Fondation Ophtalmologique Adolphe de Rothschild and Université Paris Descartes, Paris, France.
Human Developmental Genetics Unit, Institute Pasteur, Paris, France.
PLoS One. 2020 Dec 3;15(12):e0242358. doi: 10.1371/journal.pone.0242358. eCollection 2020.
Pituitary stalk interruption syndrome is a rare disorder characterized by an absent or ectopic posterior pituitary, interrupted pituitary stalk and anterior pituitary hypoplasia, as well as in some cases, a range of heterogeneous somatic anomalies. A genetic cause is identified in only around 5% of all cases. Here, we define the genetic variants associated with PSIS followed by the same pediatric endocrinologist. Exome sequencing was performed in 52 (33 boys and 19 girls), including 2 familial cases single center pediatric cases, among them associated 36 (69.2%) had associated symptoms or syndromes. We identified rare and novel variants in genes (37 families with 39 individuals) known to be involved in one or more of the following-midline development and/or pituitary development or function (BMP4, CDON, GLI2, GLI3, HESX1, KIAA0556, LHX9, NKX2-1, PROP1, PTCH1, SHH, TBX19, TGIF1), syndromic and non-syndromic forms of hypogonadotropic hypogonadism (CCDC141, CHD7, FANCA, FANCC, FANCD2, FANCE, FANCG, IL17RD, KISS1R, NSMF, PMM2, SEMA3E, WDR11), syndromic forms of short stature (FGFR3, NBAS, PRMT7, RAF1, SLX4, SMARCA2, SOX11), cerebellum atrophy with optic anomalies (DNMT1, NBAS), axonal migration (ROBO1, SLIT2), and agenesis of the corpus callosum (ARID1B, CC2D2A, CEP120, CSPP1, DHCR7, INPP5E, VPS13B, ZNF423). Pituitary stalk interruption syndrome is characterized by a complex genetic heterogeneity, that reflects a complex phenotypic heterogeneity. Seizures, intellectual disability, micropenis or cryptorchidism, seen at presentation are usually considered as secondary to the pituitary deficiencies. However, this study shows that they are due to specific gene mutations. PSIS should therefore be considered as part of the phenotypic spectrum of other known genetic syndromes rather than as specific clinical entity.
垂体柄中断综合征是一种罕见的疾病，其特征为后垂体缺失或异位、垂体柄中断和前垂体发育不良，以及在某些情况下存在一系列异质性的躯体异常。只有约 5%的病例能够确定遗传原因。在这里，我们定义了与 PSIS 相关的遗传变异，随后由同一位儿科内分泌学家进行研究。在 52 名患者（33 名男孩和 19 名女孩）中进行了外显子组测序，包括 2 例家族性单中心儿科病例，其中 36 例（69.2%）存在相关症状或综合征。我们在已知参与中线发育和/或垂体发育或功能的基因（37 个家族中的 39 个个体）中发现了罕见和新的变异体（BMP4、CDON、GLI2、GLI3、HESX1、KIAA0556、LHX9、NKX2-1、PROP1、PTCH1、SHH、TBX19、TGIF1）、促性腺激素缺乏性性腺功能减退症的综合征和非综合征形式（CCDC141、CHD7、FANCA、FANCC、FANCD2、FANCE、FANCG、IL17RD、KISS1R、NSMF、PMM2、SEMA3E、WDR11）、促性腺激素缺乏性性腺功能减退症的综合征和非综合征形式（FGFR3、NBAS、PRMT7、RAF1、SLX4、SMARCA2、SOX11）、小脑萎缩伴视神经异常（DNMT1、NBAS）、轴突迁移（ROBO1、SLIT2）和胼胝体发育不全（ARID1B、CC2D2A、CEP120、CSPP1、DHCR7、INPP5E、VPS13B、ZNF423）。垂体柄中断综合征的遗传异质性复杂，反映了表型异质性复杂。就诊时出现的癫痫、智力障碍、小阴茎或隐睾通常被认为是垂体缺陷的继发表现。然而，本研究表明这些是由于特定的基因突变所致。因此，应将 PSIS 视为其他已知遗传综合征的表型谱的一部分，而不是作为特定的临床实体。
