Discussion

Pulmonary valve and infundibular stenosis has been documented in the past with twin-to-twin transfusion syndrome and attributed to right ventricular volume and pressure overload in the recipient twin. Right ventricular hypertrophy may cause varying degrees of right ventricular outflow tract obstruction and lead to hypoplasia of the pulmonary valve and pulmonary artery branches.Reference Lougheed, Sinclair and Fung ^{1 ,} Reference Nicosia, Krouse and Mobini ⁵ The three earliest reported in utero cases of pulmonary artery calcifications in the recipient twin of twin-to-twin transfusion syndrome were those by Popek et al in 1993Reference Popek, Strain, Neumann and Wilson ³ and all occurred in the volume-overloaded twin. In addition, there might have been a relationship between pulmonary artery calcifications and the severity of the cardiac volume overload based on the weight difference between the twins in each pair. Saxena et alReference Saxena and Soni ² and Cha et alReference Cha, Kim, Kwon, Bae, Noh and Kim ⁴ reported one and three similar cases, respectively, with the same hypothesis for causation.

The etiology for the pulmonary, and rarely aortic,Reference Saxena and Soni ² calcifications in recipients of twin-to-twin transfusion syndrome has been largely speculative to date. Intimal thickening without calcification has been reported in the aorta in recipient twins in twin-to-twin transfusion syndrome,Reference Nicosia, Krouse and Mobini ⁵ possibly secondary to volume overload. In addition, recipient fetuses have been shown to have increased pulmonary and aortic velocities compared with their donor co-twins.Reference Murakoshi, Yamamori and Tojo ⁶ Endothelin-1, a potent vasoconstrictor, has been found to be higher in recipient twins and even higher in those with right ventricular outflow tract obstruction than in those with normal cardiac function. The mitogenic and vasoconstrictor effects of endothelin-1 may contribute indirectly to ventricular hypertrophy and hypertension.Reference Bassil Eter, Dulac and Acar ⁷ Increased resistance in the monochorionic placenta may lead to systemic hypertension and increased right ventricular afterload in the recipient twin. However, there have been reports of right ventricular outflow tract obstruction without systemic hypertension.Reference Nizard, Bonnet, Fermont and Ville ⁸

Idiopathic infantile arterial calcification is a rare entity (<200 cases described), inherited in an autosomal recessive manner, most cases of which are fatal before 6 months of age and usually diagnosed at autopsy. Most sporadic case reports of pulmonary artery calcifications in the recipient twin in twin-to-twin transfusion syndrome have not been likened with the calcifications found in idiopathic infantile arterial calcification and not as widespread.Reference Saxena and Soni ^{2 –} Reference Cha, Kim, Kwon, Bae, Noh and Kim ^{4 ,} Reference Bassil Eter, Dulac and Acar ⁷ Idiopathic infantile arterial calcification has been associated with inactivating mutations of the ENPP1Reference Rutsch, Ruf and Vaingankar ⁹ gene or loss of function mutations in the ABCC6 gene. Both are potent inhibitors of calcification – hydroxyapatite deposition – in soft tissue and vessel walls. These mutations lead to unregulated and widespread calcium deposition. Loss-of-function mutations of ENPP1 cause a wide spectrum of phenotypes, ranging from lethal idiopathic infantile arterial calcification to hypophosphatemic rickets along with early-onset hearing loss, and progressive diabetic nephropathy. ABCC6 has also been associated with pseudoxanthoma elasticum.

Our patient was negative for both ENPP1 and ABCC6 loss-of-function mutations seen in idiopathic infantile arterial calcification. Severely calcified aortic valve stenosis has been noted in Williams–Beuren syndrome.Reference Yetkin, Bal, Bayata and Gürbüz ¹⁰ Our patient was negative for this as well. His clinical picture was more consistent with previously reported recipient twins in twin-to-twin transfusion syndrome with arterial calcifications. He did, however, have aortic calcifications as well as pulmonic calcifications, the former being reported only once previously in twin-to-twin transfusion syndrome.Reference Saxena and Soni ² Therefore, the diagnosis of idiopathic infantile arterial calcification was considered initially until his genetic testing returned negative. The various theories discussed above for the development of pulmonary artery and aortic calcifications are promising but may need further study to elucidate the exact mechanism and develop possible treatment strategies in the future.