Development, behaviour and sensory processing in Marshall-Smith syndrome and Malan syndrome: phenotype comparison in two related syndromes.

BACKGROUND: Ultrarare Marshall-Smith and Malan syndromes, caused by changes of the gene nuclear factor I X (NFIX), are characterised by intellectual disability (ID) and behavioural problems, although questions remain. Here, development and behaviour are studied and compared in a cross-sectional study, and results are presented with genetic findings. METHODS: Behavioural phenotypes are compared of eight individuals with Marshall-Smith syndrome (three male individuals) and seven with Malan syndrome (four male individuals). Long-term follow-up assessment of cognition and adaptive behaviour was possible in three individuals with Marshall-Smith syndrome. RESULTS: Marshall-Smith syndrome individuals have more severe ID, less adaptive behaviour, more impaired speech and less reciprocal interaction compared with individuals with Malan syndrome. Sensory processing difficulties occur in both syndromes. Follow-up measurement of cognition and adaptive behaviour in Marshall-Smith syndrome shows different individual learning curves over time. CONCLUSIONS: Results show significant between and within syndrome variability. Different NFIX variants underlie distinct clinical phenotypes leading to separate entities. Cognitive, adaptive and sensory impairments are common in both syndromes and increase the risk of challenging behaviour. This study highlights the value of considering behaviour within developmental and environmental context. To improve quality of life, adaptations to environment and treatment are suggested to create a better person-environment fit.

PUF60-SCRIB fusion transcript in a patient with 8q24.3 microdeletion and atypical Verheij syndrome.

Expression of the fusion genes is considered to be an important mechanism of tumorigenesis. However it is hardly ever discussed in relation to the neurodevelopmental disorders. Here we report on an 18-years-old female patient with 13.1 kb deletion of 8q24.3 fusing the 5'-portion of SCRIB with the 3'-portion of PUF60 and presenting with borderline intellectual disability, eye coloboma, short stature, scoliosis, heart defects and interestingly postnatal megalencephaly, in contrast to microcephaly, which is usually associated with 8q24.3 deletion (Verheij syndrome). Using next generation sequencing we mapped the breakpoints at nucleotide resolution and showed that the deletion preserved the reading frame. In contrast to the laborious techniques previously used for the precise mapping of deletion breakpoints, our approach identified an accurate interval very rapidly. We demonstrated the expression of the PUF60-SCRIB fusion gene in patient's cells and suggest that the fusion transcript might be a cause of the atypical clinical presentation.

Histological evaluation of ureteral involvement in women with deep infiltrating endometriosis: analysis of a large series.

STUDY QUESTION: In women with deeply infiltrating endometriosis (DIE) what is the prevalence of involvement of endometriotic tissue and fibrosis in ureteral endometriosis (UE), as assessed by histological staining? SUMMARY ANSWER: In women with DIE, ureteral involvement is more often due to endometriotic tissue rather than fibrosis. WHAT IS KNOWN ALREADY: In the current literature, histological evaluation of ureteral endometriosis is mainly based on the degree of wall infiltration by endometriosis instead of the tissue composition. A few studies reported ill-defined and contradictory histological data on the tissue composition of UE. STUDY DESIGN, SIZE, DURATION: Retrospective observational study based on clinical records of women affected by DIE, laparoscopically treated for UE at a tertiary referral center, between January 2010 and March 2013. All cases of ureteral nodule excision or ureterectomy with histological examination of the specimens were included. Exclusion criteria were other identified causes of hydroureteronephrosis, medical therapy for a period of at least 3 months before surgery and previous surgery for DIE. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 77 patients were included in the study and among them seven (9%) presented with bilateral ureteral involvement, giving a total of 84 cases of UE available for analysis. All patients had stage IV endometriosis. According, respectively, to the presence of endometrial glands and/or stroma cells or of fibrotic tissue only, the endometriotic UE and fibrotic UE groups were compared with regard to hydroureteronephrosis at pre-operative urinary tract computerized tomography scan, type of surgical procedure performed to treat UE (nodule removal or ureterectomy), association with other locations of the disease and post-operative complications (ureteral fistula or stenosis). MAIN RESULTS AND THE ROLE OF CHANCE: For the 84 cases of UE, 65 (77%) and 19 (23%), respectively, showed endometriotic tissue and fibrotic tissue only. Presence of hydroureteronephrosis and endometriotic pattern of UE showed a significant association [endometriotic UE 44/65 (68%) versus fibrotic UE 8/19 (42%); P = 0.04]. Fibrotic pattern of UE and presence of concomitant recto-vaginal endometriosis showed a significant association [endometriotic group: 29/65 (45%) versus fibrotic group 18/19 (95%); P < 0.001]. LIMITATIONS, REASONS FOR CAUTION: The retrospective and monocentric (tertiary referral center) study design. WIDER IMPLICATIONS OF THE FINDINGS: Besides the distinction between extrinsic and intrinsic UE based on the degree of wall infiltration by endometriosis, a new classification according to the histological pattern of UE could be useful for clinicians, both in the diagnostic and therapeutic fields. STUDY FUNDING/COMPETING INTERESTS: None.

Interstitial deletion 1p36.32 in two brothers with a distinct phenotype--overgrowth, macrocephaly and nearly normal intellectual function.

We report on two adult patients, who both presented with overgrowth and one of them additionally with macrocephaly while carrying an 1p36 microdeletion of about 2.1 Mb. They are full brothers born to unaffected parents. Although both brothers attended special schools, they lived independently without a legal guardian and were able to succeed in regular jobs. One of the brothers received a professional education. Genetic analysis of the parents revealed neither the microdeletion nor a cryptical translocation or inversion. We suggest that the recurrent deletion is a result of germline mosaicism, a phenomenon reported only once in the context of the 1p36 microdeletion syndrome. Our report confirms the recurrence of the apparently de novo 1p36 microdeletion due to a likely germline mosaicism of one of the parents. Furthermore, it illustrates the possibility of the distinct phenotype with a nearly normal intellectual outcome of the 1p36 microdeletion syndrome that might be due to the region involved in our patients.

Distinct phenotype of PHF6 deletions in females.

We report on two female patients carrying small overlapping Xq26.2 deletions of 100 kb and 270 kb involving the PHF6 gene. Mutations in PHF6 have been reported in individuals with Borjeson-Forssman-Lehmann syndrome, a condition present almost exclusively in males. Two very recent papers revealed de novo PHF6 defects in seven female patients with intellectual disability and a phenotype resembling Coffin-Siris syndrome (sparse hair, bitemporal narrowing, arched eyebrows, synophrys, high nasal root, bulbous nasal tip, marked clinodactyly with the hypoplastic terminal phalanges of the fifth fingers and cutaneous syndactyly of the toes, Blaschkoid linear skin hyperpigmentation, dental anomalies and occasional major malformations). The clinical presentation of these patients overlaps completely with our first patient, who carries a germline deletion involving PHF6. The second patient has a mosaic deletion and presented with a very mild phenotype of PHF6 loss in females. Our report confirms that PHF6 loss in females results in a recognizable phenotype overlapping with Coffin-Siris syndrome and distinct from Borjeson-Forssman-Lehmann syndrome. We expand the clinical spectrum and provide the first summary of the recommended medical evaluation.

Severe forms of Baraitser-Winter syndrome are caused by ACTB mutations rather than ACTG1 mutations.

ACTB and ACTG1 mutations have recently been reported to cause Baraitser-Winter syndrome (BRWS) - a rare condition characterized by ptosis, colobomata, neuronal migration disorder, distinct facial anomalies and intellectual disability. One of the patients carrying an ACTB mutation was previously diagnosed with Fryns-Aftimos syndrome (FAS), which is a rare and severe, multiple congenital anomaly (MCA) syndrome whose symptoms partially overlap with that of BRWS. However, several patients with Fryns-Aftimos were considered not to fit into the ACTB and ACTG1 spectrum because of their severe impairment and additional malformations. We report on three patients who had been diagnosed with FAS. All three patients carry a mutation in the ACTB gene. On the basis of the ACTB mutations and analysis of the clinical findings, we reclassify the diagnosis of these patients as severe BRWS. We suggest that mutations in ACTB cause a distinctly more severe phenotype than ACTG1 mutations, despite the structural similarity of beta- and gamma-actins and their overlapping expression pattern. We expand the spectrum of BRWS and confirm that FAS is not a separate entity but an early and severe manifestation of BRWS.

Use of a preventive sling surgery for the simultaneous correction of latent stress urinary incontinence during the cystocele repair: two year follow-up.

AIM: The aim of this paper was to assess the feasibility and utility of adding a preventive trans obturatory tape (TOT) during the same intervention for anterior prolapse repair, in patients with masked urinary incontinence and massive cystocele. METHODS: A retrospective trial was conducted in a Tertiary care University Hospital. Ninety-nine women with a massive cystocele (Ba ≥2 cm of pelvic organ prolapse quantification) and an occult stress urinary incontinence were recruited from 2004 to 2010: 53 women were subjected to an anterior fascial reconstruction alone while 46 underwent the same intervention with the addition of TOT. Patients were also asked to rate their overall quality of life, using the International Consultation on Incontinence Modular Questionnaire-Lower Urinary Tract Symptoms Quality Of Life (ICIQ-LUTSqol). All patients were assessed at one, six, twelve and twenty-four months of follow-up. Statistical analysis was performed with SPSS 15.0 software; SPSS inc., Chicago IL, USA was performed using the Chi-square test with Fisher's post-hoc correction. RESULTS: At 24 month follow-up the rate of appearance of stress urinary incontinence at the urogynecological examination, was higher in the group without TOT (81% vs. 19%, P=0.004). In terms of overall quality of life, significantly higher rates of satisfaction have been reported by the group treated with additional TOT (P=0.006). CONCLUSION: The addition of TOT during the anterior prolapse correction seems to give a greater durability to the correction, resulting, in the long term, in a lower rate of urinary symptoms onset (first latency) and in a better quality of life compared to the traditional anterior colporrhaphy alone.

Laparoscopic management of early stage ovarian cancer: is it feasible, safe, and adequate? A retrospective study.

INTRODUCTION: Minimally invasive surgery to stage early ovarian cancer is still regarded as pioneering among gynecologic oncologists. Previous retrospective experiences demonstrated the safety and feasibility of laparoscopy in this field. AIMS: To review the laparoscopic staging procedure in a series of patients with early ovarian cancer and compare results with the literature. MATERIALS AND METHODS: From January 2004 to September 2011, 19 patients with apparent early stage ovarian/fallopian tube cancer Stage IA to IC underwent either primary treatment or completion staging by laparoscopy. Surgical, pathologic, and oncologic outcomes were analyzed. RESULTS: The mean operative time was 212 +/- 69 minutes. Three patients (16%) underwent fertility sparing surgery. The mean estimated blood loss was two +/- two g/dl. The mean number of pelvic and para-aortic lymph nodes collected was 17 (range 7-27) and 14 (range 8-21), respectively. The mean volume of ovarian/tubal tumor was 119 cm3 (range 1.5-500). The disease was reclassified to a higher stage in ten women (52%). One major intraoperative complication (five percent) occurred which required the conversion to laparotomy. The mean follow up period was 30 +/- 16 months (range 10-74). Overall survival and disease-free survival were 100% and 84%, respectively. CONCLUSIONS: Laparoscopic staging of early ovarian cancer appears to be feasible and comprehensive when performed by gynecologic oncologists experienced with advanced laparoscopy.

Macrocephaly, obesity, mental (intellectual) disability, and ocular abnormalities: alternative definition and further delineation of MOMO syndrome.

MOMO syndrome, previously defined as Macrosomia, Obesity, Macrocephaly, and Ocular abnormalities (OMIM 157980) is a rare intellectual disability syndrome of unknown cause. We describe two further patients with MOMO syndrome. Reported data of patients with MOMO syndrome and our own findings indicate that overgrowth does not appear to be a specific feature. We propose to form the acronym "MOMO" from Macrocephaly, Obesity, Mental (intellectual) disability, and Ocular abnormalities, excluding macrosomia from the syndrome name. The combination of obesity, macrocephaly, and colobomas is unique, therefore these features can be used as major diagnostic criteria of MOMO syndrome.

A further patient with van Maldergem syndrome.

We report on a male patient with the proposed diagnosis of the rare but very distinct entity of van Maldergem syndrome. His parents are first cousins. At the age of 4 years the boy presented with severe developmental delay, talipes equinovarus, finger camptodactyly with interphalangeal pterygium, joint laxity, bilateral microtia, and a dysmorphic facies. He showed bilateral epicanthus, telecanthus, short palpebral fissures, broad flat nasal bridge, and dental malocclusion. The combination of the specific facial features with camptodactyly, interphalangeal pterygium, joint laxity and developmental delay led to the diagnosis of van Maldergem syndrome. The medical history was further on significant for pharyngeal instability requiring the placement of a tracheostomy tube, an inguinal hernia, hip subluxation, small kidneys and genital abnormalities (micropenis, bifid scrotum, cryptorchidism). Due to severe feeding difficulties permanent tube feeding was required. Metabolic tests (newborn metabolic screening, 7-dehydrocholesterol, amino acids, organic acids in urine) and chromosomal analysis (450-500 bands; 46,XY) were normal. Molecular karyotyping revealed two parental CNVs (paternal deletion of 9q33.1; maternal duplication of 11p15.1), which are unlikely to contribute to the patient's phenotype. Taken together, the report on a further patient with van Maldergem syndrome expands the clinical spectrum of the condition by adding genital malformations, hernia, pharyngeal instability, and subluxation of the hip.

Endometriosis of the abdominal wall: ultrasonographic and Doppler characteristics.

OBJECTIVES: To describe the sonographic and clinical features of abdominal wall endometriosis (AWE), a frequently misdiagnosed condition. METHODS: This was a retrospective study of 21 consecutive women with pathologically proven endometriosis of the abdominal wall. Ultrasonographic and Doppler examinations were performed, before surgery, with a high-frequency linear transducer. The clinical data and the results of the sonographic examinations were reviewed and described. RESULTS: At ultrasound, all the nodules appeared as discrete solid masses that were less echogenic than the surrounding hyperechoic fat. The nodules had a median diameter of 20 (range, 5-50) mm and in 18/21 (86%) cases the nodules had a round/oval shape. In eight of 21 (38%) women the AWE was located at the umbilicus, in six of 21 (29%) it was between the transverse suprapubic line and the umbilicus, in five of 21 (24%) it was found along the scar of a previous Cesarean section and in two of 21 (9%) it was in the right inguinal canal. The content was homogeneously hypoechoic in 12/21 (57%) women and inhomogeneous in the other nine (43%). The outer borders were invariably ill defined. Scarce blood vessels were found by power Doppler. Cyclic or continuous spontaneous pain at the level of the AWE was present in 19/21 (91%) cases, and two (9%) patients were asymptomatic. CONCLUSIONS: Hypoechoic round/oval nodules with ill-defined borders and a hyperechoic rim should raise the suspicion of abdominal wall endometriosis, even in patients with no history of endometriosis or previous laparotomic surgery. Pressing the ultrasound probe against the nodule should reinforce a suspected diagnosis because of the pain it induces.

[Laparoscopic surgery for endometrial cancer in overweight women]. / Utilizzo della laparoscopia nel trattamento chirurgico delle sovrappese affette da cancro dell' endometrio.

AIM: The aim of this study was to investigate the feasibility and safety of laparoscopic staging of overweight women with endometrial cancer and to compare the surgical outcomes among these patients with those managed by laparotomy. METHODS: This was a retrospective analysis (Canadian Task-force Classification II-3). We reviewed operative and hospital records of 70 patients with a body mass index >25 kg/m2 who underwent surgical treatment for endometrial cancer between 2001 and 2008. Thirty-five patients treated laparoscopically were compared to an equivalent group of patients treated by laparotomy. Operative and postoperative variables were afterwards assessed. RESULTS: Women in laparoscopic group had a significantly lower blood loss (median, 25th-75th percentiles: 1.2, 0.8-2.0 in laparoscopic versus 1.8, 1.0-2.8 in laparotomic group, P<0.05). No differences between both group in terms of operative time (median, 25th-75th percentiles: 165 min, 130-183 in laparoscopic versus 135 min, 110-170 in laparotomic; P>0.05) and mean number of pelvic and para-aortic lymph nodes removed (22 ± 8.4 versus 24 ± 6.2 and 9.2 ± 2.5 versus 9.3 ± 5 respectively; P>0.05). Length of urethral catheter and hospital stay were statistically higher in laparotomic group (two days versus three days; four days versus seven days respectively; P<0.05). CONCLUSION: Laparoscopic surgery in overweight women with endometrial cancer had equivalent surgical staging than women operated by laparotomy. With regard to postsurgical variables, overweight women who underwent laparoscopic surgery had better results than those treated by laparotomy.