American Journal of Medical Genetics 36488-494 (1990)

Bone Dysplasias: The Prenatal Diagnostic Challenge ~

Luis F. Escobar, David Bixler, David D. Weaver, Lillie-Mae Padilla, and Alan Golichowski Regional Genetics Center Memorial Hospital of South Bend, Department of Biological Sciences, University of Notre Dame, South Bend (L.F.E.), and Departments of Oral Facial Genetics (L.F.E.,D.B.), Medical Genetics (D.B., D.D.W.), and Obstetrics and Gynecology (L.M.P., A.G), Indiana University School of Medicine, Indianapolis

The prenatal diagnosis of bone dysplasias presents difficult challenges for the clinician involved in monitoring pregnancies. Such diagnoses highlight delicate etiical issues and may require difficult decision-making when the differential diagnosis includes a lethal bone dysplasia. Despite the rapid technological advances in ultrasonography, the ability to make prenatal diagnoses within this group of disorders is limited by the restricted ultrasonographic capabilityto appreciatefully the detailed fetal anatomy. However, we perceive that a significant further limitation involves the lack of a systematic protocol to guide the clinician in the ultrasonographic evaluation of a fetus suspected of having a skeletal dysplasia. In an attempt to aid the clinician who is evaluating these suspected pregnancies, we report here 8 cases and propose a model protocol for the ultrasonographic diagnostic approach to fetal skeletal problems in utero.

KEY WORDS: ultrasonography, skeletal disorders INTRODUCTION The disorders of the skeleton that are collectively called “bone dysplasias” are a heterogeneous group of conditions associated with abnormalities in size, shape, and density of the skeleton as manifested by abnormal limbs, chest, trunk, andor skull [Rimoin and Lachman, 19831. Frequently this group of disorders involves disproportionate short stature of prenatal onset and structural abnormalities that may lead to intrauterine death or fatal perinatal complications. Because of this the prenatal recognition of skeletal disorders is an important issue for the clinician involved in pregnancy monitoring

Received for publication August 31, 1989; revision received December 12, 1989. Address reprint requests t o Luis F. Escobar, M.D., Regional Genetics Center Memorial Hospital of South Bend, 615 North Michigan Street, South Bend, IN 46601-9986.

0 1990 Wiley-Liss, Inc.

and management. However, this is not a n easy task, especially for bone dysplasias where the lack of systematic diagnostic protocols hinders the examiner searching for a differential diagnosis. We propose here a protocol (Table I, Figs. 1-6) for a n approach to the fetus in which structural abnormalities suggest a bone dysplasia.

CLINICAL REPORTS Patient 1 HK (9329422) was a 34-year-old white woman who was seen in our high risk clinic on 2/11/85. Ultrasonography a t that time showed a fetus with very small limbs. She was referred to our center for extensive ultrasonographic evaluation which showed the following: A single fetus with a calculated occipito-frontal circumference (OFC) equivalent to 23 weeks gestation (21.5 cm). The biparietal diameter (BPD) was 6.7 cm, consistent with a 26 weeks gestational age, occipitofrontal diameter (OFD) 7 cm. A cephalic index (CI) of 95.7 suggested brachicephaly. The thorax appeared to be compressed with the heart filling most of the thoracic cavity. All 4 limbs were visualized and found to be grossly short in both the proximal and distal segments (humerus 1.7 cm, radius and ulna 1.7 cm), femoral length (FL) was 1.5 cm. Tibiae and fibulae were 1.3 cm. All measurements were below the 5th centile. Only the fingers of the right hand could be visualized; 5 digits were observed. The most likely diagnosis suggested was thanatophoric dysplasia; less likely was the short ribpolydactyly syndrome. The parents elected to terminate the pregnancy. Postnatal fetal examination confirmed the diagnosis of thanatophoric dysplasia. Patient 2 NR (984844D) was a 34-year-old white woman with mild hydramnios in the second trimester. An ultrasound evaluation showed a short-limb fetus. The spine was examined in detail and there was no evidence of vertebral dysplasia or any widening of the distance between the lateral ossification centers. Structural abnormalities included short limbs, both distal and proximal, humeral length (HL) 2.4 cm, radio-ulnar length 2 cm, tibio-fibular length 3.10 cm without evidence of bowing of any of the bones or pathologic fractures. Five digits were counted on each limb. No increased angulation of the fetal thumb was noted. Further fetal biometric data include a TC of 22.2 cm, AC 25.6 cm, and a TC/AC ratio of

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TABLE I. Grouping of Bone Dysplasias According to Figures 1-6 I. Thanatophoric dysplasia Chondrodysplasia punctata rhizomelic type Jarcho-Levin syndrome 11. Thanatophoric dysplasia Achondroplasia heterozygous type Jarcho-Levin syndrome 111. Campomelic dysplasia Osteogenesis imperfecta type I1 Osteopetrosis IV. Chondrodysplasia punctata, rhizomelic type V. Achondrogenesis types IA and IB Cleidocranial dysplasia Osteogenesis imperfecta type I1 VI. Cleidocranial dysplasia Osteogenesis imperfecta types I and I1 VII. Cleidocranial dysplasia VIII. Thanatophoric dysplasia Achondroplasia heterozygous type Campomelic dysplasia Cleidocranial dysplasia Diastrophic dysplasia Dyssegmental dysplasia Mesomelic dysplasia, Langer type Osteogenesis imperfecta type I Femoral hypoplasia-unusual-face syndrome Spondyloepihyseal dysplasia congenita. IX. Femoral hypoplasia-unusual-face syndrome Short rib polydactyly syndrome, Majewski type X. Cleidocranial dysplasia XI. Amelia Jarcho-Levin svndrome Spondyloepiphyseal dysplasia congenita XII. Amelia GraffILaxova lethal skeletal dysplasia Osteopetrosis Schneckenbecken dysplasia Short rib polydactyly syndrome, Majewski type Short rib polydactyly syndrome, SaldinoNoonan type Cleidocranial dysplasia Ellis-Van Creveld syndrome XIII. Thanatophoric dysplasia Cleidocranial dysplasia Jarcho-Levin syndrome XIV. Osteogenesis imperfecta type I1 Osteogenesis imperfecta type I11 XV. Thanatophoric dysplasia Achondrogenesis types IA and IB Osteogenesis imperfecta type I11 XVI. Hypochondroplasia Jarcho-Levin syndrome Osteogenesis imperfecta type I11 Short rib polydactyly syndrome, SaldinoNoonan type Spondyloepiphyseal dysplasia congenita XVII. Femoral hypoplasia-unusual-face syndrome

3 7 . The diagnosis of achondroplasia was suggested and confirmed neonatally.

Patient 3 CH (956529Y) was a 29-year-old white woman. She had severe hydramnios and gestational diabetes. An ultrasound at 32 weeks’ gestation showed hydramnios and a single vertex fetus. Fetal cardiac activity, gross body movements, and fetal breathing movements were

XVIII. Mesomelic dysplasia Femoral hypoplasia-unusual-face syndrome XIX. Osteogenesis imperfecta type I1 XX. Achondrogenesis types IA and IB Dyssegmental dwarfism Osteogenesis imperfecta types I and I11 XXI. Osteogenesis imperfecta type I1 XXII. Thanatophoric dysplasia Amelia Campomelic dysplasia Diastrophic dysplasia Graff-Laxova lethal dysplasia Short rib polydactyly syndrome, SaldinoNoonan type XXIII. Achondrogenesis types IA and IB Dyssegmental dwarfism Graff-Laxova lethal skeletal dysplasia Femoral hypoplasia-unusual face syndrome Schneckenbecken dysplasia Short rib polydactyly syndrome, SaldinoNoonan type XXIV. Chondrodysplasia punctata, rhizomelic type XXV. Campomelic dysplasia XXVI. Amelia Diastrophic dysplasia XXVII. Camptomelic dysplasia Chondrodysplasia punctata, rhizomelic type XXVIII. Ellis-van Creveld syndrome XXIX. Ellis-van Creveld syndrome XXX. Mesomelic dysplasia Spondyloepiphyseal dysplasia congenita XXXI. Osteogenesis imperfecta type I Short rib polydactyly syndrome, Majewski type Spondyloepiphyseal dysplasia congenita XXXII. Osteogenesis imperfecta type I XXXIII. Ellis-van Creveld syndrome Jarcho-Levin syndrome Femora hypoplasia-unusual face syndrome Short rib polydactyly syndrome, Majewski type XXXIV. Femoral hypoplasia-unusual face syndrome XXXV. Jarcho-Levin syndrome Femoral hypoplasia-unusual face syndrome XXXVI. Achondrogenesis IA and IB Short rib polydactyly syndrome, Majewski type XXXVII. Achondrogenesis IA and IB Short rib polydactyly syndrome, SaldinoNoonan type XXXVIII. Short rib polydactyly syndrome, SaldinoNoonan type XXXIX. Arthrogryposis congenita XL. Thanatophoric dysplasia Achondrogenesis IA and IB Amelia XLI. Thanatophoric dysplasia Graff-Laxova skeletal dvsdasia

seen during the examination. A stomach, 2 kidneys, and bladder were identified. There was marked shortness of the limbs. The humerus measured 2.4 cm, the radius and ulna 2 cm each, and the femur was 3 cm with no significant bowing of the long bones. A posterior placenta was identified. Thorough examination of the right upper limb showed the presence of 4 fingers and a thumb with no displacement of the latter. Although the thoracic structures appeared small, this could not be con-

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firmed. The diagnosis of thanatophoric dysplasia was suggested and confirmed postnatally.

Patient 4 TT (934894H) was a 25-year-old white woman who was admitted for termination of pregnancy because of severe fetal abnormalities. She was at approximately 20 weeks’ gestation by calculated gestational age. This evaluation showed poor calcification of the fetal skull and spine, a BPD and OFD of 4.7 and 5.8 cm, respectively, and an OFC of 16.5 cm. There was regular cardiac activity and symmetric thorax with no breathing activity. Short limbs were noted (HL 1.5 cm, radio-ulnar length 0.8 cm, FL 1 cm). Other fetal biometric data included a TC of 11.5, an AC of 13.3 cm, and a TC/AC ratio of 0.87. The differential diagnoses included osteogenesis imperfecta, achondrogenesis, and other types of short-limb dwarfism, Postnatal exam showed a 300 g male, with osteogenesis imperfecta type 11. Patient 5 DB (996532P) was a 18-year-old black woman. She was seen by us at 35 weeks’ gestation (last menstrual period),because of suspected fetal abnormalities. Ultrasonographicevaluation showed a normal amount of amniotic fluid, and a single fetus in breech presentation. Outer- and inner-orbital distance were 10.5 and 5.7 cm, respectively, indicating hypertelorism. The BPD was 8.4 cm, OFC 30.6 cm. Chest size, although small, did not appear to be in the range of asphyxiating thoracic dystrophy. Generalized shortness of the limbs was observed and it seemed to be more severe in the lower limbs (HL 4.6 cm, radio-ulnar length 4.5 cm, femoral length 2.7 cm, tibio-fibular length 2.9 cm). Postnatal examination showed signs of metaphyseal chondrodysplasia (probably Jansen type). Patient 6 BL (1023537X) was a 20-year-old white woman who was referred to evaluate multiple fetal anomalies detected by ultrasound. Ultrasonographic evaluation showed a slight increase of amniotic fluid volume and a single fetus in a cephalic presentation. The BPD was 8.1 cm, OFD 11.10, OFC 30.8 cm. Evaluation of the thorax showed a 4 chamber fetal heart with no indication of abnormalities. Long bones were all shorter than expected (FL 4.8, tibio-fibular length 4.5 cm, HL 4.8 cm, radio-ulnar length 4.7 cm).No definitive diagnosis could be made at this time, but achondroplasia was suggested in addition to other forms of short limb dwarfism. Postnatally, the diagnosis of achondroplasia was confirmed. Patient 7 RH (1018725A) was a 28-year-old black woman was seen at 36 weeks’ gestation due to multiple fetal anomalies. Our ultrasonographic evaluation showed a single gestational sac with slight increase of amniotic fluid and a single fetus in a cephalic presentation. The BPD was 8.7 cm and with an OFD of 11 cm. All fetal limbs appeared to be short (HL 4.8 cm, radio-ulnar length 4.8 cm, FL 5.2 cm). No significant degree of compression of the fetal lung was evident and it was thought that the TC/

AC ratio was in the low normal range. No definitive diagnosis was possible at this time. Postnatal examination lead to a diagnosis of achondroplasia.

Patient 8 GB (996746x1 was a 24-year-old white woman in her second pregnancy. She was referred because of polyhydramnios and multiple fetal abnormalities. Ultrasonographic examination showed a single fetus in transverse situation. An unusual shape of the head was noticed. Cranial measurements included a BPD of 9.3 cm and OFD of 10.5 cm with a C1 of 0.89, which suggested an abnormally round head and an OFC of 31.1 cm. The spine was difficult to evaluate because of the tortuosity of the thoracic and the cervical spine. The long bones were all unusually short (HL 2.7 cm, radioulnar length 1.2 em, FL 2.3 cm, tibio-fibular length 2 cm). The TCiAC ratio was 0.74, which was markedly diminished. In addition, on visual examination there appeared to be a significant degree of thoracic constriction. It was thought that a type of short-limb dwarfism was present, probably thanatophoric dysplasia. This diagnosis was confirmed postnatally. DISCUSSION The growing use of ultrasound for fetal monitoring has increased the number of pregnancies referred to specialized centers for suspicion of fetal anomalies such as the bone dysplasias [Manchester et al., 19881. However, the lack of a systematic approach to guide the clinician in the search for specific anomalies that will fit a specific skeletal problem makes bone dysplasias one of the most challenging diagnoses in prenatal ultrasonography. Ultrasound has limitations in differentiating one skeletal disorder from the other, mainly because it does not yet give the integrated view that an overt clinical inspection can offer [Vandenbergheet al., 19841. All these factors make the delineation of a systematic approach to the skeletal anomalies with ultrasound a necessity for the clinician involved in prenatal monitoring and pregnancy management. We outline here a protocol-approach to the prenatal diagnosis of bone dysplasias by ultrasonography (Table I, Figs. 1-6) that is based in our own experience and on previous published data [Rimoin and Lachman 1983; Jahoda et al., 1982; McGuire et al., 19871. From the available information on skeletal dysplasias, it becomes clear that the ultrasonographer needs to direct the examination to specific fetal structures in order to provide a better differential diagnosis. Head, face, thorax, limbs, kidneys, and fetal movements should be included in the basic evaluation of a fetus at risk of having an skeletal disorder. Each of the above areas will be discussed below. Head (Fig.1). Recent advances in fetal head evaluation allow the careful measurement of the craniofacial structures [Escobar et al., 19881. The ultrasonographer should be aware of the significance of macrocephaly as it occurs in osteopetrosis (increased biparietal diameter) [El Khazen et al., 19861 and the Jarco-Levin syndrome (increased occipitofrontal diameter) [Tolmire et al., 19871. Hydrocephalus as a cause of macrocephaly has

a I Q

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morphology

Macrocephaly

Microcaphaly

I Normal

shaped

Fig. 1. Ultrasonographic evaluation of the fetal head when a fetus is suspected to have a bone dysplasia.

also been found to be associated with skeletal disorders such as campomelic dysplasia [Winter et al., 19851 and osteogenesis imperfecta type I1 [Bader and Warner, 19871. Even though microcephaly is rarely associated with a skeletal dysplasia, it has been seen in chondrodysplasia punctata, rhizomelic type [Harrod et al., 19851, probably due to craniostenosis. Head shape also plays a n important diagnostic role since it usually relates to ossification processes in the skull. A prominent forehead is seen in thanatophoric dysplasia [Chevernak et al., 19831,achondroplasia [Leonard et al., 19791, cleidocranial dysplasia [Noonan, 19741, hypochondroplasia [Stoll et al., 19851, and osteopetrosis [El Khazen et al., 19861. Brachycephaly is often associated with cleidocranial dysplasia [Noonan, 19741, chondrodysplasia punctata [Harrod et al., 19851, and diastrophic dysplasia [Mantagos et al., 19811. Spondyloepiphyseal dysplasia congenita [Donnenfeld and Mennuti, 19871 shows a variable head shape. Enhanced intracranial detail and poor cranial ossification of the calvaria with an indentation created by maternal aorta pulsations suggest osteogenesis imperfecta type I [Bader and Warner, 19871, achondrogenesis IA and IB [Bingol et al., 19873, cleidocranial dysplasia [Noonan, 19741, and osteogenesis imperfecta type I1 [Bader and Warner, 19871. Finally, even though standards for skull thickness do not exist a t the present time, a careful estimation of the calvaria thickness should be made. A thin skull can be seen in cleidocranial dysplasia [Noonan, 19741while a thickened skull appears in early lethal forms of osteopetrosis [El Khazen et al., 19861. Face (Fig.2). A sagittal view of the head permits the determination of midface hypoplasia [Escobar et al., 19881 which occurs in several disorders such as thanatophoric dysplasia [Chevernak et al., 19831, achondroplasia [Leonard et al., 19791, campomelic dysplasia [Winter et al., 19851, cleidocranial dysplasia [Noonan, 19741,osteogenesis imperfecta type I [Hobbins and Mahoney, 19851, and spondyloepiphyseal dysplasia congenita [Donnenfeld and Mennuti, 19871. This ultrasonographic view will also allow the evaluation of micrognathia, as seen in dyssegmental dysplasia [Kim et al., 19861 (with Pierre Robin sequence), mesomelic dwarfism [Quigg e t al., 19851, femoral hypoplasia-unusual facies syndrome [Graham, 19851 and spondyloepiphy-

seal dysplasia congenita [Donnenfeld and Mennuti, 19871. The presence of facial clefts needs to be ruled out as they may occur in disorders like dyssegmental dwarfism [Kim et al., 19863, short-rib polydactyly syndrome, Majewski type [Gembruch et al., 19851, and spondyloepiphyseal dysplasia congenita [Donnenfeld and Mennuti, 19871. A rare finding in bone dysplasias is hypertelorism; however, it has been associated with cleidocranial dysplasia [Noonan, 19741. Thorax (Fig.3). A careful thoracic evaluation represents one of the most important parts of the prenatal examination of a fetus thought to have a bone dysplasia. A small or constricted thorax often leads to neonatal death because of respiratory difficulties. A bell-shaped thorax has been described in thanatophoric dysplasia [Chevernak et al., 19831, amelia [Russell, 19731, and osteogenesis imperfecta type I1 [Bader and Warner, 19873; a narrow chest with achondrogenesis [Bingol et al., 19871 and Ellis-Van Creveld syndrome [Gollop and Eigier, 19861, Schneckenbecken dysplasia [Borochowitz et al., 19861, short rib polydactyly type I and I1 [Gembruch et al., 19851,and a barrel-shaped chest are seen in spondyloepiphyseal dysplasia congenita [Donnenfeld and Mennuti, 19871. These shapes of the thoracic cavity are also found in association with a variety of rib anomalies such as absence of one or more ribs as described in Jarcho-Levin syndrome [Tolmire et al., 19871, with absence of clavicles in cleidocranial dysplasia [Noonan,

structures

hypoplasia

lip/palate

hypertelorism

Fig. 2. Ultrasonographic evaluation of the fetal face when a fetus is suspected to have a bone dysplasia.

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a a P w\T I Thorax

Small

Normal

I

I

I

Narrowed

barrel type

anomalies

Short-horizontal

Hypo-echogenic

Fig. 3. Ultrasonographic evaluation of the fetal thorax when a fetus is suspected to have a bone dysplasia.

19741, and with abnormal rib shape and clavicles as seen in osteopetrosis [El Khazen et al., 19863. Limbs (Fig. 4). About 90% of the prenatally diagnosed skeletal disorders involve abnormalities of the limbs and are frequently the findings that alert the clinician that the fetus may have a skeletal disorder. Difficulty in obtaining appropriate long bone measurements also should alert the sonographer to the presence of a skeletal dysplasia [Bader and Warner, 19871. Fetal biometry is very useful for the determination of short long bones and will allow a differentiation between asymmetric shortness of the limbs, mesomelia, rhizomelia, and rhizomesomelia (Fig. 4). When the ultrasonographicconditions allow, careful examination of the fetal hands may demonstrate polydactyly which has been described in the Ellis-Van Creveld syndrome [Gollop and Eigier, 19861and short rib polydactyly syndromes, Majewski type [Gembruch et al., 19851. It has been suggested that an examination of all 4 limbs does not increase the diagnostic sensitivity for detecting limb abnormalities since 2 limbs are usually enough [Kim et al., 19861. However, we believe that an attempt to visualize all 4 limbs can be important in detecting asymmetry, size differences, and unilateral malformations of the limbs. Kidneys (Fig. 5). Fknal abnormalities are not an infrequent finding in the fetus at risk for a skeletal disorder. The spectrum of renal defects ranges from unilateralhilateral agenesis of the kidneys to obstructive uropathies that lead to hydronephrosis. Skeletal disorders that have been associated with renal anomalies include achondrogenesis IA and IB [Bingol et al., 19871, Ellis-Van Creveld syndrome [Gollop and Eigier, 19861, Jarcho-Levin syndrome [Tolmire et al., 19871, femoral

hypoplasia-unusual face syndrome [Graham, 19851, and short rib polydactyly syndrome, Majewski and Saldino-Noonan types [Gembruch et al., 19851. Other structures that need to be evaluated during the ultrasonographic evaluation of the fetus at risk of skeletal problems include the spinal cord, vertebrae, and heart. Fetal movement (Fig, 6). Fetal movements are usually decreased in fetuses with bone dysplasias. This is especially true in those situations in which the mobility of a joint is involved such as found in achondrogenesis [Bingol et al., 19871, thanatophoric dysplasia [Chevernak et al., 19831, amelia [Russell, 19731, Graff-Laxova skeletal dysplasia [Graff et al., 19721, and spondyloepiphyseal dysplasia congenita [Donnenfeld and Mennuti, 19871. Thus, we recommend a repeat examination several minutes after the first observation of decreased fetal movements has been made, looking for changes in fetal limb positioning. Other structures that need to be evaluated during the ultrasonographic evaluation of the fetus at risk of skeletal problems include the spinal cord, vertebrae, and heart. If we take into consideration that major structural abnormalities occur at least once in every 50 births [Heinomen et al., 19861 and that the ability to detect these defects by prenatal ultrasound has increased in the past 10 years at a remarkable rate, it is inevitable that physicians and parents will come to rely more on the information obtained by ultrasonography. This in turn will increase the need to make decisions about management of these pregnancies. For this reason, we believe that a fetus suspected to have a skeletal disorder requires a careful multisystem examination that will

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7 1 abnormalities

I Echogenicity

w

a Decreased

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Limb shortening

limb length

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LI Ahlzo and/or mesomelia

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(ulnalfemurs)

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xx

xxI

I

XIX

f-l

Severe

Moderate

k-J Rhlzomesomelia

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Fig. 4. Ultrasonographic evaluation of the fetal limbs when a fetus is suspected to have a bone dysplasia.

movements

Q ~pqp=q-xq~~

Positional attitudes

Agenesis

I

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Fig. 5. Ultrasonographic evaluation of the fetal kidneys when a fetus is suspected to have a bone dysplasia.

Fig. 6. Ultrasonographic evaluation of fetal activity when a fetus is suspected to have a bone dysplasia.

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probably not offer a specific diagnosis but will provide sufficient information for the clinician and parents to establish a differential diagnosis upon which to base management decisions.

ACKNOWLEDGMENTS We would like to thank Dr. Harvey Bender and Mrs. Julie Mahon for reviewing this manuscript, and Mr. John Harlan for his editorial contribution. This work was supported in part by the National Research Service Award l-F32-DE05456-01Al. REFERENCES Bader B, Warner RW (1987): Osteogenesis imperfecta type 11: A review for sonographers. JDMS 3:275-280. Bingo1 N, F’uchs M, Pagan M, Pearl M, Stone RK (1987): In utero ultrasound diagnosis of achondrogenesis type 11. Am J Hum Genet 41:A48. Borochowitz Z, Jones KL, Silbey R, Adoman G, Lachman R, Rimoin DL (1986): A distinct lethal neonatal chondrodysplasia with snail-like pelvis: Schneckenbecken dysplasia. Am J Med Genet 2547-52. Chevernak FA, Blakemore KJ, Isaacson G, Mayden K, Hobbins J C (1983): Antenatal sonographic findings of the thanatophoric dysplasia with cloverleaf skull. Am J Obstet Gynecol 146:948-987. Donnenfeld AE, Mennuti MT (1987): Second trimester diagnosis of fetal skeletal dysplasias. Obstet Gynecol S u n 42:199-201. El Khazen M, Faverly D, Vamos E, Van Regemorter M, FlamentDurand J (1986): Lethal osteopetrosis with multiple factures in utero. Am J Med Genet 23:811-813. Escobar LF, Bixler D, Padilla LM, Weaver DD (1988): Fetal craniofacial morphometrics In utero, evaluation at 16 weeks’ gestation. Obstet Gynecol 72:674-679. Gembruch V, Hasmann M, Fodisch H J (1985): Early prenatal diagnosis of short rib polydactyly syndrome type I by ultrasound in a case at risk. Prenat Diagn 5357-360. Gollop TR, Eigier A (1986):Ellis-Van Creveld syndrome: Early prenatal diagnosis with ultrasound. Rev Bras Genet 9:555-556. Graff G, Chemke J, Lancet M (1972): Familial recurring thanatophoric dwarfism: A case report. Obstet Gynecol 39:515-518. Graham P (1985):Congenital short femur: Prenatal sonographic diagnosis. J Ultrasound Med 4:361-365. Grannum PA, Hobbins J C (1983): Prenatal diagnosis of fetal skeletal dysplasias. Semin Perinatol 7:125-137. Harrod MJE, Santos-Ramos R, Cuarrino G, Maravilla A (1985):Prenatal diagnosis of rhizomelic chondrodysplasia punctata. Proc Greenwood Genet Ctr 4:148-149.

Heinomen OP, Slone D, Shapiro S (1986):“Birth Defects and Drugs in Pregnancy.” Littleton, MA: Publishing Sciences Group, pp 65-81. Hobbins JC, Mahoney MJ (1985): Skeletal dysplasia: In Sanders RC, James AE, Jr (eds): “The Principles and Practice of Ultrasonography in Obstetrics and Gynecology,” 3rd edition. Norwalk Connecticut: Appleton-Century-Croft, pp 267-277. Jahoda MGJ, Wladimiroff JW, Niermeijer MF, Sachs ES, Beemer FA (1982):Ultrasonic diagnosis of fetal limb deformities. In Papadatos CJ, Bartsocas CS (eds): “Skeletal Dysplasias.”, New York: Alan R. Liss, Inc., pp 501-504. Kim HJ, Costales F, Bouzonki H, Wallech RC (1986): Prenatal diagnosis of dyssegmental dwarfism. Prenat Diagn 6:143-145. Leonard CO, Sanders RC, Law HL (1979): Prenatal diagnosis of the Turner syndrome, a familial chromosomal rearrangement and achondroplasia by amniocentesis and ultrasonography. Johns Hopkins Med J 145:25-29. Manchester DK, Pretorius DH, Avery C, Manco-Johnson ML, Wiggins J , Meier PR, Clewell WH (1988): Accuracy of ultrasound diagnoses in pregnancies complicated by suspected fetal anomalies. Prenat Diagn 8:109-117. McGuire J , Manning F, Lange I, Lyons E, deSa DJ (1987):Antenatal diagnosis of skeletal dysplasias using ultrasound. New York: Alan R. Liss, Inc., for the National Foundation-March of Dimes. BD:OAS XXIII(1):367-384. Mantagos S, Weiss RR, Mahoney M, Hobbins J C (1981):Prenatal diagnosis of diastrophic dwarfism. Am J Obstet Gynecol 139:lll-113. Noonan CD (1974):Antenatal diagnosis of fetal abnormalities. Radio1 Clin North Am 12:13-32. Quigg MH, Evans MI, Zador EI, Budew I, Belsky R, Niederlucke D, Nadler HL (1985): Ultrasonographic prenatal diagnosis of Langer type mesomelic dwarfism. Am J Hum Genet 37:A225. Rimoin DL, Lachman RS (1983): The Chondrodysplasias. In Emery AEH, Rimoin DL (eds): “Principles and Practice of Medical Genetics.” New York: Churchill Livingstone, Vol. 2, pp 703-733. Russell JGB (1973): “Radiology in the Diagnosis of Fetal Abnormalities.” London: Butterworths, pp 79-80. Stoll C, Manini P, Bloch J, Roth MP (1985): Prenatal diagnosis of hypochondroplasia. Prenat Diagn 5:423-442. Thomas RL, Hess WL, Johnson TRB (1987): Prepartum diagnosis of limb-shortening defects with associated hydramnios. Am J Perinatol 4:293-299. Tolmire J1, Whittle MJ, McNay MB, Gibson AAM, Connor JM (1987): Second trimester prenatal diagnosis of the Jarcho-Levin syndrome. Prenat Diagn 7:129-133. Vandenberghe K, DeWolf F, Fryns JP, Eggermont E, Van Den Berghe H (1984): Antenatal ultrasound diagnosis of fetal malformations: Possibilities, limitations and dilemmas. Eur J Obstet Gynecol Reprod Biol 18:279-297. Winter R, Rosenbranz W, Hofman H, Zierler H, Becker H, Borkenstein M (1985): Prenatal diagnosis of campomelic dysplasia by ultrasonography. Prenat Diagn 51-5.