Holt-Oram Syndrome Associated with Aortic Atresia: A Rare Association.

Holt-Oram syndrome (HOS) is a rare autosomal dominant disorder that causes abnormalities of the upper limbs and heart. It is seen in 1:1, 00, 000 live births. It is linked to a single-gene TBX5 "protein-producing" mutation with gene map locus 12q24. Most commonly it is characterized by the cardiac septation defects and pre-axial radial ray abnormalities. We are reporting a case of HOS with aortic atresia which is a rare association.

INTRODUCTION

Holt-Oram syndrome (HOS) is an autosomal dominant condition with complete penetrance. Manifested in 1:1, 00, 000 live births[1] and characterized by forelimb deformities, congenital heart disease and/or cardiac conduction abnormalities.[2] It is linked to a single-gene TBX5 “protein-producing” mutation[34] with gene map locus 12q24 and is the most commonly occurring heart-hand syndrome. Congenital cardiac and upper limb malformations frequently occur together and are classified as heart hand syndromes.[5] The most common among the heart hand disorders is HOS, which is characterized by cardiac septation defects[6] and preaxial radial ray abnormalities.

This condition with a high rate (30–85%) of new non-familial cases was first described by Holt and Oram in 1960 in a 4-generation family with atrial septal defects (ASD) and thumb abnormalities.[1] The most common cardiac disorder is an ostium secundum ASD,[6] followed by ventricular septal defect (VSD)[7] and ostium primum ASD.[8] Electrocardiogram (ECG) abnormalities such as various degrees of atrioventricular (AV) block have also been reported.[9] Herein, we report a rare case of HOS with aortic atresia.

CASE REPORT

A full term female neonate born out of a nonconsanguineous marriage by cesarean section (indication-previous cesarean section with polyhydramnios) to a 25-year-old (weight – 58 Kg, height – 155 cm) booked G3P1L1A1 with unremarkable antenatal history. There is no significant history of drug intake. Family history revealed that the father has radial ray deformity of left upper limb without any cardiac anomaly.

Physical examination revealed an active baby weighing 2790 g and length of 49 cm, heart rate of 146/min, blood pressure of 70/30 mm of Hg, respiratory rate of 40/min, and systemic oxygen saturation of right upper limb being 83% in room air and that of right lower limb being 74% in room air [Figure 1]. On musculoskeletal examination, left upper limb shortening was noticed with absent radius bone, radial flexion deformity of the wrist and also absent thumb [Figure 2]. Triphalangeal thumb was seen in the right upper limb [Figure 3]. No obvious deformities were noticed elsewhere. On cardio-vascular system examination, the pansystolic murmur of grade III at the mitral and left parasternal area was heard. Per abdominal and respiratory system examination was within normal limits.

Figure 1

Picture showing the baby of Holt-Oram syndrome

Figure 2

Left upper limb showing radial ray deformity with absent thumb

Figure 3

Right hand showing triphalangeal thumb

On further investigation, chest X-ray showed normal thoracic situs with cardiomegaly, plain radiograph of both upper limbs revealed absent radius on left side with absent carpal bones and absent first metacarpal bone and phalanges (thumb), right side showing absent carpal bones and triphalangeal thumb [Figure 4]. No obvious bony deformities elsewhere were noted.

Figure 4

Plain radiograph showing the bony deformities of the upper limb with cardiomegaly

The baby developed cyanosis couple of hours after delivery, following which an ECG was done which was normal and a 2D echocardiography was done which revealed severe aortic atresia with hypoplastic arch, large perimembranous VSD and ASD as well [Figure 5]. These findings were confirmed by coronary angiography. The neonate was referred to a cardiac center for further management, however due to lack of resources the baby died on day 4 of life.

Figure 5

Echocardiography showing aortic atresia

DISCUSSION

Holt-Oram syndrome is an autosomal dominant disorder characterized by distinctive malformation of bones of the upper limbs and abnormalities of the heart. Holt and Oram first described this syndrome in 1960.[2] Cardinal manifestations of HOS are dysplasia of upper limb that ranges from minor findings including hypoplasia of thumb, clinodactyly, brachydactyly, triphalangeal thumbs, carpal bone dysmorphism, shortness of ulna, shortness of humerus, aplasia of radius to phocomelia[10] and cardiac abnormalities. Although bilateral, left side is often affected more significantly. In a study of 98 subjects with hypoplastic thumbs, 16% proved to be the cases of HOS.[11]

There are many well described heart-hand syndromes characterized by deformities of the radial ray and congenital heart defects such as thrombocytopenia absent radius syndrome, Roberts syndrome, thalidomide embryopathy, and Fanconi anemia. The unique feature that helps to differentiate these from HOS is that the radial aplasia is associated with hypoplasia/absence of the thumb without any hematological abnormalities and there is often a family history of heart and limb defects. The associated congenital heart defects are the most important determining factors in morbidity and mortality in these patients. More than 85% of affected individuals have cardiac malformations particularly ASD or VSD.[12] Other cardiac associations include pulmonary stenosis, mitral valve prolapse and arrhythmias in the form of atrioventricular blocks. More complex cardiac lesions such as tetralogy of Fallot, endocardial cushion defects, and total anomalous pulmonary venous return are observed in 18% of subjects with HOS.[6] The association with aortic atresia is extremely rare. As per best of our knowledge, till date there were no cases reported in the literature having a description of HOS with aortic atresia. The electrocardiographic abnormalities such as variable degree of AV blocks have also been reported, but in our case no conduction defects were noted.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.