Fetal autopsy for the diagnosis of skeletal dysplasia and comparison with prenatal ultrasound findings over a 16-year period.

OBJECTIVES: To evaluate the relationship between prenatal ultrasonography (USG) and fetal autopsy findings. METHODS: Among 453 pregnancy terminations performed because of fetal anomalies on prenatal USG, 54 with skeletal dysplasia on fetal autopsy were included in this retrospective study. RESULTS: The most common diagnoses among the 54 fetal autopsies were osteogenesis imperfecta (n=12), dysostosis (n=10), achondroplasia (n=9), arthrogryposis (n=6), and thanatophoric dysplasia (n=6). The prenatal USG and fetal autopsy findings showed complete agreement in 35 cases (64.8%), partial agreement in nine cases (16.6%), and disagreement in 10 cases (18.5%). CONCLUSIONS: Fetal autopsy via perinatal pathology is essential for precise identification of the type of skeletal dysplasia; it should be routinely performed to confirm the diagnosis of prenatally detected fetal anomalies. Autopsy is vital for accurate prenatal diagnosis and the 'gold standard' technique for the identification of clinically important abnormalities.

Dilemma after termination of pregnancy due to urogenital fetal anomalies: Discrepancy between prenatal ultrasonographic diagnosis and autopsy.

OBJECTIVE: To evaluate the agreement and disagreement between prenatal ultrasound and fetal autopsy findings in pregnancy terminations due to urogenital anomalies. METHODS: Of 453 pregnancy terminations performed due to fetal anomalies, 82 cases with urogenital anomalies on either prenatal ultrasound or fetal autopsy were included in this retrospective study. The discrepancy between prenatal ultrasound and fetal autopsy findings on urogenital anomaly findings was evaluated. RESULTS: Complete agreement between prenatal ultrasound and fetal autopsy findings was noted in 33 (40.2%) cases (particularly for megacystis, bilateral renal agenesis, and infantile polycystic kidney), whereas partial agreement (anal atresia and horseshoe kidney as additional minor findings) and altered diagnosis were noted in 12 (14.6%) and 8 (9.8%) cases, respectively. Disagreement was noted in 29 (35.4%) cases including anomaly only on autopsy in 20 (24.3%) cases (renal agenesis, horseshoe kidney and multicystic dysplastic kidney in particular) and anomaly only on ultrasound in 9 (10.9%) cases. CONCLUSIONS: Accordingly, our findings indicate fetal autopsy to be a method of vital importance in complementing prenatal diagnosis; it may add valuable information that may improve future pregnancy management and counseling of parents, and hence prenatal ultrasound and fetal autopsy should be regarded as complementary techniques.

Comparison of prenatal central nervous system abnormalities with postmortem findings in fetuses following termination of pregnancy and clinical utility of postmortem examination.

OBJECTIVES: In this study, we aimed to compare prenatal ultrasound (USG) and postmortem examination findings of central nervous system (CNS) abnormalities in fetuses following termination of pregnancy (TOP). METHODS: A total of 190 fetuses with USG-confirmed fetal CNS abnormalities of terminated pregnancies between January 2001 and January 2017 were retrospectively analyzed and USG and postmortem examination findings were compared. RESULTS: The most frequent CNS abnormalities were acrania/anencephaly (n=45, 24%), spina bifida (n=43, 23%), and ventriculomegaly (n=35, 18%). In 144 of the 190 (76%) cases, there was total agreement between USG and postmortem examination diagnosis. Postmortem examination provided minor findings which did not change the major clinical diagnosis in two (1%) cases with spina bifida and ventriculomegaly. In six (3%) cases, the diagnosis changed after postmortem examination. In 25 of the 190 (13%) cases with multiple abnormalities as evidenced by USG, CNS abnormality was unable to be confirmed at postmortem examination. CONCLUSIONS: Our study results show an overall high agreement (76%) between USG and postmortem examination findings for CNS malformations. Due to autolysis and fluid structure, USG-confirmed CNS diagnosis cannot be always confirmed by postmortem examination. This potential discrepancy should be explained to patients before considering TOP. Postmortem examination is the gold standard to confirm prenatal diagnosis.

The Role of Different Molecular Markers in Papillary Thyroid Cancer Patients with Acromegaly.

PURPOSE: Prevalence of papillary thyroid cancer (PTC) is increased in patients with acromegaly. We aimed to determine the protein expression of BRAF, RAS, RET, insulin like growth factor 1(IGF1), Galectine 3, CD56 in patients with PTC related acromegaly and to compare the extensity of these expressions with normal PTC patients and benign thyroid nodules. METHODS: We studied 313 patients with acromegaly followed in Cerrahpasa Medical Faculty, Endocrinology and Metabolism Clinic between 1998 and 2015. On the basis of availability of pathological specimen of thyroid tissues, thyroid samples of 13 patients from 19 with acromegaly related PTC (APTC), 20 normal PTC and 20 patients with multinodulary goiter (MNG) were histopathologically evaluated. Protein expressions were determined via immunohistochemical staining in ex-vivo tumor samples and benign nodules. RESULTS: The incidence of PTC in acromegaly patients were 6% (n=19). Among patients with PTC, APTC and MNG, all the immunohistochemical protein expressions we have studied were higher in papillary thyroid cancer groups (p<0.01, for all). Between PTC group without acromegaly and APTC, galectin 3 and IGF1 expression was significantly higher in acromegalic patients (p<0.01 for all) while RAS was predominantly higher in PTC patients without acromegaly (p<0.01). CONCLUSION: BRAF expression was not higher in PTC with acromegaly patients compared to PTC patients without acromegaly. Galectine 3 and IGF1 were expressed more intensively in APTC. These positive protein expressions may have more influence on determining malign nodules among acromegaly patients.

Investigation of BRAF V600E mutation in papillary thyroid carcinoma and tumor-surrounding nontumoral tissues.

The aim of this study was to investigate the association between the BRAF V600E mutation incidence and histopathologic prognostic risk factors for papillary thyroid carcinoma (PTC) on the Turkish population. The contribution of BRAF V600E mutation in both tumor and tumor-surrounding nontumoral tissues of 108 patients with PTC was assessed using mutant allele-specific amplification-polymerase chain reaction. The BRAF V600E mutation was found in 52.8% of the tumor tissues, and 7.4% of the tumor-surrounding nontumoral tissues. The BRAF V600E mutation was significantly higher in the tumor tissues of the classic variant of PTC (CVPTC) cases than the follicular variant of PTC cases (p=0.001). The presence of the BRAF V600E mutation was more frequent in women, but this gender difference was not statistically significant. BRAF V600E mutation was more frequent in patients with either one of adenomatous hyperplasia or diffuse hyperplasia in tumor-surrounding nontumoral tissues (p=0.012). There was no significant difference in the BRAF V600E mutation distribution among tumor-surrounding nontumoral tissues of the two PTC variants, but it was more frequent in the CVPTC. Recent data suggest that BRAF V600E is an important marker, especially, for CVPTC. We propose that patients who had subtotal thyroid resection might have an increased risk of recurrence at the residual thyroid tissue if they have BRAF V600E mutation in their tumor-surrounding nontumoral tissues.

A novel mutation in the interleukin-1 receptor antagonist associated with intrauterine disease onset.

Deficiency of the IL-1 receptor antagonist (DIRA) is a recently described rare autoinflammatory disease, caused by loss of function mutations in IL1RN leading to the unopposed activation of the IL-1 pathway. We describe a novel nonsense mutation in the IL1RN gene, associated with early intrauterine onset, death and multiorgan involvement in a prematurely born baby. The protein prediction model indicated that the novel Q119X mutation would result in a nonfunctional protein by impairing the ability of the IL-1Ra to bind and antagonize signaling through the IL-1R. Since the disorder may mimic severe bacterial infections and the treatment with anakinra is life saving, we intend to raise awareness of the syndrome and the possibility of a founder mutation that may lead to the diagnosis of additional cases in Turkey. The clinical suspicion of DIRA is critical to avoid improper management of the patients with antibiotics alone and death from multiorgan failure.

Multiple fetal anomalies in association with topiramate and oxcarbezepine treatment.

We present a case of a woman who used topiramate (100 mg) and oxcarbazepine (300 mg) continuously during pregnancy. Multiple fetal anomalies including limp defects of the lower extremities, pericardiac fluid collection, cardiomegaly, cleft lip and palate, absent right kidney, and dysplastic left kidney were found by ultrasonography. Labor was induced and anomalies were confirmed by autopsy. The malformation rate after exposure to oxcarbazepine in utero as a monotherapy was calculated to be 2.4%, which is compatible with the malformation rate seen in the general population. Topiramate is teratogenic in mice, rats, and rabbits, but there are very few reports about its teratogenicity in humans.

Craniorachischisis with a variant of pentalogy of Cantrell, with lung extrophy.

A case of cranioraschischisis including incomplete pentalogy of Cantrell (PC) is described. The female fetus had a large omphalocele with evisceration of the heart, left lung, liver, stomach, and intestines accompanying anencephaly, cervical, thoracal lumbar, spina bifida. The fetus had ectopia cordis and diaphragmatic agenesia with an intact sternum. We present a case of a neonate with the stigmata for PC with the exception of a sternal defect. A literature review is also included. Sonographers should check for ventral and dorsal anomalies with PC because they may occur simultaneously.

VACTERL-H syndrome: first trimester diagnosis.

We present two consecutive female fetuses with identical upper limb anomalies. The first of the cases was found to have ventriculomegaly, atrial septal defect, anal atresia, narrowing of the duodenal lumen and unilateral renal agenesis at the end of the second trimester. These abnormalities were characteristic of autosomal recessive VACTERL-H syndrome. The second case was diagnosed to have absent radii and thumbs at 11 weeks. Detailed examination of fetal limbs in the first trimester screening in cases with high risk is useful for early detection of this malformation.

Antenatal Bartter syndrome: analysis of two cases with placental findings.

The prenatal diagnosis of Bartter syndrome can be based on the high chloride level in the amniotic fluid. Microscopic examination of the placenta in untreated cases showed extensive mineralization in the chorionic villi in previous studies. Two cases were presented at 26-29 weeks of gestation with severe polyhydramnios. The mothers were treated with Indomethacin, KCl, and serial amniocentesis in order to reduce the amniotic fluid volume and prevent fetal hypokalemia. The microscopic examination of the placenta revealed focal calcification and acute atherosis in placental vessels. The treatment with Indomethacin in the antenatal period can prevent severe nephrocalcinosis.

Clinical variability of asphyxiating thoracic dystrophy (Jeune) syndrome: Evaluation and classification of 13 patients.

Asphyxiating thoracic dystrophy-Jeune syndrome (JS) is a rare autosomal recessive disease characterized by small thorax and short limb dwarfism. Besides the clinical variability, prognosis also differs greatly among patients. Pulmonary involvement is predominant in some cases whereas renal involvement is much more evident in others. We aimed to investigate the clinical variability and prognosis in 13 patients with JS from 11 families. Two of them, who had been diagnosed in the prenatal period were assessed by autopsy findings. All patients had a bell-shaped or long narrow short thorax and brachydactyly at varying degrees from mild to severe. Short stature was common feature emerging in the postnatal period. One patient had atlantoaxial instability and spinal cord compression which have not been reported in JS before. In the postnatal follow up of 11 patients, respiratory distress was observed in eight patients and proved lethal in six, one patient died of chronic renal failure, and the remaining four patients were still alive at the end of the study. Patients were classified into three groups consisting of severe pulmonary involvement, renal involvement, and mild form in terms of prognosis. Patients with severe pulmonary involvement had bell-shaped thorax and mild brachydactyly, the one patient with renal involvement had long narrow thorax and severe brachydactyly, and patients with mild involvement presented with polydactyly and moderate to severe brachydactyly. It is important to establish a correct diagnosis both in severe and mild forms since JS might recur within the same family.

Semilobar holoprosencephaly with associated cyclopia and radial aplasia: first trimester diagnosis by means of integrating 2D-3D ultrasound.

INTRODUCTION: Holoprosencephaly (HPE) is commonly associated with facial malformations. We present a case of semilobar HPE associated with distal limb defect which was detected at 12 weeks of gestation. CASE: The fetus had a crown-rump length of 60 mm (12 weeks-4 days), had nuchal translucency thickness of 1.5 mm. Initial two-dimensional (2D) ultrasound revealed the absence of nasal bone, decreased BPD and abnormal profile. Transvaginal 2D ultrasound was effective in the detection of HPE (partially absence of the interhemispheric fissure, fused thalami, the choroid plexuses were not visualized bilateraly: absent 'butterfly' sign), cylopia, absence of the nose and unilateral radial aplasia. Three dimensional (3D) ultrasound provided a better visualization of the associated anomalies. The necropsy result confirmed the sonographic findings: the diagnosis was semilobar HPE, cyclopia, absence of the nose, and the absence of the radius and the thumb in the left arm. DISCUSSION: Transvaginal 2D sonographic examination is effective in detection of the cases with HPE at first trimester. Fetal morphological study through 3D ultrasound may facilitate the diagnosis of associated anomalies.

Jarcho-Levin syndrome presenting as neural tube defect: report of four cases and pitfalls of diagnosis.

Jarcho-Levin syndrome (JLS) causes severe vertebral and thoracic deformity and has an autosomal-recessive mode of inheritance. Prenatal diagnosis may be difficult in some cases without the history of an affected baby. We present 4 cases of JLS with neural tube defects as the prominent finding. In 2 of them the deformity of the thorax was minimal and was not detected by ultrasonography. Rib anomalies were revealed with radiological and pathological examinations after the termination. The location of the vertebral defect may be the determinant factor for the severity of the thoracic deformity. The real recurrence risk could only be found out after postnatal examinations in cases with neural tube defects.

Immunohistochemical analysis of orbital connective tissue specimens of patients with active Graves ophthalmopathy.

PURPOSE: To explore the immune mechanism of Graves ophthalmopathy (GO) by analyzing infiltrating cells in orbital connective tissue (OCT) specimens of patients with active GO using immunohistochemical methods. METHODS: Five OCT specimens obtained from patients with active GO and five control specimens obtained from forensic cadavers who died from nonmedical reasons were stained with anti-CD3, CD4, CD8, CD45RO, HLA-Dr, CD25, and TNF-alpha monoclonal antibodies. Positively stained cells were counted and results were interpreted as cell counts/mm2. Four of five GO patients had never been treated with any immunomodulating therapy. Only one had received oral prednisolone prior to tissue sampling, but this treatment had ceased 5 months before surgery. RESULTS: The retro-orbital tissue specimens obtained from forensic cadavers did not show any significant positive staining for any monoclonal antibody tested. However, the specimens from GO patients showed positively stained means of 36.66 +/- 4.61 HLA-Dr+, 12.8 +/- 3.42 CD8+, 11.8 +/- 1.78 CD4+, 16.6 +/- 1.81 CD3+, 21.2 +/- 3.12 CD45RO+, 10.4 +/- 2.07 TNF-alpha+, 7.2 +/- 1.48 CD25+, 3.2 +/- 1.09 CD4+CD8+, 4.6 +/- 1.67 CD4+CD45RO+, 2.8 +/- 0.83 CD8+CD45RO+, 1.6 +/- 0.89 CD4+CD25+, and 1.8 +/- 1 0.83 CD8+CD25+ cells/mm2. CONCLUSIONS: Our study supports that most of the infiltrating lymphocytic cells in the active stage of GO are T cells, and a significant proportion of them are CD45RO+ cells. Infiltration of OCT by HLA-Dr+, CD25+, and TNF-alpha cells suggests that Th1-type immune reaction with the interference of proinflammatory cytokine(s) (TNF-alpha) may be important in the pathogenesis of disease. Further studies are needed to understand the disease pathogenesis and may provide a scientific basis for future treatment alternatives for the disease (e.g., anti-cytokine treatment).

Congenital mediastinal immature teratoma: a case report with autopsy findings.

A full-term newborn with karyotype 46, XX was delivered by cesarean section. She had severe respiratory distress and substernal retraction, and underwent emergency operation, but she died on the same day due to respiratory failure. The mother, 26-year-old prima gravida with no history of twinning, had been examined with ultrasonography at the 34th week of her pregnancy, which revealed a fetus with edema of head and neck region, a probable diaphragmatic hernia, polyhydramnios, and a large mediastinal mass with solid and multicystic parts with hypoplasia of the lungs. Autopsy revealed a 9 x 5 x 3 cm lobulated mediastinal mass with both solid and cystic areas, displacing the lungs and the heart postero-inferiorly and thymus anteriorly. The lungs were hypoplasic. Microscopically, the mass showed mature epithelial and mesenchymal tissues with primitive mesenchyme and immature neuroepithelium. All these findings led to the diagnosis of an immature teratoma. Mediastinal teratomas are rare and life-threatening, but early diagnosis and surgical intervention in a newborn with sufficient lung maturation may provide a long survival.

Prenatal diagnosis of arthrogryposis multiplex congenita with increased nuchal translucency but without any underlying fetal neurogenic or myogenic pathology.

Arthrogryposis multiplex congenita is a general term for congenital multiple joint contractures, the aetiology of which is variable. Prenatal diagnosis is usually based on the detection of diminished fetal movements and joint contractures on ultrasound. There are also reports of early diagnosis of arthrogryposis in the first and early second trimester by detection of subcutaneous oedema. We report another case of arthrogryposis multiplex congenita with increased nuchal translucency and scoliosis diagnosed by ultrasonography at 15 weeks of gestation. The pregnancy was terminated at the request of the parents. Post-mortem examination revealed that it was not associated with fetal myopathy or neuropathy. Multiple joint contractures with increased nuchal translucency without any underlying fetal neurogenic and myogenic pathology may be a distinct form of arthrogryposis multiplex congenita.