Phenotype of five cases of prenatally diagnosed campomelic dysplasia harboring novel mutations of the SOX9 gene.

OBJECTIVES: Campomelic dysplasia is a rare congenital skeletal disorder characterized by bowing of the long bones and a variety of other skeletal and extraskeletal defects, many of which can now be identified prenatally using advanced ultrasound equipment. The disorder is caused by mutations in SRY-box 9 (SOX9), a gene that is abundantly expressed in chondrocytes as well as in other tissues. However, the correlation between genotype and phenotype is still unclear. We report five cases of prenatally detected campomelic dysplasia in which the diagnosis was confirmed by molecular analysis. METHODS: Ultrasound examinations were performed between 12 and 32 weeks. Standard fetal biometric measurements were obtained. Fetal sex was determined sonographically and confirmed by chromosomal analysis. Genomic DNA was obtained in four cases before termination of pregnancy from chorionic villi or amniocytes and in one case postnatally from peripheral blood. RESULTS: Skeletal dysplasia, most often limb shortening and bowed femora, was observed in one case in the first trimester, in three cases in the second trimester and in one case, presenting late for antenatal care, in the third trimester. Four of the pregnancies were terminated and one was carried to term. Postmortem/postnatal physical and radiographic examinations confirmed the presence of anomalies characteristic of campomelic dysplasia. A de novo mutation in the SOX9 gene was detected in all four cases that underwent termination. The father of the proband in the case that went to term was a carrier of a somatic mosaic mutation without clinical or radiographic signs of campomelic dysplasia. CONCLUSIONS: It is likely that the integrated expertise of ultrasonographers, obstetricians, pediatricians and clinical geneticists will markedly improve the likelihood of accurate prenatal clinical diagnoses of campomelic dysplasia. This will, in turn, encourage more specific molecular testing and facilitate comprehensive genetic counseling.

A familial case of achondrogenesis type II caused by a dominant COL2A1 mutation and "patchy" expression in the mosaic father.

Achondrogenesis type II (ACG2) is the most severe disorder that can be produced by dominant mutations in COL2A1. We report on four pregnancies of an apparently healthy, nonconsanguineous young couple. The father had scoliosis as a child, and has slight body disproportion with short trunk. The first child was born at 32 weeks and died neonatally. In the second pregnancy, short limbs and fetal hygroma were noted on ultrasound at 17 weeks' gestation. Similar findings were observed in the third fetus. Clinical, radiological, and histological evaluation of the fetuses after termination of the pregnancies showed findings consistent with ACG2. Molecular analysis of genomic DNA extracted from amniotic cells of the second and third fetuses revealed heterozygosity for a 10370G > T missense mutation (G346V) in the COL2A1 gene. This mutation was also found in the father, as a mosaic. The couple had a fourth pregnancy, and at 11 weeks fetal hydrops with a septated cystic hygroma were obvious. DNA from CVS demonstrated the same COL2A1 mutation.

Non protein bound iron concentrations in amniotic fluid.

OBJECTIVES: To investigate whether amniotic fluid concentrations of non protein bound iron (NPBI) vary with growth in healthy fetuses and also offer a reference curve in the second trimester of pregnancy. DESIGN AND METHODS: Amniotic fluid concentrations of NPBI were measured by HPLC in 118 women with physiological singleton pregnancies, who underwent amniocentesis for fetal karyotype between weeks 15 and 18 of gestation. RESULTS: NPBI increased progressively from weeks 14--15 to weeks 15--16, peaking at 17--18 weeks of gestation. NPBI values regressed positively with gestational age (GA). Multiple linear regression analysis between NPBI, as dependent variable, and various fetal parameters, as independent variables, showed a statistically significant regression coefficient with GA, bi-parietal diameter and transverse cerebellar diameter. CONCLUSIONS: The present data constitutes the first quantification of NPBI concentrations in amniotic fluid under physiological conditions. Correlations with GA and ultrasound fetal biometry suggest that NPBI may play a role in fetal growth.

Ultrafast MR imaging of the foetus: a study of 25 non-central nervous system anomalies.

PURPOSE: The aim of this paper is to suggest Magnetic Resonance (MR) Imaging as a useful tool in prenatal diagnosis. Although ultrasonography (US) is the imaging technique of choice for prenatal screening, in cases of complex malformations US findings may be sub-optimal and give rise to diagnostic difficulties requiring further investigation. Our study is focused on non-central nervous system (CNS) abnormalities of the foetus imaged using the ultrafast sequence EXPRESS. MATERIALS AND METHODS: 38 women whose foetuses were between 21-34 gestational age were studied. Indications for the examinations included the evaluation of non-CNS abnormalities in 25 cases. Foetal MR imaging was performed on a 1.5 T system (Edge, Marconi Medical System Italia SpA, Vimercate, MI) with the half-Fourier, single-shot, fast spin-echo EXPRESS sequence. Mild maternal and foetal sedation was obtained by oral administration of benzodiazepine (1 mg). RESULTS: In the 25 foetuses investigated for non-CNS pathologies the abnormalities were localised in the chest (9), abdomen (15) and extremities (1). The MR imaging diagnoses were: in the chest - congenital diaphragmatic hernia (CDH) (5), congenital cystic adenomatoid malformation (CCAM) (1), hydrothorax (1), cystic lymphangioma (1), Jeune syndrome (1); in the abdomen - 10 cases of urinary tract diseases - polycystic kidney (4), crossed renal ectopia (2), unilateral renal agenesis (1), solitary pelvic kidney (1), bilateral stenosis of ureteropelvic junction (1), duplex collecting system in association with controlateral hydroureteronephrosis (1)#151;5 cases of non-urinary tract pathologies#151;cystic lymphangioma of the liver (1), abdominal cystic lymphangioma (1), gastroschisis (1), gastric duplication (1), cavernous haemangioma of the liver (1); in the extremities - longitudinal hemimelia (1). CONCLUSIONS: In our experience MR is to be considered a useful though adjunct study to prenatal US particularly in the evaluation of lung parenchyma, congenital diaphragmatic viscera herniation, thoracic masses, pleural effusion, abdominal cystic masses, and urinary tract malformations. The ultrafast EXPRESS sequence enables a complete study to be performed in a very short time; as a consequence the examination is well tolerated by the patient. Currently there is no legislation which regulates the use of magnetic fields in MR, only a series of recommendations based on studies on animal embryos and foetuses, on pregnant women exposed to magnetic fields and follow-up studies of children exposed to MR during gestation. Therefore the decision to proceed with foetal MR should be made on a case-by-case basis in close consultation with the referring obstetrician. Considering the results, in our opinion the potential of MR in the evaluation of a wide variety of non-CNS foetal diseases will increase in the near future.

S100B protein cord blood levels and development of fetal behavioral states: a study in normal and small-for-dates fetuses.

OBJECTIVE: We aimed to determine whether S100B protein levels in cord blood and the development of fetal behavioral states were altered and interrelated in small-for-dates (SFD) fetuses. METHODS: Umbilical cord blood samples were collected from 12 SFD fetuses with normal umbilical artery (UA) Doppler findings, from six SFD fetuses with abnormal Doppler waveform patterns and from 36 controls matched for gestational age. S100B protein levels were measured by means of a specific radioimmunoassay. Fetal behavioral state recordings were made before delivery by Cesarean section and data were expressed as percentage of quiet sleep coincidence (C1F), of activity state coincidence (C2-4F) and of no coincidence (NOC). Flow velocimetry waveforms were recorded from the uterine artery, UA and fetal middle cerebral artery (MCA). RESULTS: Mean S100B protein levels in umbilical plasma were significantly higher in the six SFD infants with abnormal prenatal Doppler findings (3.31 +/- 0.65 microg/l) than in SFD infants with normal Doppler findings (1.56 +/- 0.35 microg/l) and in controls (1.23 +/- 0.43 microg/l). Similarly in these fetuses NOC was higher and C2F significantly lower (p < 0.05), but there was no significant difference in C1F. S100B concentrations were correlated with the UA pulsatility index (PI) (r = 0.78, p < 0.01), with the MCA PI (r = -0.78, p < 0.01) and with the UA PI/MCA PI ratio (r = 0.80, p < 0.01). Also, NOC and C2F percentages were correlated with the UA PI (r = 0.61, p < 0.01 and r = -0.61, p < 0.01, respectively), with the MCAPI (r = -0.72, p < 0.001 and r = 0.66, p < 0.01, respectively), and with the UA PI/MCA PI ratio (r = 0.60, p < 0.01 and r = -0.54, p < 0.05, respectively). NOC was also correlated with S100B protein (r = 0.48, p < 0.05); the correlation of S100B protein and C2F almost reached significance (r = -0.47, p < 0.05). CONCLUSIONS: This study provides evidence of a relationship between a biochemical marker of brain development and/or integrity and the development of fetal behavioral states, offering additional information on brain maturation in normal and high-risk pregnancies.

Prenatal diagnosis of 30 fetuses at risk for fragile X syndrome.

The results of 30 prenatal diagnoses for fragile X syndrome are reported. Amniotic fluid cells were examined in 1 case, fetal blood in 4, and chorionic villi samples in the others. Of the 5 fetuses analyzed by cytogenetic methods, 1 had showed 4% of fraXq27.3 expression sites and the pregnancy was terminated. For 1 diagnosis, linkage analysis was used: the female fetus turned out to be normal. In 24 fetuses, the direct analysis of the mutation by StB12.3 probe was performed: 6 female and 3 male fetuses were found to carry a full mutation and 1 female fetus was found to carry a premutation. In 3 cases, the diagnoses were verified on fetal blood samples. Several tissues of 2 aborted male fetuses were analyzed for the fragile X mutation. The results are reported and discussed.

[Sacrococcygeal teratomas: diagnosis and treatment]. / Teratomi sacro-coccigei: diagnosi e trattamento.

The Authors present ten cases of sacro-coccygeal teratomas observed during the last ten years at the G. Gaslini Children Institute, Genova. Two cases was diagnosed in the pre-natal period. Diagnostic methods, histologic aspect and surgical treatments are discussed.

Study of foetal hip: intrauterine positions and sonographic aspects.

The authors present their initial experience in the US Study of the foetal hip. Focusing on difficulties found and the possible advantages. The US foetal hip study shows that it is most likely to obtain qualitative morphologic data rather than quantitative that are interesting in case of occasional identification remark during US.

Holoprosencephaly and primary craniosynostosis: the Genoa syndrome.

We report on 2 sibs with holoprosencephaly of the semilobar type, unusual facial appearance not diagnostic of holoprosencephaly, and primary craniosynotosis involving the coronal and lambdoid sutures. The condition represents a newly recognized syndrome, possibly having autosomal recessive inheritance.

Transverse limb reduction defects after chorion villus sampling: a retrospective cohort study. GIDEF--Gruppo Italiano Diagnosi Embrio-Fetali.

A retrospective cohort study was performed in five Italian obstetrical centres from 1984 to 1991 in order to verify the association between chorionic villus sampling (CVS) and transverse limb reduction defects (TLRDs). TLRD rates by period of gestation at CVS were calculated, and the study's results were compared with data from the general population. Of the 3430 pregnancies for which CVS was performed, 2759 had a known outcome. The overall rate for TLRDs was 1 in 1143 CVS pregnancies, four times higher than that of the general population in Italy (1 in 4458). The rate of TLRDs was 2.9/1000 for CVS performed at 9 weeks' gestation and 1.0/1000 for CVS at 10 weeks' gestation. A scalp defect was detected in a pregnancy in which CVS was performed at 10 weeks. A high proportion of pregnancies lost to follow-up and the poor quality of the data may have affected the results. Nevertheless, our results suggest an association between CVS carried out at less than 10 weeks' gestation and TLRDs which is consistent with the findings of other studies. CVS should not be prepared at less than 10 weeks' gestation until additional evidence is obtained.

Ultrasonographic features in a case of heterozygous achondroplasia at 25 weeks' gestation.

Prenatal diagnosis of heterozygous achondroplasia at 25 weeks is described. First-level fetal ultrasonography demonstrated short long bones of the lower limbs. Second-level examination showed a large head; shortened femur, fibula, and tibia; a 'trident'-shaped hand; and an abnormal facial profile.