Rothacker Karen M, Ayers Katie L, Tang Dave, Joshi Kiranjit, van den Bergen Jocelyn A, Robevska Gorjana, Samnakay Naeem, Nagarajan Lakshmi, Francis Kate, Sinclair Andrew H, Choong Catherine S
1Department of Endocrinology and Diabetes, Princess Margaret Hospital, Subiaco, WA Australia.
11Department of Endocrinology and Diabetes, Princess Margaret Hospital, GPO Box D 184, Perth, WA Australia.
Int J Pediatr Endocrinol. 2018;2018:2. doi: 10.1186/s13633-018-0056-3. Epub 2018 Mar 2.
() mutations have been described in only a limited number of individuals with 46, XY disorders of sex development (DSD) presenting as either partial or complete gonadal dysgenesis. Gonadal tumours and peripheral neuropathy have been associated with mutations. Herein we report a novel, homozygous mutation of identified through a targeted, massively parallel sequencing (MPS) DSD panel, in a patient presenting with partial gonadal dysgenesis. This novel mutation is two amino acids away from a previously described mutation in a patient who presented with complete gonadal dysgenesis. Adding to the complexity of work-up, our patient also expressed gender identity concern.
A 14-year-old, phenotypic female presented with primary amenorrhoea and absent secondary sex characteristics. Investigations revealed elevated gonadotrophins with low oestradiol, testosterone of 0.6 nmol/L and a 46, XY karyotype. Müllerian structures were not seen on pelvic ultrasound or laparoscopically and gonadal biopsies demonstrated dysgenetic testes without neoplasia (partial gonadal dysgenesis). The patient expressed gender identity confusion upon initial notification of investigation findings. Formal psychiatric evaluation excluded gender dysphoria. Genetic analysis was performed using a targeted, MPS DSD panel of 64 diagnostic and 927 research candidate genes. This identified a novel, homozygous mutation in exon 2 of (DHH:NM_021044:exon2:c.G491C:p.R164P). With this finding our patient was screened for the possibility of peripheral neuropathy which was not evident clinically nor on investigation. She was commenced on oestrogen for pubertal induction.
The evaluation of patients with DSD is associated with considerable psychological distress. Targeted MPS enables an affordable and efficient method for diagnosis of 46, XY DSD cases. Identifying a genetic diagnosis may inform clinical management and in this case directed screening for peripheral neuropathy. In addition to the structural location of the mutation other interacting factors may influence phenotypic expression in homozygous mutations.
在仅少数表现为部分或完全性腺发育不全的46, XY性发育障碍（DSD）个体中发现了（）突变。性腺肿瘤和周围神经病变与该突变有关。在此，我们报告了通过靶向大规模平行测序（MPS）DSD检测板在一名表现为部分性腺发育不全的患者中鉴定出的一种新的纯合突变。这种新突变与一名表现为完全性腺发育不全的患者中先前描述的突变相差两个氨基酸。此外，我们的患者还表达了对性别认同的担忧，这增加了检查的复杂性。
一名14岁的表型女性，表现为原发性闭经且无第二性征。检查发现促性腺激素升高，雌二醇水平低，睾酮为0.6 nmol/L，核型为46, XY。盆腔超声或腹腔镜检查未发现苗勒氏结构，性腺活检显示发育不全的睾丸且无肿瘤（部分性腺发育不全）。在最初告知检查结果时，患者表达了性别认同困惑。正式的精神病学评估排除了性别焦虑症。使用包含64个诊断基因和927个研究候选基因的靶向MPS DSD检测板进行基因分析。这在（DHH:NM_021044:exon2:c.G491C:p.R164P）的外显子2中鉴定出一种新的纯合突变。基于这一发现，对我们的患者进行了周围神经病变可能性的筛查，临床上和检查中均未发现明显异常。她开始接受雌激素诱导青春期发育。
DSD患者的评估会带来相当大的心理困扰。靶向MPS为诊断46, XY DSD病例提供了一种经济有效的方法。确定基因诊断可能为临床管理提供依据，在本病例中指导对周围神经病变的筛查。除了突变的结构位置外，其他相互作用的因素可能会影响纯合（）突变的表型表达。
