Prenatal diagnosis of hypochondroplasia: Report of two cases

Abstract

Hypochondroplasia (HCH) is an autosomal dominant skeletal dysplasia characterized by short extremities, short stature and lumbar lordosis, usually exhibiting a phenotype similar to but milder than achondroplasia (ACH). Mutations in the fibroblast growth factor receptor 3 (FGFR3) gene are present in a significant proportion of HCH patients. Reports of prenatal diagnosis of HCH are very rare and the phenotype/genotype correlation in these patients is poor. Here we present two sporadic cases with second trimester ultrasound findings consistent with a diagnosis of a non-lethal skeletal dysplasia. Ultrasound evaluation after 23 weeks of gestation showed a decreased rate of development of the femora (femur length <fifth centile), while biparietal diameter, abdominal circumference, and foot length were within normal limits. Femur length/foot and femur length/abdominal circumference ratios were <0.87 and <0.18, respectively. Prenatal cytogenetic and molecular genetic analysis was performed. Karyotype was normal and FGFR3 G380R mutation characteristic of ACH was excluded in both fetuses. Molecular genetic analysis carried out retrospectively revealed that both fetuses were heterozygous for the C1620A mutation resulting in N540K substitution in FGFR3, the most common mutation in HCH. We conclude that the combination of ultrasound and molecular genetic approach is helpful for establishing an accurate diagnosis of HCH in utero and subsequently for appropriate genetic counseling and perinatal management.

Prenatal diagnosis of skeletal dysplasia due to FGFR3 gene mutations: a 9-year experience

“…In those cases with a positive molecular study of skeletal dysplasia due to FGFR3 mutations in a previous pregnancy or in an affected son, a prenatal diagnosis in a following pregnancy may be done for anxiety since germ line mosaicims must be very rare and have not been reported [21]. In our 19 CVS group, only 7 cases were really indicated for molecular study because there was a positive familial case.…”

“…Reports of prenatally diagnosed HCH foetuses are very rare. The prenatal sonographic detection of HCH is the most difficult due to the absence of specific US markers because many of the subtle symptoms of the disease are not present in utero and infancy [21]. The remarkable deviation of the foetal growth curve of femur length from the normal values in conjunction with a normal growth curve of biparietal diameter has been suggested to be a useful US indication for prenatal non-lethal skeletal dysplasia [28].…”

Successful birth with preimplantation genetic diagnosis using single-cell allele-specific PCR and sequencing in a woman with hypochondroplasia due toFGFR3mutation (c.1620C>A, p.N540K)

“…The prenatal diagnosis of HCH has been published in several antecedent reports [6,13,14]. For the prenatal diagnosis, ultrasound findings usually provide a clue to detecting fetal skeletal dysplasia and identifying the mutation can ensure the diagnosis.…”

“…HCH is a rare condition, of which the reported prevalence is approximately 1 per 50,000 births [14], but if the affected parent wants to have an unaffected baby, this brand new method using direct sequence analysis accompanied by allele-specific PCR can be successfully applied to improve the detection rate of the precise mutation site and finally to select a wild-type embryo for PGD, providing a new option applicable to many kinds of monogenic disorders for which the causative single-gene mutation is known. This case illustrates the reliability and feasibility of new single-cell analysis for PGD, reporting a healthy birth following application of the PGD method.…”

De novo achondroplasia causing four consecutive unsuccessful pregnancies: a case report

“…The ultrasound features of fetal achondroplasia include a femur length in less than the fifth centile with biparietal diameter, abdominal circumference and foot length within normal limits, a femur-to-foot length ratio of less than 0.87, and a femur length-to-abdominal circumference ratio of less than 0.18. In high-risk couples, a combination of ultrasongraphy and genetic studies would establish an accurate diagnosis, which is required for appropriate counseling [12]. A misdiagnosis chance of 7.8%, based on sonographic biometric data, has been reported [13].…”