Abnormalities of pubertal development and gonadal function in Noonan syndrome

Abstract

BackgroundNoonan syndrome (NS) is a genetic multisystem disorder characterised by variable clinical manifestations including dysmorphic facial features, short stature, congenital heart disease, renal anomalies, lymphatic malformations, chest deformities, cryptorchidism in males.MethodsIn this narrative review, we summarized the available data on puberty and gonadal function in NS subjects and the role of the RAS/mitogen-activated protein kinase (MAPK) signalling pathway in fertility. In addition, we have reported our personal experience on pubertal development and vertical transmission in NS.ConclusionsAccording to the literature and to our experience, NS patients seem to have a delay in puberty onset compared to the physiological timing reported in healthy children. Males with NS seem to be at risk of gonadal dysfunction secondary not only to cryptorchidism but also to other underlying developmental factors including the MAP/MAPK pathway and genetics. Long-term data on a large cohort of males and females with NS are needed to better understand the impact of delayed puberty on adult height, metabolic profile and well-being. The role of genetic counselling and fertility related-issues is crucial.

Gonadal dysfunction in a man with Noonan syndrome from the LZTR1 variant: case report and review of literature

“…showed Sertoli cell dysfunction (raised FSH level in combination with low inhibin B concentration) in one BRAF patient with normal testicular descent ( 22 ). SHOC2 and KRAS variants were associated with delayed puberty and/or low testicular volume in the study of Patti et al., but no information on fertility was available in these patients ( 11 ). In the other cases of male gonadal dysfunction, genetic characterization was lacking or only the PTPN11 gene was tested.…”

“…Several articles report that gonadal dysfunction in NS is secondary to cryptorchidism (which is present at birth in the majority of cases) and consequent testes damage ( 13 , 15 , 17 , 18 , 21 ). However, recent evidence suggests that gonadal dysfunction is a feature of the syndrome and is rather related to abnormal testes development ( 9 , 11 , 19 , 22 ). Gonadal impairment can also affect NS individuals with normal testicular descent ( 19 , 22 , 23 ).…”

“…Several previous studies recognized cryptorchidism as the main factor contributing to infertility ( 13 , 15 , 17 , 18 ). However, recent evidence suggests that it could be the result of primary gonadal dysgenesis occurring during fetal development with intrinsic Sertoli cell defects with/without Leydig cell impairment ( 9 , 11 , 19 ). However, only a few studies have focused on gonadal function and fertility in NS patients.…”