The preferential association between Turner's syndrome and congenital heart defects (CHD) have been well known since the first description by Morgagni. There are few studies about the different cardiologic problems stemming from different chromosomal patterns of X monosomies. We reviewed a large series of 136 patients with Turner syndrome without cardiologic preselection, 29 of whom had some kind of CHD (21.5%). Partial anomalous pulmonary venous drainage (PAPVD; 2.9%), aortic valve disease (stenosis and/or incompetence) (AoVD; 5. 1%), aortic coarctation (AoCo; 4.4%), and bicuspid aortic valve (BicAo; 14.7%) are much more frequent in Turner's syndrome than in the normal population, with the difference being statistically highly significant. In our cases, only the 45, X subjects showed severe CHD and multiple lesions, whereas the X-ring pattern was associated with an elevated prevalence of BicAo. Patients with X-deletion showed no signs of congenital heart malformations. Eleven patients, all with 45, X pattern, and significant CHD, underwent cardiac surgery at a mean age of 7.7 +/- 5.3 years (range 7 days-18 years) without complications. At follow-up of 3-18 years (8.6 +/- 5. 2), we were unable to observe any type of evolution of the remaining untreated cardiovascular anomalies.

KBG syndrome is an autosomal dominant disorder caused by pathogenic variants within ANKRD11 or deletions of 16q24.3 which include ANKRD11. It is characterized by distinctive facial features, developmental delay, short stature, and skeletal anomalies. We report 12 unrelated patients where a clinical diagnosis of KBG was suspected and confirmed by targeted analyses. Nine patients showed a point mutation in ANKRD11 (none of which were previously reported) and 3 carried a 16q24.3 deletion. All patients presented with typical facial features and macrodontia. Skeletal abnormalities were constant, and the majority of patients showed joint stiffness. Three patients required growth hormone treatment with a significant increase of height velocity. Brain malformations were identified in 8 patients. All patients showed behavioral abnormalities and most had developmental delay. Two patients had hematological abnormalities. We emphasize that genetic analysis of ANKRD11 can easily reach a detection rate higher than 50% thanks to clinical phenotyping, although it is known that a subset of ANKRD11-mutated patients show very mild features and will be more easily identified through the implementation of gene panels or exome sequencing. Joint stiffness was reported previously in few patients, but it seems to be a common feature and can be helpful for the diagnosis. Hematological abnormalities could be present and warrant a specific follow-up.

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RASopathies are developmental disorders caused by heterozygous germline mutations in genes encoding proteins in the RAS-MAPK signaling pathway. Reduced growth is a common feature. Several studies generated data on growth, final height (FH), and height velocity (HV) after growth hormone (GH) treatment in patients with these disorders, particularly in Noonan syndrome, the most common RASopathy. These studies, however, refer to heterogeneous cohorts in terms of molecular information, GH status, age at start and length of therapy, and GH dosage. This work reports growth data in 88 patients affected by RASopathies with molecularly confirmed diagnosis, together with statistics on body proportions, pubertal pattern, and FH in 33, including 16 treated with GH therapy for proven GH deficiency. Thirty-three patients showed GH deficiency after pharmacological tests, and were GH-treated for an average period of 6.8 ± 4.8 years. Before starting therapy, HV was -2.6 ± 1.3 SDS, and mean basal IGF1 levels were -2.0 ± 1.1 SDS. Long-term GH therapy, starting early during childhood, resulted in a positive height response compared with untreated patients (1.3 SDS in terms of height-gain), normalizing FH for Ranke standards but not for general population and Target Height. Pubertal timing negatively affected pubertal growth spurt and FH, with IGF1 standardized score increased from -2.43 to -0.27 SDS. During GH treatment, no significant change in bone age velocity, body proportions, or cardiovascular function was observed.