Prenatal Diagnosis of Fetus with Short Limbs Caused by Three Abnormal Chromosomes Inherited from Parents

A 29 year old woman with history of G2P0+1 and shortening of limbs in past pregnancy referred herself to undergo a fetal anomaly scan at 18th week of gestation. The ultrasonographic imaging of the present pregnancy admeasuring the growth of 12-13 weeks at 18th week detected hydrocephalous condition with short limbs and kyphotic spine. This report aimed at looking for chromosomal aberrations in association with the imaging results and discussed the case in light of available literature. Amniocentesis and conventional cytogenetic analysis was performed following the standard protocol of tissue culture and chromosome banding. Karyotypic analysis of 50 metaphases detected an abnormal female karyotype with 46,XX,inv(9)(p11q13),t(15;16)(q15;q22) pattern. The karyotype revealed two constitutive abnormalities involving four break-points on three different chromosomes in a female genome. Upon counseling, the parents decided to terminate the pregnancy. However, at delivery the external genitalia of the female fetus was found to be of male phenotype and ambiguous. Parental karyotyping revealed transmission of inversion from mother and the balanced translocation from father. Finally the fetal karyotype was expressed as 46,XX,inv(9)(p11q13)mat,t(15;16)(q15;q22)pat. Address for correspondence: Dr. Bani Bandana Ganguly, Ph.D, FICMCH MGM Centre for Genetic Research and Diagnosis MGM Institute of Health Scineces MGM Medical College Building, Ground floor, Kamothe Sector 1, Navi Mumbai 410209, Maharashtra, India Telephone: 91 22 27437895, 91 9869214680, Fax: 91 22 27430320 E-mail: [email protected], [email protected] INTRODUCTION Chromosomal analysis in prenatal diagnostic practice has long been considered a gold standard technique, which not only recognizes numerical alterations but also structural rearrangements to a large extent. The facility also guides for prenatal karyotyping of fetus to understand inherited or de novo origin and drives urgency on decision for a medical termination of pregnancy (MTP) and genetic counseling for parents, siblings and close blood-relatives. Such information on chromosomal abnormalities in adults is typically extracted retrospectively since balanced translocations and inversions do not generally express phenotypically in first generation carriers. Occurrence of chromosomal abnormalities in the general population has been shown to vary over age groups, 5-13% in adults, 2-5% in children (excluding Down syndrome), 510% in aborted fetus, 3-5% in live fetus, etc. (Jeong et al. 2010; Kaur and Singh 2010; WHO 2010); however, these statistics stem from referred cases only. Thus, the actual frequency in general population can be expected to be much higher and this has been reflected at least in the case of recurrent miscarriage where more than 50% fetuses are reported with major chromosomal abnormalities. Changes in numerical alteration lead to significant phenotypic and clinical manifestation with trisomy 21 being the most common autosomal variation. Structural anomalies, if balanced, are generally not suspected in adults to express clinically. Among all such structural aberrations, pericentric inversion in 9(p11q13 or p11q12) is the most common at any age (1-2% fetuses) and is considered a polymorphic variant since it is not associated with a specific phenotypic or clinical expression. However, a number of abnormalities have been reported in carriers of inv(9) and more frequently in adults having history of primary or secondary infertility (Akbas et al. 2010; Dana and Stoian 2012; Kumar et al. 2012). Abnormalities involving other chromosomes have also been recorded in prenatal diagnosis. Whether the abnormality is numerical or structural, involvement of mostly single and rarely dual chromosomes have been reported. In prenatal diagnostic practice, generally terminations of such 84 B. B. GANGULY AND N. N. KADAM fetuses have been a choice of the couples to avoid clinical complications in future life of the children where mental retardation is a common problem. In the present report the researchers describe a fetus with three abnormal chromosomes causing shortening of limbs and growth retardation as major abnormality detected in ultrasound imaging. Further genetic counseling has detected transmission of all aberrations from both parents and guided the family for future course of action with possible risk and recurrence of aberrations in future pregnancy. The report highlights the importance of chromosome analysis in prenatal diagnosis. The case is deemed important to the research community since the fetus is carrying three abnormal chromosomes with a unique clinical expression not directly linked to either of the involved chromosome viz. 9, 15 or 16 and their break-points and most importantly, neither parents show any phenotypic abnormality.