Case description: A 34- year old man presented to the emergency department (ED) with palpitations and worsening dyspnea on exertion over the last months. He reported, that he has always been physically active, but since childhood never had the same stamina as his peers. Angina, dizziness or syncope were denied. The patient has no prior cardiac history and even reported having had a normal echo several years ago. The physician in the ED noticed that the patient had surgery on both hands and the patient stated being born without thumbs (Fig.1).


The EKG (Fig.2) was presented to the cardiologist on - call.



Because of the young age and the abnormal EKG a bedside echo was performed and a large atrial septal defect (ASD) was suspected (Fig.3).




Diagnosis and Treatment: On further questioning, the patient recalled that the eldest and the youngest of his three children had open heart surgery for an ASD. The oldest also had minor abnormalities on their hand, the youngest none. According to the patient, anyone had ever investigated for a genetic disorder. The patient was placed on telemetry to monitor for high grade AV block. A transoesophageal echo was performed and revealed a large secundum type ASD almost without a rim leaving interventional closure out of the question (Fig.4). A left- and right heart catheter ruled out coronary artery anomalies or disease and pulmonary hypertension. The Nt-BNP was elevated 786 pg/ml (<125 pg/ml), blood gas analysis showed respiratory alkalosis due to hyperventilation with mild hypoxemia. A higher degree AV block was not observed. An internet search for the combination of upper body and cardiac abnormalities suggested Holt-Oram-Syndrome (HOS). The patient was referred for elective surgical ASD closure. A genetic specialist was involved in the case. Subsequently, in the TBX5 gene, encoding the transcription factor T-box 5, the heterozygous, pathogenic variant c.709C>T (p.Arg237Trp) was detected by Sanger sequencing. This variant is well known in the literature as a cause of HOS and has been biofunctionally characterized. He finally received a minimally invasive surgical ASD closure without complications.
Discussion: An ASD of the septum secundum makes up to 7% of the heart defects. The HOS is a very rare disease with an incidence around 1:100 000 and is  inherited in an autosomal dominant manner. The TBX 5 gene is involved in the separation of the heart chambers and the development of the bones in the arms and hands. Most striking about this case is that despite the suspicious personal and family history no physician explored the possibility of a genetic condition. Additionally, the patient’s large ASD must have been missed on echo before. A quick internet search enabled the authors to reach this differential diagnosis as they had not heard about that syndrome before in their work as cardiologists. Nevertheless, not assuming an inherited condition in this family seemed even more unlikely.
Conclusions: Careful history taking and physical examination are still the foundation of making a differential diagnoses. Online research platforms make it much easier to quickly find even a rare diagnosis. Techniques like DNA sequencing enable us in the best cases to make a waterproof diagnosis. The fact that no colleague has thought about it before, should not keep one from investigating further.