PRENATAL DIAGNOSIS, VOL. 7,189-196 (1987)

EARLY PRENATAL DIAGNOSIS OF A LETHAL SYNDROME OF MULTIPLE CONGENITAL

CONTRACTURES

P. KIRKINEN*, R. HERVAT AND J. LEISTIS Departments of Obstetrics and Gynecology*, Pathology? and Clinical Genetics$, University of Oulu,

Finland

SUMMARY An ultrasonic diagnosis of a lethal, autosomally recessive syndrome of multiple congenital contractures was made in seven high-risk pregnancies on the 13rd to 17th gestational weeks. The diagnostic findings were the development of progressive subcutaneous oedema from the 13th gestational week on and the decrease of fetal limb movements.

KEY WORDS Prenatal diagnosis Arthrogryposis multiplex congenita, Fetal hydrops Ultrasound Early diagnosis

INTRODUCTION

In 1985 a lethal syndrome was delineated in 16 fetuses with a specific, previously unrecognized type of arthrogryposis multiplex congenita (Herva et al., 1985). The main features of this autosomally recessively inherited disorder were: marked fetal hydrops, facial dysrnorphic features, multiple joint contractures due to muscular atrophy and paucity of anterior horn motor neurons and lethality with a mean gestational age of 3 1 weeks. The syndrome has recently been proposed to represent a clearly recognizable subtype of the Pena-Shokeir phenotype or the fetal akinesia/ hypokinesia sequence (Hall, 1986). Ultrasonic examination seemed to be the only applicable method for prenatal diagnosis, because maternal serum and amniotic fluid alphafetoprotein concentrations were normal and no pathology at routine laboratory analysis of amniotic fluid biochemistry or amniotic fluid cell karyotyp- ing existed.

Because of the lethality and 25 per cent recurrence risk, an early prenatal diagnosis of this abnormality is most desirable for rational treatment of the affected pregnancy. We describe here the development of the typical ultrasonic features, which have proved to be diagnostic in this syndrome.

MATERIAL AND METHODS

The material consists of ten pregnancies monitored by ultrasound from the end of the first trimester or the early beginning of the second trimester. In all cases

Addressee for correspondence: P. Kirkinen, M.D., Department of Obstetrics, University of Zurich, Frauenklinikstr 10 8091 Zurich, Switzerland

0197-3851/87/030189-08$05.00 0 1987 by John Wiley & Sons, Ltd.

Received 28 May I986 Revised 18 September 1986 Accepted I November 1986

190 P. KIRKINEN ETAL.

the previous family history included one or more pregnancies affected by this syn- drome, as confirmed by a detailed autopsy. Eight of the pregnancies were affected by a similar fetal abnormality, resulting in six cases in therapeutic abortion and in two cases in intrauterine death at the beginning of the third trimester (Figure 1).

Figure I . A 19 week old female fetus with extreme hydrops, typical malpositions of the limbs and micrognathia

Two of the high-risk pregnancies resulted in the birth of a healthy newborn. The ultrasonic monitoring of the pregnancies was initiated in all but one case

at 8 to 16 weeks of gestation by the same experienced obstetrician. In one case the first ultrasonic examination was made in another hospital on the 17th ges- tational week resulting in normal (apparently false negative) findings, but the cor- rect diagnosis of the syndrome was made at re-examination on the 29th gestational week.

LETHAL SYNDROME OF CONGENITAL CONTRACTURES 191

RESULTS

In six affected cases the first ultrasonic examination was made on the 8th to the 12th gestational week. In all these cases the findings were considered to be normal. No abnormalities of the crown-rump growth, gestational sac diameters, whole body fetal movements or the appearance of the fetus or placenta were found at this stage of the pregnancy.

Three of the above-mentioned six cases were re-examined subsequently on the 13th-14th gestational week. Two of them where considered to be normal, and in one case (Figures 2 and 3) moderate subcutaneous oedema was diagnosed at the fetal thorax and abdomen, leading to an abnormal head/abdomen ratio, which exceeded 1. The femoral length was normal, but fetal movements were almost com- pletely absent.

Figure 2. An arthrogrypotic fetus at longitudinal ultrasonic image in the 14th gestational week. Slight oedema (between the crosses) can be seen around the fetal body (FB). FH = fetal head

Five cases were examined during the 15th to 16th gestational weeks. Abnormal findings were recorded in all these cases. All presented with severe (8 to 15 mm thick) subcutaneous oedema, which was most prominent at the thoracic and sacral levels, and less pronounced in the scalp (Figure 4). Ascites or hydrothorax was found in two fetuses. Fetal body and limb movements were unrecognizable during a 30 min systematic follow-up, but the heart activities were normal. Femoral lengths and biparietal diameters fell between the normal 50th and 25th percentiles, and

192 P. KIRKINEN ETAL.

Figure 3. The same fetus at transversal image. Oedema can be seen between the crosses. L=fetal liver SP= fetal spine A =amniotic fluid P = placenta

in one case a flexion contracture of the limbs was suspected (Figure 5). In four pregnancies the amount of amniotic fluid was considered to be normal by visual estimation, and in one case reduced. No abnormalities of the intracranial or intra- abdominal organs or placental structures were found.

Two cases were further examined during the 19th or 20th gestational weeks. Gross subcutaneous oedema (thickness 1 to 2 cm) was present, but there was only slight amount of ascites or pleural fluid. Fetal movements were absent and the amount of the amniotic fluid was slightly reduced.

One mother was sent for ultrasonic evaluation in the 29th gestational week due to suspected fetal abnormalities at routine ultrasonic screening. No anomalies had been detected in the 17th gestational week when screened by a midwife, but in the 29th week marked subcutaneous oedema, slight hydrothorax and slight ascites were found (Figure 6). Biparietal diameter was on the 50th and femoral length on the 25th percentile curve for normal pregnancy. Slight dilatation of the right cardiac ventricle accompanied by reduced aortic diastolic flow was found, and moderate pericardial effusion was detected. No clear abnormalities of the intracranial or intra-abdominal organs was present, and the fetal urinary bladder was recognized. There was marked polyhydramnios. Fetal limb movements were reduced.

Amniotic fluid alphafetoprotein was determined and fetal chromosomes were studied in four affected pregnancies and maternal serum alphafetoprotein in five. The findings were normal in all cases.

LETHAL SYNDROME OF CONGENITAL CONTRACTURES 193

Figure 4. A typical ultrasonic finding of affected fetus at the end of the 16th gestational week. A transver- sal image from the fetal abdomen. SP= fetal spine 0 =subcutaneous oedema

Ultrasonic findings in both two high-risk pregnancies with normal outcome revealed from the first trimester to term normal findings of the fetus, placenta and amniotic fluid.

DISCUSSION

Within the large and heterogenous group of fetuses with arthrogryposis multiplex congenita a tendency for fetal hydrops and polyhydramnios has been already reported (Shenker et al., 1985; Hageman and Willemse, 1983; Moerman et al., 1983). In this hereditary syndrome of congenital contractures the development of marked fetal oedema has been the rule. The majority of fetuses will die in utero before the 35th gestational week (Herva et al., 1985). The oedema has been marked and located on the body and less on the scalp. As in Goldberg’s case, there did not seem to be any accumulation of marked ascites or pleural effusions (Goldberg et al., 1986). The cause of this oedema is not known. In contrast to the findings in cystic hygroma, as in Turner’s syndrome, no subcutaneous cystic holes could be found in these cases. In our cases the oedema could be diagnosed at ultrasono- graphy before the 17th gestational week, and even at the 13th week. Thus high-risk pregnancies can be reliably monitored by ultrasound, allowing termination of the affected pregnancy.

194 P. KIRKINEN ETAL.

Figure 5 . A longitudinal scan of left leg of an affected fetus in the 16th gestational week. Femoral length (between the crosses) is within normal limits for gestational age. S=sacral area T=tibia. The leg was at a permanent, slightly flexed position for the whole time. No deformities of the long bones

could be seen

Only a few reports of the prenatal diagnosis ofjoint contractures exist (Goldberg et al., 1986; Miskin et al., 1979), and experience about early diagnosis has been minimal. At late pregnancy it is possible to visualize by ultrasound abnormal limb positions of the fetus, such as constant flexion at the elbow (Goldberg et al., 1986). According to our experience, this is not possible in early pregnancy, in particular if the amount of amniotic fluid is not increased. Human motor activity, which begins between 7 and 8 weeks from the last menstrual period, is first expressed by wormlike whole body movements, which did not seem to be affected in this syndrome. The more differentiated limb and arm movements from the 10th ges- tational week onwards (Hill et al., 1983), on the other hand, were no doubt severely affected in this syndrome, indicating a disturbance in the normal development of neurogenic control of the musculoskeletal system. These can be monitored by care- ful ultrasonic examination from the 15th week. Quite probably the cause of the diminution of the movements, poor development of the muscular system and per- manent joint contractures may be found in the pathology of spinal anterior horn neurones (Moerman et al., 1985).

The ultrasonic signs do not seem to be pathognomonic and a definitive diagnosis of this syndrome is not possible in low-risk pregnancies in families without earlier affected outcomes. In such low-risk pregnancies also other causes of nonimmune

LETHAL SYNDROME OF CONGENITAL CONTRACTURES 195

Figure 6. Ultrasonic finding of the syndrome at late pregnancy. A transversal ultrasonic image of fetal body in the 30th gestational week. SP= fetal spine P=pulmonary area with slight pleural effusions

S = left cardiac ventricle D =right cardiac ventricle A = amniotic fluid

hydrops must be considered. Anyway, early development of homogenous sub- cutaneous oedema around the fetal body, not accompanied by marked ascites, and reduced limb movements ought to arouse the suspicion of the lethal type of arth- rogryposis multiplex congenita. Detailed evaluation of the joints in the arms and legs later during the course of the pregnancy can reveal congenital contractures, because these pregnancies usually develop polyhydramnios, which improves the diagnostic accuracy.

REFERENCES

Goldberg, J. , Chervenak, F., Lipman, R., Berkowitz, R. (1986). Antenatal sonographic diagnosis of arthrogryposis multiplex congenita, Prenut. Diugn., 6,45-49.

Hageman, G., Willemse, J. (1983). Arthrogryposis multiplex congenita. Review with com- ment, Neuroped., 14,611.

Hall, J . (1986). Analysis of Pena-Shokeir phenotype. Invited editorial comment, Am. J. Med. Genet., 2599-1 17.

Herva, R., Leisti, J., Kirkinen, P. (1985). A lethal autosomal recessive syndrome of multiple congenital contractures, Am. J. Med. Genet., 20,431439.

Hill, L., Breckle, R., Wolfgram, R. (1983). An ultrasonic view of the developing fetus, Obstet. Gynecol. Surv., 38,375-398.

Miskin, M., Rothberg, R., Rudd, N., Benzie, R., Shime, J. (1979). Arthrogryposis multiplex congenita-prenatal assessment with diagnostic ultrasound and fetoskopy, J. Ped., 95, 463464.

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Moerman, P., Fryns, J., Goddeeris, P., Lauweryns, J. (1983). Multiple ankyloses, facial anomalies, and pulmonary hypoplasia associated with severe antenatal spinal muscular atrophy, J. Ped., 103,238-239.

Moerman, P., Fryns, J., Van Dijck, H., Lauweryns, J. (1985). Congenital muscular dystro- phy associated with lethal arthrogryposis multiplex congenita, Virchows Arch., 408,4348.

Shenker, L., Reed, K., Anderson, A., Hauck, L., Spark, R. (1985). Syndrome ofcamptodac- tyly, ankyloses, facial anomalies, and pulmonary hypoplasia (Pena-Shokier syndrome) : obstetric and ultrasound aspects, Am. J. Obstet. Gynecol., 152,303-307.