Vitamin K deficiency embryopathy: A phenocopy of the warfarin embryopathy due to a disorder of embryonic vitamin K metabolism

Abstract

Three unrelated infants presented with radiographic punctate calcifications, nasal hypoplasia, and abnormalities of the spine. Additional anomalies included cupped ears in 2 patients and one each with Dandy-Walker malformation with hydrocephaly, congenital cataracts, and peripheral pulmonary artery stenosis. The mothers of these 3 patients had chronic conditions associated with intestinal malabsorption requiring total parenteral nutrition for varying periods of time. The underlying causes of malabsorption were celiac disease, short bowel syndrome secondary to surgical resection, and jejuno-ileal bypass, respectively. Bleeding diathesis occurred in one mother requiring vitamin K supplementation during the second and third trimesters of pregnancy. We speculate that the chondrodysplasia punctata and other abnormalities in these children were caused by an acquired maternal vitamin K deficiency manifested during early pregnancy. However, the involvement of other vitamin deficiencies cannot be excluded. Thus, vitamin K deficiency of the embryo secondary to maternal malabsorption appears to be a third vitamin K-related mechanism leading to chondrodysplasia punctata in addition to warfarin embryopathy and epoxide reductase deficiency (pseudo-warfarin embryopathy).

Phenocopy of Warfarin Syndrome in an Infant Born to a Mother With Sickle Cell Anemia and Severe Transfusional Iron Overload

“…Absence of hemorrhage or coagulopathy has been observed in other cases of CDP. 3,22 Vitamin K levels probably fluctuated in the mother during her gestation, and might have improved in late pregnancy. Furthermore, coagulation studies were not performed in the newborn until after he had received the intramuscular injection of vitamin K (minutes after birth) and had vitamin K-containing formula, this might explain why the coagulation tests in the infant were normal.…”

“…Causes of CDP include abnormalities of peroxisomal and cholesterol metabolisms, teratogen (phenytoin, warfarin) exposure in utero, maternal vitamin K deficiency secondary to intestinal malabsorption, celiac disease, short bowel syndrome, or bariatric surgery. [1][2][3][4][5] Although these disorders may present with epiphyseal stippling, some can be differentiated easily because of other unique clinical features (Table 1). Embryopathy due to warfarin, and other causes of vitamin K deficiency, is a well-described etiology of CDP.…”

“…Embryopathy due to warfarin, and other causes of vitamin K deficiency, is a well-described etiology of CDP. 3,4 Vitamin K deficiency can occur in the setting of severe hepatic hemosiderosis due to persistently high liver iron concentration and resulting liver damage. Here, we describe a newborn with CDP born to a woman with sickle cell anemia (SCA), demonstrating that women with SCA of childbearing capacity who have liver dysfunction due to iron overload from chronic transfusions can develop vitamin K deficiency, similar to that from warfarin use during pregnancy.…”

Chondrodysplasia punctata: a clinical diagnostic and radiological review

“…A number of reports describe CDP occurring in infants after fetal exposure to phenytoin. (Keith and Gallop, 1979;Menger et al, 1997;Wester et al, 2002). The observation that phenytoin interferes with the formation of vitamin K-dependent proteins (Keith et al, 1983) suggests this as another example of CDP related to disrupted vitamin K metabolism.…”

Role of vitamin K in the regulation of calcification

“…Effects similar to that of fetal warfarin embryopathy are seen in pregnant women who have malabsorptive abnormalities and in a genetic deficiency of γ-carboxylase activity [110,111]. In warfarintreated rats, excessive mineralization of growth plate cartilage and early fusion of the epiphysis is seen after 2-3 months of age [108].…”