Intragenic KANSL1 mutations and chromosome 17q21.31 deletions: broadening the clinical spectrum and genotype-phenotype correlations in a large cohort of patients.

BACKGROUND: The 17q21.31 deletion syndrome phenotype can be caused by either chromosome deletions or point mutations in the KANSL1 gene. To date, about 60 subjects with chromosome deletion and 4 subjects with point mutation in KANSL1 have been reported. Prevalence of chromosome deletions compared with point mutations, genotype-phenotype correlations and phenotypic variability have yet to be fully clarified. METHODS: We report genotype-phenotype correlations in 27 novel subjects with 17q21.31 deletion and in 5 subjects with KANSL1 point mutation, 3 of whom were not previously reported. RESULTS: The prevalence of chromosome deletion and KANSL1 mutation was 83% and 17%, respectively. All patients had similar clinical features, with the exception of macrocephaly, which was detected in 24% of patients with the deletion and 60% of those with the point mutation, and congenital heart disease, which was limited to 35% of patients with the deletion. A remarkable phenotypic variability was observed in both categories, mainly with respect to the severity of ID. Cognitive function was within normal parameters in one patient in each group. Craniosynostosis, subependymal heterotopia and optic nerve hypoplasia represent new component manifestations. CONCLUSIONS: In KANSL1 haploinsufficiency syndrome, chromosome deletions are greatly prevalent compared with KANSL1 mutations. The latter are sufficient in causing the full clinical phenotype. The degree of intellectual disability (ID) appears to be milder than expected in a considerable number of subjects with either chromosome deletion or KANSL1 mutation. Striking clinical criteria for enrolling patients into KANSL1 analysis include speech delay, distinctive facial dysmorphism, macrocephaly and friendly behaviour.

Mucopolysaccharidosis type II in a female patient with a reciprocal X;9 translocation and skewed X chromosome inactivation.

Mucopolysaccharidosis type II (MPS II or Hunter syndrome) is a rare X-linked disorder caused by deficient activity of the lysosomal enzyme, iduronate-2-sulfatase (IDS). Phenotypic expression of MPS II in female patients rarely occurs and may be the result of (i) structural abnormalities of the X chromosome, (ii) homozygosity for disease-causing mutations, or (iii) skewed X-chromosome inactivation, in which the normal IDS allele is preferentially inactivated and the abnormal IDS allele is active. We report here on a female patient with clinical MPS II manifestations, deficiency of IDS enzyme activity and a de novo balanced reciprocal X;9 translocation. As our patient has a skewed XCI pattern, but neither genomic IDS mutations nor abnormal IDS transcripts were detected, we speculate about the possible role of the chromosomal rearrangement in reducing the IDS translation efficiency.

Genetic Drift: the Salernitan school of medicine: women, men, and children. A syndromological review of the oldest medical school in the western world.

Ever since the 9th century during the High Middle Ages, the "Schola Medica Salernitana," believed to be the first medical school in the western world, flourished in Salerno, a city in southern Italy. Although an important role is attributed to several men of this school, who were recognized as wise and learned doctors, modern historiography has also reevaluated and extolled the praiseworthy role of women. Contrary to the common beliefs and expectations of a woman's "place" at the time, these women were fully titled physicians. Attention was also paid to the health and welfare of children. However, there are no apparent references to physical disabilities, a mysterious omission that seems incompatible with an institution that stood as a beacon of knowledge for centuries. Mysteries, discoveries, and potential hidden messages are mingled in a fascinating medieval codex yet to be fully deciphered. The medical school reached its maximum splendor between the years of 1000 and 1300 AD. After alternating fortunes, the Salernitan institution began a slow decline due to the explosive development of other universities, such as those in Paris, Bologna, Padua, and most significantly, the nearby University of Naples. It was eventually closed by the King of Naples, Joachim Murat, November 29, 1811.

Science, art, and mistery in the statues and in the anatomical machines of the prince of sansevero: the masterpieces of the "Sansevero Chapel".

During the 18th century in Naples, Raimondo di Sangro, Prince of Sansevero, completed works on the family chapel, the so-called "Cappella Sansevero." The chapel houses statues of extraordinary beauty and spectacularly detailed but also, in the basement, two human skeletons known as the "Anatomical Machines" ("Macchine Anatomiche"). These two skeletons, a man and a pregnant woman, are entirely surrounded by their circulatory systems, just as if these were suddenly fixed. Legend, believed as truth until few years ago, says that Prince Raimondo had prepared and injected an unknown embalming substance in the blood vessels of two of his servants convicting them to eternal fixity. Recent investigations have demonstrated that, while the bones are authentic, the blood vessels are actually extraordinary artifacts that also reproduce some congenital malformations. The dreadful aspect of these two skeletons appears to be in strident contrast with the classic beauty of the statues which glorify and celebrate the ideal of morphology. Conversely, the two Anatomical Machines, protagonists of legends and superstitions since centuries, represent a marvelous example of science mixed with art.

Clinical, cytogenetic and molecular-cytogenetic characterization of a patient with a de novo tandem proximal-intermediate duplication of 16q and review of the literature.

Partial trisomy 16 is rare and most of the reported cases are secondary to chromosome rearrangements resulting in concurrent monosomies or trisomies of a second chromosome. Only a few patients survive the neonatal period and the duplication of the long arm seems to be mainly responsible for the prenatal lethality of the full trisomy 16. The reported patients with a partial 16q trisomy have a wide spectrum of congenital anomalies that include dysmorphic features, central nervous system malformations, failure to thrive, and club feet. The patients with duplications of proximal 16q frequently have short stature, developmental delay, speech delay, learning difficulties, and mild to severe behavioral problems. Here we describe a patient with an inverted de novo tandem duplication of 16q with breakpoints evaluated in detail by molecular-cytogenetic techniques. Main clinical features include postural, motor and speech delay with severe learning difficulties and behavioral problems, obesity, microcephaly, and mild dysmorphic features. In the report we attempt to classify the few reported patients with pure partial duplications of 16q in more narrow and homogeneous groups: proximal, proximal-intermediate, intermediate, and intermediate-distal duplications. Moreover, we emphasize the importance of proper cytogenetic investigation and complete molecular cytogenetic refinement in all cases with a suspected chromosomal anomaly.

Application of a non-pharmacological technique in addition to the pharmacological protocol for the management of children's preoperative anxiety: A 10 years' experience.

The aim of the study was to investigate how Non- Pharmacological Techniques (NPT), in addition to standard pharmacological techniques, can help to manage and reduce the preoperative anxiety of children waiting for Day Surgery procedures (DS). Isola Serena activity started in 2008 to manage the preoperative time of children waiting for surgery in the playing room. The latter is run by a pedagogist. NPT includes use of games and toys, readings and drawings. A descriptive and comparative study was conducted on 50 children, aged 4 to 12 years, randomly assigned to Isola Serena group ISG and control group CG. All children received standard pharmacological techniques, while those of the ISG also received the NPT. The evaluation of the preoperative anxiety level (modified Yale Preoperative Anxiety Scale) and parent's coping style (Coping Inventory for Stressful Situation) compared the two groups. The ISG showed a significantly lower level of preoperative anxiety than the CG. Parents' coping style was not related to the preoperative anxiety. The activity performed in the Isola Serena Project resulted to be effective for the reduction of preoperative anxiety in children undergoing DS procedures.

A ZFHX4 mutation associated with a recognizable neuropsychological and facial phenotype.

Several patients with chromosomal deletions including ZFHX4 gene have been described, whereas point mutations are very rare. This gene encodes for a transcription factor involved in the development of several embryonal processes, including brain differentiation. Patients with 8q21.11 deletions usually show intellectual disability, short stature, peculiar facial features, and severe eye abnormalities. We describe a female patient with mild intellectual disability, autism spectrum disorder, strabismus, ptosis, low-set and prominent ears, high-arched palate, microretrognathia. Clinical Exome Sequencing revealed the presence of a de novo heterozygous variant in ZFHX4. Therefore, we further investigate the different phenotypes of ZFHX4 mutations and 8q21.11 deletions.

De Novo Inverted Duplication Deletion of 4p in a 14-Week-Old Male Fetus Aborted Due to Multiple Anomalies.

Inverted duplications deletions are rare, complex, and nonrecurrent chromosomal rearrangements associated with a variable phenotype. In this case report, we described the phenotype and genotype of a 14-week-old male fetus, who was aborted after discovery of multiple anomalies (septal cystic hygroma, open abdominal wall, and a nonidentifiable lower limb). At autopsy, fluorescence in situ hybridization and array comparative genomic hybridization identified an inverted duplication with terminal deletion of 4p [46,XY,der(4)del(p16.3)dup(4)(p15.2p16.3)]. Only five genotypically similar cases have been reported, and we hope our case contribution will add meaningful to the body of knowledge.