American Journal of Medical Genetics 3:371-375 (1979)

Invited Editorial Comment: Failure of Early Prenatal Diagnosis in Classic Achondroplasia Judith G. Hall, Mitchell S. Golbus, C. Benjamin Graham, Roberta A. Pagon, David A. Luthy, and Roy A. Filly

Departments of Medicine and of Pediatrics (J.G.H., R.A.P.), Department of Obstetrics and Gynecology (D.A. L.), and Department of Radiology (C.B.G.), University of Washington School of Medicine Division of Medical Genetics, Seattle; Childrens‘ Orthopedic Hospital and Medical Center (J.G.H., R.A.P., C.B.G.), Seattle; and Departments of Obstetrics and Gyn- ecology and of Reproductive Sciences (M.S.G.), and Department of Radiology (R.A.F., M.S. G.), University of California, San Francisco

INTRODUCTION

Fetal skeletal anomalies have been detected radiographically before 20 weeks of gesta- tion in a number of instances [Omenn et al, 1973; Richardson et al, 19771. We report that radiographic and ultrasonographic examinations during the first half of pregnancy failed to demonstrate diagnostic bone changes in two infants with classic achondroplasia. It appears that early prenatal radiographic diagnosis of heterozygous achondroplasia is currently not possible.

CLINICAL REPORTS

Case 1

A 29-year-old woman and her nonconsanguineous husband had achondroplasia. They requested prenatal diagnostic tests during her second pregnancy in view of the fact that her first pregnancy had ended at 33 weeks with the stillbirth of a male infant with apparent homc zygous achondroplasia [Hall et al, 19691. Roentgenographic examination of that fetus at 30 weeks gestation had demonstrated gross skeletal manifestations of presumed homozygous achondroplasia.

Received for publication November 28, 1978; accepted December 26, 1978.

Address reprint requests t o Judith G. Hall, MD, Division of Medical Genetics, Children’s Orthopedic Hospital and Medical Center, 4800 Sand Point Way NE, Seattle, WA 98105.

0148-7299/79/0304-0371$01.40 @ 1979 Alan R. Liss, Inc.

372 Hall et a1

Prenatal diagnosis during the second pregnancy was undertaken at 19 weeks. Sedation, localization, and radiation considerations have been discussed previously [Omenn et al, 19 771 . On this occasion, the fetus was sedated through intravenous administration of 5 mg of mor- phine sulfate t o the mother immediately before localization through ADR real-time ull rasound scanning. Homozygous achondroplasia was excluded with confidence (Fig. 1) but it was not possible to answer with certainty whether the infant was normal or had heterozygous achon- droplasia. Therefore, additional films were taken at 23 weeks. Initially, suspicion of heterozy- gous achondroplasia was high because most of the well-visualized long bones appeared some- what short, but this was finally thought to be due to their angulation in relation to the X-ray beam, since a radius and ulna seen in excellent profile had reasonably normal proportions (Fig. 2). Thus, it was concluded that the fetus was probably unaffected. However, a fetogram at 33 weeks clearly showed classic achondroplasia, and the otherwise healthy 3,400-gm, 48-cm-long female infant was delivered at 38 weeks by cesarean section.

Case 2

A 32-year-old woman with achondroplasia and her 34-year-old nonconsanguineous hus- band with hypochondroplasia [Frydman et al, 19741 requested prenatal diagnosis during her first pregnancy to determine if the fetus was a compound heterozygote for both conditions. Sonographic examination, by means of a linear nonphased array real-time system and a stan- dard static gray-scale imaging machine, and roentgenographic examination were perforrned at 19 and 29 weeks, using 10 mg of diazepam for fetal sedation given orally to the mother one hour before the studies. The radiographic findings at 19 weeks were similar to those seen in Figure 1. No abnormalities of the fetal skeleton were identified at the later examination At term, a 3,460-gm 48-cm-long infant with heterozygous achondroplasia was delivered by ce- sarean section.

DISCUSSION

Prenatal diagnosis was undertaken in both cases because of the 25% risk to each couple of having a severely affected child, homozygous achondroplasia in Case 1 and compound achondroplasia/hypochondroplasia in Case 2. Achondroplasia homozygotes have severe thora- cic dystrophy and contracted foramen magnum with hydrocephalus that is almost always le- thal within weeks or months of birth [Hall et al, 19691. Those with the achondroplasia/ hypochondroplasia compound condition, in addition to marked skeletal changes, have hydro- cephalus and mental retardation [McKusick et al, 19731.

Achondroplasia homozygotes have skeletal manifestations similar to but more severe than those of heterozygotes, and genetic compounds for the achondroplasia and hypochon- droplasia genes have bone changes intermediate between those seen in heterozygous achon- droplasia and homozygous achondroplasia. In both disorders the skeletal abnormalities are so severe as to allow for definite prenatal radiographic diagnosis.

Although the risk of having an infant with typical heterozygous achondroplasia was 50% in Case I and 25% in Case 2, neither couple was interested in definitive diagnosis of a heterozygous fetus for the purpose of abortion.

fore 20 weeks of gestation in genetic disorders such as the syndrome of thrombocytopenia and absent radius [Omenn et al, 19731 , or Saldino-Noonan dwarfism [Richardson et al, 19771, in which the bone abnormalities appear to be of sufficient severity to allow for early visuali-

Intrauterine radiographic identification of skeletal anomalies can be accomplished be-

Failure To Diagnose Achondroplasia Prenatally 373

Fig. 1. Case 1 at 18 weeks.

374 Hall et a1

Fig. 2. Case 1 at 23 weeks. Radius and ulna well visualized (arrow).

Fai lure To Diagnose Achondroplas ia Prena ta l ly 375

zation. Whether skeletal dysplasias with less pronounced long bone changes such as achondro- plasia are amenable to early prenatal diagnosis by roentgenographic examination has not been determined, and only one such attempt has been reported [Golbus and Hall, 19741 . The findings in our two cases suggest that, even under the best conditions of fetal sedation and localization with ultrasound, either the long bone changes are too mild to be detected be- fore 20 weeks or that current radiographic resolution is inadequate to identify the subtle mor- phologic changes present. Standardization of fetal limb lengths or better demonstration of bone detail through improvements in ultrasound technology may provide a technique for in- trauterine diagnosis of certain dwarfing conditions; however, the current inability to dis- tinguish fetuses for the heterozygous achondroplasia gene early in pregnancy should be re- cognized by those counseling couples at risk.

ACKNOWLEDGMENTS

This work was supported by Gene Center grant GMI 5253 from the US Public Health Service, Fellowship Training grant CA-90, National Foundation March of Dimes 6-44 and the James Picker Foundation.

The authors wish to thank Susan Conrad, MD, Roger Warner, MD, and Carl Dorsey, RT, for technical assistance and clinical information, and Bonnie McLoughlin for technical and editorial assistance.

RE FE R ENCES

Frydman M, Hertz M, Goodman RM (1974): The genetic entity of hypochondroplasia. Clin Genet 5:

Golbus MS, Hall BD (1974): Failure to diagnose achondroplasia in utero. Lancet 1 :629. Hall JG, Dorst JP, Taybi H, Scott CI, Langer LO J r , McKusick VA ( I 969): Two probable cases of homo-

223-229.

zygosity for the achondroplasia gene. In Bergsma D (ed): “Skeletal Dysplasias, Part IV.” Birth Defects Original Article Series.Baltimore: Williams & Wilkins, vol 5, No. 4 , pp 24-34.

McKusick VA, Kelly TE, Dorst JP ( 1 973): Observations suggesting allelism for the achondroplasia and hypo- chondroplasia genes. J Med Genet 1O:ll-16.

Omenn GS, 1:igley MM, Graham CB, Heinrichs WL (1973): Prospects for radiographic intrauterine dia- gnosis - the syndrome of thrombocytopenia with absent radii. N Engl J Med 288:777-778.

Omenn GS, Hall JG, Graham CB, Karp LE (1977): The use of radiographic visualization for prenatal diagnosis. In Bergsma D (ed): “Embryology and Pathogenesis, and Prenatal Diagnosis.” Birth De- fects Original Article Series. New York: Alan R. Liss, vol 13, No. 3 D, pp 217-229.

Richardson MM, Beaudet AL, Wagner ML, Malini S , Rosenberg HS, Lucci JA (1977): Prenatal diagnosis of recurrence of Saldino-Noonan dwarfism. J Pediatr 91:467-471.

C o m m u n i c a t e d by John M . O p i t z