In this prospective cohort study, we identified a total of 1653 patients with congenital upper extremity malformations.We found that the prevalence of HHS was 12.1%, which showed a similar result as in our previous retrospective study . Type I congenital upper limb malformations (Failure of formation of parts) was most likely to present with congenital cardiac disease, which was also in line with the result of our previous study. In this study, 60.5% of HHS patients had thumb malformations, similar to what we found in the previous study (69.2%). Some studies have shown that the thumb is remarkably different from the other four digits and developed in a different molecular environment, which provides the underlying mechanisms for the strong association between thumb malformations and HHS [9, 10], suggesting that genes related to thumb formation might be related to HHS.
Our previous study was based on patients treated with upper extremity malformations from October 1st, 2013 to October 1st, 2016 in the same hospital. The number of beds and surgeons in this hospital did not change after the previous study. However, the number of patients who were treated with upper extremity was increased by 13% ((1653–1462)/1462 = 0.13). The underlying reasons are not clear as we did not find a change of the referral pattern of patients and and no therapeutic centers nearby were closed. This phenomenon may be related to the Chinese policy changed from “One family, one child” to “one family, two children”. The increased rate of upper extremity malformations might be due to the increased number of elderly pregnant women associated with this policy change .
HHS is well documented since first reported by Kato in 1924 . It has been reported by many others subsequently [13, 14]. HHS includes the most common type – HHS I: Holt–Oram syndrome  (congenital heart disease and radial ray anomalies) and several rare types – HHS II: Tabatznik syndrome (arrhythmias and brachytelephalangy) , HHS III: Spanish type (arrhythmia and brachydactyly type C) , and a potential HHS IV: Slovenian type (arrhythmia, dilated cardiomyopathy, and brachydactyly) . However, there were only 16 patients (8%) in this study who could be classified according to previous classifications. These 16 patients met the clinical diagnosis of Holt–Oram syndrome. ASD (7 patients, 44%) was the commonest cardiovascular anomaly for these patients, the rate of which was lower than that of the study reported by Wall, L.B. (ASD 53%) .
Most HHS patients in this study could not be classified according to current knowledge, suggesting that there might be ethnic variance of HHS. It is thus necessary to create a new classification for HHS in China. According to the clinical characteristics of these patients, we made a new classification. This new classification was based on the malformations of the hand and could be used easily. The commonest type of hand malformations of HHS patients in this study was related to thumb malformation (121, 60.5%), including thumb hypoplasia, thumb duplication, triphalangeal thumb, et al. Lam et al. found that preaxial polydactyly (thumb duplication) and forearm radial deficiencies may share a common developmental origin . So, we put all malformations related to thumb into one type. The second type (53, 26.5%) is related to malformations including syndactyly, brachydactyly, and symbrachydactyly. This type included previous HHS II, HHS III, and HHS IV. The third type was related to congenital contractures (25 12.5%). Joint movement limitations in HHS might be considered close to the classical joint contractures observed in Emery–Dreifuss muscular dystrophy, which was LMNA generelated disease . Renou et al. reported an intronic LMNA mutation that co-segregated with the HHS clinical features . The fourth type included other hand malformations except for the malformations mentioned above. This new classification based on clinical characteristics is easy to use and could cover all of the HHS patients in this study. However, we cannot identify the molecular causes regarding different subcategories based on current evidence and further studies are higher needed.
We analyzed the distribution of blood types of HHS patients. Blood type B had the highest morbidity rate (13.4%), but there was no significant difference between blood types. We need further research on this field because around half of the patients did not attend blood type test. Further studies with enough samples are needed to explore the association of HHS with blood type in detail. The gene related to ABO type has been identified and resides on chromosome 9 at the band 9q34. 2 with 7 exons, it is thus higher possible to identify the underlying genes of HHS based on genetic linkage analyses if we can observe the association between specific blood type with HHS. In this study, 122 patients (7.4%) had comorbidity conditions except for the heart. The lower extremity malformations were the commonest. HHS patients had a much higher morbidity rate (11%) than non-HHS patients (6.9%) (P < 0.05). The comorbidity conditions were reported previously [21, 22], but this is the first time to report the morbidity rate for HHS. It is highly necessary to inform patients who had multiple congenital malformations because the prevalence of HHS was higher than that with only upper extremity malformations.
There were a few limitations in this study. First, all the patients were recruited from the hand surgery department in one Chinese national orthopedics center, which might not be a comprehensive representative of the Chinese population. In addition, the classification that we proposed in this study needs to be confirmed by other studies.