Types of Recognisable Syndromes Observed in Patients with Hypoplastic Left Heart Syndrome (HLHS)

In 1 to 2% of the patients with congenital heart defect (CHD) a Hypoplastic Left Heart Syndrome (HLHS) is observed. About 15% of these patients present with extracardiac congenital abnormalities and only ~5% can be sufficiently diagnosed on the molecular level. The majority of these patients present with Turner syndrome. Other chromosomal aberrations or monogenic disorders known to be associated with HLHS are trisomy 18, 13, Jacobsen-, Smith-Lemli-Opitz-, Holt-Oram- and Kabuki syndrome.

By accessing the clinical database of the North German Heart Centre we were able to identify for the period of 1996 and 2016 a total of 281 cases. 19 patients presented with an extracardiac malformation. For seven patients without a defined molecular diagnosis, we observed a wide range of extracardiac phenotypes including gastrointestinal abnormalities (i.e. oesophageal and duodenal atresia), multicystic kidneys, caudal regression, hydrocephaly, cleft palate and skeletal abnormalities. A diagnosis was made in 12 patients. Six patients presented with a chromosomal aberration (three patients with Turner syndrome and three single patients with a deletion in Xp, trisomy 13 and Pallister-Killian syndrome). In one patient VACTERL association was suspected. Three other cases have been diagnosed with Kabuki syndrome. In total, we observed 614 HLHS cases when looking at the National Register for Congenital Heart Defects. 66 (11%) of cases showed extracardiac abnormalities and only six of these cases had a defined diagnosis (Turner syndrome N = 3, trisomy 18 N = 3 and a singleton with oculo-auriculo-vertebral spectrum, and VACTERL association). This observation highlights the importance of a close collaboration between pediatric cardiologists and clinical geneticists to adequately diagnose these types of rare conditions. Our data shows that the percentage of patients with extracardiac malformations is lower especially in the North German cohort. One possible explanation would be that in Germany pregnancies with a foetus known to be affected by HLHS in combination with extracardiac malformations are more likely to be aborted. In addition, our study highlights Kabuki syndrome is an important diagnosis in children with HLHS and additional malformations.