Xq21.1q21.31 Duplication in Two Male Siblings

Despite the increased use of array comparative genomic hybridisation, duplications of Xq remain rarely reported in the literature. Xq21.1q21.31 duplication has previously been reported only once in a boy with features of Prader Willi syndrome (PWS). We report 2 malesiblings with maternally inherited duplication of Xq21.1q21.31 who demonstrate a variable phenotype. The proband has Prader Willi-like features such as global developmental delay, autism, obesity, short hands, and small genitalia with a history of food seeking behaviour, while his younger brother has isolated speech delay with some autistic features under evaluation. Both siblings have features such as bitemporal narrowing and small hands. It is therefore likely that the phenotype of duplications in this region is broader than PWS phenocopy, and further cases would be required to elucidate this.

Role of High-Resolution Ultrasound in Detection and Assessment of Disease Activity in Rheumatoid Arthritis

Background Ultrasound imaging is currently a well-known, now frequently used method in the diagnosis of Rheumatoid arthritis. In recent years, it has become an essential supplement of physical examination in Rheumatologist practice. B-mode US & PDUS are very sensitive in detecting synovial hypertrophy, joint effusion, activity, tenosynovitis and any early bony erosions. Aim of the Work to demonstrate the role of Ultrasonography and Power Doppler in proper detection of activity of rheumatoid arthritis in the wrist and small hands joints among different aged population, compared with the laboratory results. Patients and Methods A prospective study was conducted on 40 patients (35 females & 5 males). They were referred from the Rheumatology Department to Ultrasound Unit at Ain Shams University hospitals for US examination of hand and wrist joints mainly. Results In our study, most of the 40 patients enrolled showed one or more of the B-mode or PDUS findings for Rheumatoid Arthritis or its activity. On adding the findings of US & PD to the clinical examination and laboratory protocol of Rheumatoid Arthritis, sensitivity and specificity for diagnosis of disease and disease activity raises. Conclusion Ultrasound and Power Doppler have additional value to clinical examination both in improving early detection of RA and defining true RA remission. B-mode US & PDUS are very sensitive in detecting synovial hypertrophy, joint effusion, activity, tenosynovitis and any early bony erosions.

MO1023BARDET-BIEDL SYNDROME OR SENIOR-LOKEN SYNDROME? GOING BEYOND THE OBVIOUS

Background and Aims Nephronophthisis (NPHP), a ciliopathy which almost always causes end-stage kidney disease (ESKD), may have extrarenal symptoms such as Bardet-Biedl syndrome (BBS) and Senior-Loken syndrome (SLS), and these are called NPHP-related ciliopathies (NPHP-RC). Bardet-Bield syndrome and SLS share similar clinical features, so that definitive diagnosis might depend on genetic analysis. Bardet-Bield syndrome diagnosis is typically based on clinical manifestations, which comprise, for example, renal defects, polydactyly, obesity, retinitis pigmentosa (RP), learning difficulties, in addition to secondary manifestations such as development delay, speech defects, hypertension, among others. Senior-Loken syndrome classical encompasses familial NPHP and RP; additional variable features can include skeletal, liver, neurologic and other visual defects, as well as obesity. NPHP genes are the most commonly affected in NPHP. Although disruption of the NPHP5 and NPHP6 genes are the most frequent cause of SLS, at least variants in ten genes have been reported. We present a case of a young girl clinically diagnosed with BBS, later known to be a SLS based on genetic analysis, revealing an unusual affected gene. Method We reviewed this case based on medical records. Results The patient presented with polydactyly at birth and pre-obesity in the first six months of age. At the age of 4 years she was first evaluated by ophthalmology due to reduced visual acuity which evolved unfavorably with severe generalized retinal dysfunction and moderate maculopathy at the age of 9 years. Delayed development and poor social skills were increasingly evident, as wells as short stature, small hands and dysmorphic facial features. At the age of 12 years bilateral transmission hearing loss was diagnosed and two years later she was referred to Endocrinology due to hirsutism, stretch marks and cushingoid facies. In this context, blood work was performed and surprisingly revealed plasma creatinine of 2.19 mg/dL and urea of 65 mg/dL. Kidney ultrasound revealed reduced dimensions and increased parenchymal echogenicity; an obstructive component was excluded. She rapidly progressed to ESKD and dialysis dependence. Bardet-Biedl syndrome was considered. She was referred for transplant assessment and underwent genetic testing. A homozygous likely pathogenic variant was identified in TRAF3IP1 gene, compatible with SLS 9 (autosomal recessive inheritance). Conclusion Although phenotype-based diagnosis was common in ciliopathies, genetic testing is now regularly used for definitive diagnosis. Mutations in the geneTRAF3IP1 were only recently described, particularly in patients presenting with NPHP, RP, skeletal defects, hepatic fibrosis and hexadactyly; ESKD is frequent between 3 and 16 years and SLS is formally associated. Our patient had several clinical manifestations suggestive of BBS, and presumptive diagnosis was assumed (although noticeable phenotypic overlap with SLS exists). Genetic analysis was crucial; the identified mutation in TRAF3IP1 justifies some of the extra-SLS/BBS-like manifestations. Patients must be monitored carefully, namely related to ESKD and extrarenal manifestations; there is also the need for segregation analysis (divorced parents and half-brothers). Ultimately this case represents a consequence of genetics evolution, with a wide genetic and clinical variability now described within these syndromes.

O-Fucosylation of ADAMTSL2 is required for secretion and is impacted by geleophysic dysplasia-causing mutations

ADAMTSL2 mutations cause an autosomal recessive connective tissue disorder, geleophysic dysplasia 1 (GPHYSD1), which is characterized by short stature, small hands and feet, and cardiac defects. ADAMTSL2 is a matricellular protein previously shown to interact with latent transforming growth factor-β binding protein 1 and influence assembly of fibrillin 1 microfibrils. ADAMTSL2 contains seven thrombospondin type-1 repeats (TSRs), six of which contain the consensus sequence for O-fucosylation by protein O-fucosyltransferase 2 (POFUT2). O-fucose–modified TSRs are subsequently elongated to a glucose β1-3-fucose (GlcFuc) disaccharide by β1,3-glucosyltransferase (B3GLCT). B3GLCT mutations cause Peters Plus Syndrome (PTRPLS), which is characterized by skeletal defects similar to GPHYSD1. Several ADAMTSL2 TSRs also have consensus sequences for C-mannosylation. Six reported GPHYSD1 mutations occur within the TSRs and two lie near O-fucosylation sites. To investigate the effects of TSR glycosylation on ADAMTSL2 function, we used MS to identify glycan modifications at predicted consensus sequences on mouse ADAMTSL2. We found that most TSRs were modified with the GlcFuc disaccharide at high stoichiometry at O-fucosylation sites and variable mannose stoichiometry at C-mannosylation sites. Loss of ADAMTSL2 secretion in POFUT2−/− but not in B3GLCT−/− cells suggested that impaired ADAMTSL2 secretion is not responsible for skeletal defects in PTRPLS patients. In contrast, secretion was significantly reduced for ADAMTSL2 carrying GPHYSD1 mutations (S641L in TSR3 and G817R in TSR6), and S641L eliminated O-fucosylation of TSR3. These results provide evidence that abnormalities in GPHYSD1 patients with this mutation are caused by loss of O-fucosylation on TSR3 and impaired ADAMTSL2 secretion.

A Thirteen-Year-Old Girl with Cornelia de Lange Syndrome – The First Case Described in Litigation

AIM: The aim of this paper is to accentuate importance of the expert witness role, occupational medicine specialist, in litigation. The OM specialist proved his importance in broad spectrum of administrative court proceedings, assessment of working capacity, and different type of claims. CASE REPORT: Here is presented a case of a 13-year-old girl suffering Cornelia de Langue syndrome. The occupational medicine specialist concludes that the girl’s claim toward the Ministry of Demography, Family and Social Affairs is legitimate. Expert witness representing the above ministry came to conclusion that the patient is not heavily disabled due to her mobility and regular school attendance. Due to hearing aid her hearing is satisfactory and she is capable of dressing and feeding herself. In 2012, the girl was diagnosed with Langer-Giedion syndrome 8q23.3-q24.13 deletions and due to the development of molecular diagnosis only in 2015 RAD 21 gene deletion was discovered and she was correctly diagnosed. On examination, occupational medicine specialist found the patient suffering heavy deformations of locomotor system, small hands and feet, genua valga, and flat feet. The hearing is severely impaired in right and moderately in her left ear. Her mother states that she stopped soiling bed at the age of 8 and at present when going to toilette during night she becomes disoriented, sleeps badly, and screams. In the morning, she is not capable of preparing her own food. The patient needs to be examined by endocrinologist, her body is covered in exostoses and she heavily depends on other people. CONCLUSION: The patient is heavily disabled and in need of help for essential functioning at least until completion of secondary education.

De novo 2q36.3q37.1 deletion encompassing TRIP12 and NPPC yields distinct phenotypes

We report a patient with developmental delay, extremely short stature, small hands, dysmorphic facial features, hearing loss, and epilepsy carrying a de novo 2.76-Mb deletion of 2q36.3q37.1, including TRIP12 and NPPC. TRIP12 haploinsufficiency causes developmental delay with isolated dysmorphic facial features, whereas NPPC haploinsufficiency causes short stature and small hands. This is the first report of a unique phenotype, which is secondary to a microdeletion encompassing TRIP12 and NPPC.

11p15.4 Microdeletion Associates with Hemihypertrophy

We report a preterm female infant with intrauterine growth retardation, dysmorphic facies, missing rib, small hands and feet, and hemihypertrophy. The results of whole genome SNP microarray analysis showed approximately 77 Kb interstitial deletion of the short arm of chromosome 11 (11p15.4). We report novel clinical findings of this rare genetic condition.