SRD5A3-CDG: Emerging Phenotypic Features of an Ultrarare CDG Subtype

Background: SRD5A3-CDG is a rare N-glycosylation defect caused by steroid 5 alpha reductase type 3 deficiency. Its key feature is an early severe visual impairment with variable ocular anomalies often leading to diagnosis. Additional symptoms are still poorly defined. In this case study, we discuss 11 genetically confirmed cases, and report on emerging features involving other systems in addition to the eye phenotype.Methods: In total, 11 SRD5A3-CDG patients in five sets of sibships were included in the study. Data on 9 of 11 patients are as of yet unpublished. Patients’ results on biochemical and genetic investigations and on in-depth phenotyping are presented.Results: Key diagnostic features of SRD5A3-CDG are ophthalmological abnormalities with early-onset retinal dystrophy and optic nerve hypoplasia. SRD5A3-CDG is also characterized by variable neurological symptoms including intellectual disability, ataxia, and hypotonia. Furthermore, ichthyosiform skin lesions, joint laxity, and scoliosis have been observed in our cohort. We also report additional findings including dystonia, anxiety disorder, gastrointestinal symptoms, and MRI findings of small basal ganglia and mal-rotated hippocampus, whereas previous publications described dysmorphic features as a common finding in SRD5A3, which could not be confirmed in our patient cohort.Conclusion: The detailed description of the phenotype of this large cohort of patients with SRD5A3-CDG highlights that the key clinical diagnostic features of SRD5A3-CDG are an early onset form of ophthalmological problems in patients with a multisystem disorder with variable symptoms evolving over time. This should aid earlier diagnosis and confirms the need for long-time follow-up of patients.

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Comparison of MRI findings with actual HPE findings in case of carcinoma endometrium

10.1055/s-0039-1685340 ◽

2016 ◽

Author(s):

Shaveta Gupta

Keyword(s):

Endometrial Cancer ◽

Lymph Node ◽

Myometrial Invasion ◽

Lymph Node Involvement ◽

Common Finding ◽

Mri Findings ◽

Pelvic Mri ◽

Histopathological Findings ◽

Node Involvement ◽

Cervical Involvement

Objectives: The objectives of this study is to investigate the correlation of magnetic resonance imaging (MRI) in predicting the depth of myometrial invasion, cervical involvement and lymph node involvement and actual histopathological findings in the women with endometrial cancer. Methods: This is a reterospective study of the patients of endometrial cancer from Nov 2011 to Jan 2016 who underwent Surgery (Total abdominal Hystrectomy with B/l salpingoophorectomy with peritoneal washings with b/l pelvic lymphadenectomy with or without para aortic lymphadenectomy) at our centre Max Superspeciality Hospital. CE MRI Pelvis has been done pre operatively in every patient. After the surgery Histopathological reports of the specimen checked and compared with MRI findings of that case. The purpose of the study is to evaluate the validity of MRI findings of endometrial cancer in comparison to final histopathological findings. Results: For the detection of myometrial invasion, overall sensitivity of MRI is 93.9%, specificity is 66.6%, for cervical involvement Senstivity is 60% and specificity 1s 93.75% and for detection of lymph node involvement sensitivity is 66.6% and specificity is 93.5%. Most common Finding on MRI is thickened endometrium with disruption of Junction jone. Conclusions: Preoperative pelvic MRI is a sensitive method of identifying invasion to the myometrium in endometrial cancer. MRI Is a sensitive noninvasive modality in predicting locoregional spread in ca endometrium. Senstivity in detecting Myometrial invasion is high but sensitivity is less in detecting cervical involvement and lymph node involvement is less.

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Novel TTLL5 Variants Associated with Cone-Rod Dystrophy and Early-Onset Severe Retinal Dystrophy

International Journal of Molecular Sciences ◽

10.3390/ijms22126410 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6410

Author(s):

Vasily Smirnov ◽

Olivier Grunewald ◽

Jean Muller ◽

Christina Zeitz ◽

Carolin D. Obermaier ◽

...

Keyword(s):

Early Onset ◽

Retinal Dystrophy ◽

Copy Number Variants ◽

Cone Dystrophy ◽

The Novel ◽

Targeted Next Generation Sequencing ◽

Large Deletions ◽

Gene Panels ◽

Generation Sequencing

Variants of the TTLL5 gene, which encodes tubulin tyrosine ligase-like family member five, are a rare cause of cone dystrophy (COD) or cone-rod dystrophy (CORD). To date, only a few TTLL5 patients have been clinically and genetically described. In this study, we report five patients harbouring biallelic variants of TTLL5. Four adult patients presented either COD or CORD with onset in the late teenage years. The youngest patient had a phenotype of early onset severe retinal dystrophy (EOSRD). Genetic analysis was performed by targeted next generation sequencing of gene panels and assessment of copy number variants (CNV). We identified eight variants, of which six were novel, including two large multiexon deletions in patients with COD or CORD, while the EOSRD patient harboured the novel homozygous p.(Trp640*) variant and three distinct USH2A variants, which might explain the observed rod involvement. Our study highlights the role of TTLL5 in COD/CORD and the importance of large deletions. These findings suggest that COD or CORD patients lacking variants in known genes may harbour CNVs to be discovered in TTLL5, previously undetected by classical sequencing methods. In addition, variable phenotypes in TTLL5-associated patients might be due to the presence of additional gene defects.

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Pathogenic STX3 variants affecting the retinal and intestinal transcripts cause an early-onset severe retinal dystrophy in microvillus inclusion disease subjects

Human Genetics ◽

10.1007/s00439-021-02284-1 ◽

2021 ◽

Author(s):

Andreas R. Janecke ◽

Xiaoqin Liu ◽

Rüdiger Adam ◽

Sumanth Punuru ◽

Arne Viestenz ◽

...

Keyword(s):

Early Onset ◽

Single Nucleotide Polymorphism Array ◽

Outer Nuclear Layer ◽

Retinal Dystrophy ◽

Geographic Origin ◽

Retinal Disease ◽

Homozygosity Mapping ◽

Rod Photoreceptor ◽

Loss Of Function ◽

Knockout Mouse Model

AbstractBiallelic STX3 variants were previously reported in five individuals with the severe congenital enteropathy, microvillus inclusion disease (MVID). Here, we provide a significant extension of the phenotypic spectrum caused by STX3 variants. We report ten individuals of diverse geographic origin with biallelic STX3 loss-of-function variants, identified through exome sequencing, single-nucleotide polymorphism array-based homozygosity mapping, and international collaboration. The evaluated individuals all presented with MVID. Eight individuals also displayed early-onset severe retinal dystrophy, i.e., syndromic—intestinal and retinal—disease. These individuals harbored STX3 variants that affected both the retinal and intestinal STX3 transcripts, whereas STX3 variants affected only the intestinal transcript in individuals with solitary MVID. That STX3 is essential for retinal photoreceptor survival was confirmed by the creation of a rod photoreceptor-specific STX3 knockout mouse model which revealed a time-dependent reduction in the number of rod photoreceptors, thinning of the outer nuclear layer, and the eventual loss of both rod and cone photoreceptors. Together, our results provide a link between STX3 loss-of-function variants and a human retinal dystrophy. Depending on the genomic site of a human loss-of-function STX3 variant, it can cause MVID, the novel intestinal-retinal syndrome reported here or, hypothetically, an isolated retinal dystrophy.

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The protean phenotype of MSH6 pathogenic variants (PV) in Lynch syndrome (LS) patients (pts).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.10537 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 10537-10537

Author(s):

Michelle J McSweeny ◽

Susan Montgomery ◽

Kristen Danielle Whitaker ◽

Mary Beryl Daly ◽

Michael J. Hall

Keyword(s):

Skin Disease ◽

Early Onset ◽

Skin Lesions ◽

Published Data ◽

Pedigree Data ◽

Skin Manifestations ◽

Pathogenic Variants ◽

Ca 50 ◽

Uncertain Variant ◽

Histologic Types

10537 Background: LS is among the most common hereditary cancer (CA) syndromes. PVs in MSH6 are 2-4 fold more common in the population (1/758) than those in MLH1 (1/1946) or MSH2 (1/2841), and are increasingly regarded as lower penetrance for CRC due to published data supporting later mean age of CRC onset and lower CRC risk. Unlike for MLH1/MSH2, NCCN 2020 CA risk estimates recognize only endometrial CA (EC) and CRC risks in MSH6+ carriers as clearly above SEER population estimates. Further, risks of other LS manifestations such as skin disease/Muir-Torre, ovarian CA (OC), and possible rare tumors in LS like sarcoma, have been minimally characterized in MSH6+ carriers. Methods: Pedigree data for 44 MSH6+ index (first-evaluated family member by our program) pts consecutively ascertained since 2009 at Fox Chase (FCCC) were reviewed. 1 pt w/a rare MSH6 uncertain variant w/personal history (PHx) of MSH6-expression deficient EC (age 50) and MSH6-deficient sebaceous skin CA (age 50) and a strong family history (FHx) c/w LS is also included here. 34% (15/44) index pts were referred to FCCC for cascade testing due to a known MSH6 PV in the family. Of the remaining 29 index pts, ascertainment included: 14% w/positive universal LS tumor screening, 21% w/early-onset or synchronous LS CA, 14% w/multi-gene panel for PHx of OC, 10% w/incidental MSH6+ result (2 had testing for PHx breast CA, 1 tumor genomic profiling), and 28% w/PHx and/or FHx of LS CA warranting genetic testing. Age of CA onset and path data were verified in > 90% index pts. Results: Index pts had a mean age of 55.5 yrs, and 77% were female. Overall, 11% (5/44) of MSH6+ index pts were found to have LS at diagnosis of synchronous primary CAs (3 EC/OC, 1 CRC/CRC, 1 CRC/EC), and 4/5 of these occurred <50 yrs. An additional 20% (9/44) index pts reported PHx of >2 metachronous LS CAs. OC was the presenting CA in 14% (6/44) female index pts; 2 additional index pts had rarer OC variants (Mullerian duct @ 41, primary peritoneal CA @ 50). Skin manifestations of LS were documented in 9.1% (4/44) index pts (3 sebaceous, 1 SCC in-situ/Bowen’s disease); 1 other family had documented sebaceous CAs in an FDR (father) but the 2 daughters seen @FCCC (both 30s) had yet to develop skin lesions. 2 index pts were found to have LS after developing early-onset breast CA (age 39) and contralateral breast CA (ages 50 and 54). Finally, 7% (3/44) index pts had a PHx of sarcoma: 2 were liposarcomas (ages 57 and 67), and 1 was a dermatofibrosarcoma. 2 other index pts had siblings w/childhood sarcomas. Conclusions: Our data, encompassing 44 MSH6+ pts evaluated in our clinic and consecutively ascertained, suggest MSH6 PV carriers develop synchronous primaries (11%), common and rare OC histologic types (18%), sarcomas (7%) and skin disease/Muir-Torre (9%). While common in the population and lower penetrance for CRC, MSH6 PV can behave in uncommon ways and may have significant extra-colonic CA risks such as OC, sarcoma and skin manifestations.

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Molecular Screening of 43 Brazilian Families Diagnosed with Leber Congenital Amaurosis or Early-Onset Severe Retinal Dystrophy

Genes ◽

10.3390/genes8120355 ◽

2017 ◽

Vol 8 (12) ◽

pp. 355 ◽

Cited By ~ 7

Author(s):

Fernanda Porto ◽

Evan Jones ◽

Justin Branch ◽

Zachry Soens ◽

Igor Maia ◽

...

Keyword(s):

Early Onset ◽

Retinal Dystrophy ◽

Molecular Screening ◽

Leber Congenital Amaurosis

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DIAGNOSTIC FEATURES OF COMPLICATED CHOLELITHIASIS IN PREGNANT WOMEN

Kuban Scientific Medical Bulletin ◽

10.25207/1608-6228-2019-26-1-168-174 ◽

2019 ◽

Vol 26 (1) ◽

pp. 168-174

Author(s):

Karen D. Antinyan ◽

Evgenii S. Babenko ◽

Vladimir M. Durleshter

Keyword(s):

Pregnant Women ◽

Conflict Of Interest ◽

Magnetic Resonance Cholangiopancreatography ◽

Abdominal Ultrasound ◽

Perinatal Complications ◽

Laparoscopic Ultrasonography ◽

Endoscopic Retrograde ◽

Diagnostic Features ◽

Ultrasound Diagnostics ◽

Long Time

The aimis to describe modern approaches used in the diagnostics of cholelithiasis in pregnant women.Results.Cholelithiasis diagnostics in pregnant women is a rather difficult task, frequently taking a long time and significantly worsening the prognosis for both the mother and the fetus. Abdominal ultrasound is the “gold standard” for the diagnosis of cholelithiasis in pregnant women, allowing the diagnosis to be clarified and the treatment tactics to be adjusted. The possibilities of such modern methods as endoscopic ultrasound diagnostics, magnetic resonance cholangiopancreatography, endoscopic retrograde cholangiopancreatography, and laparoscopic ultrasonography used in difficult diagnostic cases are presented.Conclusion.The use of a maximal range of diagnostic studies in pregnant women makes it possible to establish the diagnosis as soon as possible and to reduce the frequency of surgical and related perinatal complications. As a result, the prolongation of pregnancy and a decrease in maternal and intrauterine mortality can be achieved.Conflict of interest: the authors declare no conflict of interest.

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Diabetes in Patients with Ataxia telangiectasia: A National Cohort Study

10.21203/rs.3.rs-21121/v1 ◽

2020 ◽

Author(s):

Helena Donath ◽

Ursula Hess ◽

Matthias Kieslich ◽

Marius Theis ◽

Ute Ohlenschläger ◽

...

Keyword(s):

Retrospective Analysis ◽

Ataxia Telangiectasia ◽

Autosomal Recessive ◽

Fasting Glucose ◽

Therapy Response ◽

Common Finding ◽

Oral Glucose ◽

Multisystem Disorder ◽

National Cohort

Abstract Background: Ataxia telangiectasia (A-T) is a rare autosomal-recessive multisystem disorder characterized by pronounced cerebellar ataxia, telangiectasia, cancer predisposition and altered body composition. In addition, evidence is rising for endocrine dysfunction. Objectives: To determine the evolution of diabetes and its prevalence in a larger A-T cohort. Methods: A retrospective analysis of the patient charts of 39 subjects from the Frankfurt A-T cohort was performed between August 2002 and 2018 concerning HbA1c and oral glucose tolerance (OGTT). The median follow-up period was 4 years (1-16 years). In addition, in 31 A-T patients aged 1 to 38 years HbA1c and fasting glucose were studied prospectively from 2018-2019. Results: In the retrospective analysis, we could demonstrate a longitudinal increase of HbA1c. The prospective analysis showed a significant increase of HbA1c and fasting glucose with age (r = 0.79, p <0.0001). OGTT has a good sensitivity for IR screening, whereas HbA1c can be used to evaluate individual courses and therapy response. Seven out of 39 (17.9%) patients suffered from diabetes. Metformin did not always lead to sufficient diabetes control; one patient was treated successfully with repaglinide. Conclusion: Diabetes is a common finding in older A-T patients and often starts in puberty. Our data clearly demonstrate the need for an annual diabetes screening in patients > 12 years.

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Pattern of upper gastrointestinal diseases: an audit of 1000 cases based on endoscopic findings from a tertiary care hospital in Mysore

International Surgery Journal ◽

10.18203/2349-2902.isj20182395 ◽

2018 ◽

Vol 5 (7) ◽

pp. 2412

Author(s):

Shashikumar H. B. ◽

Madhu B. S. ◽

Motati Harshini

Keyword(s):

Tertiary Care Hospital ◽

Tertiary Care ◽

Gastrointestinal Symptoms ◽

Gastrointestinal Diseases ◽

Cross Sectional Study ◽

Common Finding ◽

Care Hospital ◽

Cross Sectional ◽

Endoscopic Findings ◽

Upper Gastrointestinal

Background: Fibreoptic endoscopy is a highly efficient diagnostic tool, which is now increasingly being used in the diagnosis of upper gastrointestinal diseases. This study has been carried out to evaluate the distribution of various upper gastrointestinal diseases based on endoscopic findings in a tertiary care hospital in Mysore.Methods: A cross-sectional study was conducted based on data from endoscopic register of 1000 subjects who underwent endoscopy for various upper gastrointestinal symptoms from 1st January 2017 to 31st December 2017(one year).Results: Mean age of the study population was 50.23 years (SD-15.46). Minimum age was 12 years and maximum was 88 years. About 44.7% of the study subjects belonged to 40-60 age group.61.6% of the study subjects were males. Most common indication was pain abdomen (32.1%) followed by dysphagia (22.2%). Of the 1000 study subjects 18.6% had normal findings. Most common finding was Gastritis / Duodenitis /Gastric erosions (28%). Malignant lesions were noted among 11.1%, of which esophagus and stomach are 5.4% and 4.9% respectively.Conclusions: Endoscopic diagnosis is useful for early detection of UGI diseases and helpful for their management.

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Incontinentia Pigmenti and Bipolar Aphthosis: An Unusual Combination

ISRN Dermatology ◽

10.5402/2011/814186 ◽

2011 ◽

Vol 2011 ◽

pp. 1-3 ◽

Cited By ~ 1

Author(s):

G. Márquez Balbás ◽

M. A. González-Enseñat ◽

A. Vicente ◽

L. Creus-Vila ◽

J. Antón ◽

...

Keyword(s):

Skin Eruption ◽

Skin Lesions ◽

In Utero ◽

Incontinentia Pigmenti ◽

Multisystem Disorder ◽

Cutaneous Manifestations ◽

Vascular Abnormalities ◽

Unusual Combination ◽

Lines Of Blaschko ◽

Genital Ulcers

Incontinentia pigmenti (IP) is an uncommon X-linked dominant multisystem disorder, lethal in the majority of affected males in utero and variably expressed in females. The cutaneous manifestations are diagnostic and classically occur in four stages: vesicular, verrucous, hyperpigmented, and atrophic. The skin lesions are typically spread along the lines of Blaschko, and they are usually present at birth. It may be variably accompanied by dental, ocular, neurologic, bones and joints, and development anomalies. The genes IP has been mapped to Xq28. Mutations in the NEMO/IKKγ gene, located at Xq28, have been found to cause expression of the disease. Behçets disease is a multisystem disorder consisting of recurrent oral aphtae, genital ulcers, pustular skin eruption, and uveitis. Occasionally there are other articular, neurological, intestinal, or vascular abnormalities. This disease is rare in children. Here, we report a case of a 16-year-old female with the rare combination of incontinentia pigmenti and an aphthosis bipolar, and we discuss the probably relationship between these two diseases.

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Genetic and clinical findings in a Chinese cohort with Leber congenital amaurosis and early onset severe retinal dystrophy

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2019-314281 ◽

2019 ◽

Vol 104 (7) ◽

pp. 932-937 ◽

Cited By ~ 3

Author(s):

Ke Xu ◽

Yue Xie ◽

Tengyang Sun ◽

Xiaohui Zhang ◽

Chunjie Chen ◽

...

Keyword(s):

Early Onset ◽

Retinal Dystrophy ◽

Case Series ◽

Clinical Findings ◽

Chinese Patients ◽

Pcr Analysis ◽

Common Mutation ◽

Essential Information ◽

Leber Congenital Amaurosis ◽

Targeted Next Generation Sequencing

BackgroundLeber congenital amaurosis (LCA) and early onset severe retinal dystrophy (EOSRD) are clinically and genetically heterogeneous inherited retinal disorders that cause severe visual impairment in children. The objective of this study was to describe the mutation profile and phenotypic characteristics in Chinese patients with LCA or EOSRD.MethodsRetrospective consecutive case series (2010–2017) study was performed in 148 probands (91 with LCA and 57 with EOSRD). All patients underwent ophthalmic evaluation. Mutations were revealed using targeted next-generation sequencing, followed by Sanger DNA-sequencing and real-time quantitative PCR analysis.ResultsWe identified two diseasing-causing mutations in 88 unrelated patients, heterozygous autosomal dominant mutations in 11 probands and X-linked hemizygous mutations in 11 patients, for an overall mutation detection rate of 74.3% (110/148). We detected 158 different disease-causing mutations involving 14 LCA genes, 16 retinitis pigmentosa or cone-rod dystrophy genes and 3 syndromic retinal dystrophy genes. Of these 158 mutations, 98 were novel. The most common mutation was p.Q141X of AIPL1, with a gene-specific allele frequency of 60%. The first five most frequently mutated genes were AIPL1 (11.0%), RPGRIP1 (8.8%) and CEP290, GUCY2D and RPE65 (each 7.7%) in the patients with LCA and RPGR (12.3%), CRB1 (10.5%), RPE65 (10.5%), RDH12 (7.0%) and RP2 (5.3%) in the patients with EOSRD.ConclusionsOur results revealed that the mutation spectrum of patients with LCA differs from that of the patients with EOSRD and established the configuration of the mutation frequencies for each LCA gene in Chinese patients, thereby providing essential information for future genetic counselling and gene therapy.

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