Clinical and molecular evaluations of siblings with “pure” 11q23.3-qter trisomy or reciprocal monosomy due to a familial translocation t (10;11) (q26;q23.3)

11qter trisomy is rare, mostly occurs in combination with partial monosomy of a terminal segment of another chromosome due to unbalanced segregation of parental translocations. Pure 11qter trisomy is rarer, only five cases have so far been reported. Here we report a family with all four siblings affected with neurodevelopmental disorders and facial dysmorphism. Chromosomal microarray analysis (CMA) identified 11q23.3-qter (15.1 Mb) deletion in one and reciprocal duplication in the other three siblings. Both father and grandfather are balanced translocation (46, XY, t (10;11) (q26;q23)) carriers. The genetic material involved on chromosome 10 is very limited (270 kb). Thus, the pedigree presented rare cases with “pure” 11qter trisomy or reciprocal 11qter monosomy (Jacobsen syndrome), offering a unique opportunity to examine clinical presentations of multiple individuals with identical genomic imbalance. The proband with 11qter monosomy presented with many features of Jacobsen syndrome. The three 11qter trisomy carriers presented with shared craniofacial features including brachycephaly and short philtrum. They are also significant for the following neurodevelopmental and neuropsychiatric defects: intellectual disability, expressive language deficiency, autistic features, auditory hallucination, self-talking and pain insensitivity. To our knowledge, this is the smallest “pure” trisomy 11qter so far reported and this is the first report to describe the neuropsychiatric features of patients with 11qter trisomy. Our observation also revealed dissimilar features in our patients compared with those of previously published trisomy 11qter cases. The pedigree also revealed phenotypic heterogeneity among siblings with identical genomic imbalance

Mutation screening of the SLC26A4 gene in a cohort of 192 Chinese patients with congenital hypothyroidism

ABSTRACT Objective: Pendred syndrome (PS) is an autosomal recessive disorder characterised by sensorineural hearing loss and thyroid dyshormonogenesis. It is caused by biallelic mutations in the SLC26A4 gene encoding for pendrin. Hypothyroidism in PS can be present from birth and therefore diagnosed by neonatal screening. The aim of this study was to examine the SLC26A4 mutation spectrum and prevalence among congenital hypothyroidism (CH) patients in the Guangxi Zhuang Autonomous Region of China and to establish how frequently PS causes hearing impairment in our patients with CH. Subjects and methods: Blood samples were collected from 192 CH patients in Guangxi Zhuang Autonomous Region, China, and genomic DNA was extracted from peripheral blood leukocytes. All exons of the SLC26A4 gene together with their exon-intron boundaries were screened by nextgeneration sequencing. Patients with SLC26A4 mutations underwent a complete audiological evaluation including otoscopic examination, audiometry and morphological evaluation of the inner ear. Results: Next generation sequencing analysis of SLC26A4 in 192 CH patients revealed five different heterozygous variations in eight individuals (8/192, 4%). The prevalence of SLC26A4 mutations was 4% among studied Chinese CH. Three of the eight were diagnosed as enlargement of the vestibular aqueduct (EVA), no PS were found in our 192 CH patients. The mutations included one novel missense variant p.P469S, as well as four known missense variants, namely p.V233L, p.M147I, p.V609G and p.D661E. Of the eight patients identified with SLC26A4 variations in our study, seven patients showed normal size/location of thyroid gland, and one patients showed a decreased size one. Conclusions: The prevalence of SLC26A4 pathogenic variants was 4% among studied Chinese patients with CH. Our study expanded the SLC26A4 mutation spectrum, provided the best estimation of SLC26A4 mutation rate for Chinese CH patients and indicated the rarity of PS as a cause of CH. Arch Endocrinol Metab. 2016;60(4):323-

Mutation screening of the SLC26A4 gene in a cohort of 192 Chinese patients with congenital hypothyroidism

ABSTRACT Objective: Pendred syndrome (PS) is an autosomal recessive disorder characterised by sensorineural hearing loss and thyroid dyshormonogenesis. It is caused by biallelic mutations in the SLC26A4 gene encoding for pendrin. Hypothyroidism in PS can be present from birth and therefore diagnosed by neonatal screening. The aim of this study was to examine the SLC26A4 mutation spectrum and prevalence among congenital hypothyroidism (CH) patients in the Guangxi Zhuang Autonomous Region of China and to establish how frequently PS causes hearing impairment in our patients with CH. Subjects and methods: Blood samples were collected from 192 CH patients in Guangxi Zhuang Autonomous Region, China, and genomic DNA was extracted from peripheral blood leukocytes. All exons of the SLC26A4 gene together with their exon-intron boundaries were screened by next-generation sequencing. Patients with SLC26A4 mutations underwent a complete audiological evaluation including otoscopic examination, audiometry and morphological evaluation of the inner ear. Results: Next generation sequencing analysis of SLC26A4 in 192 CH patients revealed five different heterozygous variations in eight individuals (8/192, 4%). The prevalence of SLC26A4 mutations was 4% among studied Chinese CH. Three of the eight were diagnosed as enlargement of the vestibular aqueduct (EVA), no PS were found in our 192 CH patients. The mutations included one novel missense variant p.P469S, as well as four known missense variants, namely p.V233L, p.M147I, p.V609G and p.D661E. Of the eight patients identified with SLC26A4 variations in our study, seven patients showed normal size/location of thyroid gland, and one patients showed a decreased size one. Conclusions: The prevalence of SLC26A4 pathogenic variants was 4% among studied Chinese patients with CH. Our study expanded the SLC26A4 mutation spectrum, provided the best estimation of SLC26A4 mutation rate for Chinese CH patients and indicated the rarity of PS as a cause of CH

A Novel Error Model of Optical Systems and an On-Orbit Calibration Method for Star Sensors

In order to improve the on-orbit measurement accuracy of star sensors, the effects of image-plane rotary error, image-plane tilt error and distortions of optical systems resulting from the on-orbit thermal environment were studied in this paper. Since these issues will affect the precision of star image point positions, in this paper, a novel measurement error model based on the traditional error model is explored. Due to the orthonormal characteristics of image-plane rotary-tilt errors and the strong nonlinearity among these error parameters, it is difficult to calibrate all the parameters simultaneously. To solve this difficulty, for the new error model, a modified two-step calibration method based on the Extended Kalman Filter (EKF) and Least Square Methods (LSM) is presented. The former one is used to calibrate the main point drift, focal length error and distortions of optical systems while the latter estimates the image-plane rotary-tilt errors. With this calibration method, the precision of star image point position influenced by the above errors is greatly improved from 15.42% to 1.389%. Finally, the simulation results demonstrate that the presented measurement error model for star sensors has higher precision. Moreover, the proposed two-step method can effectively calibrate model error parameters, and the calibration precision of on-orbit star sensors is also improved obviously

Model and Simulation of Globoidal Cam Mechanisms with Oscillating and Dual Stopping Followers

Globoidal cam mechanisms with oscillating and dual stopping followers are necessary to accomplish the rise-dwell-fall-dwell periodic motion.The trajectory surface of roller axis of oscillating globoidal cam mechanism is the offset surface of working surface of the cam, and its mathematical model is relatively simple. According to the spatial geometric relationship, the coordinate equation of trajectory surface of roller axis is derived and the original angle positions for dual stopping followers are analyzed. As a result, the three-dimension (3D) model of globoidal cam mechanism with oscillating and dual stopping followers is generated based on the offset surface method based on the UG software. Finally, the dynamic model is realized using Adams software, and through the dynamic simulation, the oscillating angle displacement, angular velocity and angular acceleration of the double-stop swinging cam mechanism are studied. According to the simulation results, it can be concluded that the input speed of globoidal cam mechanism is an important factor that affects the output performance of the mechanism. Through the above research, it can provide some reference for the design of spatial cam mechanism

Model and Simulation of Globoidal Cam Mechanisms with Oscillating and Dual Stopping Followers

Globoidal cam mechanisms with oscillating and dual stopping followers are necessary to accomplish the rise-dwell-fall-dwell periodic motion.The trajectory surface of roller axis of oscillating globoidal cam mechanism is the offset surface of working surface of the cam, and its mathematical model is relatively simple. According to the spatial geometric relationship, the coordinate equation of trajectory surface of roller axis is derived and the original angle positions for dual stopping followers are analyzed. As a result, the three-dimension (3D) model of globoidal cam mechanism with oscillating and dual stopping followers is generated based on the offset surface method based on the UG software. Finally, the dynamic model is realized using Adams software, and through the dynamic simulation, the oscillating angle displacement, angular velocity and angular acceleration of the double-stop swinging cam mechanism are studied. According to the simulation results, it can be concluded that the input speed of globoidal cam mechanism is an important factor that affects the output performance of the mechanism. Through the above research, it can provide some reference for the design of spatial cam mechanism

EPHA4 haploinsufficiency is responsible for the short stature of a patient with 2q35-q36.2 deletion and Waardenburg syndrome

Background: Waardenburg syndrome type I (WS1), an auditory-pigmentary genetic disorder, is caused by heterozygous loss-of-function mutations in PAX3. Abnormal physical signs such as dystopia canthorum, patchy hypopigmentation and sensorineural hearing loss are common, but short stature is not associated with WS1. Case presentation: We reported a 4-year and 6 month-old boy with a rare combination of WS1 and severe short stature (83.5 cm (−5.8SD)). His facial features include dystopia canthorum, mild synophrys, slightly up-slanted palpebral fissure, posteriorly rotated ears, alae nasi hypoplasia and micrognathia. No heterochromia was noticed. He had a normal intelligence quotient and hearing. Insulin-like growth factor-1 (IGF-1) was 52.7 ng/ml, lower than the normal range (55 ~ 452 ng/ml) and the peak growth hormone level was 7.57 ng/ml at 90 minutes after taking moderate levodopa and pyridostigmine bromide. The patient exhibited a good response to human growth hormone (rhGH) replacement therapy, showing a 9.2 cm/year growth rate and an improvement of 1 standard deviation (SD) of height after one year treatment. CMA test of patient’s DNA revealed a 4.46 Mb de novo deletion at 2q35-q36.2 (hg19; chr2:221,234,146-225,697,363). Conclusions: PAX3 haploinsufficiency is known to cause Waardenburg syndrome. Examining overlapping deletions in patients led to the conclusion that EPHA4 is a novel short stature gene. The finding is supported by the splotch-retarded and epha4 knockout mouse models which both showed growth retardation. We believe this rare condition is caused by the haploinsufficiency of both PAX3 and EPH4 genes. We further reported a growth response to recombinant human growth hormone treatment in this patient