Σύνδρομο Koolen de Vries

H αναγνώριση των συνδρόμων μικροελλείμματος και μικροδιπλασιασμού της χρωμοσωμικής περιοχής 17q21.31 έχει γίνει δυνατή μόνο μετά την εφαρμογή της νέας τεχνολογίας του μοριακού καρυοτύπου ή μικροσυστοιχίας του συγκριτικού γενωμικού υβριδισμού (array-CGH). Στη βιβλιογραφία έχουν αναφερθεί τουλάχιστον 80 περιστατικά με το σύνδρομο Koolen de Vries (KdVS). Με τη μοριακή ανάλυση αναδείχθηκε ότι στην περιοχή 17q21.31 εντοπίζονται τουλάχιστον 6 κρίσιμα για το φαινότυπο γονίδια, με σημαντικότερα τα STH και MAPT. Η συχνότητα του συνδρόμου μικροελλείματος 17q21.31 εκτιμάται στις 1/16000 γεννήσεις ενώ, μέχρι στιγμής έχουν περιγραφεί μόνο επτά ασθενείς με σύνδρομο μικροδιπλασιασμού 17q21.31. Ο φαινότυπος που σχετίζεται με μικροδιπλασιασμούς 17q21.31 φαίνεται να είναι ηπιότερος σε σχέση με τα σύνδρομα μικροελλείμματος 17q21.31. Πρόσφατα περιγράφηκε επίσης ό,τι η απλοανεπάρκεια του KANSL1 και μόνο αρκεί να οδηγήσει στον πλήρη φαινότυπο του συνδρόμου, εξαιτίας ενός πολυμορφισμού ή ενός γονιδιακού ελλείματος. Στην παρούσα μελέτη καταγράφηκαν από το τμήμα Kλινικής Γενετικής του Πανεπιστημίου Αθηνών, 19 ασθενείς με το σύνδρομο Koolen de Vries, 6 απο αυτούς ήταν ενήλικες. Η πλειοψηφία των ασθενών παραπέμφθηκαν από τον παιδίατρο ή τον αναπτυξιολόγο για γενετικό έλεγχο λόγω ψυχοκινητικών διαταραχών . Σε 17 ασθενείς διαγνώσθηκε έλλειμα στην περιοχή 17q21.31, σε έναν ασθενή μικροδιπλασιασμό στην περιοχή 17q21.31 και στον τελευταίο μια παθολογική de novo σημειακή μετάλλαξη (c.1448G>A) του KANSL1 γονιδίου. Oι ψυχοκινητικές διαταραχές, η νοητική στέρηση, τα δυσμορφικά χαρακτηριστικά προσώπου και η καθυστέρηση λόγου φαίνεται να είναι οι πιο συχνές εκδηλώσεις του συνδρόμου. Ενδιαφέρον εύρημα στην μελέτη μας είναι ο,τι η ανάλυση μέσω του μοριακού καρυρότυπου ανέδειξε ο,τι σε 4 ασθενείς με ψυχοκινητική καθυστέρηση εκτός από το ελλείμμα στην περιοχή 17q21.31 υπήρχε και έλλειμμα ή μικροδιπλασιασμός στην περιοχή του μακριού σκέλους του χρωμοσώματος 15 .The deletion or microduplication of the 17q21.31 region was recognised only with the development of the array-CGH technique. The 17q21.31 region, typically encompassing at least 6 critical genes related to the phenotype (ie STH and MAPT). Recently, it has been shown that haploinsufficiency of KANSL1 by itself, due to single nucleotide variants or gene deletion, is sufficient to cause the full-blown phenotype of the disorder of Koolen-de Vries syndrome. The frequency of this syndrome is estimated at 1/16000 whereas only seven cases have been described so far with microduplication of the 17q21.31 region. Patients with microduplications have a less severe phenotype compare to the syndrome with deletions. In total at least 80 cases of Koolen de Vries syndrome have been described in the literature. In the present study, 19 patients with Koolen de Vries syndrome have been registrated and diagnosed in the laboratory of Medical Genetics of the National and Kapodistrian University of Athens, 6 of them were adults. The majority of the patients was addressed for genetical analysis due to psychomotor retardation. Seventeen patients presented deletion of the 17q21.31 region, 1 patient presented microduplication and the last one, de novo pathological mutation (c.1448G>A) of the KANSL1 gene. Interestingly, we also found 4 patients with the phenotype of KdVS due to the deletion in the 17q21.31 region indluding KANSL1 who also presented (through array-CGH technique) deletion or microduplication of the 15q region

The value of PRL in predicting prolactinοma in hyperprolactinemic PCOS

Background To identify a serum prolactin (PRL) cut‐off value indicative of a PRL‐producing adenoma in women with Polycystic Ovarian Syndrome (PCOS) and hyperprolactinemia and characterize such patients. Materials and methods In the present retrospective case‐control study the medical records of 528 PCOS women were reviewed. Pituitary magnetic resonance imaging (MRI) was performed in PCOS patients with PRL levels ≥94.0 ng/mL and/or symptoms suspicious of a pituitary adenoma (PA). Prolactinoma diagnosis was made in the presence of an MRI‐identifiable PA with biochemical and radiological response to dopamine agonists. Receiver operating characteristic (ROC) curve analysis was performed to determine a serum PRL threshold that could identify hyperprolactinemic PCOS subjects with prolactinomas. Clinical, metabolic and endocrine parameters were also analysed. Results Among 528 patients with PCOS, 60 (11.4%) had elevated PRL levels. Of 44 (73.3%) patients who had pituitary imaging, 19 had PAs, 18 normal MRI and 7 other abnormalities. Patients harboring prolactinomas had significantly higher PRL levels compared to patients without adenomas (median PRL 95.4 vs. 49.2 ng/mL, p<0.0001). A PRL threshold of 85.2 ng/mL could distinguish patients with prolactinomas with 77% sensitivity and 100% specificity [Area Under the curve (AUC) (95%) 0.91(0.8‐1.018), p=0.0001]. PCOS women with prolactinomas were younger and had lower LH levels compared to women without prolactinomas. Conclusions In women with PCOS, PRL levels exceeding 85.2 ng/mL are highly suggestive of a prolactinoma warranting pituitary imaging. Pituitary MRI could also be considered in young PCOS patients with milder PRL elevation and low LH levels

Association of thyroid disease with histopathological parameters of breast tissue

Aim: This study evaluated the association of thyroid function abnormalities with the risk of primary breast cancer (BC) as well as the immunochemical expression of NIS (Sodium Iodide Symporter) in human breast tissues.Methods: We measured baseline levels of thyrotropine (TSH), free triidothyronine (fT3), free thyroxine (fT4) and thyroid autoantibodies (TPO Ab, Tg Ab and TRAK) in a cohort of 97 women with primary BC, 27 women with benign breast disease (BBD) and 4 women with atypical ductal hyperplasia compared to 48 healthy women. Human breast tissue samples (41 with BC, 11 with BBD and 4 with normal breast tissues adjacent to carcinoma) were analysed by immunochemistry using a monoclonal anti –NIS antibody.Results: No statistically significant association was found between history of thyroid disease and BC (p=0.33). Mean baseline values of fT4 plasma concentration were found to be significantly higher in the BC group (p=0.035) compared to other groups. BC cases with thyroid disease had statistically significant lower incidence of lymph node metastasis (p=0.005).NIS presented cytoplasmic positive immunoreactivity, in 45% of BBD samples, in 32% of BC samples and in 3 out of 4 normal breast tissues adjacent to carcinoma (75%), without statistical significant difference (p=0.426).Conclusions: These results confirm the proliferative effect of fT4 on breast cells, already shown in vitro. NIS higher expression in BBD and ‘normal’ breast samples compared to BC, suggests a down regulation of NIS expression during carcinogenesis.Σκοπός: Σκοπός αυτής της μελέτης είναι η συσχέτιση της θυρεοειδικής λειτουργίας με τον κίνδυνο εμφάνισης πρωτοπαθούς καρκίνου του μαστού όπως και η ανοσοιστοχημική ανίχνευση της πρωτείνης NIS (Sodium Iodide Symporter) σε δείγματα ιστών του μαστού.Μεθοδολογία: Έγιναν βασικές μετρήσεις των θυρεοειδικών ορμονών (fT3, fT4), της TSH και των θυρεοειδικών αυτοαντισωμάτων (TPO Abs, Tg Abs, TRAB) σε έναν πληθυσμό 97 ασθενών με καρκίνο μαστού, 27 ασθενών με καλοήθη πάθηση μαστού, 4 ασθενών με άτυπη πορογενή υπερπλασία και 48 υγειών γυναικών χωρίς πάθηση μαστού. Πενήντα έξι δείγματα ιστών μαστου (41 με καρκίνο, 11 με καλοήθη πάθηση and 4 υγειών ιστών) χρησιμοποιήθηκαν για ανοσοιστοχημική ανάλυση με το μονοκλωνικό αντίσωμα anti-NIS (FP5A).Αποτελέσματα: Η συχνότητα ιστορικού θυρεοειδοπάθειας δεν παρουσίασε στατιστικά σημαντική διαφορά μεταξύ των συγκρινόμενων ομάδων (p=0.33). Η μέση τιμή της fΤ4 ήταν στατιστικά σημαντικά υψηλότερη στην ομάδα του καρκίνου μαστού συγκριτικά με τις υπόλοιπες ομάδες (p=0.035). Ασθενείς με ιστορικό θυρεοειδοπάθειας παρουσιάζαν στατιστικα χαμηλότερη επίπτωση λεμφαδενικών μεταστάσεων (p=0.005) . Σε οτι αφορά την παρουσία της πρωτείνης ΝΙS, το ποσοστό της έκφρασηςτης στα καρκινικά κύτταρα ήταν 32%, στα καλοήθη κύτταρα 45% και στους υγιείς ιστούς 75% (p=0.426). Ωστόσο η εντόπιση της ήταν κατεξοχήν κυτταροπλασματική γεγονός που πιθανότατα δείχνει ότι η πρωτεΐνη είναι μη λειτουργική.Συμπεράσματα Τα αποτελέσματα επιβεβαιώνουν τον διεγερτικό ρόλο της fT4 κατά τη καρκινογένεση του μαστού ήδη γνωστός in vitro αλλά και την εντονότερη έκφραση της NIS στους καλοήθεις ιστούς σε σύγκριση με τους καρκινικούς υποδηλώνοντας έναν μηχανισμό κατασταλμένης έκφρασης της NIS κατά την καρκινογένεσ

Atypical manifestation of parathyroid carcinoma with late-onset distant metastases

Parathyroid carcinoma is an extremely rare endocrine malignancy that accounts for less than 1% of cases of primary hyperparathyroidism. We report a 44-year-old woman who presented with fatigue and diffuse bone pain. Laboratory findings revealed highly elevated serum calcium and parathyroid hormone (PTH) levels and a 4.5 × 3 × 2.5 cm cystic lesion in the lower pole of the right thyroid lobe that was shown histologically to be a parathyroid carcinoma. Ten years later, the patient developed brain and pulmonary metastases and recurrence of PTH-related hypercalcemia. Treatment of hypercalcemia along with localized radiotherapy and various chemotherapy regimens failed to induce a biochemical or radiological response. In conclusion, parathyroid carcinoma is a rare neoplasia that may develop metastases even after prolonged follow-up, for which there is no evidence-based treatment besides surgery. Different chemotherapeutic schemes did not prove to be of any benefit in our case highlighting the need for registering such patients to better understand tumor biology and develop specific treatment

Atypical manifestation of parathyroid carcinoma with late-onset distant metastases

Parathyroid carcinoma is an extremely rare endocrine malignancy that accounts for less than 1% of cases of primary hyperparathyroidism. We report a 44-year-old woman who presented with fatigue and diffuse bone pain. Laboratory findings revealed highly elevated serum calcium and parathyroid hormone (PTH) levels and a 4.5 x 3 x 2.5 cm cystic lesion in the lower pole of the right thyroid lobe that was shown histologically to be a parathyroid carcinoma. Ten years later, the patient developed brain and pulmonary metastases and recurrence of PTH-related hypercalcemia. Treatment of hypercalcemia along with localized radiotherapy and various chemotherapy regimens failed to induce a biochemical or radiological response. In conclusion, parathyroid carcinoma is a rare neoplasia that may develop metastases even after prolonged follow-up, for which there is no evidence-based treatment besides surgery. Different chemotherapeutic schemes did not prove to be of any benefit in our case highlighting the need for registering such patients to better understand tumor biology and develop specific treatment

The role of epithelial growth factors and insulin growth factors in the adrenal neoplasms

Human fetal and adult adrenal gland express both insulin growth factor-1 (IGF-1) and IGF-2, their receptors (IGF-Rs) and a variety of specific IGF binding proteins suggesting their potential role in the regulation of adrenal growth and function. IGF-2 overexpression is essential for the growth of monoclonal lesions, such as large benign adenomas (ACA) and adrenocortical carcinomas (ACC) and has been found to contribute to tumorigenesis in Beckwith-Wiedemann syndrome. IGF-2 is the most highly expressed gene observed in more than 85% of ACCs. However, no significant differences in clinical, biological and transcriptomic traits were found between tumors with high and low expression of IGF-2. On the contrary, the expression of IGF-1R, mediating the IGF-2 effects in vivo, was more discriminant between malignant (overexpression) and benign tumors. Data on the role of epithelial growth factor (EGF) and its receptor (EGF-R) in adrenocortical tumorigenesis are controversial. Several studies have shown EGF-R overexpression in ACCs but not in benign ACAs, suggesting that EGF-R could potentially be used as a marker for the differential diagnosis of ACAs and ACCs. Although, in vitro and animal studies provide promising results in the therapeutic role of IGF and EGF pathway inhibitors, the available data in humans are still not encouraging. Herein, we aim to present recent data on the role of IGF and EGF pathways in adrenal development and tumorigenesis and their potential implication in the treatment of the ACC, a rare malignancy with very poor prognosis

Molecular targeted therapies in adrenal, pituitary and parathyroid malignancies

Tumourigenesis is a relatively common event in endocrine tissues. Currently, specific guidelines have been developed for common malignant endocrine tumours, which also incorporate advances in molecular targeted therapies (MTT), as in thyroid cancer and in gastrointestinal neuroendocrine malignancies. However, there is little information regarding the role and efficacy of MTT in the relatively rare malignant endocrine tumours mainly involving the adrenal medulla, adrenal cortex, pituitary, and parathyroid glands. Due to the rarity of these tumours and the lack of prospective studies, current guidelines are mostly based on retrospective data derived from surgical, locoregional and ablative therapies, and studies with systemic chemotherapy. In addition, in many of these malignancies the prognosis remains poor with individual patients responding differently to currently available treatments, necessitating the development of new personalised therapeutic strategies. Recently, major advances in the molecular understanding of endocrine tumours based on genomic, epigenomic, and transcriptome analysis have emerged, resulting in new insights into their pathogenesis and molecular pathology. This in turn has led to the use of novel MTTs in increasing numbers of patients. In this review, we aim to present currently existing and evolving data using MTT in the treatment of adrenal, pituitary and malignant parathyroid tumours, and explore the current utility and effectiveness of such therapies and their future evolution