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American Journal of Medical Genetics 87:226–229 (1999)

Brief Clinical Report Prenatal Sonographic Diagnosis of Hypochondroplasia in a High-Risk Fetus Marlene J. Huggins,1 John R. Mernagh,2 Leslie Steele,3 John R. Smith,1 and Małgorzata J. M. Nowaczyk4,5* 1

Department of Obstetrics and Gynecology, Hamilton Health Sciences Corporation, and McMaster University, Hamilton, Ontario, Canada 2 Department of Radiology, Hamilton Health Sciences Corporation, and McMaster University, Hamilton, Ontario, Canada 3 The DNA Diagnostic Laboratory, The Hospital for Sick Children, Toronto, Ontario, Canada 4 Department of Pathology and Molecular Medicine, Hamilton Health Sciences Corporation, and McMaster University, Hamilton, Ontario, Canada 5 Department of Pediatrics, Hamilton Health Sciences Corporation, and McMaster University, Hamilton, Ontario, Canada

Hypochondroplasia (HCH) is caused by mutations in the fibroblast growth factor receptor type 3 (FGFR 3). Prenatal diagnosis of HCH based exclusively on the sonographic measurements of the fetal skeleton is difficult and has not been reported. We describe a newborn infant with HCH who was born to a mother with achondroplasia (ACH) and a father with HCH. Serial sonographic measurements were recorded from 16 weeks of gestation. All measurements remained normal up to 22 weeks of gestation. At 25 weeks of gestation, the long bones began to appear shorter than expected for gestational age, while the head measurements (biparietal diameter and head circumference) remained normal. The measurements were sufficiently different to distinguish from findings in normal and achondroplastic fetuses. Our findings suggest that it is possible to distinguish the normal fetus from a fetus affected with HCH and to distinguish HCH and ACH from each other based on the sonographic measurements alone. To our knowledge, this is the first report of longitudinal sonographic measurements of HCH in the second and third trimesters. Am. J. Med. Genet. 87:226–229, 1999. © 1999 Wiley-Liss, Inc. KEY WORDS: hypochondroplasia; achondroplasia; FGFR3; prenatal diagnosis; skeletal dysplasia *Correspondence to: Dr. Małgorzata J.M. Nowaczyk, Room 3N16, McMaster Hospital, The Hamilton Health Sciences Corporation, 1200 Main Street West, Box 2000, Hamilton, Ont., Canada, L8N 3Z5. E-mail: [email protected] Received 19 March 1999; Accepted 24 July 1999

© 1999 Wiley-Liss, Inc.

INTRODUCTION Hypochondroplasia (HCH) [Hall and Spranger, 1979] and achondroplasia (ACH) are allelic conditions caused by mutations in the fibroblast growth factor receptor 3 (FGFR3) gene [Bonaventure et al., 1996]. Approximately 70% of HCH patients have a C→A or C→G transversion at nucleotide 1620 (C1620A or C1620G, respectively) in FGFR3 [Bonaventure et al., 1996; Rousseau et al., 1996]. More than 98% of all ACH patients have a missense mutation in FGFR3, a G→A transition at nucleotide 1138 [Shiang et al., 1994; Stoilov et al., 1995; Bellus et al., 1995]. These two alleles may be inherited in a codominant fashion. A compound heterozygote for an ACH and a HCH mutation presents clinically with a severe type of rhizomelic skeletal dysplasia known as the achondroplasia-hypochondroplasia complex (ACH-HCH) [Sommer et al., 1987; Huggins et al., 1999; Chitayat et al., 1999]. Prenatal molecular diagnosis of ACH, HCH, and ACH-HCH is available. Prenatal diagnosis of HCH based on sonographic measurements has been described in a family at risk for HCH [Stoll et al., 1985]. Ultrasound findings at 35 weeks of gestation of a child identified later to be affected with HCH have been reported [Jones et al., 1990]. Another report alluded to a misdiagnosis of a fetus with hypochondroplasia as being affected with a lethal skeletal dysplasia; no details regarding the measurements were provided [Tretter et al., 1998]. The prenatal radiographic findings in ACH [Patel and Filly, 1995] and ACH-HCH [Huggins et al., 1999] have been well described. We report the prenatal sonographic findings from 16 weeks of gestation onward in a male fetus affected with HCH. The prenatal clinical and sonographic diagnoses were confirmed by molecular DNA analysis after birth. CLINICAL REPORTS A 23-year-old woman with ACH was referred to the high-risk perinatal clinic at 16 weeks of gestation. This

Hypochondroplasia

was her first pregnancy with her partner, who had been diagnosed with HCH as a child. Neither of the baby’s parents had received genetic counseling regarding their respective conditions and the implications for their offspring, nor had they undergone molecular testing to confirm their clinical diagnoses. Molecular testing of the parents, undertaken at the time of the original consultation, confirmed the clinical diagnoses: the mother was heterozygous for the G1138A mutation in FGFR 3, whereas the father was heterozygous for the C1620G mutation in FGFR 3. Following counseling regarding these results and their implications for the pregnancy, the couple declined invasive testing of the pregnancy, opting instead for serial ultrasound examinations to monitor fetal growth and development. At that time they were told that their child had equal chances of being normal, of having ACH, of having HCH, or of having the more severe condition, ACHHCH. The findings of the first ultrasound study in the pregnancy, done at 16 weeks of gestation, were normal, and the measurements were consistent with menstrual dates; the femur length was just under the 25th centile for gestational age, and the biparietal diameter (BPD) was at the 90th centile (Table I). When plotted against BPD age (17.3 weeks), the femur length was at the 3rd centile (Fig. 1). At 19 weeks of gestation the biparietal diameter was within normal limits (90–95th centile), femur length was at 25th centile, and the long bone measurements were within normal limits (Table I). The profile views of the face were normal. Follow-up ultrasound evaluations at 3-week intervals documented long bone measurements that were increasingly shorter than the measurements expected for the gestational age and head size, which was minimally larger than that expected for gestational age (Fig. 1). The lack of linear growth of the femur was most striking in the third trimester (Fig. 1). When plotted against BPD age, the femur length fell below the third centile at 22 weeks of gestation. The clinical impression at that time was that the fetus was not normal and was likely affected with HCH. The baby was born by elective Cesarean section at 35 weeks of gestation because of cephalopelvic disproportion. Apgar scores were 6 at 1 min and 8 at 5 min of age. Birth weight was 2,706 g (50th centile), occipitofrontal

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circumference (OFC) 34.5 cm (90–95th centile), length 43 cm (5th centile), and chest circumference 28 cm (approximately 25th centile). On physical examination at 6 hr of life, rhizomelic shortness of all limbs was apparent (Fig. 2). He had downward-slanting palpebral fissures and bitemporal narrowing of the skull, but no frontal bossing and no depressed nasal bridge. The anterior fontanel was 3 × 2 cm (within +1 SD of the mean). There was first-degree hypospadias with descended testes. Chest radiograph showed hyaline membrane disease. Skeletal radiographs showed short femora and humeri and no abnormalities characteristic of ACH. Cranial ultrasound study showed a small subependymal hemorrhage and slight increase in the size of the anterior horns of the cerebral ventricles. Followup cranial ultrasonography on day 7 of life showed mild dilatation of the left lateral ventricle. Bilateral hip ultrasound findings were normal. An echocardiogram on day 3 of life detected a small patent ductus arteriosus (PDA) and mitral regurgitation. He required respirator support for 5 days because of hyaline membrane disease; he received 3 doses of synthetic surfactant with good response. Subsequently he required low-flow oxygen supplementation for 7 days and a 5-day course of dexamethasone with good response. He was discharged home at age 16 days. MOLECULAR ANALYSIS Genomic DNA from cord blood obtained at delivery and from peripheral blood of the patient and both parents was extracted, and the analysis for the common ACH and HCH mutations was performed as previously described [Huggins et al., 1999]. Molecular analysis of the FGFR 3 in the patient and his parents showed that the mother, but not the baby, carried the ACH mutation G1138A in FGFR 3, and that the patient and his father carry the HCH mutation, C1620G in FGFR 3 (data not shown). Hence, molecular analysis confirmed that the patient had HCH. DISCUSSION We present serial antenatal radiographic data on a fetus with HCH. The clinical diagnosis of HCH was confirmed by DNA mutation analysis showing the pres-

TABLE I. Sonographic Measurements of Long Bones and Growth Parameters During the Pregnancy Gestational age by dates Biparietal diameter (mm) Biparietal diameter centilea Head circumference (mm) Femur (mm) Femur length centilea Humerus (mm) Radius (mm) Ulna (mm) Tibia (mm) Fibula (mm) Abdominal circumference (mm) a

15w6d

18w6d

21w6d

24w6d

28w5d

31w1d

38 (17.4) 90th 132 (16.7) 18 (15.1) 25th 18 (15.0) 15 (15.0) 17 (15.3) 16 (15.0) 13 (14.8)

47 (20.2) 90th 175 (19.9) 26 (17.6) 25th 26 (17.7) 23 (18.5) 25 (18.6) 22 (17.0) 20 (17.3)

56 (23.2) 95th 216 (23.5) 32 (19.6) 10th 32 (20.0) 25 (19.3) 30 (20.5) 28 (19.8) 26 (19.8)

67 (27.2) > 97th 240 (26) 38 (21.8) 5th nmb 30 (21.5) 34 (22.5) 30 (20.5) 31 (22)

76 (30.8) > 97th 283 (30.7) 44 (24.1) 3rd 40 (23.7) 34 (24.0) 37 (24.0) 36 (23.0) 36 (24.5)

86 (34.8) > 97th 308 (33.9) 43 (23.7) < 3rd nmb nmb nmb nmb nmb

109 (16.4)

147 (19.7)

187 (23.3)

219 (26.2)

263 (30.4)

295 (33.6)

Elejalde and Elejade [1986]. nm, not measured. Numbers in parentheses denote the gestational age corresponding to measurement. b

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Huggins et al.

Fig. 1. Femur length versus gestational age (䊉) and BPD age (+) compared with the 97th, 50th, and 3rd centile standards.

ence of the common FGFR 3 mutation, C1620G. Because of the parental diagnoses and the early referral to a high-risk pregnancy unit, we had the opportunity to follow this pregnancy prospectively and to obtain reliable fetal measurement as of 16 weeks of gestation. The measurements obtained during this pregnancy showed that the long bone lengths in a fetus affected

Fig. 2.

with HCH are sufficiently different to allow the distinction from ACH, from ACH-HCH complex, and from the normal fetus. As late as 22 weeks of gestation the measurements of the long bones were within the normal ± 2 weeks. However, when plotted against the BPD age, the femur length was below the 3rd centile at 22 weeks [Elejalde and Elejalde, 1986]. By 25 weeks of gestation,

Patient at age 10 days, showing normal size head with bitemporal narrowing, short limbs, small chest, and normal hands and feet.

Hypochondroplasia

the long bones were shorter than expected for gestational age and remained so for the remainder of the pregnancy. The BPD and head circumference originally at the upper end of normal, rose to slightly above the 97th centile after 25 weeks of gestation. The discrepancy between the actual long bone measurements and those expected for gestational age became more prominent as the pregnancy progressed. The fact that the head measurements remained within normal values throughout the pregnancy, and that fetal profile was normal, allowed the distinction between HCH, ACH, and ACH-HCH. In cases with family history of HCH and no other skeletal dysplasia, it would be possible to make the diagnosis of HCH as early as 22–23 weeks when the long bone measurements become obviously shorter than expected for gestational age. For at-risk couples wishing noninvasive fetal assessment, this may be an acceptable alternative to molecular testing. Another approach might be to base a decision to undergo invasive prenatal molecular diagnosis on ultrasound findings. Molecular testing should always be used for definitive diagnosis if there is any consideration of pregnancy termination. Recent series on antenatal diagnosis of skeletal dysplasia showed that up to 7.8% of sonographic diagnoses of skeletal dysplasia were incorrect and that the fetus did not have any evidence of a skeletal dysplasia even in cases considered to represent lethal types of conditions [Chan et al., 1998; Sharony et al., 1993; Tretter et al., 1998]. Although lethal skeletal dysplasia is more commonly identified correctly, milder forms of skeletal dysplasias may be missed or misdiagnosed such as in cases of asymmetric intrauterine growth retardation [Tretter et al., 1998]. Our report provides antenatal sonographic measurements of a fetus affected with HCH in the second trimester of pregnancy. The measurements obtained during this pregnancy show that it is possible to distinguish a fetus with HCH from one affected with ACH or ACH-HCH and from a normal fetus, suggesting that prenatal diagnosis of HCH is possible in a high-risk pregnancy based on sonographic appearance alone. Caution is needed, however, in applying these results to low-risk pregnancies (i.e., in the absence of family history) with ultrasound findings suggestive of skeletal dysplasia; ultrasound findings may be used to direct molecular testing but should never be considered a definitive diagnosis in the absence of molecular testing antenatally. At the present time, prenatal sonographic measurements of the fetal skeleton remain the mainstay of prenatal screening for skeletal dysplasias in the general population. More reliable sonographic norms for the common osteochondrodysplasias will allow clinicians to direct prenatal molecular diagnosis in cases in which it would be most appropriate.

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ACKNOWLEDGMENTS We thank the many physicians and health care professionals at the Maternal Fetal Medicine Unit and the Neonatal Intensive Care Unit at the Hamilton Health Sciences Corporation and McMaster University who provided the prenatal and postnatal care for this patient and his mother. We also thank Ms. Del Hurst for excellent secretarial assistance. REFERENCES Bellus GA, McIntosh I, Smith EA, Aylsworth AS, Kaitila I, Horton WA, Greenhaw GA, Hecht JT, Francomano CA. 1995. A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia. Nat Genet 10:357–359. Bonaventure J, Rousseau F, Legeai-Mallet L, Le Merrer M, Munnich A, Maroteaux P. 1996. Common mutations in the fibroblast growth factor receptor 3 (FGFR 3) gene account for achondroplasia, hypochondroplasia, and thanatophoric dwarfism. Am J Med Genet 63:148–154. Chan AKJ, Chitayat D, Silver MM, Sirkin W, Lachman RS, Rimoin DL, Toi A. 1998. The accuracy of prenatal diagnosis of skeletal dysplasia. Am J Hum Genet [Suppl] 63:A160. Chitayat D, Fernandez B, Gardner A, Moore L, Glance P, Dunn M, Chun K, Ray P, Allingham-Hawkins D. 1999. A compound heterozygote for the achondroplasia-hypochondroplasia FGFR3 mutations: prenatal diagnosis and postnatal outcome. Am J Med Genet 84:401–405. Elejalde BR, De Elejalde MM. 1986. The prenatal growth of the human body determined by the measurement of bones and organs by ultrasonography. Am J Med Genet 24:575–598. Hall BD, Spranger J. 1979. Hypochondroplasia: clinical and radiological aspects in 39 cases. Radiology 133:95–100. Huggins MJ, Smith JR, Chun K, Ray PN, Shaw JK, Whelan DT. 1999. Achondroplasia-hypochondroplasia complex in a newborn infant. Am J Med Genet 84:396–400. Jones SM, Robinson LK, Sperrazza R. 1990. Prenatal diagnosis of skeletal dysplasia identified postnatally as hypochondroplasia. Am J Med Genet 36:404–407. Patel MD, Filly RA. 1995. Homozygous achondroplasia: US distinction between homozygous, heterozygous, and unaffected fetuses in the second trimester. Radiology 196:541–545. Rousseau F, Bonaventure J, Legeai-Mallet L, Schmidt H, Weissenbach J, Maroteaux P, Munnich A, Le Merrer M. 1996. Clinical and genetic heterogeneity of hypochondroplasia. J Med Genet 33:749–752. Shiang R, Thompson L M, Zhu Y-Z, Church DM, Fielder TJ, Bocian M, Winokur ST, Wasmuth JJ. 1994. Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell 78:335–342. Sharony R, Browne C, Lachman RS, Rimoin DL. 1993. Prenatal diagnosis of the skeletal dysplasias. Am J Obstetr Gynecol 169:668–675. Sommer A, Young-Wee T, Frye T. 1987. Achondroplasia-hypochondroplasia complex. Am J Med Genet 26:949–957. Stoilov I, Kilpatrick MW, Tsipouras P. 1995. A common FGFR3 gene mutation is present in achondroplasia but not in hypochondroplasia. Am J Med Genet 55:127–133. Stoll C, Manini P, Bloch J, Roth M-P. 1985. Prenatal diagnosis of hypochondroplasia. Prenat Diagn 5:423–426. Tretter AE, Saunders RC, Meyers CM, Dungan JS, Grumbach K, Sun CCJ, Campbell AB, Wulfsberg EA. 1998. Antenatal diagnosis of lethal skeletal dysplasia. Am J Med Genet 75:518–522.

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