The pathways leading to female sexual determination in mammals are incompletely defined. Loss-of-function mutations in the WNT4 gene appear to cause developmental abnormalities of sexual differentiation in women and mice. We recruited six patients with different degrees of Müllerian abnormalities, with or without renal aberrations and a normal female 46,XX karyotype. A clear androgen excess was found only in one patient. This 19-year-old woman was affected by primary amenorrhoea, absence of Müllerian ducts derivatives, clinical (acne and hirsutism) and biochemical (repeatedly high levels of testosterone) signs of androgen excess. Direct sequencing of her WNT4 gene followed by functional studies in human ovarian cells (OVCAR3) was performed. This patient carried the novel R83C loss-of-function dominant negative mutation in her WNT4, confirming the role of WNT4 in the development and maintenance of the female phenotype in women. Our study can also help refine the phenotype of WNT4 deficiency in humans. In fact, it appears that at least in this limited casuistic small group of patients, the absence of a uterus (and not other Müllerian abnormalities) and the androgen excess are the pathognomonic signs of WNT4 defects, suggesting that this might be a clinical entity distinct from the classic Mayer-Rokitansky-Kuster-Hauser syndrome.

SUMMARYTerminal complement complex and S protein were searched for in term placentae obtained from 13 women with normal pregnancy and 15 paticnls wilh moderate or severe form of pre-eclampsia. Terminal complement complex was found to localize in the fibrinoid material of the decidua of the basal plate, in the stroma of the chorionic villi and in the vessel walls, as subendothelial deposits. S protein had a quite dilTerent distribution, being detected in the syncytiotrophoblast located both in the chorionic villi and in the decidua of the basal plale(DBP)and also on the endothelial cells of fetal stem vessels. Mild deposits of C3 were found in the decidua of the basal plate and also in the stroma and on the basal membranes of the villi. Reactivity for C9 neoantigen was also observed in the cytoplasm of some cells, which were recognized to be macrophages by the presence in their eytoplasm of acid phosphatase and by their reaction with a monoclonal antibody specific for macrophages. Differences in complement deposition in normal and pre-eclamptic placentae were essentially quantitative. Possible mechanisms of complement activation are discussed.

Pfeiffer syndrome is characterized by bilateral coronal craniosynostosis, midface hypoplasia, beaked nasal tip, broad and medially deviated thumbs and great toes. Originally, it was described in eight persons from three generations in a pedigree consistent with an autosomal dominant transmission. Since then, several reports have documented its high clinical and genetic heterogeneity. The condition is usually detected in the newborn period or later, and very few prenatal ultrasound diagnoses have been reported. We present a case of Pfeiffer syndrome prenatally diagnosed at 20 weeks' gestation, in which the sonographic features of craniosynostosis, hypertelorism associated with an extreme proptosis, and broad thumb led to the diagnosis, confirmed after termination of pregnancy by dysmorphological, pathological and radiological evaluation. DNA analysis of the fibroblast growth factor receptor 2 (FGFR2) showed a missense mutation consisting in a transversion G --> C at nucleotide 870. This led to a Trp290Cys amino acidic substitution. We discuss the relevant findings of our and previously published cases. Our report demonstrates that a careful sonographic examination can lead to an early prenatal diagnosis of Pfeiffer syndrome also in cases without cloverleaf skull.

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Aim: To evaluate the use of baseline inhibin B (INHB) levels to differentiate the progressive form (PF) from the non-progressive form (NPF) of central precocious puberty (CPP). Methods: A total of 62 girls were enrolled, 31 with PF and 31 with NPF. Using receiver operating characteristic (ROC) curves, we analysed the diagnostic performance of INHB in addition to other diagnostic tools used to differentiate the 2 forms of CPP. Results: INHB levels were higher in PF versus NPF (29.1 vs. 13.1 pg/ml; p < 0.001). The ROC area under the curve (AUC) was greatest for luteinizing hormone [LH; 0.807, standard error (SE) 0.069], followed by INHB (0.800, SE 0.067), ovarian volume (OV; 0.782, SE 0.070) and uterine volume (0.723, SE 0.076). In ROCs relative to a combination of such parameters, the AUC was greater for LH + INHB (0.972, SE 0.010), followed by OV + LH (0.841, SE 0.084) and OV + INHB (0.836, SE 0.075). The combination of INHB and LH (with cut-offs of 20 pg/ml and 0.2 IU/l, respectively) results in 98% sensitivity and specificity. Conclusion: Our results suggest that the addition of basal INHB values to baseline LH levels provides a reliable method to identify PF. Further replication studies are needed to definitively prove or disprove the utility and advantages of INHB levels as part of the work-up of CPP.