Jeffrey S. Dungan

Antenatal diagnosis of lethal skeletal dysplasias

Lethal skeletal dysplasias (LSD) are a heterogeneous group of rare but important genetic disorders characterized by abnormal growth and development of bone and cartilage. We describe the diagnosis and outcome of 29 cases of lethal skeletal dysplasias evaluated between January 1989 and December 1996 at the University of Maryland Medical Center and the Ultrasound Institute of Baltimore. Two cases presented at delivery with no prenatal care while the remaining 27 cases were identified by antenatal sonography. Final diagnoses included thanatophoric dysplasia (14), osteogenesis imperfecta, type II (6), achondrogenesis (2), short rib syndromes (3), campomelic syndrome (2), atelosteogenesis (1), and no evidence of a skeletal dysplasia (1). Twenty out of 27 pregnancies were terminated with an average at detection of 21.6 weeks. The other 7 pregnancies that went on to deliver had an average age at detection of 29.2 weeks. Fetal abnormalities in the terminated pregnancies were identified at a significantly earlier gestational age (P = 0.0016) than the pregnancies that continued. While the identification of LSD by sonography was excellent (26/27), only 13/27 (48%) were given an accurate specific antenatal diagnosis. In 8/14 (57%) cases with an inaccurate or nonspecific diagnosis there was a significant or crucial change in the genetic counseling. Thus, while antenatal sonography is an excellent method for discovering LSD, clinical examination, radiographs, and autopsy are mandatory for making a specific diagnosis.

Aneuploidy in twin gestations : When is maternal age advanced?

Objective To determine the maternal age at which twin gestations have a risk of fetal aneuploidy comparable to that of singleton pregnancies at maternal age 35, accounting for variation in dizygotic twinning rates by maternal age and race. Methods Known aneuploidy risks and rates of dizygotic twinning by maternal age and race were used to calculate the risk of fetal aneuploidy at term and in the second trimester by maternal age and race in twin gestations, using previously published calculations. Results The risk of at least one aneuploid twin at term is 1/193 at maternal age 31 for both white and African-American women, which is comparable to the risk of 1/192 for an aneuploid singleton term pregnancy at amniocentesis at maternal age 31 is 1/190 for white and 1/187 for African-American women, which slightly lower than the rate in sinletons of 1/135. Conclusion Invasive prenatal diagnosis for detection of fetal aneuploidy should be offered to all women with twin gestations at age 31, regardless of race.

Correlation of Prenatal Ultrasound Diagnosis and Pathologic Findings in Fetal Anomalies

ABSTRACT This retrospective study compared the prenatal ultrasound (US) diagnosis with autopsy findings in 61 intact fetuses following induced abortion and 36 fragmented fetuses from dilatation and evacuation (D&E). In intact fetuses, complete agreement between US diagnosis and autopsy findings was achieved in 65.6% of cases in the central nervous system (CNS) and 47.5% in other somatic organ systems (SOS). There were major differences between US and autopsy findings involving the CNS in 6.5% of cases and SOS in 27.9%. Correlation was better for evaluation of renal anomalies (complete agreement in 63.6% of 11 suspected cases, 2 false-positive and no false-negative cases) than congenital heart disease (complete agreement in 27.3% of 11 suspected cases, 5 false-positive and 3 false-negative cases). In D&E specimens, a prenatal diagnosis of neural tube defect (NTD) was confirmed in 90% of cases. However, due to fragmentation of fetal parts, the US diagnosis in the CNS could not be confirmed totally (69.4%) or partially (2.8%) in fetuses with chromosomal abnormalities (ChA) or multiple congenital anomalies (MCA). Nonetheless, the US diagnosis of SOS was confirmed in six cases on D&E, including Meckel-Gruber syndrome, cystic hygroma, renal agenesis with contralateral renal dysplasia, cardiac defect, fetal hydrops, and tracheal atresia. Our results show that a thorough autopsy of an intact fetus after abortion is necessary to confirm prenatal diagnosis and allow proper management and counseling. The pathologic examination of D&E specimens can reliably confirm the US diagnosis of NTD, but it is very limited in identifying other fetal anomalies.

Severity of abnormality influences decision to terminate pregnancies affected with fetal neural tube defects

We examined parental decision concerning pregnancy management in women having fetuses with neural tube defects (NTDs) to determine whether severity of defect or method of detection has an impact on the decision making process. Analysis of decisions by 50 women, whose pregnancies were affected by an isolated neural tube defect (NTD) and characterized by a singleton gestation at 24 gestational weeks or less with normal chromosomal complement (46,XX or 46,XY), were assessed. All 23 women carrying fetuses with anencephaly elected to terminate their pregnancies. Of the 27 women carrying fetuses with spina bifida, 21 (77.8%) elected to terminate their pregnancies and 6 (22.2%) elected to continue their pregnancies. Of the 6 pregnancies that were continued, 4 were initially detected by ultrasonography and 2 were ascertained by maternal serum alpha-fetoprotein screening; defects ranged from 2 to 14 vertebral bodies, and none of the defects were craniad to the T9 level. This is in comparison to 5 of the 21 spina bifida cases that were elective pregnancy terminations, which were characterized by fetal lesions craniad to the T9 level. Severity of NTD thus appears to influence the decision to continue or terminate an affected pregnancy.

Diagnosis and management of prenatally detected myelomeningocele: A preliminary report

Our experience with 23 cases of fetal myelomeningocele provides preliminary information on the outcome of these infants diagnosed in utero and managed by a multidisciplinary team. The mean age of diagnosis was 23.7 weeks (range, 16 to 34 weeks). Mean gestational age at delivery was 36.9 weeks in the 14 patients who elected to continue their pregnancies. None of the 11 infants with lumbosacral or sacral lesions developed significant ventriculomegaly before term. Of the three patients diagnosed with thoracolumbar lesions, two had progression of ventriculomegaly necessitating early delivery at 32 to 34 weeks of gestation. These preliminary findings suggest that a coordinated prenatal and neonatal approach appears to result in a favorable prognosis for infants with myelomeningocele, but that neonatal complications are common, requiring careful monitoring and aggressive management.

Founder Fukutin mutation causes Walker–Warburg syndrome in four Ashkenazi Jewish families

Walker‐Warburg syndrome (WWS) is a genetically heterogeneous congenital muscular dystrophy caused by abnormal glycosylation of α‐dystroglycan (α‐DG) that is associated with brain malformations and eye anomalies. The Fukutin (FKTN) gene, which causes autosomal recessively inherited WWS is most often associated with Fukuyama congenital muscular dystrophy in Japan. We describe the clinical features of four nonconsanguinous Ashkenazi Jewish families with WWS and identify the underlying genetic basis for WWS.

Positive serum screening for fetal Down syndrome does not predict adverse pregnancy outcome in absence of fetal aneuploidy.

OBJECTIVE: The purpose of this study was to determine whether false-positive maternal serum screening for fetal Down syndrome is predictive of poor pregnancy outcome. METHODS: The pregnancy outcomes of 99 women having positive serum screening for fetal Down syndrome (study group)—based upon maternal serum alpha-fetoprotein (MSAFP), un conjugated estriol (uE3), hCG, and maternal age—were compared to the outcomes of matched control patients having negative serum screening results (control group). The outcome indices analyzed were fetal death, intrauterine growth retardation (IUGR), preeclampsia, and fetal anomalies. RESULTS: Between the study group and the control group, there were no statistically significant differences in pregnancy outcome with respect to fetal death, IUGR, preeclampsia, or fetal anom alies. CONCLUSIONS: Our findings demonstrate no apparent increase in the adverse perinatal out comes analyzed in women having unexplained positive serum screening for fetal Down syndrome. Although further investigation is needed, these results provide no evidence to support increased antepartum surveillance in such patients. (J Soc Gynecol Invest 1994;1:55-8)

3‐D ultrasound of the fetal ear and fetal autosomal trisomies: a pilot study of a new screening protocol

We hypothesize that the rotation of the ear in fetuses with common autosomal trisomies will be markedly different from euploid fetuses and amenable to detection by 3‐D ultrasound in the render mode.

Carrier screening for cystic fibrosis.

Cystic fibrosis is the first genetic disorder for which universal screening of preconceptional or prenatal patients became a component of standard prenatal care. The molecular genetics and mutation profile of the CFTR gene are complex, with a wide range of phenotypic consequences. Carrier screening can facilitate risk assessment for prospective parents to have an affected offspring, although there remains a small residual risk for carrying a mutation even with a negative screening result. There are ethnic differences with respect to disease incidence and effectiveness of carrier testing, which may complicate counseling.

Cancer Genetics: Risks and Mechanisms of Cancer in Women with Inherited Susceptibility to Epithelial Ovarian Cancer

Epithelial ovarian cancer (EOC) is a highly lethal malignancy, mostly due to the fact that the majority of cases are not detected until the disease has progressed to an advanced stage. The reason for this is that unlike endometrial cancer and cervical cancers, there are no unique symptoms associated with early (and more treatable) disease and there is currently no effective screening protocol. While most cases of EOC are not associated with an inherited predisposition, a small percentage of cases are so characterized, with such women at an increased risk not only for developing EOC but also for developing the disease at an earlier age than is observed in the general population. Nonetheless, there are effective interventions to reduce the likelihood of developing EOC. In high-risk women, consideration of such interventions should be entertained during the reproductive years; however, these interventions either temporarily (e.g., breast feeding, oral contraceptives) or permanently (e.g., tubal ligation, bilateral salpingo-oophorectomy) prevent pregnancy. It is thus imperative to identify such women early so as to offer preventive measures; conversely, the offering of such interventions must be coordinated with a frank discussion of pregnancy aspirations and family planning. Currently, the optimal approach to determine a women’s risk for developing EOC is evaluating one’s family history and offering genetic testing to those women at increased risk for having mutations in cancer susceptibility genes associated with EOC. While oncofertility is usually associated with individuals currently being treated for cancer, women at increased risk for developing EOC based on a genetic predisposition should likewise be considered for oncofertility counseling and potentially for novel fertility-sparing interventions.