; Haruna, Hidenori; Igarashi, Maki; Kon, Masafumi; Fukuzawa, Ryuji; Tanaka, Yukichi; Fukami, Maki; Hasegawa, Tomonobu; Narumi, Satoshi.

In: PLoS One, Vol. 13, No. 11, e0206184, 01.11.2018.

Research output: Contribution to journalArticle

Shima, H, Hayashi, M, Tachibana, T, Oshiro, M, Amano, N, Ishii, T, Haruna, H, Igarashi, M, Kon, M, Fukuzawa, R, Tanaka, Y, Fukami, M, Hasegawa, T & Narumi, S 2018, 'MIRAGE syndrome is a rare cause of 46,XY DSD born SGA without adrenal insufficiency', PLoS One, vol. 13, no. 11, e0206184. https://doi.org/10.1371/journal.pone.0206184
Shima, Hirohito ; Hayashi, Mie ; Tachibana, Takashi ; Oshiro, Makoto ; Amano, Naoko ; Ishii, Tomohiro ; Haruna, Hidenori ; Igarashi, Maki ; Kon, Masafumi ; Fukuzawa, Ryuji ; Tanaka, Yukichi ; Fukami, Maki ; Hasegawa, Tomonobu ; Narumi, Satoshi. / MIRAGE syndrome is a rare cause of 46,XY DSD born SGA without adrenal insufficiency. In: PLoS One. 2018 ; Vol. 13, No. 11.
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abstract = "Background MIRAGE syndrome, a congenital multisystem disorder due to pathogenic SAMD9 variants, describes a constellation of clinical features including 46,XY disorders of sex development (DSD), small for gestational age (SGA) and adrenal insufficiency (AI). It is poorly understood whether SAMD9 variants underlie 46,XY DSD patients born SGA (46,XY DSD SGA) without AI. This study aimed to define the frequency and phenotype of SAMD9 variants in 46,XY DSD SGA without AI. Methods Forty-nine Japanese patients with 46,XY DSD SGA (Quigley scale, 2 to 6; gestational agematched birth weight percentile, <10) without history of AI were enrolled. The single coding exon of SAMD9 was PCR-amplified and sequenced for each patient. Pathogenicity of an identified variant was verified in vitro. Placenta tissues were obtained from the variant-carrying patient, as well as from another previously described patient, and were analyzed histologically. Results In one 46,XY DSD SGA patient, a novel heterozygous SAMD9 variant, p.Phe1017Val, was identified. Pathogenicity of the mutant was experimentally confirmed. In addition to DSD and SGA, the patient had neonatal thrombocytopenia, severe postnatal grow restriction, chronic diarrhea and susceptibility to infection, all features consistent with MIRAGE, leading to premature death at age 14 months. The patient did not have any manifestations or laboratory findings suggesting AI. Placenta tissues of the two variant-carrying patients were characterized by maldevelopment of distal villi without other findings of maternal underperfusion. Conclusions MIRAGE syndrome is a rare cause of 46,XY DSD SGA without AI. This study exemplifies that AI is a common feature of MIRAGE syndrome but that the absence of AI should not rule out a diagnosis of the syndrome.",
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AU - Tachibana, Takashi

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AU - Amano, Naoko

AU - Ishii, Tomohiro

AU - Haruna, Hidenori

AU - Igarashi, Maki

AU - Kon, Masafumi

AU - Fukuzawa, Ryuji

AU - Tanaka, Yukichi

AU - Fukami, Maki

AU - Hasegawa, Tomonobu

AU - Narumi, Satoshi

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N2 - Background MIRAGE syndrome, a congenital multisystem disorder due to pathogenic SAMD9 variants, describes a constellation of clinical features including 46,XY disorders of sex development (DSD), small for gestational age (SGA) and adrenal insufficiency (AI). It is poorly understood whether SAMD9 variants underlie 46,XY DSD patients born SGA (46,XY DSD SGA) without AI. This study aimed to define the frequency and phenotype of SAMD9 variants in 46,XY DSD SGA without AI. Methods Forty-nine Japanese patients with 46,XY DSD SGA (Quigley scale, 2 to 6; gestational agematched birth weight percentile, <10) without history of AI were enrolled. The single coding exon of SAMD9 was PCR-amplified and sequenced for each patient. Pathogenicity of an identified variant was verified in vitro. Placenta tissues were obtained from the variant-carrying patient, as well as from another previously described patient, and were analyzed histologically. Results In one 46,XY DSD SGA patient, a novel heterozygous SAMD9 variant, p.Phe1017Val, was identified. Pathogenicity of the mutant was experimentally confirmed. In addition to DSD and SGA, the patient had neonatal thrombocytopenia, severe postnatal grow restriction, chronic diarrhea and susceptibility to infection, all features consistent with MIRAGE, leading to premature death at age 14 months. The patient did not have any manifestations or laboratory findings suggesting AI. Placenta tissues of the two variant-carrying patients were characterized by maldevelopment of distal villi without other findings of maternal underperfusion. Conclusions MIRAGE syndrome is a rare cause of 46,XY DSD SGA without AI. This study exemplifies that AI is a common feature of MIRAGE syndrome but that the absence of AI should not rule out a diagnosis of the syndrome.

AB - Background MIRAGE syndrome, a congenital multisystem disorder due to pathogenic SAMD9 variants, describes a constellation of clinical features including 46,XY disorders of sex development (DSD), small for gestational age (SGA) and adrenal insufficiency (AI). It is poorly understood whether SAMD9 variants underlie 46,XY DSD patients born SGA (46,XY DSD SGA) without AI. This study aimed to define the frequency and phenotype of SAMD9 variants in 46,XY DSD SGA without AI. Methods Forty-nine Japanese patients with 46,XY DSD SGA (Quigley scale, 2 to 6; gestational agematched birth weight percentile, <10) without history of AI were enrolled. The single coding exon of SAMD9 was PCR-amplified and sequenced for each patient. Pathogenicity of an identified variant was verified in vitro. Placenta tissues were obtained from the variant-carrying patient, as well as from another previously described patient, and were analyzed histologically. Results In one 46,XY DSD SGA patient, a novel heterozygous SAMD9 variant, p.Phe1017Val, was identified. Pathogenicity of the mutant was experimentally confirmed. In addition to DSD and SGA, the patient had neonatal thrombocytopenia, severe postnatal grow restriction, chronic diarrhea and susceptibility to infection, all features consistent with MIRAGE, leading to premature death at age 14 months. The patient did not have any manifestations or laboratory findings suggesting AI. Placenta tissues of the two variant-carrying patients were characterized by maldevelopment of distal villi without other findings of maternal underperfusion. Conclusions MIRAGE syndrome is a rare cause of 46,XY DSD SGA without AI. This study exemplifies that AI is a common feature of MIRAGE syndrome but that the absence of AI should not rule out a diagnosis of the syndrome.

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