Goldberg-Shprintzen syndrome is determined by the absence, or reduced expression levels, of KIFBP.

Goldberg-Shprintzen syndrome (GOSHS) is caused by loss of function variants in the kinesin binding protein gene (KIFBP). However, the phenotypic range of this syndrome is wide, indicating that other factors may play a role. To date, 37 patients with GOSHS have been reported. Here, we document nine new patients with variants in KIFBP: seven with nonsense variants and two with missense variants. To our knowledge, this is the first time that missense variants have been reported in GOSHS. We functionally investigated the effect of the variants identified, in an attempt to find a genotype-phenotype correlation. We also determined whether common Hirschsprung disease (HSCR)-associated single nucleotide polymorphisms (SNPs), could explain the presence of HSCR in GOSHS. Our results showed that the missense variants led to reduced expression of KIFBP, while the truncating variants resulted in lack of protein. However, no correlation was found between the severity of GOSHS and the location of the variants. We were also unable to find a correlation between common HSCR-associated SNPs, and HSCR development in GOSHS. In conclusion, we show that reduced, as well as lack of KIFBP expression can lead to GOSHS, and our results suggest that a threshold expression of KIFBP may modulate phenotypic variability of the disease

Genotype-phenotype associations in a large PTEN Hamartoma Tumor Syndrome (PHTS) patient cohort

Background: Pathogenic PTEN germline variants cause PTEN Hamartoma Tumor Syndrome (PHTS), a rare disease with a variable genotype and phenotype. Knowledge about these spectra and genotype-phenotype associations could help diagnostics and potentially lead to personalized care. Therefore, we assessed the PHTS genotype and phenotype spectrum in a large cohort study. Methods: Information was collected of 510 index patients with pathogenic or likely pathogenic (LP/P) PTEN variants (n = 467) or variants of uncertain significance. Genotype-phenotype associations were assessed using logistic regression analyses adjusted for sex and age.Results: At time of genetic testing, the majority of children (n = 229) had macrocephaly (81%) or developmental delay (DD, 61%), and about half of the adults (n = 238) had cancer (51%), macrocephaly (61%), or cutaneous pathology (49%). Across PTEN, 268 LP/P variants were identified, with exon 5 as hotspot. Missense variants (n = 161) were mainly located in the phosphatase domain (PD, 90%) and truncating variants (n = 306) across all domains. A trend towards 2 times more often truncating variants was observed in adults (OR = 2.3, 95%CI = 1.5-3.4) and patients with cutaneous pathology (OR = 1.6, 95%CI = 1.1-2.5) or benign thyroid pathology (OR = 2.0, 95%CI = 1.1-3.5), with trends up to 2-4 times more variants in PD. Whereas patients with DD (OR = 0.5, 95%CI = 0.3-0.9) or macrocephaly (OR = 0.6, 95%CI = 0.4-0.9) had about 2 times less often truncating variants compared to missense variants. In DD patients these missense variants were often located in domain C2.Conclusion: The PHTS phenotypic diversity may partly be explained by the PTEN variant coding effect and the combination of coding effect and domain. PHTS patients with early-onset disease often had missense variants, and those with later-onset disease often truncating variants

Recording on genetic disorders and syndromes in the Greek-Cypriot population

The clinical genetics services were established in Cyprus in 1994. Patients were referred to this clinic from all over Cyprus for investigation of possible genetic disorders or for genetic counseling for a known or unknown diagnosis. Patients were referred from physicians of various specialties and sometimes from other health professionals. The population referred was mainly of Greek-Cypriot origin, but gradually as patients of other origin increased we included also patients of mixed descent, Turkish-Cypriots and others. A registry was created which reports on several demographic data and on medical data such as reason for referral and diagnosis. Reasons for referrals included all common indications such as: mental retardation, developmental delay, dysmorphic features, congenital anomalies, history of cancer, abnormalities of the skeleton, hearing of vision problems, history of infertility, recurrent miscarriages, consanguinity and some rare ones. This study reports on the diversity of diagnosis established for 3400 individuals in the years 1995-2009. 1007 patients were aetiologically diagnosed while 1099 were not. It has been shown that more than 50% of individuals remain without an aetiological diagnosis, a result that is in accordance with similar studies. Among the list of diagnosis it has been proved that monogenic disorders represented the largest category of diagnosis while chromosomal aberrations were less frequent. Among the monogenic disorders the largest group was neurofibromatosis type I while the commonest chromosomal abnormality was trisomy 21. 96 patients were reported with multifactorial congenital anomalies and exposures accounted for 24 patients. Congenital anomalies are probably under-represented. We assume that the main reason for this is the fact that there is no consistency in reporting congenital anomalies to a registry in Cyprus. Also in Cyprus there is a well established prenatal surveillance program (ultrasound and NT measurement of the first trimester, scan anomaly of the second trimester and biochemical markers) which has a very high uptake. Therefore we consider that many congenital anomalies are detected prenatally and several pregnancies are terminated. There is no communication of these outcomes to the genetics clinic or to a national registry. Apart from recording on “common” genetic disorders and syndromes, in the population of this study, several rare and very rare syndromes were recognized. It was also noted that the “Founders’ effect” is found in several areas or communities accounting for the high frequency of disorders such as Sandhof disease among the Maronites, Freidreich ataxia in Paphos etc. Genetic counseling is a new service established in Cyprus by the genetics clinic. This service is organized and offered based on the well established principles of practice for genetic counseling, in the western countries: confidentiality, non-directiveness and autonomy. Genetic counseling is now increasingly demanded and well accepted in Cyprus. 986 individuals were referred for genetic counseling for various common and rare indications with the exception of Thalassemia screening which is managed by the National Thalassemia center. Presymptomatic genetic counseling and testing is offered to individuals for hereditary cancer syndromes as well as for specific neurological disorders of late onset and the referrals for this service accounted for 290 individuals. In conclusion in this study we are recording on genetic disorders and syndromes in the greek-cypriot population, as these were diagnosed or represented through the clinical evaluation performed within the Clinical Genetics service, in the years 1995-2009.Η διδακτορική αυτή διατριβή είχε σαν στόχο να καταγράψει τα γενετικά νοσήματα στον Ελληνοκυπριακό πληθυσμό όπως αυτά παρουσιάστηκαν μέσα από την πορεία του ιατρείου κλινικής γενετικής από το 1995-2009 (πρώτο εξάμηνο). Μέσα από την καταγραφή αυτή επιχειρήθηκε μια αναδρομή στη διαδρομή του ιατρείου κλινικής γενετικής καθώς και συνολικά στην πορεία εξέλιξης της ιατρικής γενετικής στην Κύπρο. Το ιατρείο κλινικής γενετικής ιδρύθηκε τον Ιούλιο του 2004 και έχει έδρα στο Νοσοκομείο Αρχιεπίσκοπος Μακάριος ΙΙΙ και στο Ινστιτούτο Νευρολογίας και Γενετικής στη Λευκωσία της Κύπρου. Λειτουργεί σαν ιατρείο αναφοράς για όλα τα γενετικά νοσήματα και για ολόκληρη την Κύπρο καθώς είναι το μοναδικό στο είδος του. Παραπέμπονται ασθενείς όλων των ηλικιών, νεογνά, παιδιά, ενήλικες, ζεύγη και οικογένειες για οποιαδήποτε ένδειξη γενετικής αξιολόγησης καθώς και για οποιαδήποτε ένδειξη γενετικής συμβουλευτικής. Εξαίρεση αποτελεί η θαλασσαιμία για την οποία οι υπηρεσίες προσφέρονται από το αρμόδιο εθνικό κέντρο θαλασσαιμίας. Στις αιτίες παραπομπής καταγράφτηκαν οι πιο κάτω: νοητική υστέρηση, ψυχοκινητική καθυστέρηση, παλινδρόμηση, δυσμορφικά χαρακτηριστικά, συγγενείς ανωμαλίες στη διάπλαση, διαταραχές στη σωματική ανάπτυξη κ.α. Οι ειδικοί που παρέπεμψαν ασθενείς στο ιατρείο κλινικής γενετικής προέρχονται από όλες σχεδόν τις ιατρικές ειδικότητες, καθώς επίσης και από άλλους επαγγελματίες της υγείας (λογο-,εργο-, φυσιο-θεραπευτές) και από εκπαιδευτικούς της ειδικής εκπαίδευσης. Για την εργασία αυτή συστάθηκε αρχείο στο οποίο καταχωρήθηκαν όλοι οι ασθενείς που εξετάσθηκαν στο ιατρείο κλινικής γενετικής καθώς και τα άτομα που προσήλθαν για γενετική συμβουλευτική. Από πλευράς δημόσιας υγείας η σύσταση και συντήρηση ενός αρχείου για γενετικά νοσήματα και συγγενείς ανωμαλίες έχει συγκεκριμένες προϋποθέσεις και είναι απαραίτητη για την εφαρμογή προγραμμάτων αντιμετώπισης και πρόληψης. Ο πληθυσμός που μελετήθηκε συμπεριλάμβανε 3400 ασθενείς που παραπέμφθηκαν στο ιατρείο κλινικής γενετικής από το 1995-2009. Η συντριπτική πλειοψηφία αφορούσε Ελληνοκύπριους, πλην όμως καταγράφονται τα νοσήματα που διαγνώσθηκαν και σε παιδιά από μικτούς γάμους καθώς και σε μικρό αριθμό Τουρκοκυπρίων και άλλων με σπάνια γενετικά νοσήματα. Από την καταγραφή των αποτελεσμάτων της διαγνωστικής προσέγγισης προέκυψαν τα πιο κάτω: 986 άτομα (ποσοστό 29%) προσήλθαν στο ιατρείο γενετικής για γενετική συμβουλευτική για ποικίλους λόγους. 80 άτομα (ποσοστό 2%) δεν παρουσίαζαν λόγο διερεύνησης (φυσιολογικές παραλλαγές). 1007 ασθενείς (ποσοστό 29%) διαγνώσθηκαν με χρωμοσωμικό, μονογονιδιακό νόσημα η άλλο γνωστό γενετικό νόσημα. 8 ασθενείς είχαν μιτοχονδριακό νόσημα. 24 ασθενείς είχαν εκτεθεί σε τερατογόνα και 96 ασθενείς είχαν συγγενείς ανωμαλιες πολυπαραγοντικής αιτιολογίας. 1199 ασθενείς (ποσοστό 31%) παρέμειναν χωρίς αιτιολογική διάγνωση. Συνεπώς συγκριτικά η διαγνωστική προσπέλαση πέτυχε να δώσει αιτιολογική διάγνωση σε λιγότερους από τους μισούς ασθενείς που έτυχαν αιτιολογικής διερεύνησης. Το ποσοστό αυτό δεν αποκλείνει ιδιαίτερα από παρόμοιες μελέτες σε άλλους πληθυσμούς και ιατρεία κλινικής γενετικής και καταδεικνύει τις δυσκολίες στην αιτιολογική διερεύνηση των ασθενών με γενετικά νοσήματα και στην αποτύπωση σπάνιων φαινοτύπων παρά την μεγάλη πρόοδο της γενετικής στις μέρες μας. Οι διαγνώσεις που τέθηκαν κάλυψαν ένα εκτεταμένο φάσμα χρωμοσωμικών και μονογονιδιακών νοσημάτων. ...........................................................................................................

`Dalmatian dog'-like skin eruption (two cases of multifocal fixed drug eruption induced by mefenamic acid)

Mefenamic acid is a common widely prescribed drug with analgesic activity. Authors report two cases of multifocal fixed drug eruption induced by mefenamic acid. Cases were diagnosed on basis of clinical examination and histopathology of skin lesion. Only a few cases have been reported in the literature and these are the first two described in Greece

Seborrhoeic keratosis or occult malignant neoplasm of the skin?

Background Seborrhoeic keratosis is generally considered to be a benign lesion of the skin. Observation We present the case of a 68-year-old male who presented with clinically typical seborrhoeic keratosis that later histological examination showed partially covered an occult basal cell carcinoma. Objective To have an indication of what percentage of clinically apparent seborrhoeic keratoses may be associated with some form of histologically proven skin malignancy. Methods We carried out a retrospective analysis of approximately 23 000 histopathological examinations done on specimens from dermatological lesions. Results Fifty-nine (11.9%) clinically apparent seborrhoeic keratoses were later histologically diagnosed as basal cell carcinomas, 17 (3.4%) as squamous cell carcinomas, and five (1.01%) as malignant melanomas. Conclusions Although the association of seborrhoeic keratosis and skin malignancy appears to be relatively uncommon, the possibility of such an association cannot be ruled out

Mild Phenotype in a Patient with a De Novo 6.3 Mb Distal Deletion at 10q26.2q26.3

We report on a 29-year-old Greek-Cypriot female with a de novo 6.3 Mb distal 10q26.2q26.3 deletion. She had a very mild neurocognitive phenotype with near normal development and intellect. In addition, she had certain distinctive features and postural orthostatic tachycardia. We review the relevant literature and postulate that certain of her features can be diagnostically relevant. This report illustrates the powerful diagnostic ability of array-CGH in the elucidation of relatively mild phenotypes