Intrafamilial variability in Fraser syndrome

Fraser syndrome (OMIM 219000) is a rare, autosomal recessive disorder characterized by cryptophthalmos, cutanaeous syndactyly, malformations of the larynx and genitourinary tract, craniofacial dysmorphism, orofacial clefting, mental retardation and musculoskeletal anomalies. There is marked interfamilial clinical heterogeneity. However, there is strong phenotypic similarity and concordance of the degree of severity of the disease within a family. We report a family with two cases of Fraser syndrome with marked clinical heterogeneity. One case had lethal phenotype with bilateral renal agenesis, while the other had mild phenotype with normal kidneys. It has not been reported before and highlights the importance of careful screening of pregnancies in families with Fraser syndrome. Copyright © 2007 John Wiley & Sons, Ltd.     

Microphthalmia–prenatal ultrasonic diagnosis: A case report

Prenatal real-time ultrasonographic diagnosis of microphthalmia is presented. Diagnosis was made at 18 weeks' gestation in a fetus of a patient with a previous infant affected with the syndrome of cryptophthalmia with absence of septum nasi and ambiguous genitalia (Fraser syndrome). Recognition of microphthalmia as a part of Fraser syndrome and the easy visualization of fetal facial bones and orbits in the second trimester made the diagnosis possible.     

McKusik-Kaufman syndrome: prenatal diagnosis,genetics and follow up

McKusick-Kaufman syndrome (MKKS) is a rare autosomal recessive genetic disease with classical hexadactyly and hydrocolpos in females and sometimes cardiac abnormality. We report such a case diagnosed just before birth with a favourable outcome. From this case we describe and discuss all the prenatal sonographic signs which are not always present. On the genetic side, the gene has recently been localized together with the mutation responsible for MKKS. The phenotypic relationship between MKKS which has a good prognosis and Bardet-Biedl syndrome (BBS) with a worse prognosis requires great caution before diagnosing MKKS and a long follow-up is necessary to recognize obesity, growth retardation and pigmentary retinitis. Copyright © 2002 John Wiley & Sons, Ltd.     

Prenatal diagnosis of Juberg–Hayward syndrome

Juberg–Hayward syndrome is a rare autosomal recessive syndrome characterised by the association of growth retardation, microcephaly, cleft lip and palate, and thumb and radial ray abnormalities. To date, no prenatal cases have been reported. Here, we report on the first prenatal case of Juberg–Hayward syndrome. The diagnosis was established following fetopathological study. Besides the cardinal features of the syndrome, this prenatal case was remarkable for the severity of the short arm malformation and by the finding of big toe agenesis and cerebral abnormalities including hydrocephalus, agenesis of corpus callosum, and cerebellar hypoplasia. We conclude that the diagnosis of Juberg–Hayward syndrome can be discussed prenatally following ultrasound diagnosis of the association of intrauterine growth restriction, microcephaly, thumb/radial anomalies, and cleft lip/palate. Copyright © 2005 John Wiley & Sons, Ltd.     

Incremental cost-effectiveness of incorporating oestriol evaluation in down syndrome screening programmes

As screening for Down syndrome becomes increasingly sophisticated, it is important to evaluate the newer technologies in terms of their cost-effectiveness. One recent addition to Down syndrome screening programmes is maternal serum unconjugated oestriol (uE₃), especially when used in conjunction with maternal serum α-fetoprotein and human chorionic gonadotropin. Using assumptions used in a California proposal to justify an expanded screening programme for Down syndrome, we calculated both the average and the incremental cost-effectiveness of adding uE₃. Using the base case assumptions, including an $8 fee for the uE₃, the incremental cost-effectiveness of adding uE₃ to the proposed California programme is $119 100 per case detected, a value that compares favourably with other Down syndrome screening programmes. The sensitivity analysis supports this conclusion over a wide range of assumptions. However, because of the uncertainty with some key data, it is still too early to fully support the inclusion of uE₃ in Down syndrome screening programmes.     

Gorlin syndrome presenting as prenatal chylothorax in a girl

Gorlin syndrome (GS), also known as nevoid basal cell carcinoma syndrome, is a rare autosomal dominant condition with an estimated prevalence of 1:57 000. GS is associated with congenital malformations and predisposition to neoplasms. The main features observed in patients with GS are basal cell carcinomas, odontogenic keratocysts, skeletal anomalies including scoliosis and bifid ribs, palmar and plantar epidermal cysts, facial dysmorphism, and cerebral falx calcification. More than 100 other clinical manifestations have also been described in the literature including ovarian fibroma, enlarged cerebral ventricles, and lymphatic as well as chylous mesenteric cysts. The Patched (PTCH) gene is responsible for GS when mutated. Here, we report on a prenatal diagnosis of GS in a girl with a chylothorax, a previously unreported feature in GS. We discuss the clinical features observed in this family and we comment on the molecular studies that allowed us to describe a previously unreported Patched gene mutation. Copyright © 2005 John Wiley & Sons, Ltd.     

Maternal serum leptin concentration during the second trimester of pregnancy: association with fetal chromosomal abnormalities

Recent studies suggest that leptin, the product of the obese gene, is produced by the placenta during pregnancy. The present study addressed the question whether second trimester maternal serum leptin could be altered by fetal Down syndrome or Edwards syndrome. Maternal serum leptin concentrations were measured in 18 pregnancies complicated with Down syndrome, six pregnancies complicated with Edwards syndrome and 183 uncomplicated pregnancies during the second trimester of pregnancy. The present results demonstrate that leptin concentrations in uncomplicated pregnancies slightly decrease from the 16th week of pregnancy, reaching a minimum of 18.8 ng/ml around the 20th week, and then rapidly increase to 28.2 ng/ml by the 24th week. Leptin correlation with maternal body weight decreases from r=0.695 at 16–17 week of gestation to r=0.544 at >22 weeks of gestation. There was no significant difference between the mean MoMs of Down syndrome- (0.926) or Edwards syndrome- (0.960) affected pregnancies and normal pregnancies (1.002). A weak correlation (r=0.18, p<0.02) was observed between corrected leptin MoMs and human chorionic gonadotrophin (hCG) MoMs in normal pregnancies. It is assumed that around the 20th week of pregnancy placental leptin production is activated or at least is accelerated and it is added to the amount of leptin produced by maternal adipose tissue. Fetal Down syndrome or Edwards syndrome does not seem to alter maternal leptin concentration and therefore leptin cannot be used as a marker for these chromosomal abnormalities in the early second trimester of pregnancy. Copyright © 2002 John Wiley & Sons, Ltd.     

Early second trimester prenatal diagnosis of Neu-Laxova syndrome

Neu-Laxova is a rare, uniformly lethal, autosomal recessive condition with characteristic limb posturing, facial dysmorphic features, and central nervous system abnormalities. Forty-two cases of Neu-Laxova syndrome have been reported, with only four of these diagnosed prenatally. Three of the four cases were diagnosed at or after 32 weeks' gestation. The fourth case was diagnosed at 22 weeks' gestation in a patient who was followed with serial ultrasound studies due to having a prior affected child. At 19 weeks' gestation, we present the earliest reported prenatal diagnosis of Neu-Laxova syndrome in a primigravida with a non-informative family history. Copyright © 2002 John Wiley & Sons, Ltd.     

Prenatal detection of congenital hypospadias in the wolf-hirschhorn (4p —) syndrome

Hypospadias is one of the most prominent and characteristic midline defects in male infants with the Wolf-Hirschhorn (4p —) syndrome. In this report we present a case in which hypospadias was identified prenatally at 29 weeks' gestation in association with intrauterine growth retardation. Cytogenetic evaluation after birth confirmed a 46, XY, del(4)(p14) karyotype. The prenatal identification of hypospadias in fetuses with intrauterine growth retardation and normal amniotic fluid should suggest a diagnosis of Wolf-Hirschhorn syndrome.     

Maternal serum free beta hCG screening: Results of studies including 480 cases of down syndrome

The median maternal serum free beta human chorionic gonadotropin (hCG) multiple of the median (MOM) of 480 Down syndrome cases in the second trimester was 2·64, significantly greater than the reported median MOM of intact hCG (p<0·0001). In 234 of these cases from retrospective and prospective studies, the effectiveness of maternal serum free beta hCG was evaluated in combination with alpha-fetoprotein (AFP) and maternal age in second-trimester Down syndrome screening. Down syndrome detection in the gestational age range of 14–16 weeks was 82 per cent. In all gestational weeks (14–22), a 77·7 per cent Down syndrome detection rate was achieved. In prospective screening of 44 272 patients under the age of 35 years, 69 per cent of Down syndrome cases were detected (73 per cent in gestational weeks 14–16). The false-positive rate for the prospective study was 3·8 per cent. The use of free beta hCG combined with maternal serum AFP and maternal age-related risk for Down syndrome in a screening population (i.e., women under 35 years) yields an improved detection efficiency over other protocols.     

Late-onset growth restriction in Galloway–Mowat syndrome: a case report

Galloway–Mowat syndrome (GMS) is a rare autosomal recessive disorder and is characterized by marked intrauterine growth retardation, central nervous system anomalies, and early onset nephrotic syndrome. Of the reported cases in the literature, all were diagnosed postnatally. We describe a case of GMS in which only late-onset intrauterine growth restriction was detected by prenatal ultrasound. In her fourth pregnancy, the mother had delivered a male baby with clinical features of GMS who died at seven months of age due to early onset of nephrotic syndrome. In her fifth pregnancy, serial ultrasound examinations were normal during the first and second trimester of pregnancy. Growth restriction and microcephaly were not detectable until 28 to 32 weeks' gestation. At 40 weeks' gestation, a female baby was born with dysmorphic features of GMS. Nephrotic syndrome developed after birth and renal biopsy revealed minimal change nephrotic syndrome. The prenatal course of this case suggests GMS may not be diagnosed in early pregnancy and the only abnormality detected before birth was intrauterine growth restriction. Copyright © 2005 John Wiley & Sons, Ltd.     

Prenatally detected double trisomy: Klinefelter and Down syndrome

Double trisomies are a rare occurrence. We report the first case of a Down and Klinefelter's syndrome (48,XXY,+21) in a fetus that was prenatally diagnosed during the 15th week of pregnancy. Even though the nasal bone was present, and the color-Doppler study of the ductus venosus and the nuchal thickness were normal, the maternal serum test results indicated an increased risk of Down syndrome and consequentially a genetic amniocentesis was performed. A 48,XXY,+21 karyotype was observed and the patient decided to terminate the pregnancy. In this case, we did not find the typical ultrasound (US) signs that would have led us to the chromosomopathy; furthermore, we emphasize the advantages of using biochemical screening which, in our case, were crucial in arriving at the correct diagnosis. Copyright © 2006 John Wiley & Sons, Ltd.     

Expanding multiple marker screening for Down's syndrome to include Edward'S syndrome

Information on maternal age and maternal serum alpha-fetoprotein, unconjugated oestriol (uE₃), and human chorionic gonadotrophin (hCG) levels was used to investigate retrospectively the effect of estimating Edward's syndrome risk in women having multi-marker screening for Down's syndrome. The screened population comprised 15 pregnancies affected by Edward's syndrome, 15 with Down's syndrome and 5472 unaffected pregnancies. The use of all three markers to estimate Edward's syndrome risk would have led to the detection of 10–12 (67–80 per cent) cases with a false-positive rate of 0.3–0.6 per cent depending on the risk cut-off. A further case would have been detected as a result of screening for Down's syndrome alone. Similar results were obtained when the Edward's syndrome risk was based on uE₃ and hCG only. These data suggest that extending Down's syndrome screening to include Edward's syndrome risk will yield a high detection rate with only a small increase in the false-positive rate.     

Prenatal diagnosis of multiple pterygium syndrome associated with Klinefelter syndrome

A nonlethal form of multiple pterygium syndrome (MPS) was diagnosed prenatally at 16 weeks of gestation with associated Klinefelter syndrome in the same fetus. The ultrasound findings were cystic hygroma, hypertelorism, micrognathia, low-set ears, flexion contractures of upper and lower extremities and rocker-bottom foot. Genetic amniocentesis revealed a 47,XXY karyotype. After genetic counseling, the parents decided to have a therapeutic abortion. We presented this case for the purpose of further describing the early ultrasound findings and clinical features of multiple pterygium syndromes. Also, what makes our patient unique is the coincidental presence of Klinefelter syndrome with MPS. To our knowledge, this is the first case in the literature in which a 47,XXY karyotype has been found in a fetus with multiple pterygium syndrome. The importance of delineating the exact subtype of MPS and making a precise differential diagnosis becomes critical during the process of evaluation of patients with MPS. Copyright © 2003 John Wiley & Sons, Ltd.     

Second-trimester maternal serum immunoreactive inhibin as a marker for fetal Down's syndrome

We measured immunoreactive inhibin in the maternal serum of 80 pregnancies with a chromosomally normal fetus and ten Down's syndrome pregnancies in the second trimester. The inhibin level in all Down's syndrome pregnancies was above the normal median; the multiple of the normal median (MoM) was 1.9. We found a statistically significant difference between the levels of inhibin in unaffected and affected pregnancies (Kolmogorov–Smirnov test: p <0.002). Using an arbitrarily chosen cut-off of 2.4 MoM, 40 per cent of Down's syndrome and 5 per cent of the normal pregnancies were found. We conclude that immunoreactive inhibin may be useful as a marker for fetal Down's syndrome.     

Prenatal exclusion of Leigh syndrome due to T8993C mutation in the mitochondrial DNA

Leigh syndrome (LS) is a mitochondrial encephalopathy that is caused by a mutation either in the mitochondrial DNA (mtDNA) or in the nuclear encoded genes of the mitochondrial proteins. Prenatal diagnosis of defects in the mtDNA is usually problematic because of mtDNA heteroplasmy and tissue specificity. However, the mutations T8993 G/C in the ATP synthase subunit 6 gene of the mtDNA show a more even tissue distribution and do not appear to change significantly over time. There are only few reports of prenatal diagnosis of the T8993G mutation in Leigh disease. Here we describe the first prenatal genetic testing of T8993C in a fetus of a mother whose previous child had died of Leigh syndrome due to the T8993C mutation. Mutant load in the chorionic villus sample (CVS) as well as in amniocytes was undetectable, thus predicting a very high likelihood of an unaffected outcome, indicative of a healthy baby. The diagnosis was confirmed after birth. Gathering data on the prenatal diagnosis of mtDNA mutations is of great importance so that prenatal diagnosis of both T8993G and T8993C mutations can be offered routinely. Copyright © 2002 John Wiley & Sons, Ltd.     

Karyotypes found in the population declared at increased risk of Down syndrome following maternal serum screening

Of the 65 328 pregnancies of South Australian mothers screened by the South Australian Maternal Serum Antenatal Screening (SAMSAS) Programme between 1 January 1991 and 31 December 1997, 3431 (5.25%) were declared at increased risk of fetal Down syndrome. Fetal or neonatal karyotype was determined in 2737/3431 (79.8%) of these pregnancies, including 16 with early fetal loss. Interrogation of the database of the South Australian Neonatal Screening Service showed 643 live-born infants whose phenotype was not subsequently questioned among the 694 pregnancies whose karyotype was not determined. Of the remaining 51/3431 pregnancies, 19 ended in early fetal loss without karyotyping and no newborn screening or other records could be found for 32 cases. The 129 instances of abnormal karyotype found were Down syndrome (84), trisomy 18 (four), trisomy 13 (three), triploidy (two), female sex chromosome aneuploidy (six) and male sex chromosome aneuploidy (five), inherited balanced rearrangements (19), mosaic or de novo balanced abnormalities (four) and unbalanced karyotypes (two). In the pregnancies declared at increased risk of fetal Down syndrome, only the karyotype for Down syndrome occurred with a frequency greater than that expected for the general, pregnant population. Copyright © 2001 John Wiley & Sons, Ltd.     

Maternal serum CA 125 levels in pregnancies with chromosomally-normal and -abnormal fetuses

We measured the maternal serum cancer antigen 125 (MS-CA 125) levels in 98 nonpregnant women, 765 first- and second-trimester pregnancies with chromosomally-normal fetuses, and 54 chromosomally-abnormal pregnancies. To determine the MS-CA 125 concentration, we used a new automated microparticle enzyme immunoassay with low inter-assay variability. The median MS-CA 125 level decreased from the first to the second trimester of pregnancy and was higher than that in non-pregnant women. We found no difference between normal and Down's syndrome (n = 29) pregnancies ( t-test: t = 0·57, p >0·5). The MS-CA 125 levels in pregnancies with other chromosomal abnormalities showed no difference either, compared with the normals. We conclude that MS-CA 125 is not a useful marker for fetal Down's syndrome, nor for other chromosomal disorders in pregnancy.