The chromatin remodelling component SMARCB1/INI1 influences the metastatic behavior of colorectal cancer through a gene signature mapping to chromosome 22.

BACKGROUND: INI1 (Integrase interactor 1), also known as SMARCB1, is the most studied subunit of chromatin remodelling complexes. Its role in colorectal tumorigenesis is not known. METHODS: We examined SMARCB1/INI1 protein expression in 134 cases of colorectal cancer (CRC) and 60 matched normal mucosa by using tissue microarrays and western blot and categorized the results according to mismatch repair status (MMR), CpG island methylator phenotype, biomarkers of tumor differentiation CDX2, CK20, vimentin and p53. We validated results in two independent data sets and in cultured CRC cell lines. RESULTS: Herein, we show that negative SMARCB1/INI1 expression (11% of CRCs) associates with loss of CDX2, poor differentiation, liver metastasis and shorter patients' survival regardless of the MMR status or tumor stage. Unexpectedly, even CRCs displaying diffuse nuclear INI1 staining (33%) show an adverse prognosis and vimentin over-expression, in comparison with the low expressing group (56%). The negative association of SMARCB1/INI1-lack of expression with a metastatic behavior is enhanced by the TP53 status. By interrogating global gene expression from two independent cohorts of 226 and 146 patients, we confirm the prognostic results and identify a gene signature characterized by SMARCB1/INI1 deregulation. Notably, the top genes of the signature (BCR, COMT, MIF) map on the long arm of chromosome 22 and are closely associated with SMARCB1/INI1. CONCLUSION: Our findings suggest that SMARCB1/INI1-dysregulation and genetic hot-spots on the long arm of chromosome 22 might play an important role in the CRC metastatic behavior and be clinically relevant as novel biomarkers.

Perfusion and spectroscopy magnetic resonance imaging in a case of lymphocytic vasculitis mimicking brain tumor.

BACKGROUND: Lymphocytic vasculitis of the central nervous system is an uncommon subtype of primary angiitis of the central nervous system (PACNS) - a rare inflammatory disorder affecting parenchymal and leptomeningeal arteries and veins. CASE REPORT: Establishing diagnosis on the basis of neuroimaging only is difficult, as it can mimic a brain tumor. Thus, histological diagnosis is essential for appropriate management. We present a case of biopsy-proven lymphocytic vasculitis mimicking a brain tumor on neuroimaging that was subsequently successfully treated with steroid therapy. We also discuss the findings in perfusion MR (PWI) and MR spectroscopy (MRS). CONCLUSIONS: Regional hypoperfusion on PWI and elevation of glutamate and glutamine levels on MRS (without associated typical tumor spectra) are common findings in inflammatory disorders, including PACNS, and can be useful in differential diagnosis with tumors.

Regarding the algorithm for the diagnosis of early mycosis fungoides proposed by the International Society for Cutaneous Lymphomas: suggestions from routine histopathology practice.

BACKGROUND: Routine clinicopathologic practice is expected to refine/validate the scoring system proposed in 2005 by the International Society for Cutaneous Lymphomas (ISCL) for the diagnosing early mycosis fungoides (eMF), classical type. METHODS: An evaluation of 72 cases of erythematous and scaling dermatoses was employed with a partial implementation of the ISCL algorithm. RESULTS: The selected cases fulfilled the clinical criteria proposed by the ISCL; routine histopathology allowed to reach the ISCL minimum score for a diagnosis of eMF in 45 cases. A clonal T-cell population was found in 4 out of 12 cases tested with the polymerase chain reaction, three of which with an already established clinicopathologic diagnosis of eMF. An aberrant immunophenotype was found in 11 cases, all of which already labeled as eMF on the basis of clinical and histopathologic features. 6 out of 27 patients with inconclusive clinicopathologic data underwent a new skin biopsy, which allowed to reach a diagnosis of eMF in two cases. CONCLUSIONS: The diagnosis of eMF still rests upon clinical features and conventional histology; a new skin biopsy is recommended for cases with no clear-cut diagnostic features.

Overexpression of both CXC chemokine receptor 4 and vascular endothelial growth factor proteins predicts early distant relapse in stage II-III colorectal cancer patients.

PURPOSE: CXC chemokine receptor 4 (CXCR4) and vascular endothelial growth factor (VEGF) are implicated in the metastatic process of malignant tumors. However, no data are currently available on the biological relationship between these molecules in colorectal cancer. We studied whether CXCR4 and VEGF expression could predict relapse and evaluated in vitro the contribution of CXCR4 in promoting clonogenic growth, VEGF secretion, and intercellular adhesion molecule-1 (ICAM-1) expression of colorectal cancer cells. EXPERIMENTAL DESIGN: CXCR4 and VEGF were studied in colorectal cancer tissues and in Lovo, HT29, and SW620 colorectal cancer cell lines by immunohistochemistry. Correlations with baseline characteristics of patients and tumors were analyzed by chi2 test. VEGF secretion induced by CXCL12 was measured by ELISA. The effect of CXCL12 on ICAM-1 expression was evaluated by flow cytometry. Clonogenic growth induced by CXCL12 was determined by clonogenic assays. Functional effects induced by CXCL12 were prevented by the administration in vitro of AMD3100, a bicyclam noncompetitive antagonist of CXCR4. RESULTS: Seventy-two patients, seen between January 2003 and January 2004, were studied. CXCR4 was absent in 16 tumors (22.2%); it was expressed in < or = 50% of cells in 25 (34.7%) tumors and in >50% of cells in 31 (43.0%) tumors. VEGF was absent in 17 (23.6%) tumors; it was expressed in < or = 50% of cells in 16 (22.2%) tumors and in >50% of cells in 39 (54.2%) tumors. There was a significant association between CXCR4 expression and lymph nodal status (P = 0.0393). There were significant associations between VEGF and tumor invasion (P = 0.0386) and lymph nodal involvement (P = 0.0044). American Joint Committee on Cancer stage (P = 0.0016), VEGF expression (P = 0.0450), CXCR4 expression (P = 0.0428), and VEGF/CXCR4 expression (P = 0.0004) had a significant prognostic value for disease-free survival with univariate analysis. The predictive ability of the American Joint Committee on Cancer stage and of the concomitant and high expression of VEGF and CXCR4 was confirmed by multivariate analysis. Prognosis is particularly unfavorable for patients whose primary tumors express CXCR4 and VEGF in >50% of cells (median disease-free survival in relapsed patients, 5.8 months; hazard ratio of relapse, 8.23; 95% confidence interval, 7.24-14.29). In clonogenic assays, CXCL12 (20 ng/mL/d) significantly increased the number of clones in SW620, HT29, and Lovo cells at 7 and 14 days. Again, CXCL12 was able to stimulate VEGF secretion in SW620, HT29, and Lovo cells as well as up-regulated ICAM-1. These effects were prevented by the administration of AMD3100 (1 micromol/L). CONCLUSIONS: We have shown that concomitant and high expression of CXCR4 and VEGF is a strong and independent predictor of early distant relapse in colorectal cancer. CXCR4 triggers a plethora of phenomena, including stimulation of clonogenic growth, induction of VEGF release, and ICAM-1 up-regulation. These data support the inhibition of CXCR4 to prevent the development of colorectal cancer metastasis.

The spectrum of Spitz nevi: a clinicopathologic study of 83 cases.

OBJECTIVE: To achieve a clinicopathologic classification of Spitz nevi by comparing their clinical, dermoscopic, and histopathologic features. DESIGN: Eighty-three cases were independently reviewed by 3 histopathologists and preliminarily classified into classic or desmoplastic Spitz nevus (CDSN, n = 11), pigmented Spitz nevus (PSN, n = 14), Reed nevus (RN, n = 16), or atypical Spitz nevus (ASN, n = 14); the remaining 28 cases were then placed into an intermediate category (pigmented Spitz-Reed nevus, PSRN) because a unanimous diagnosis of either PSN or RN was not reached. SETTING: University dermatology and pathology departments and general hospital pathology departments. PATIENTS: A sample of subjects with excised melanocytic lesions. MAIN OUTCOME MEASURE: Frequency of dermoscopic patterns within the different histopathologic subtypes of Spitz nevi. RESULTS: Overlapping clinical, dermoscopic, and histopathologic findings were observed among PSN, RN, and PSRN, thereby justifying their inclusion into the single PSRN diagnostic category. Asymmetry was the most frequent indicator of histopathologic ASN (79%; n = 11); in only 4 cases did dermoscopic asymmetry show no histopathologic counterpart, and in those cases the discrepancy was probably the result of an artifact of the gross sampling technique carried out with no attention to the dermoscopic features. CONCLUSIONS: Among Spitz nevi, histopathologic distinction between PSN and RN is difficult, not reproducible, and may be clinically useless. A simple clinicopathologic classification of these neoplasms might therefore be structured as CDSN, PSRN, and ASN. Asymmetry should be assessed using both dermoscopic and histopathologic analysis, and reliability in histopathologic diagnosis may be enhanced by the simultaneous evaluation of the corresponding dermoscopic images.

Congenital scoliosis associated with agenesis of the uterine cervix. Case report.

BACKGROUND: Alterations in the normal sequence of development of müllerian ducts lead to a wide spectrum of reproductive tract abnormalities. A rare form of lack of development, regarding a short tract of the müllerian ducts, leads to the isolated agenesis of the uterine cervix. Anomalies identified among patients with müllerian agenesis include skeletal deformities (i.e., scoliosis of the spine and Klippel-Feil anomaly). CASE PRESENTATION: A 46 years old woman presenting cyphoscoliosis and very low stature (120 cm - 3,93 feet), came to our observation for acute pelvic pain; she also reported primary amenorrhoea associated with cyclic pelvic pain. Clinical and imaging evaluation, evidenced a blind vaginal duct of normal length, left cystic adnexal mass, and enlarged uterus with hematometra. FSH, LH, 17beta estradiol and CA-125, karyotype and radiographic study of limbs and vertebral column were also evaluated.At laparotomy, a left ovarian cyst was found. Uterus ended at the isthmus; under this level a thin fibrous tissue band was found, joining the uterus to the vagina. Uterine cervix was replaced by fibrous tissue containing some dilated glands lined with müllerian epithelium. Karyotype resulted 46, XX. The described skeletal deformity, were consistent with Klippel-Feil syndrome. CONCLUSION: We report a case of congenital scoliosis associated with müllerian agenesis limited to uterine cervix, association thus far seen only among patients with Mayer-Rokitansky-Kuster-Hauser syndrome (utero-vaginal agenesis). This case report supports the necessity to evaluate, for accompanying müllerian anomalies, all cases of congenital structural scoliosis in view of the possibility for many müllerian development abnormalities, if timely diagnosed, to be surgically corrected.

Multicystic mesothelioma of the liver with secondary involvement of peritoneum and inguinal region.

A case of multicystic mesothelioma of the liver with secondary involvement of the pelvic peritoneum and the inguinal region is presented. The case is of interest because of its unusual location and peculiar biological behavior.

A pilot study of a combined dermoscopic-pathological approach to the telediagnosis of melanocytic skin neoplasms.

We examined a combined (dermoscopic-pathological) approach to the telediagnosis of melanocytic skin lesions. A store-and-forward teleconsultation was simulated. Dermoscopic and histopathology images from 12 melanocytic lesions were stored in a telepathology workstation. A dermoscopy consultant, a histopathology consultant and an expert in dermoscopic-pathological correlation gave their diagnoses and comments on the images. The consensus diagnosis between two teleconsultants on the original histological slides was regarded as the gold standard. The diagnostic accuracy was 83% (including one false negative diagnosis of malignancy) for teledermoscopy and 100% for teledermatopathology. The combined approach detected one case that showed a much greater atypia on dermoscopy than on histopathology. In this case step-sections of the sample were deemed to be required for definite diagnosis. The combined approach was helpful in detecting macroscopic and microscope sampling errors of melanocytic lesions during teleconsultation.

Right-sided rhabdoid colorectal tumors might be related to the serrated pathway.

BACKGROUND: Rhabdoid colorectal tumor (RCT) is a rare, highly aggressive neoplasm recurrent in elderly patients, commonly at the caecum. The molecular mechanisms underlying RCT pathogenesis remain poorly elucidated. The differential diagnosis is with the malignant rhabdoid tumors of infancy characterized by genetic inactivation of SMARCB1 (INI1) or deletions of chromosome 22q12 locus. MATERIALS AND METHODS: To shed light on RCT pathogenesis, we investigated genetic and epigenetic alterations in two cases of pure and composite RCT and compared them with the profiles of matched adenomas and normal mucosa. Immunohistochemical analysis, FISH, methylation specific PCR and DNA sequencing analysis were performed on paraffin-embedded tissues. RESULTS: Loss of epithelial markers, (CK20, CDX2 and E-cadherin) and intense vimentin expression was observed in RCTs but neither in the normal mucosa or adenomas. INI1 expression was detected in normal mucosa, adenomas and retained in pure RCT, while it was undetected in composite RCT. Rearrangement of the 22q12 locus was found only in pure RCT. The APC/ß-catenin pathway was not altered, while MLH1 immunostaining was negative in RCTs and positive in adenomas and normal mucosa. These expression profiles were associated with V600E BRAF mutation, a progressive accumulation of promoter methylation at specific CIMP loci and additional genes from the normal mucosa to tubular adenoma and RCT. CONCLUSIONS: Right-sided RCT could be characterized by epigenetic events and molecular features likely similar to those occurring in the serrated pathway and associated with epithelial-mesenchymal transition. These extremely rare tumors may benefit from the use of new biological molecules specific for colorectal carcinoma. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1641385210804556.

Pontine extension of a tentorial schwannoma without cranial nerve involvement: a case report.

INTRODUCTION: Intracranial schwannomas unrelated to the cranial nerves are uncommon. We report a new case of tentorial schwannoma unrelated to the cranial nerves, with extension into the pons. A literature review with discussion of the most relevant pathogenetic aspects is also performed. CASE PRESENTATION: A 42-year-old Caucasian man was admitted with right-sided paresthesias and weakness of his upper and lower extremities. The neurological examination revealed right hemiparesis and hemi-hypoesthesia. A brain magnetic resonance imaging scan revealed a cerebellopontine lesion, arising from the left free edge of the tentorium, and extending into his pons. A piecemeal removal was performed through a retrosigmoid approach. The lesion was not found to be associated with any cranial nerves. The histological examination revealed a schwannoma Antoni type A. His postoperative course was uneventful. At one year follow-up, the patient was neurologically intact and the magnetic resonance imaging of his brain performed at that time showed complete removal without signs of recurrence. CONCLUSION: Tentorial schwannomas are rare clinical entities. Knowledge of their clinical, radiological and anatomical characteristics is very important for the correct diagnosis and management.

A novel case of rhabdoid colon carcinoma associated with a positive CpG island methylator phenotype and BRAF mutation.

Colon carcinoma with rhabdoid characteristics is a rare, malignant tumor whose molecular alterations have not been clarified yet. We report a novel case of a colon adenocarcinoma with rhabdoid features in a 71-year-old woman, localized to the right colon and associated with local lymph node and liver metastasis. The patient died within 8 months from surgery despite target chemotherapy. The tumor was enriched in cells with a typical rhabdoid-type morphology displaying a marked and diffuse vimentin staining. Cells were also positive for epidermal growth factor receptor (EGFR), p53, Ki67, and ß-catenin and negative for cytokeratin 20/cytokeratin 7, E-cadherin, and CDX2. Remarkably, the promoter regions of 4 of 5 specific genes that define the so-called "CpG island methylator phenotype," including mutL homolog 1 (MLH1), were methylated. Consistently, microsatellite instability was detected. A BRAF V600E mutation and no KRAS mutations were identified. Finally, 4 tumor suppressor gene promoters CDH1, CDKN1B, CDKN1C, and MGMT were not methylated. This is the first case of a colorectal carcinoma with rhabdoid features, "CpG island methylator phenotype," high microsatellite instability associated with a BRAF mutation, and patient poorer outcome.

Prognostic role of beta-catenin and p53 expression in the metastatic progression of sporadic colorectal cancer.

Beta-catenin and p53 play key roles in tumorigenesis. The relationships between these 2 signaling pathways and their contribution to colorectal cancer metastatic progression have not been completely elucidated. We analyzed 141 cases of primary sporadic colorectal cancer, 45 matched metastases, and 80 samples of normal mucosa by immunohistochemistry on paraffin-embedded specimens. The expression profiles were also related to patients' clinicopathologic features and 5-year survival. In primary tumors, beta-catenin immunoreactivity was nuclear (27%), predominantly membrane/cytosolic (46.0%) or negative (27%). This latter subgroup was strongly related to microsatellite instability, in particular to MLH-1 deficiency. Remarkably, beta-catenin membrane/cytosolic expression in primary tumors was reduced in the corresponding matched metastases. p53 showed a significant increase in immunoreactivity in (66.7%), whereas it was negative in (33.3%) of tumors. When we considered the expression of both genes, the combination of negative beta-catenin and positive p53 nuclear staining (21%) was strongly related to a higher frequency of liver metastases. Such an association was significantly related to a worse prognosis than any other combination. In a multivariate analysis, beta-catenin and distant metastases were independent prognostic markers. We suggest that a combination of low beta-catenin and high p53 expression in primary colorectal cancers may be a prognostic factor in predicting the progression of the disease, the occurrence of metastasis, and a more severe outcome.

The influence of clinical information in the histopathologic diagnosis of melanocytic skin neoplasms.

BACKGROUND: We tested the relevance of clinical information in the histopathologic evaluation of melanocytic skin neoplasm (MSN). METHODS: Histopathologic specimens from 99 clinically atypical MSN were circulated among ten histopathologists; each case had clinical information available in a database with a five-step procedure (no information; age/sex/location; clinical diagnosis; clinical image; dermoscopic image); each step had a histopathologic diagnosis (D1 through D5); each diagnostic step had a level of diagnostic confidence (LDC) ranging from 1 (no diagnostic certainty) to 5 (absolute diagnostic certainty). The comparison of the LDC was employed with an analysis of variance (ANOVA) for repeated measures. FINDINGS: In D1 (no information), 36/99 cases (36.3%) had unanimous diagnosis; in D5 (full information available), 51/99 cases (51.5%) had unanimous diagnosis (p for difference between proportions <0.001). The observer agreement expressed as kappa increased significantly from D1 to D5. The mean LDC linearly increased for each observer from D1 through D5 (p for linear trend <0.001). On average, each histopathologist changed his initial diagnosis in 7 cases (range: 2-23). Most diagnostic changes were in D2 (age/sex/location). INTERPRETATION: The histopathologic criteria for the diagnosis of MSN can work as such, but the final histopathologic diagnosis is a clinically-aided interpretation. Clinical data sometimes reverse the initial histopathologic evaluation.

Intracranial involvement in plasmacytomas and multiple myeloma: a pictorial essay.

INTRODUCTION: The purpose of this pictorial essay is to increase awareness of the clinical presentation, neuroradiological findings, treatment options, and neuroradiological follow-up of plasmacytomas and multiple myeloma with intracranial growth. METHODS: This pictorial essay reviews the clinical features and neuroradiological findings in seven patients (four women, three men; age range at diagnosis 62-82 years) followed in two institutions. Six patients, one with IgG-kappa plasmacytoma, and five with IgG-kappa (n = 3), IgG-lambda (n = 1), and nonsecretory (n = 1) multiple myeloma, had been seen over a period of 9 years in one institution, and the other patient with IgG-kappa plasmacytoma had been seen over a period of 3.5 years in the other. RESULTS: Intracranial involvement is rare, most frequently resulting from osseous lesions in the cranial vault, skull base, nose, or paranasal sinuses. Primary dural or leptomeningeal involvement is rarer. Some typical findings of a dural and/or osseous plasmacytoma include iso- to hyperdensity on CT scan, T1 equal to high signal intensity and T2 markedly hypointense signal on MRI, and high vascularity possibly documented on intraarterial digital subtraction angiography. However, the neuroradiological findings generally lack specificity, since they are generally no different from those of meningioma, metastasis, lymphoma, dural sarcoma, plasma cell granuloma, infectious meningitis, and leptomeningeal carcinomatosis. CONCLUSION: The spectrum of clinical and neuroradiological evaluation shows that intracranial involvement from plasmacytoma and multiple myeloma must be taken into account in the differential diagnosis of cranial osseous and meningeal disease.

NeuroD1 expression in human prostate cancer: can it contribute to neuroendocrine differentiation comprehension?

OBJECTIVES: Neuroendocrine differentiation is a common feature of prostate cancer (pCA). NeuroD1 is a neuronal transcription factor able to convert epithelial cells into neurons. The aim of the study is to investigate NeuroD1 expression and compare it with chromogranin-A, synaptophysin, and CD56 staining in human prostate cell lines and surgical specimens. METHODS: We detected NeuroD1 gene expression, by duplex reverse transcriptase-polymerase chain reaction, in primary human prostate fibroblasts, in EPN, LNCaP, DU145, and PC3 cell lines before and after cAMP exposure, in 6 BPH and 11 pCA samples. Thereafter 166 paraffin sections from normal and neoplastic prostates were stained with NeuroD1, chromogranin-A, synaptophysin, and CD56 antibodies. The relationships between chromogranin-A and NeuroD1 and clinicopathologic parameters were evaluated by multivariate logistic regression analysis. RESULTS: NeuroD1 is inactive in baseline prostate cell lines and BPHs, whereas it is actively expressed in cAMP-treated EPN, PC3, and DU145 cells. In our surgical series, positive chromogranin-A, synaptophysin, CD56, and NeuroD1 staining was detected in 26.5%, 4.3%, 3.1%, and 35.5%, respectively (difference between chromogranin-A and NeuroD1: p<0.05). The multivariate analysis showed a strong association between chromogranin-A and microscopic perineural invasion (OR: 2.49; 95%CI, 0.85-7.32; p=0.097) and a high primary Gleason score (OR: 1.96; 95%CI, 1.14-3.39; p=0.015), whereas NeuroD1 expression strictly correlated to microscopic perineural invasion (OR: 2.97; 95%CI, 1.05-8.41; p=0.04). CONCLUSIONS: Expression of NeuroD1 versus chromogranin-A is more frequent in pCA, and correlates to increased indicators of malignancy in moderately to poorly differentiated pCA, and could be involved in the pathophysiology of the neuroendocrine differentiation of pCA.

Prenatal ultrasound diagnosis of cloacal exstrophy associated with myelocystocele complex by the 'elephant trunk-like' image and review of the literature.

A case of cloacal exstrophy (CE) was detected by ultrasound as early as 22 weeks of gestation in association with myelocystocele complex, an unusual form of occult spinal dysraphism often associated with such a disease. The ultrasonographic diagnosis was made through the detection of a wavy cord-like segment of soft tissue protruding from the anterior abdominal wall, just below the umbilical cord insertion, strongly resembling the trunk of an elephant. Our article enforces the suggestion that the ultrasound elephant trunk-like image should be added to the existing major criteria for making prenatal diagnosis of CE.

Parotid carcinoma after autologous bone marrow transplantation for relapsed nephroblastoma.

Abdominal irradiation, especially if associated with doxorubicin administration, increases the risk of a secondary malignant neoplasm (SMN) after treatment of nephroblastoma. Secondary malignant salivary tumors are rare and usually occur in patients with previous cranial irradiation. The authors describe the case of a parotid mucoepidermoid carcinoma arising 13 years after diagnosis of nephroblastoma. This patient showed no characteristics reported in the literature as statistically significant for the development of an SMN. The authors believe that long-term, regular clinical examination is necessary even in patients at low risk of developing an SMN.

Intraepithelial carcinoma arising in an endodermal cyst of the posterior fossa.

Endodermal cysts of the central neuraxis are benign, non-neoplastic epithelium-lined cysts arising from endodermal tissue that have been displaced early in fetal life. Intracranial endodermal cysts are rare and usually located in the posterior fossa. The present study involves a 36-year-old man with a typical epithelial cyst in the posterior fossa. Microscopically, the cyst has a simple columnar epithelium with mucus-producing cells, containing an area composed of dysplastic epithelium with evidence of an intraepithelial carcinoma. The atypical cells have a high proliferative fraction demonstrated by Ki-67 immunostain. Based on these findings, the authors view this case as evidence of a malignant transformation of a classic endodermal cyst. The clinicopathologic features and a review of the literature are discussed.

Prenatal ultrasound diagnosis of a case of Pfeiffer syndrome without cloverleaf skull and review of the literature.

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.