Perspectives in Pediatric Pathology, Chapter 17. Other Hypergonadotropic Hypogonadisms

Abstract

Several complex syndromes have in common the development of hypergonadotropic hypogonadism. In a large number of them, such as Down syndrome, hypogonadism associated with myopathies (myotonic dystrophy and progressive muscular dystrophy), syndromes of Werner, Alström, and Weinstein, and the hypogonadism associated with alopecia, the testicular biopsy is similar to that observed in 47XXY Klinefelter syndrome, except for the absence of sex chromatin. In other examples, including Noonan syndrome and hypogonadism associated with cerebellar atrophy, testicular abnormalities are less severe. Noonan and Ehmke [1] first described this syndrome in 1963. Patients feature a male phenotype and 46XY karyotype, although they have somatic anomalies similar to those of Turner syndrome, including atypical facies (Fig. 17.1), hypertelorism, down-slanting palpebral fissures, ptosis, low set and posteriorly rotated ears, small mandible, short neck, pterygium colli, short stature, puffy hands and feet, short metacarpals, shield chest, widely spaced nipples, cubitus valgus, nail deformities, mental retardation, and lymphedema [2]. Approximately 62% of these patients show pulmonary artery stenosis, and 20% develop hypertrophic myocardiopathy [3,4]. Aortic coarctation may also occur, as in patients with Turner syndrome [5,6]. Peripheral vascular malformations may also develop [7,8]. The incidence of Noonan syndrome is estimated in 1:1000 to 1:2500 live births [9], with an autosomal dominant inheritance pattern in most cases. In half of the cases, the fathers show some features of the syndrome [10,11]. Noonan syndrome is a genetically heterogeneous disorder linked to the chromosomal band 12q24 [1]. In 75% of the cases Noonan syndrome is caused by activating mutations in PTPN [11,12], SOS1 [13,14], RAF1 [15,16] and less frequently in KRAS [17], NRAS [18] or SHOC2 [19]. Noonan syndrome is considered a RASopathy and is included in a group of genetic syndromes with germline mutations in genes of the