Sheffield et al. (1976) reported several children from Australia with a mild form of chondrodysplasia punctata. The patients presented during infancy with abnormal facies, and punctate calcification in the calcanerum and sometimes other sites. Growth and developmental progress ... Sheffield et al. (1976) reported several children from Australia with a mild form of chondrodysplasia punctata. The patients presented during infancy with abnormal facies, and punctate calcification in the calcanerum and sometimes other sites. Growth and developmental progress improved during childhood, and the final phenotype seemed to include low-normal height and intelligence with persistence of the typical facies. Illnesses during pregnancy were frequent, and anticonvulsants taken during pregnancy may have had an etiologic role in some patients. Happle (1981) suggested that cataracts are consistently absent in the autosomal dominant form of chondrodysplasia punctata. Rittler et al. (1990) referred to the mild 'Sheffield-type' of chondrodysplasia punctata and suggested possible autosomal dominant inheritance. They noted that patients with this form had characteristic face and symmetric stippling of upper and/or lower limbs that disappeared with age. A female patient observed by Silverman (1961, 1969) had a similarly affected brother and apparently a male cousin with the same disorder. Their fathers appeared unaffected, but this was not unexpected since the bone changes disappear during childhood. The brother of the original patient reported by Silverman (1961) had a daughter who was similarly affected (Vinke and Duffy, 1974). - Vitamin K Deficiency or Warfarin Teratogenicity Several different modes of vitamin K-related teratogenicity have been shown to cause chondrodysplasia punctata. The best described of these is warfarin embryopathy. Hall et al. (1980) placed the critical period for warfarin effects on the fetus as 6 to 9 weeks following conception. Warfarin inhibits synthesis of gamma-carboxyglutamic acid, which is involved in both clotting and calcification. See review by Gallop et al. (1980). Ingestion of warfarin during pregnancy can result in hypoplasia of the nasal bones to produce koala bear facies (Becker et al., 1975; Pettifor and Benson, 1975; Shaul et al., 1975). In addition to severe hypoplasia of the nose, sometimes with choanal atresia, stippled epiphyses and coronal vertebral clefts have also been observed. In addition, various vitamin K antagonists produce this picture. The only difference from chondrodysplasia punctata may be the absence of skin and hair changes. Harrod and Sherrod (1981) reported 2 sibs from pregnancies during which their mother took warfarin for thrombophlebitis who showed signs of chondrodysplasia punctata, and a third sib from a pregnancy without warfarin ingestion who was unaffected. Pauli et al. (1985) described a boy with the phenotype of warfarin embryopathy including nasal hypoplasia and, in infancy, cartilage stippling by x-ray, who also had combined deficiency of vitamin K-dependent coagulation factors. These observations were interpreted to mean that warfarin embryopathy is not due to hemorrhage but rather to inhibition of carboxylation of osteocalcins and/or other vitamin K-dependent bone proteins. Embryopathy due to vitamin K deficiency as a result of various maternal intestinal abnormalities leading to malabsorption was described by Menger et al. (1997) and Nivelon-Chevallier (1998). Eash et al. (2003) described a male infant with brachytelephalangic chondrodysplasia punctata who had multiple serious medical problems and striking physical abnormalities. These included cervical spine stenosis with resultant quadriplegia, severe nasal hypoplasia, and brachytelephalangy. Radiographs taken shortly after birth demonstrated extensive epiphyseal and vertebral stippling, and distal phalangeal hypoplasia. Mutation analysis excluded the ARSE gene. The 25-year-old mother's pregnancy had been complicated by severe bouts of intractable vomiting caused by a small bowel obstruction secondary to a severe high-grade synovial carcinoma. Prenatal problems began at 3 weeks of gestation with severe anemia, dehydration, prerenal failure, and weight loss. Between 5 and 18 weeks' gestation she received total parenteral nutrition on several occasions. She received no chemotherapeutic agents or warfarin. She experienced hypocalcemia and hypoalbuminemia at 17 weeks and hypokalemia at 18 weeks' gestation. Eash et al. (2003) concluded that the severity of the phenotype in this case may have been influenced by vitamin K deficiency.