FSH β-subunit mutations in two sisters: the first report from the Indian sub-continent and review of previous cases

Abstract

Isolated FSH deficiency due to mutations in the gene for β-subunit of FSH is an extremely rare autosomal recessive disease of which only eleven cases have been reported so far. The clinical features include absent breast development and primary amenorrhea in females and azoospermia with normal testosterone levels in males. In this study we report two Kashmiri sisters born to native Kashmiri consanguineous parents with failure of onset of puberty. Hormonal evaluation revealed undetectable serum FSH and estradiol and high LH. Genetic analysis of FSH β-gene identified one nonsense mutation (c.343C > T:p. Arg115Stop) in exon 3. The two sisters were homozygous for this nonsense mutation while the parents were heterozygous. Incorporation of a stop codon at 115 codon position is predicted to result in the formation of truncated FSH β protein, lacking 14 amino acid from the carboxy-terminus (p.Arg115Stop). Very recently, this same mutation was reported for the first time in a Chinese male. Ours is the first ever report of any FSH β-subunit mutation from the Indian sub-continent and this particular mutation in any female from anywhere in the world. We conclude and emphasize that this diagnosis should be considered in girls with delayed puberty and selective deficiency of FSH.

摘要

单纯FSH缺乏是一种罕见的常染色体隐性遗传疾病, 是由于FSHβ亚基基因突变引起, 至今为止仅有11例病例被报道。它的临床特征包括女性的乳房不发育和原发性闭经, 以及正常睾酮水平的男性无精症。本研究中, 报道了出生于本国克什米尔血统的两名克什米尔人姐妹, 她们缺乏青春期特征。激素水平检测提示血清中未测到FSH及雌二醇, LH呈高水平。通过对FSHβ的基因分析, 确定了一个3号外显子上的无义突变(c.343C>T:p.Arg115Stop)。这种无意义的突变在这两姐妹中显示为纯合型, 而在她们的父母身上为杂合型。推测可能是由于在115密码子的位置上插入了一个终止密码子, 造成来自羧基末端的14个氨基酸（p.Arg115Stop）缺乏, 而形成了FSHβ蛋白的缩短。最近, 在一例中国男性患者中也首次报道了同样的基因突变。我们的病例是印度次大陆有史以来的第一例FSHβ亚基突变报道, 并且这种特殊的突变可以发生在世界任何地方的任何女性身上。我们的结论要强调的是, 在青春期延迟的女孩和FSH缺乏的病例中, 应该考虑到有这种疾病的可能。

The Chinese abstracts are translated by Prof. Dr. Xiangyan Ruan and her team: Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, China.

Keywords:

• FSH β-subunit mutation
• isolated FSH deficiency
• delayed puberty

Acknowledgments

We thank the two sisters and their parents for participating in this study.

Consent

Written informed consent was obtained for publication of this case report and any accompanying images.

Ethical approval

Institutional ethical committee approval obtained.

Disclosure statement

No potential conflict of interest was reported by the authors.