We read with great interest the recent paper by Hannema et al.¹ that we found particularly illuminating in respect of our patient with 46XY gonadal dysgenesis, who continues to decline prophylactic gonadectomy.

Disorders of sex development (DSD) are a group of rare disorders involving abnormalities in karyotype, steroidogenesis, androgen action or gonadal development, resulting in various phenotypic presentations.² Among the genetic determinants of sex development, the SRY (sex-determining region of the Y chromosome) gene initiates development of the male urogenital primordia.^{2, 3} Loss-of-function variants result in congenital abnormalities of male-typical development.

Swyer syndrome or 46, XY gonadal dysgenesis (46XY GD) presents with female external genitalia and absent puberty due to gonadal insufficiency (hypergonadotrophic hypogonadism). Amidst the potential genetic culprits, variants of the SRY gene account for up to 15% of cases, as specific encoded proteins (i.e.: sex-determining region Y protein HMG-box) bind to regions of deoxyribonucleic acid (DNA) that control male-typical development. Other associated gene loci include MAP3K1, DHH, NR5A1 and SOX9.³ With no male differentiation stimulus to the urogenital ridge, Sertoli and Leydig cells do not arise within the primitive gonad, resulting in deficiencies of Anti-Müllerian hormone (AMH) and testosterone, respectively. Hence, the development of Mullerian structures and the absence of external male sexual differentiation (Figure 1).

A 17-year-old female was referred with primary amenorrhoea and absent puberty. Her past medical and family history was insignificant. She had not progressed into puberty (Tanner stage 1) and had normal female external genitalia. Biochemical evaluation revealed hypergonadotrophic hypogonadism (LH—33.7 IU/L, FSH—105.8 IU/L, Oestradiol <60 pmol/L), undetectable Sertoli cell markers and no elevation of tumour markers (AMH < 0.5 pmol/L, Inhibin B < 9.8 ng/L, alpha fetoprotein (AFP) < 1.0 kU/L, carcinoembryonic antigen (CEA) < 1.0 μg/L). Karyotype was 46 XY, indicating gonadal dysgenesis. Magnetic resonance imaging (MRI) scan showed a tiny anteverted uterus (2.9 × 0.6 × 2.0 cm), but no gonads were visualized. The diagnosis had a significant psychological impact on the patient, for which she was signposted to support groups for peer support. She was also referred to clinical psychology through her general practitioner.

She was then started on transdermal Estradiol at a dose of 6.25 μg twice weekly, gradually up-titrated to achieve normal breast (Tanner 4) and sonographic uterine development, after which she was converted to continuous-combined hormone replacement therapy (currently Estradiol 4 mg plus Norethisterone 1.05 mg daily). Laparoscopic exploration and gonadectomy were also recommended considering the risk of gonadoblastoma, but she firmly declined the procedure and continued to do so over the course of subsequent clinic visits. She remained unconvinced of the need for the procedure as no tumour had yet developed over serial monitoring, despite the increased risk of gonadoblastoma in 46 XY GD having been carefully explained to her.

Six years after her initial presentation (at 23 years of age), Sertoli cell hormones remained undetectable and a repeat pelvic MRI in 2023 confirmed a mature uterine configuration (62 × 25 × 37 mm), although gonads were again not visualized. The option of exploratory laparoscopy was revisited with input from a gynaecologist, but she remained extremely reluctant to undergo any surgical procedure.

Phenotypic female patients with DSD have an increased risk of gonadal tumour development in conjunction with the presence of the GBY region of the Y-chromossome.⁴ 46XY pure GD has one of the highest risks of neoplastic transformation in DSD, which is estimated to be around 15%–60%.² Thus, in contrast to other DSDs, having lower neoplasia risk and a chance of undergoing spontaneous puberty, prompt prophylactic gonadectomy is recommended in 46XY GD.

Although there is a consensus in the literature on the benefits of early bilateral prophylactic gonadectomy, no clear guidance is available regarding the options to pursue when the patient declines this.^{1, 4, 5} Gonadoblastoma is an initially benign tumour that occurs exclusively in dysgenetic gonads, and may then undergo transformation into dysgerminoma, or other malignancy in up to 60% of cases.³

Imaging alone, such as US or MRI, identified 40%–50% of gonads (if present), but failed to identify any of the gonadoblastomas present in 28% of the patients.⁵ Negative imaging was one of the reasons this patient declined the procedure. Clinicians can explain to such patients that imaging has poor sensitivity in identifying gonadoblastomas. Because such methods are not always successful in identifying these tumours, we then explored whether tumour markers and Sertoli cell markers had the potential to identify tumours among those who declined gonadectomy.

Measurable levels of AMH and inhibin B are correlated with the presence of germ cells, and might therefore indicate a greater potential for tumour development and measurable levels of beta-hCG and AFP might correlate to the presence of some germ cell tumours. Nevertheless, as per the study by Hannema et al.,¹ the absence of measurable levels of AMH and inhibin B does not exclude the presence of germ cells. They found that 27% of DSD cases with undetectable AMH and/or inhibin B nevertheless had germ cells present in the gonadectomy specimen (all had gonadoblastoma and/or dysgerminoma). Ninety-four percent of patients with detectable inhibin B or AMH presented with germ cells and 35% of them had abnormal germ cells.

In conclusion, the balance of evidence continues to support prophylactic bilateral gonadectomy in females with 46XY GD, irrespective of Sertoli cell markers. For those women who—despite our best efforts—continue to decline the procedure, the measurement of Sertoli cell markers has poor negative predictive value to reliably exclude the presence of germ cells. Although detectable AMH and inhibin B levels significantly increase the possibility of the presence of germ cells, and hence the risk of gonadoblastoma development, we can counsel patients that their absence by no means precludes the risk. Hopefully this provides an opportunity for these women to re-evaluate their decision. Whereas the majority of affected patients will likely accept medical recommendation to undergo gonadectomy, those who do not should ideally be recruited to the iDSD registry (https://home.i-dsd.org/), so as to gather more data in this area.

我们饶有兴趣地阅读了 Hannema 等人最近发表的论文。¹我们发现，对于我们患有 46XY 性腺发育不全的患者而言，该患者特别具有启发性，该患者继续拒绝预防性性腺切除术。

性发育障碍 (DSD) 是一组罕见疾病，涉及核型、类固醇生成、雄激素作用或性腺发育异常，导致各种表型表现。²在性别发育的遗传决定因素中，SRY（Y 染色体性别决定区）基因启动男性泌尿生殖原基的发育。^{2, 3}功能丧失变异导致男性典型发育的先天性异常。

Swyer 综合征或 46, XY 性腺发育不全 (46XY GD) 表现为女性外生殖器和由于性腺功能不全（促性腺激素亢进性性腺功能减退症）导致的青春期缺失。在潜在的遗传罪魁祸首中，SRY基因的变异占到了 15% 的病例，因为特定的编码蛋白（即性别决定区 Y 蛋白 HMG-box）与控制男性的脱氧核糖核酸 (DNA) 区域结合。典型发展。其他相关基因位点包括MAP3K1、DHH、NR5A1和SOX9。³由于泌尿生殖嵴没有雄性分化刺激，支持细胞和间质细胞不会在原始性腺内产生，从而分别导致抗苗勒氏管激素 (AMH) 和睾酮缺乏。因此，苗勒管结构的发展和外部男性性别分化的缺乏（图1）。

一名 17 岁女性因原发性闭经和青春期缺失而被转诊。她过去的病史和家族史并不重要。她尚未进入青春期（坦纳第一阶段），并且具有正常的女性外生殖器。生化评估显示促性腺激素亢进性腺功能减退症（LH—33.7 IU/L，FSH—105.8 IU/L，雌二醇<60 pmol/L），支持细胞标志物未检出，肿瘤标志物未升高（AMH < 0.5 pmol/L，抑制素 B < 9.8） ng/L，甲胎蛋白 (AFP) < 1.0 kU/L，癌胚抗原 (CEA) < 1.0 μg/L）。核型为46 XY，表明性腺发育不全。磁共振成像 (MRI) 扫描显示子宫很小，前倾（2.9 × 0.6 × 2.0 厘米），但没有看到性腺。这一诊断对患者产生了重大的心理影响，为此她被指派到支持小组寻求同伴支持。她还通过她的全科医生转诊至临床心理学。

然后，她开始接受每周两次 6.25 μg 剂量的透皮雌二醇治疗，逐渐增加剂量以实现正常的乳房 (Tanner 4) 和超声检查子宫发育，之后她转为连续联合激素替代疗法（目前为 4 mg 雌二醇）加炔诺酮 1.05 毫克每天）。考虑到性腺母细胞瘤的风险，还建议进行腹腔镜探查和性腺切除术，但她坚决拒绝了该手术，并在随后的就诊过程中继续这样做。尽管已向她仔细解释了 46 XY GD 性腺母细胞瘤的风险增加，但她仍然不相信需要进行该手术，因为通过连续监测尚未发现肿瘤。

在她初次就诊六年后（23 岁时），支持细胞激素仍然检测不到，2023 年的重复盆腔 MRI 证实了成熟的子宫形态（62 × 25 × 37 毫米），尽管性腺再次未显现。根据妇科医生的意见，重新考虑了探查性腹腔镜检查的选择，但她仍然极不愿意接受任何外科手术。

患有 DSD 的表型女性患者，由于 Y 染色体 GBY 区域的存在，发生性腺肿瘤的风险增加。⁴ 46XY 纯 GD 是 DSD 中肿瘤转化风险最高的疾病之一，估计约为 15 % –60 %。²因此，与其他 DSD 相比，46XY GD 具有较低的肿瘤风险和自发青春期的机会，建议立即进行预防性性腺切除术。

尽管文献中对早期双侧预防性性腺切除术的益处存在共识，但对于患者拒绝时应采取的选择，尚无明确的指导。^{1, 4, 5}性腺母细胞瘤最初是一种良性肿瘤，仅发生在发育不良的性腺中，然后在高达 60% 的病例中可能会转化为无性细胞瘤或其他恶性肿瘤。³

单独的成像（例如 US 或 MRI）可识别 40%–50% 的性腺（如果存在），但未能识别 28% 患者中存在的任何性腺母细胞瘤。⁵影像学阴性是该患者拒绝手术的原因之一。临床医生可以向此类患者解释影像学在识别性腺母细胞瘤方面的敏感性较差。由于此类方法并不总能成功识别这些肿瘤，因此我们随后探讨了肿瘤标记物和支持细胞标记物是否有可能在拒绝性腺切除术的患者中识别肿瘤。

AMH 和抑制素 B 的可测量水平与生殖细胞的存在相关，因此可能表明肿瘤发展的潜力更大，而 β-hCG 和 AFP 的可测量水平可能与某些生殖细胞肿瘤的存在相关。然而，根据 Hannema 等人的研究，¹缺乏可测量水平的 AMH 和抑制素 B 并不排除生殖细胞的存在。他们发现，27% 的 AMH 和/或抑制素 B 检测不到的 DSD 病例在性腺切除标本中仍存在生殖细胞（全部患有性腺母细胞瘤和/或无性细胞瘤）。94% 的可检测到抑制素 B 或 AMH 的患者存在生殖细胞，其中 35% 的生殖细胞异常。

总之，证据平衡继续支持 46XY GD 女性预防性双侧性腺切除术，无论支持细胞标记如何。对于那些尽管我们尽了最大努力但仍然拒绝手术的女性来说，支持细胞标记物的测量对于可靠地排除生殖细胞的存在的阴性预测价值很差。尽管可检测到的 AMH 和抑制素 B 水平显着增加了生殖细胞存在的可能性，从而增加了性腺母细胞瘤发展的风险，但我们可以告知患者，它们的缺失绝不排除这种风险。希望这为这些女性提供一个重新评估她们决定的机会。尽管大多数受影响的患者可能会接受接受性腺切除术的医疗建议，但理想情况下，应将那些不接受性腺切除术的患者招募到 iDSD 登记处 (https://home.i-dsd.org/)，以便在此收集更多数据区域。