Chondrodysplasia

William L.

Punctata and

Shaul, MD; Helen Emery, MD; Judith G. Hall,

MD

The mother of an infant with nasal hypoplasia and stippled epiphyses had taken warfarin sodium (Coumadin) throughout the pregnancy. Use of the drug may have had a teratological effect on the child.

wish to describe an infant whose clinical findings and are consistent with the diagnosis of Conradi-Hunermann type of chondrodysplasia punctata and whose mother had taken warfa¬ rin sodium (Coumadin) throughout her pregnancy.

We roentgenograms

REPORT OF A CASE A 1,800-gm (4.0-lb) boy was born after 35 weeks' gestation to a 29-year-old (gravida 4, abortus 1, para 3) woman whose preg¬ nancy was complicated by several factors. The mother had rheumatic fever as a child and subsequently developed mitral stenosis. Four years prior to this preg¬ nancy, while taking oral contraceptive pills, she had a cerebrovascular accident, thought to be secondary to emboli from the left atrium. She was left with a residual hemiparesis on the left and has been treated with warfarin since that time. The dose of warfarin sodium has varied be¬ tween 2.5 and 5 mg/day depending on her prothrombin time. In addition, she had ma¬ jor emotional upsets during the second and third trimesters of this pregnancy and consumed excessive amounts of alcohol, varying from 6 to 12 bottles of beer per Received for publication July 29, 1974; ac17. From the University of Washington, School of and Children's Orthopedic Hospital Medicine; and Medical Center, Seattle. Reprint requests to Children's Orthopedic Hospital, 4800 Sand Point Way NE, Seattle, WA 98105 (Dr. Hall).

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Fig 1.—Patient at 5 days of age. Note hypoplastic nose and broad, flat face.

day.

also receiving diazepam (Va¬ short time during the second trimester. She was mildly preeclamptic during the eight month with edema and mild hypertension, and was treated with furosemide (Lasix) for the two weeks prior to spontaneous onset of labor at 35 weeks. Labor lasted nine hours and was termi¬ nated by cesarean section because of a slow, irregular fetal heart beat. Poly¬ hydramnios was noted, but no uterine or fetal bleeding occurred and the placenta was normal. The father of the child is 27 years old. There is no family history of congenital She

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anomalies, stillborns, orthopedic problems,

or other affected individuals. The mother had no other pregnancies while receiving warfarin therapy. At birth, the baby was noted to have a

Maternal Warfarin Use

During Pregnancy

Fig 2.—Roentgenograms of patient at 1 day of age. Left, Note stippling along entire vertebral column, particularly in sacral area, and in proximal end of femurs. Top right, Note stippling of tarsal bones. Bottom right, Note hypoplastic nose, prominent occiput, and stippling of cervical vertebrae and acromiom process (arrows).

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severely hypoplastic nose, but he cried spontaneously without difficulty. Apgar

minute was 5 and at five min¬ 8. Physical examination sug¬ gested that gestation had been 33 weeks. Birth weight was 1,800 gm (4.0 lb) (50th percentile for 33 weeks). Length was 43 cm (17 in) (50th percentile for 33 weeks) and head circumference was 32.5 cm (12.8 in) (50th percentile for 33 weeks). Skin was smooth without defects. Facies was broad and flat (Fig 1) with a downward slant to the palpebrai fissures. The bridge of the nose and alae nasae were hypoplastic, re¬ sulting in a flattened upturned nose that appeared sunken into the face. Choanal stenosis was present. Results of ophthal¬ mologic examination were normal with no evidence of cataracts or optic atrophy. The hands were somewhat short and broad with bilateral simian creases, but the limbs were otherwise symmetric and normal. A cardiac murmur was present and thought to be functional. The rest of the physical examination showed the infant to be nor¬ mal for 33 weeks' gestation except that he was somewhat hypotonie. Peripheral lymphocyte chromosome stud¬ ies (banding technique) showed a normal 46 XY karyotype. Roentgenograms showed stippling along the entire vertebral column (Fig 2, left), particularly in the lumbosacral and cervical areas. Stippled epiphy¬ ses were also present in the proximal end of the femurs, ankles (Fig 2, top right), acromion process, and nasal areas (Fig 2, bottom right). The occiput was prominent and nasal cartilage was severely hypoplas¬ tic. The patient had respiratory distress that was relieved by an oral airway for the first few weeks of life until he learned to breathe by mouth. He was slow to feed and gain weight, and had several episodes of bradycardia and apnea during the first months of life. He has had normal sym¬ metric limb growth and appropriate in¬ crease in head size and length. At 8 months of age, development was normal. score

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COMMENT

Two abnormal infants born to receiving warfarin therapy have been described previously.1"3 We are also aware of two other unpub¬ lished, unrelated cases in which the mothers were receiving warfarin dur¬ ing the pregnancy and the babies had similar clinical findings. The infants in the reported cases had nasal defor¬ mity and stippled epiphyses similar to those found in our patient. These sim¬ ilarities suggest that warfarin comwomen

pounds or their analogues may have a teratological effect on embryonic car¬ tilage, particularly nasal and verte¬ bral cartilage. In some cases in which

warfarin had been taken later in the pregnancy (ie, not during the first tri¬ mester of organogénesis), there have been no teratological effects re¬ ported.4 Other reports suggest that warfarin therapy late in pregnancy may lead to fetal and placental hem¬ orrhage.-8 One could speculate that the teratological effect of warfarin could be related to bleeding in fetal or embryonic cartilage at an early and critical stage in development, which leads subsequently to abnormal carti¬ lage growth and scarring, which in turn calcifies, giving the stippling ob¬ served. However, the presence of other abnormalities in at least two of the patients (eg, optic atrophy and mental retardation) raises the possi¬ bility that a more generalized insult occurs

during organogénesis.

Stippled epiphyses

in a number of conditions, but the best known, and the one in which the most severe stippling occurs, is Conradi are seen

syndrome or chondrodysplasia punc¬ 1971, Spranger et ale distin¬ guished two types of chondrodys¬ plasia punctata or congenital stippled epiphyses: a severe, symmetric, rhizomelic, autosomal recessive type; and a milder, frequently asymmetric, autosomal dominant type that they tata. In

called

Al¬ tends to fit into the latter category, it is possi¬ ble that a third group of sporadic cases may exist. This third group could represent a phenocopy of Con¬ radi-Hunermann that was the result of environmental or teratological in¬ fluences. Previous reports of Conradi syndrome have implicated phenacetin,10 maternal febrile illness,11 thyroid dis¬ ease,12 and salpingitis13 as possible etiologic factors. Thus, other environ¬ mental agents and drugs may give similar clinical features and account for the heterogeneity seen in patients who have been given the designation of Conradi syndrome. We have reported this case in order to point out the association of this very rare congenital anomaly with the also rare use of warfarin during

"Conradi-Hunermann."

though the present

case

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Clearly, this mother was receiving several other drugs that might be implicated, but we believe strong suspicion must be raised about the teratogenic effect of warfarin during the first trimester of human pregnancies. pregnancy.

This investigation was supported in part by Public Health Service grant 5501 RR 0565505 and National Foundation-March of Dimes grant 5P01 GM 15253-07. Samuel Tarica, MD, and Yukio Kamasaka, MD, referred the patient; Tom Shepard, MD, provided advice and encouragement; and Wil¬ liam Miller, MD, provided initial care of the pa¬ tient.

Nonproprietary Name and Trademarks of Drug Warfarin sodium-Coumadin, Prothromadin.

Panwarfin,

References

Pregnancy and delivery of patient with a Starr-Edwards mitral valve prosthesis: Report of a case. Obstet Gynecol 28:469-472, 1966. 2. Kerber IJ, Warr OS III, Richardson C: Pregnancy in a patient with a prosthetic 1. DiSaia PJ:

a

mitral valve: Associated with a fetal anomaly attributed to wafarin sodium. JAMA 203:223-225, 1968. 3. Holmes B, Moser HW, Halld\l=o'\rssonS, et al: Mental Retardation: An Atlas of

Disease With Associated Physical Abnormalities. New York, Macmillan Co, 1972, p 136. 4. Mansell RV: Antepartum dicumarol therapy. Am J Obstet Gynecol 64:155-161, 1952. 5. Sydow G von: Hypoprothrombinemia and cerebral injury in infant after dicumarol treatment of mother. Nord Med 34:1171-1172, 1947. 6. Sach JJ, Labate JS: Dicumarol in the treatment of antenatal thrombo-embolic disease: Report of a case with hemorrhagic manifestations in the fetus. Am J Obstet Gynecol 57:965-971, 1949. 7. Gordon RR, Dean T: Foetal deaths from antenatal anticoagulant therapy. Br Med J 2:719-721, 1955. 8. Villasanta U: Thromboembolic disease in pregnancy. Am J Obstet Gynecol 93:142-160, 1965. 9. Spranger JW, Opitz, JM, Bidder U: Heterogeneity of chondrodysplasia punctata. Humangenetik 11:190-212, 1971. 10. Yakovac WC: Calcareous chondropathies in the newborn infant. Arch Pathol 57:62-79, 1954. 11. Ford GD, Schneider M, Brandon JR: Congenital stippled epiphyses. Pediatrics 8:380-392, 1951. 12. Josephson BM, Oriatti MD: Chondrodystrophia calcificans congenita. Pediatrics 28:425-435, 1961. 13. Berrey BH, Kimball CH: Chondrodystrophia calcificans congenita. J Pediatr 42:474-477, 1953.

Chondrodysplasia punctata and maternal warfarin use during pregnancy.

Chondrodysplasia William L. Punctata and Shaul, MD; Helen Emery, MD; Judith G. Hall, MD The mother of an infant with nasal hypoplasia and stipple...
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