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Putting the pieces of the puzzle together

Sun, 20/12/2020

Medical diagnosis is always a challenge. You have to take a thorough clinical history, perform a meticulous examination, and conduct the appropriate diagnostic tests.Sometimes you have to face a major challenge, which may include difficulties in identifying a specific disease as well as correlating several ones to determine a syndrome. This could be likened to putting the pieces of a jigsaw puzzle together.

An orthopedic case?

A 41-year-old man was admitted to the hospital for planned surgery in the right shoulder.  He was born in a different country; his parents were seasonal farm workers. He had evident agenesis in the left hand's phalanges as well as other musculoskeletal abnormalities, which were attributed to potential maternal exposure to thalidomide. Nevertheless, he was in good condition and performed sports regularly.

Musculoskeletal abnormalities.

The patient had the following musculoskeletal defects: pectus excavatum, agenesis of the left hand's phalanges, agenesis of the distal phalanx in the right first toe, cavus foot, radioulnar synostosis in the left elbow, partial glenohumeral dislocation in the right shoulder, and partial dislocation of the right knee cap.

Agenesis of the left hand's phalanges.

Are you unable to see the forest for the trees?

He was referred to the cardiologist after the preoperative study. A pectus excavatum and other musculoskeletal defects were found.Cardiac auscultation revealed a characteristic systolic murmur with fixed split S2. A transthoracic echocardiography showed an atrial septal defect with a shunt left-to-right dilatation of the right cavities, a pulmonary/systemic output ratio (QP/QS)>2, mild tricuspid regurgitation, a systolic pulmonary artery pressure of 45 mmHg, and a normal left ventricular ejection fraction.

Ostium secundum atrial septal defect with a left-to-right shunt.

Transesophageal echocardiography confirmed the presence of an ostium secundum atrial septal defect of 22 mm.

Transesophageal echo showing the defect (ASD II) in the interatrial septum. Transesophageal echo: Color Doppler showing shunt flow across the defect.

Real-time 3D TEE reveals the abnormally large opening in the atrial septum from a different perspective.

Afterwards a complete AV block was also detected in the electrocardiogram.

Afterwards a complete AV block was also detected in the electrocardiogram.

Complete AV block.

A genetic disease was suspected due to the combination of skeletal abnormalities, an atrial septal defect, and a complete AV block. The patient underwent open-heart surgery. The atrial septal defect was closed with an autologous pericardial patch without any complications. A bicameral pacemaker was implanted.

Two-chamber pacemaker.

Follow the clues - solve the mystery

The patient's genealogical tree showed some cases of musculoskeletal defects.

Genealogical tree.

So we have skeletal abnormalities, an atrial septal defect and a complete AV block….. maybe a heart-hand syndrome? Finally, the genetic test confirmed a mutation (c.100-101insG) in the TBX5 gene, chromosome 12,  and established a Holt-Oram syndrome - a case of atriodigital dysplasia detected rather late.

What is a Holt Oram-syndrome?

The Holt Oram syndrome is a heterogenous autosomal disease, first described in 1960. It is characterized by skeletal upper-limb dysplasias and congenital cardiac defects. In most cases there is a mutation in gene TBX5 on the long arm of chromosome 12. TBX5 is a member of the T-box transcription factor family and plays a crucial role in the development of the heart and the upper extremities during embryogenesis. Mutations in TBX5 account for more than 70% of patients with the syndrome. The condition must be distinguished from heart-hand syndrome type II (Tobatznik’s syndrome) and heart-hand syndrome type III (Spanish type), which are phenotypically similar. Other similar conditions include the Okihiro syndrome, Townes-Brocks syndrome, Fanconi anemia, and the effects of thalidomide. Potential complications which may be life threatening include heart block, arrhythmias, congestive heart failure, pulmonary hypertension, and infective endocarditis. It is important a adopt an interdisciplinary diagnostic approach based on the use of noninvasive fetal imaging techniques to define phenotypic manifestations, and then perform an exhaustive clinical examination, genetic tests, an electrocardiogram, echocardiogram studies, and genetic counseling.
Best regards,
José Carlos

José Carlos Moreno Samos.

PS: My special thanks to Dr Javier Mora Robles.
PPS: Have you encountered similar cases? What is your experience in regard of syndromes? Please post them below. Do let our 123sonography community know. Your case might be rare, but if we join our experience it may well make a difference.   
PPS: If you want to read more from Jose Carlos, here are some more spectacular cases:
Small is Beautiful
Dragon Heart

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