GPC3 mutation analysis in a spectrum of patients with overgrowth expands the phenotype of Simpson-Golabi-Behmel syndrome.

Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked overgrowth syndrome caused by deletions in glypican 3 (GPC3). SGBS is characterized by pre- and postnatal overgrowth, a characteristic facial appearance, and a spectrum of congenital malformations which overlaps that of other overgrowth syndromes. We performed GPC3 deletion screening on 80 male patients with somatic overgrowth in the following categories: SGBS (n = 19), possible SGBS (n = 26), including families in which individuals had previously been diagnosed with other overgrowth syndromes, and Wiedemann-Beckwith syndrome (WBS) (n = 35). Using exon-specific PCR and Southern blot analysis, we identified seven GPC3 deletions. In most cases a clear X-linked family history was not present. In two cases, GPC3 deletions were identified in patients belonging to pedigrees published previously as other overgrowth syndromes: one with a diagnosis of Sotos syndrome and the other Perlman syndrome with nephroblastomatosis. A third patient developed hepatoblastoma, a tumor type not previously described in SGBS. No GPC3 deletions were identified among the WBS patients. Direct sequencing of all GPC3 exons in the remaining 13 SGBS patients without GPC3 deletions did not identify any further mutations, raising the possibility of alternative silencing mechanisms and/or other genes in the pathogenesis of SGBS. Our results validate the clinical specificity of the facial appearance, skeletal/hand anomalies, and supernumerary nipples in patients with GPC3 deletions. Our data also suggest that nephroblastomatosis and hepatoblastoma are included in the phenotypic spectrum of GPC3 deletions and SGBS, underscoring the importance of tumor surveillance in these children.

Oculo-palatal-cerebral syndrome: a second case.

Oculo-palato-cerebral syndrome is an extremely rare disorder consisting of low birth weight, microcephaly, short stature, persistent hyperplastic primary vitreous, microphthalmia, large ears, small hands and feet, cleft palate, joint hypermobility, developmental delay, and cerebral atrophy. There has been one report of a consanguineous family with three affected children, suggesting autosomal recessive inheritance. We report on the second case of this disorder. Our patient, a 2-year-old boy, had growth delay, microcephaly, bilateral persistent hyperplastic primary vitreous with right microphthalmia, long ears with thickened helices, small hands and feet, highly arched palate, joint hypermobility, hypoplastic nails, frontal cerebral atrophy and thinning of the corpus callosum on brain magnetic resonance imaging, and mild developmental delay. He has much milder features than those seen in the previously reported cases.

Cost-benefit analysis of prenatal diagnosis for Down syndrome using the British or the American approach.

OBJECTIVE: To compare the cost and benefits of prenatal diagnosis for Down syndrome using the British and American approaches. METHODS: This cost-benefit analysis was based on a decision-analytic approach. The British strategy included screening by a first-trimester ultrasound at 10-14 weeks for nuchal translucency thickness, and the American strategy included only second-trimester screening by using maternal age and maternal serum screening. The key probabilities of the decision-tree analysis and all cost estimates were based on American standards. The best scenario of the British strategy assumed ultrasound nuchal translucency thickness sensitivity (for detecting Down syndrome) of 80% and a false-positive rate of 5% and the worst scenario assumed a sensitivity of 50% and a false-positive rate of 10%. The results were expressed in annual costs based on approximately 4 million births per year in the United States. RESULTS: As compared with do-nothing, the American strategy was found to allow savings of approximately $96 million per year and the best scenario for the British strategy was savings of approximately $5 million per year. The financial costs of the British and American strategies would be comparable only if the first-trimester ultrasound had a sensitivity of 80% and a false-positive rate of 5% in detecting Down syndrome. CONCLUSION: The British strategy does not appear to be economically beneficial in the United States even under the most ideal scenarios of ultrasound accuracy.

Indication-specific accuracy of second-trimester genetic ultrasonography for the detection of trisomy 21.

OBJECTIVE: The object of this study was to determine whether there are any clinically significant indication-specific variations in the accuracy of second-trimester genetic ultrasonography and to provide a risk adjustment for fetal trisomy 21 according to the results of genetic ultrasonography. STUDY DESIGN: From November 1, 1992, to September 30, 1998, a second-trimester genetic sonogram was offered to all pregnant women who were at an increased risk for fetal trisomy 21 (>/=1:274) because of either advanced maternal age (>/=35 years) or abnormal serum biochemical profile or both of these. Outcome information included the results of genetic amniocentesis if performed and the results of pediatric assessment and follow-up after birth. In determining diagnostic accuracy of the genetic sonogram the presence of >/=1 abnormal ultrasonographic marker was considered an abnormal test result. RESULTS: A total of 1835 fetuses with known outcomes underwent genetic ultrasonography between 15 and 24 weeks' gestation; of these 1792 had normal results, 34 had trisomy 21, and 9 had other chromosomal abnormalities. The likelihood of fetal trisomy 21 was reduced by 80% after a normal result of genetic ultrasonography. The overall sensitivity, specificity, and positive and negative predictive values of genetic ultrasonography for the detection of trisomy 21 were 82%, 91%, 15%, and 99.6%, respectively. There were no significant indication-specific variations in the accuracy of second-trimester ultrasonography. The sensitivity for the detection of fetal trisomy 21 ranged from 80% among women with advanced maternal age to 100% among women with both an abnormal biochemical profile and advanced maternal age. CONCLUSIONS: The likelihood of fetal trisomy 21 risk was reduced 80% after a normal result of genetic ultrasonography. In addition there were no significant indication-specific variations in the detection rate of genetic ultrasonography.

Economic evaluation of prenatal carrier screening for fragile X syndrome.

OBJECTIVE: The objective of this study was to conduct an economic evaluation of routine prenatal carrier testing for fragile X syndrome. METHODS: This economic analysis was conducted from the societal perspective. A cost-benefit equation was developed based on the premise that the cost of routinely offering prenatal carrier testing for fragile X syndrome should be at least equal to, or less than, the cost of the current practice of not offering such testing. Sensitivity analyses included key assumptions regarding therapeutic abortion rates (50-100%) and patient screening acceptance rates (50-80%). RESULTS: A policy of routinely offering prenatal carrier testing for fragile X syndrome may be beneficial only if the cost per screening test is less than $120 during the first year of the screening program, or less than $240 when the program reaches its full maturity. Given the current cost per screening test of $250, prenatal screening for carrier status for fragile X syndrome carries the potential for annual losses of approximately $10 to $195 million in the United States. In addition, approximately 46-115 fetal lives may be lost due to invasive genetic procedures. CONCLUSIONS: Prenatal screening for fragile X syndrome may be economically beneficial only if the cost of the prenatal screening test for carrier identification is considerably less than the current cost.

Cost-benefit analysis of targeted ultrasonography for prenatal detection of spina bifida in patients with an elevated concentration of second-trimester maternal serum alpha-fetoprotein.

OBJECTIVE: The objectives of this study were to examine (1) the diagnostic accuracy requirements (from the cost-benefit point of view) of targeted ultrasonography versus genetic amniocentesis for prenatal detection of spina bifida in women with an elevated level of maternal serum alpha-fetoprotein, (2) the ultrasonographic accuracy of previously published studies from the cost-benefit point of view, and (3) the possible economic impact for the United States of offering targeted ultrasonography instead of routine amniocentesis to this group of patients. STUDY DESIGN: Our cost-benefit formula was based on the hypothesis that the cost of universal genetic amniocentesis in patients with an elevated concentration of maternal serum alpha-fetoprotein in the second trimester should be at least equal to the cost of universal targeted ultrasonography, with amniocentesis used only for those with abnormalities on a sonogram. The main components of the formula included the diagnostic accuracy of targeted ultrasonography (sensitivity and specificity for detecting spina bifida), the cost of the amniocentesis package, the cost of targeted ultrasonography, and the lifetime cost of spina bifida not detected by targeted ultrasonography. After appropriate manipulation of the formula, a graph was constructed to represent the balance between the sensitivity and false-positive rate of targeted ultrasonography and was used to examine the accuracy of previously published ultrasonographic studies from the cost-benefit point of view. Sensitivity analyses included a range of prevalences of spina bifida in women with elevated maternal serum alpha-fetoprotein from 1:50 to 1:200 and false-positive rates of targeted ultrasonography from 1% to 10%. RESULTS: Assuming overall prevalences of spina bifida of 1:50, 1:100, or 1:200 among women with elevated maternal serum alpha-fetoprotein, we found targeted ultrasonography to be beneficial only if the overall sensitivities for detecting fetal spina bifida were >88%, >76%, and >51%, respectively. All 17 studies published after the mid-1980s, which used the "cranial signs" for detecting spina bifida, had accuracies compatible with economic benefits (sensitivities, 92% to 100%; false-positive rates, 0% to 3%). CONCLUSION: The benefit of second-trimester targeted ultrasonography for fetal spina bifida depends on diagnostic accuracy (ie, sensitivity and false-positive rate). Currently achieved ultrasonographic accuracies are compatible with net benefits. Targeted ultrasonography in patients with an elevated level of second-trimester maternal serum alpha-fetoprotein in the United States has the potential for annual savings of approximately $36 million to $49 million and for avoiding 268 fetal deaths.

Sonographic identification of fetuses with Down syndrome in the third trimester: a matched control study.

OBJECTIVE: To determine sonographic findings in Down syndrome fetuses in the third trimester. METHODS: Down syndrome fetuses who had third-trimester ultrasound examinations between 25 and 41 weeks' gestation were matched for gestational age with three controls each. Fetal structural anomalies, Down syndrome dysmorphology markers (abnormal facial profile, sandal gap, tongue thrusting, clinodactyly, or hypoplastic middle phalanx of the fifth finger), and abnormal long-bone biometry (femur, humerus, tibia, and fibula; femur length to biparietal diameter ratio; and femur length to abdominal circumference ratio were abstracted from the ultrasound reports. The fetal face, hands, feet, profile, and cardiac outflow tracts are routinely evaluated in our center. RESULTS: Seventeen fetuses with Down syndrome who had third-trimester ultrasound evaluations were identified. Anomalies included cardiac defects (five), tongue thrusting (three), clinodactyly (three), abnormal profile (three), sandal gap (two), and duodenal atresia (two). Of the 17 fetuses, at least one long-bone abnormality was found in 13, at least one structural or biometric anomaly was found in 15, and at least two abnormal findings existed in 11. Abnormal ultrasound findings, including structural anomalies, short bones, and Down syndrome dysmorphology markers, were more common in cases than in matched controls. CONCLUSION: At least one abnormal ultrasound finding was present in 15 of 17 fetuses, and abnormal bone measurements or ratios were discovered in 13 of 17. Abnormal long-bone biometry at third-trimester ultrasound should raise the suspicion of fetal Down syndrome.

Blepharophimosis, hypoplastic radius, hypoplastic left heart, telecanthus, hydronephrosis, fused metacarpals, and "prehensile" halluces: a new syndrome?

We report on the prenatal ultrasound and postnatal findings in an infant born to a healthy, nonconsanguineous couple. The infant had microcephaly, telecanthus, blepharophimosis, cleft palate, micrognathia, abnormally modeled ears, hypoplastic left heart, hypoplastic radii and ulnae with radial subluxation, pseudoarthrotic distal humeri, fused metacarpals, tibial bowing, unusual feet with long halluces, hydronephrosis, patent urachus, abnormal electroencephalogram, and normal karyotype. To our knowledge, this combination of anomalies has not been recognized previously and may represent a new condition.

An economic evaluation of second-trimester genetic ultrasonography for prenatal detection of down syndrome.

OBJECTIVE: The objective of this study was to perform an economic evaluation of second-trimester genetic ultrasonography for prenatal detection of Down syndrome. More specifically, we sought to determine the following: (1) the diagnostic accuracy requirements (from the cost-benefit point of view) of genetic ultrasonography versus genetic amniocentesis for women at increased risk for fetal Down syndrome and (2) the possible economic impact of second-trimester genetic ultrasonography for the US population on the basis of the ultrasonographic accuracies reported in previously published studies. STUDY DESIGN: A cost-benefit equation was developed from the hypothesis that the cost of universal genetic amniocentesis of patients at increased risk for carrying a fetus with Down syndrome should be at least equal to the cost of universal genetic ultrasonography with amniocentesis used only for those with abnormal ultrasonographic results. The main components of the equation included the diagnostic accuracy of genetic ultrasonography (sensitivity and specificity for detecting Down syndrome), the costs of the amniocentesis package and genetic ultrasonography, and the lifetime cost of Down syndrome cases not detected by the genetic ultrasonography. After appropriate manipulation of the equation a graph was constructed, representing the balance between sensitivity and false-positive rate of genetic ultrasonography; this was used to examine the accuracy of previously published studies from the cost-benefit point of view. Sensitivity analyses included individual risks for Down syndrome ranging from 1:261 (risk of a 35-year-old at 18 weeks' gestation) to 1:44 (risk of a 44-year-old at 18 weeks' gestation). This economic evaluation was conducted from the societal perspective. RESULTS: Genetic ultrasonography was found to be economically beneficial only if the overall sensitivity for detecting Down syndrome was >74%. Even then, the cost-benefit ratio depended on the corresponding false-positive rate. Of the 7 published studies that used multiple ultrasonographic markers for genetic ultrasonography, 6 had accuracies compatible with benefits. The required ultrasonographic accuracy (sensitivity and false-positive rate) varied according to the prevalence of Down syndrome in the population tested. CONCLUSIONS: The cost-benefit ratio of second-trimester genetic ultrasonography depends on its diagnostic accuracy, and it is beneficial only when its overall sensitivity for Down syndrome is >74%.

An economic evaluation of prenatal strategies for detection of trisomy 18.

OBJECTIVE: The objective of this study was to perform an economic evaluation of prenatal diagnostic strategies for women who are at increased risk for fetal trisomy 18 caused by either fetal choroid plexus cysts discovered in a conventional sonogram or an abnormal triple screen. STUDY DESIGN: The prevalence of trisomy 18 in the presence of second-trimester fetal choroid plexus cysts and also in the presence of abnormal triple screen were made on the basis of previously reported studies. A cost/benefit analysis and cost-effectiveness determination of 3 strategies were performed: (1) no prenatal diagnostic workup of at-risk patients, (2) universal genetic amniocentesis of all at-risk patients, and (3) universal second-trimester targeted genetic ultrasonography of all at-risk patients with amniocentesis (for fetal karyotyping) reserved only for those with abnormal ultrasonography results. RESULTS: The strategy of no prenatal diagnostic workup was the least expensive approach, costing $1,650,000 annually in the United States. The more costly approach was the strategy of universal amniocentesis for detecting fetal trisomy 18 in the presence of either second-trimester choroid plexus cysts or abnormal maternal serum screening, generating an annual cost of approximately $12 million and 40 fetal losses as a result of amniocenteses. The strategy of targeted genetic ultrasonography generated an annual cost of only $5 million and 8 fetal losses as a result of amniocenteses. CONCLUSIONS: Routine second-trimester amniocentesis in patients at increased risk for fetal trisomy 18 caused by either the presence of fetal choroid plexus cysts or abnormal triple screening is not justified from the cost/benefit point of view.

A cost-effectiveness analysis of prenatal carrier screening for cystic fibrosis.

OBJECTIVE: To examine the cost-effectiveness of prenatal carrier screening for cystic fibrosis. METHODS: A cost-benefit equation was developed that was based on the hypothesis that the cost of prenatal diagnosis required to diagnose and prevent one case of cystic fibrosis should be equal to or less than the lifetime cost generated from the birth of a neonate with cystic fibrosis. The formula was adjusted because a woman's positive or negative carrier status remains unchanged, thus eliminating the need for testing in subsequent pregnancies. The formula was manipulated to identify the optimal cost per screening test, as well as the net cost savings per prenatally diagnosed case of cystic fibrosis for various racial or ethnic groups. Sensitivity analyses included some key assumptions regarding the cost per screening test ($50-150), patient screening acceptance rates (25-100%), and therapeutic abortion rates (50-100%). RESULTS: Assuming therapeutic abortion rates of 50-100%, the net savings per prenatally diagnosed case of cystic fibrosis are $58,369-$382,369 among whites. Given the previously reported patient screening acceptance rates of 50-78%, the overall annual cost savings in the United States for whites are $161-251 million. However, the screening program was not found to be cost-effective for blacks, Asians, or Hispanics. CONCLUSION: Under most assumptions and sensitivity analyses, a prenatal cystic fibrosis-carrier screening program appears to be cost-effective.

An economic evaluation of first-trimester genetic sonography for prenatal detection of Down syndrome.

OBJECTIVE: To determine 1) the diagnostic accuracy requirements of first-trimester genetic sonography from the cost-benefit point of view and 2) the economic impact of first-trimester genetic sonography for the United States on the basis of the accuracy of previously published studies. METHODS: A cost-benefit equation was developed on the basis of the hypothesis that the cost of chorionic villus sampling (CVS) in pregnant women with advanced maternal age (at least 35 years old) should be at least equal to the cost of genetic sonography with CVS used only for those with abnormal ultrasound results. The components of the equation included the diagnostic accuracy of genetic ultrasound (sensitivity and specificity for detecting Down syndrome), the costs of the CVS package and genetic ultrasound, and the lifetime cost of Down syndrome cases. RESULTS: First-trimester genetic sonography was found to be beneficial if the overall sensitivity for detecting Down syndrome was greater than 70%, and even then, the cost-benefit ratio depended on the corresponding false-positive rate. The required minimum ultrasound sensitivity varied according to the maternal age-specific prevalence of Down syndrome and ranged between 40% (for women 35 years old) to 96% (for women 44 years old). Of eight published cohorts using nuchal translucency thickness for genetic sonography, five had accuracies of genetic ultrasound compatible with net benefits. CONCLUSION: The benefits of first-trimester genetic sonography depend on its diagnostic accuracy. First-trimester genetic sonography has the potential for annual savings of 22 million dollars in the United States.

Intrauterine growth and ultrasound findings in fetuses with Beckwith-Wiedemann syndrome.

OBJECTIVE: To assess intrauterine growth in a series of nine fetuses diagnosed with Beckwith-Wiedemann syndrome. METHODS: Infants confirmed postnatally to have Beckwith-Wiedemann syndrome were identified from records maintained in the Division of Clinical Genetics. Antenatal ultrasound and birth records were evaluated. Head circumference (HC), abdominal circumference (AC), and estimated fetal weight (EFW) were assigned percentiles based on gestational age. Newborn HC and birth weight were also assigned percentiles. Polyhydramnios was diagnosed using either amniotic fluid index or documented subjective assessment. RESULTS: Nine infants with Beckwith-Wiedemann syndrome had antenatal ultrasound examinations. Seven of these had more than one examination. Two infants were suspected to have Beckwith-Wiedemann syndrome in utero. Important ultrasound findings included omphalocele (four), enlarged liver and kidneys (one), and enlarged liver (one). Fetal tongue protrusion on ultrasound was not identified in any fetus. Six of nine fetuses (66%) with ultrasound examinations after 25 weeks' gestation had polyhydramnios. Evaluation of the fetal HC, AC, and EFW percentiles demonstrated that fetuses with Beckwith-Wiedemann syndrome may exhibit accelerated growth as early as 25-30 weeks' gestation, but may exceed the 90th percentile only after 36 weeks' gestation. CONCLUSIONS: Fetuses with omphalocele, polyhydramnios, and an AC less than the 90th percentile may have Beckwith-Wiedemann syndrome. Polyhydramnios and accelerated growth beginning between 25 and 36 weeks' gestation, even without omphalocele, should alert the physician to the possibility of Beckwith-Wiedemann syndrome.

Low level mosaicism for a balanced 7;14 translocation in the father of an abnormal 7q+ child.

A child with a 7q+ chromosome abnormality had a father with 0.5% mosaicism for a balanced 7;14 translocation. This mosaicism was not found in 100 fibroblasts. This degree of mosaicism is well below the limits usually detected by standard clinical cytogenetic protocols. However, the one abnormal cell cannot be disregarded in this case, since it can serve as an explanation of the child's genotype. This case serves to illustrate the need for detecting subtle degrees of mosaicism for structural anomalies in humans and brings to question the true population frequencies of mosaic balanced translocation carriers.