warfarin and Chondrodysplasia-Punctata

Punctate epiphyses are caused by a diverse group of conditions. They may be an inherited part of certain bone dysplasias or an incidental finding occurring occasionally in various disorders. The pattern of the puncta together with other radiologic findings aid in making the correct diagnosis.

Topics: Child; Child, Preschool; Chondrodysplasia Punctata; Epiphyses; Female; Genetic Linkage; Humans; Infant; Infant, Newborn; Male; Pregnancy; Prenatal Exposure Delayed Effects; Radiography; Vitamin K Deficiency; Warfarin; X Chromosome; Zellweger Syndrome

Chondrodysplasia punctata is abnormal calcification in the cartilage of developing bones and has been seen in association with deranged vitamin K metabolism. Warfarin, an oral anticoagulant acting on vitamin K dependent clotting factors is known to cause chondrodysplasia punctata. Despite the knowledge of the condition the management of patients with prosthetic heart valves might require use of the drug for anticoagulation. Here, we present a case of a fetal warfarin syndrome in a second born child of a 27 year lady under warfarin for prosthetic heart valve. The pregnancy was complicated by polyhydramnios in third trimester and terminated at term by normal vaginal delivery. The baby was well, except for facial dysmorphism in the form of depressed nasal bridge, narrow nares and suspected left choanal atresia. Radiograph revealed stippled ephiphysis of vertebra, femora and humera supporting diagnosis of fetal warfarin syndrome. The baby did not develop any perinatal complication and was discharged home.

Topics: Abnormalities, Drug-Induced; Adult; Anticoagulants; Chondrodysplasia Punctata; Female; Heart Valve Prosthesis; Humans; Infant, Newborn; Nasal Bone; Nepal; Pregnancy; Pregnancy Complications, Cardiovascular; Warfarin

Neonatal chondrodysplasia punctata (CDP) is characterized by epiphyseal stippling and midfacial hypoplasia. CDP is usually inherited, but can be acquired because of maternal vitamin K deficiency. We describe an infant with CDP born to a teenager with sickle cell anemia and transfusional iron overload. The mother had severe liver fibrosis, elevated liver iron concentration (34 mg Fe/g), and coagulopathy, but no gestational use of warfarin. Fetal abnormalities were attributed to vitamin K deficiency secondary to liver dysfunction from iron toxicity. Treatment of iron overload among women with sickle cell anemia of childbearing potential is important to avoid possible CDP in newborns.

Topics: Abnormalities, Drug-Induced; Adolescent; Anemia, Sickle Cell; Chondrodysplasia Punctata; Female; Humans; Infant, Newborn; Iron Overload; Liver Diseases; Male; Nasal Bone; Pregnancy; Pregnancy Complications; Transfusion Reaction; Vitamin K Deficiency; Warfarin

Topics: Anticoagulants; Arylsulfatases; Chondrodysplasia Punctata; Femur; Finger Phalanges; Humans; Lumbar Vertebrae; Pelvic Bones; Radiography; Warfarin

During the period 1991-2007, autopsy was undertaken in 13 fetuses with warfarin embryopathy. Pregnancy data and radiographic babygrams were available in each instance. Gestational age ranged from 17 to 37 weeks. Eleven of the fetuses had the characteristic nasal hypoplasia, but only three had radiological epiphyseal stippling. Cerebral hemorrhage was a major feature of autopsy in 8 of the fetuses, and it is evident that bleeding is a significant factor in the pathogenesis of warfarin embryopathy. A wide variety of additional visceral manifestations which were observed at autopsy have been tabulated. There was no obvious correlation between maternal or gestational age and the presence and severity of any specific embryopathic feature. No information was available concerning the dose and timing of warfarin administration in this series.

Topics: Abnormalities, Drug-Induced; Adolescent; Adult; Anticoagulants; Autopsy; Cerebral Hemorrhage; Chondrodysplasia Punctata; Female; Fetal Development; Heart Valve Diseases; Humans; Hyperplasia; Nose; Pregnancy; Retrospective Studies; Warfarin; Young Adult

We report a case of warfarin embryopathy. This disease affects more than 6% of fetuses exposed in utero to a vitamin K antagonist.. A child whose mother was treated with acenocoumarol because of a mechanical heart valve presented with signs of warfarin embryopathy. He showed chondrodysplasia punctata with telebrachydactyly, facial dysmorphism with nasal hypoplasia, a cataract, and a bilateral pyeloureteral junction syndrome.. Characteristics of this drug induced embryopathy are reminded, while bearing in mind the conflict of interests between the mother and the fetus. The mechanisms of this embryopathy are debated in light of the recent knowledge concerning fetal metabolism of vitamin K.

Topics: Abnormalities, Drug-Induced; Acenocoumarol; Adult; Age Factors; Anticoagulants; Child, Preschool; Chondrodysplasia Punctata; Female; Fetus; Follow-Up Studies; Heart Valve Prosthesis; Humans; Infant; Male; Pregnancy; Pregnancy Complications, Cardiovascular; Prenatal Exposure Delayed Effects; Time Factors; Warfarin

Topics: Anticoagulants; Arylsulfatases; Chondrodysplasia Punctata; Female; Fetal Diseases; Genetic Linkage; Gestational Age; Humans; Infant, Newborn; Male; Maternal Exposure; Mutation; Phenotype; Pregnancy; Warfarin; X Chromosome

Topics: Abnormalities, Drug-Induced; Adult; Anticoagulants; Chondrodysplasia Punctata; Female; Femur; Fetal Death; Fetal Growth Retardation; Gestational Age; Humans; Male; Nose; Pregnancy; Syndrome; Ultrasonography, Prenatal; Warfarin

A patient with warfarin embryopathy developed progressive cervical spinal myelopathy owing to bony cervical spinal damage. While there are several descriptions of warfarin embryopathy, the long-term complication of cervical spinal instability has not been reported. This cervical instability may, as in our patient, cause severe neurological dysfunction or even sudden death; therefore, it is important that pediatric radiologists should be alert to this condition.

Topics: Abnormalities, Drug-Induced; Anticoagulants; Cervical Vertebrae; Chondrodysplasia Punctata; Female; Follow-Up Studies; Humans; Infant, Newborn; Male; Pregnancy; Pregnancy Complications, Hematologic; Pulmonary Embolism; Radiography; Spinal Cord Compression; Warfarin

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).

Topics: Abnormalities, Drug-Induced; Anticoagulants; Child, Preschool; Chondrodysplasia Punctata; Female; Fetal Diseases; Humans; Infant; Infant, Newborn; Magnetic Resonance Imaging; Malabsorption Syndromes; Pregnancy; Pregnancy Complications; Radiography; Vitamin K; Vitamin K Deficiency; Warfarin

X-linked recessive chondrodysplasia punctata (CDPX) is a congenital defect of bone and cartilage development characterized by aberrant bone mineralization, severe underdevelopment of nasal cartilage, and distal phalangeal hypoplasia. A virtually identical phenotype is observed in the warfarin embryopathy, which is due to the teratogenic effects of coumarin derivatives during pregnancy. We have cloned the genomic region within Xp22.3 where the CDPX gene has been assigned and isolated three adjacent genes showing highly significant homology to the sulfatase gene family. Point mutations in one of these genes were identified in five patients with CDPX. Expression of this gene in COS cells resulted in a heat-labile arylsulfatase activity that is inhibited by warfarin. A deficiency of a heat-labile arylsulfatase activity was demonstrated in patients with deletions spanning the CDPX region. These data indicate that CDPX is caused by an inherited deficiency of a novel sulfatase and suggest that warfarin embryopathy might involve drug-induced inhibition of the same enzyme.

Topics: Abnormalities, Drug-Induced; Amino Acid Sequence; Arylsulfatases; Base Sequence; Cell Line; Chondrodysplasia Punctata; Chromosome Mapping; Cloning, Molecular; Fibroblasts; Gene Expression Regulation, Enzymologic; Humans; Male; Molecular Sequence Data; Multigene Family; Organ Specificity; Point Mutation; RNA, Messenger; Sequence Analysis, DNA; Sequence Homology, Amino Acid; Warfarin; X Chromosome

Topics: Abnormalities, Drug-Induced; Chondrodysplasia Punctata; Female; Humans; Maxilla; Nasal Bone; Phenotype; Pregnancy; Syndrome; Terminology as Topic; Warfarin

Topics: Bone and Bones; Cartilage; Child; Chondrodysplasia Punctata; Female; Humans; Metabolism, Inborn Errors; Mixed Function Oxygenases; Nose; Pregnancy; Teratogens; Vitamin K; Vitamin K Epoxide Reductases; Warfarin

Administration of warfarin during pregnancy may cause a rare syndrome characterized by nasal hypoplasia, usually associated with stippled epiphyseal and extraepiphyseal calcifications resembling chondrodysplasia punctata. A case of chondrodysplasia punctata after warfarin with 18 months follow-up is reported.

Topics: Abnormalities, Drug-Induced; Adult; Chondrodysplasia Punctata; Female; Follow-Up Studies; Heart Valve Prosthesis; Humans; Infant, Newborn; Male; Mitral Valve; Pregnancy; Pregnancy Complications, Cardiovascular; Warfarin

This is a case report of an infant born with nasal hypoplasia, stippling of epiphyses, and toe deformities. This embryopathy is due to maternal ingestion of Warfarin during pregnancy. Other defects including ophthalmologic and neurologic abnormalities also occur, but the nasal malformation is the only constant clinical feature.

Topics: Abnormalities, Drug-Induced; Chondrodysplasia Punctata; Female; Humans; Infant, Newborn; Nose; Toes; Warfarin

Two siblings were noted to have the physical stigmata of the fetal warfarin syndrome. Their mother had received warfarin sodium for thrombophlebitis during both pregnancies but not during that of an unaffected sibling. Teratogens may produce syndromes that mimic genetic disease in both phenotype and familial aggregation.

Topics: Abnormalities, Drug-Induced; Adult; Cataract; Child, Preschool; Chondrodysplasia Punctata; Female; Humans; Infant; Infant, Newborn; Male; Maternal-Fetal Exchange; Nose; Pregnancy; Pregnancy Complications, Cardiovascular; Teratogens; Thrombophlebitis; Warfarin

Prenatal exposure to oral anticoagulants during pregnancy may result in defective fetal development or life-threatening hemorrhage. Fetal exposure during the first eight weeks of pregnancy may cause abnormal development of the facial structures, hypoplastic digits, strippled epiphyses, and mental retardation. Midtrimester exposure may result in optic atrophy, faulty brain growth, and developmental retardation. Third-trimester exposure may produce fetal anticoagulation, predisposing the infant to life-threatening hemorrhage in the perinatal period. Anticoagulation with heparin sodium does not provide a clearly safe alternative, since this therapy has been associated with excessive fetal loss.

Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Administration, Oral; Adult; Anticoagulants; Body Weight; Chondrodysplasia Punctata; Female; Fetus; Gestational Age; Humans; Infant, Newborn; Maternal-Fetal Exchange; Optic Atrophy; Pregnancy; Pregnancy Complications, Cardiovascular; Rheumatic Heart Disease; Vitamin K; Warfarin

A third case of chondrodysplasia punctata after exposure to warfarin alone in early pregnancy is described. The clinical course of the child during the first 18 months is outlined. The use of warfarin in early pregnancy must be avoided because of its established teratogenic effects in causing this syndrome, in addition to an overall increase in perinatal mortality.

Topics: Chondrodysplasia Punctata; Female; Humans; Infant, Newborn; Maternal-Fetal Exchange; Pregnancy; Warfarin

Topics: Chondrodysplasia Punctata; Female; Humans; Infant; Nasal Septum; Syndrome; Warfarin

Topics: Abnormalities, Drug-Induced; Chondrodysplasia Punctata; Female; Humans; Infant, Newborn; Maternal-Fetal Exchange; Pregnancy; Warfarin

Two mothers with heart valve prosthesis were treated with warfarin during pregnancy. In the first case a caesarean section was done one week after replacement of warfarin with heparin. The baby died of cerebral and pulmonary hemorrhage. The second mother had a male infant by caesarean section. The baby showed warfarin-induced embryopathy with nasal hypoplasia and stippled epiphyses (chondrodysplasia punctata). Nasal hypoplasia with or without stippled epiphyses has now been reported in 11 infants born to mothers treated with warfarin during the first trimester, and a causal association is probable. In view of the risks to both mother and fetus in women with prosthetic cardiac valves it is recommended that therapeutic abortion be advised as the first alternative.

Topics: Abnormalities, Drug-Induced; Adult; Cerebral Hemorrhage; Cesarean Section; Chondrodysplasia Punctata; Female; Fetus; Heart Valve Prosthesis; Hemorrhage; Heparin; Humans; Infant, Newborn; Infant, Newborn, Diseases; Lung Diseases; Maternal-Fetal Exchange; Pregnancy; Pregnancy Complications, Cardiovascular; Warfarin

An infant is described who has clinical manifestations and roentgenographic features consistent with the diagnosis of chondrodysplasia punctata. The mother of this infant received warfarin during pregnancy. Eight cases demonstrating an association between warfarin therapy during pregnancy and chondrodysplasia punctata in the child have been reported; in the present case therapy was initiated following conception (see following case report). Warfarin may be teratogenic, producing a phencopy of the heritable forms of chondrodysplasia punctata. Because of the evident association we suggest (1) warfarin is contraindicated in pregnancy and alternative anticoagulants should be used; (2) products of at-risk pregnancies should be screened for the characteristic radiologic findings; and (3) preconceptual counselling and antenatal diagnosis of the disease may be beneficial.

Topics: Chondrodysplasia Punctata; Female; Fetus; Humans; Infant, Newborn; Phenotype; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Trimester, First; Warfarin

Topics: Abnormalities, Drug-Induced; Alcoholism; Chondrodysplasia Punctata; Diazepam; Digitalis Glycosides; Erythromycin; Female; Fetus; Heart Valve Prosthesis; Heparin; Humans; Infant, Newborn; Penicillin G Benzathine; Pregnancy; Pregnancy Complications; Sulfisoxazole; Syphilis; Thrombosis; Warfarin

Topics: Abnormalities, Drug-Induced; Adult; Chondrodysplasia Punctata; Digitoxin; Digoxin; Female; Fetus; Heart Valve Prosthesis; Heparin; Humans; Infant, Newborn; Male; Placenta Diseases; Pregnancy; Pregnancy Complications; Radiography; Sulfisoxazole; Thrombosis; Warfarin

Topics: Abnormalities, Drug-Induced; Alcoholism; Cerebrovascular Disorders; Chondrodysplasia Punctata; Contraceptives, Oral; Diazepam; Female; Fetus; Furosemide; Humans; Hypertension; Infant, Newborn; Male; Pregnancy; Pregnancy Complications; Radiography; Rheumatic Heart Disease; Stress, Psychological; Warfarin

A case of congenital stippled epiphyses is presented, and attention is drawn to the possibility that this condition was caused by maternal ingestion of warfarin during early pregnancy.

Topics: Abnormalities, Drug-Induced; Adult; Chondrodysplasia Punctata; Female; Humans; Infant, Newborn; Pregnancy; Warfarin