Orpha disease – FRASER syndrome (ORPHA:2052) in children: phenotype and genotype characteristics

2021 ◽  
Vol 25 (3) ◽  
pp. 28-35
Author(s):  
J. G. Leviashvili ◽  
N. D. Savenkova
Keyword(s):  
Rare Disease ◽  
Respiratory System ◽  
Umbilical Hernia ◽  
Autosomal Recessive ◽  
Molecular Genetic ◽  
Genetic Diagnosis ◽  
Molecular Genetic Testing ◽  
Fraser Syndrome ◽  
Recessive Type ◽  
Icd 10

Fraser syndrome (OMIM # 219000; ORPHA: 2052; ICD-10: Q87.0) is a rare, disease with an autosomal recessive type of inheritance is characterized by abnormalities in the development of the eyes, kidneys, larynx, ears, and bone systems (cryptophthalmos, syndactyly, abnormalities of the kidneys, urogenital tract, and respiratory system). The article presents current literature data on the phenotypic and genotypic features of Fraser syndrome, the management of patients with new opportunities for genetic diagnosis and treatment. The syndrome, described by D. Fraser in 1962, is caused by mutations in the FRAS1, FREM2, GRIP genes. The diagnosis of the Fraser syndrome phenotype is established in the presence of the main criteria (cryptophthalmos, syndactyly, abnormalities of the urinary and respiratory system, genitals, family history indicating a closely related marriage) and secondary (congenital malformations of the nose and ears, skull ossification defects, anorectal abnormalities, umbilical hernia, etc.). Molecular genetic testing proves a rare disease, requires genetic counseling. The management of patients is carried out jointly by an ophthalmologist, an otolaryngologist, an audiologist, a nephrologist, a urologist, a maxillofacial surgeon and other specialists.

scholarly journals Multimorbidity in Pediatric Dermatology: Clinical Case

2020 ◽  
Vol 19 (6) ◽  
pp. 483-489
Author(s):  
Nikolay N. Murashkin ◽  
Alexander I. Materikin ◽  
Eduard T. Ambarchian ◽  
Roman V. Epishev ◽  
Leonid A. Opryatin ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Autosomal Recessive ◽  
Clinical Case ◽  
Correct Diagnosis ◽  
Molecular Genetic ◽  
Final Diagnosis ◽  
Molecular Genetic Testing ◽  
Pediatric Dermatology ◽  
Dominant Type ◽  
Recessive Type

Background. Nowadays, dermatoses with mixed clinical picture and resistant to classical management become more common. The presence of various genetic disorders typical for most chronic dermatoses may indicate possible combination of several nosologies.Clinical Case Description. The article presents the clinical case of multimorbid condition in 10 years old patient who has nucleotide variants in CARD14 and EXPH5 genes. Mutations in CARD14 gene are typical for patients with type 2 psoriasis and pityriasis rubra pilaris (autosomal dominant type), while mutations in EXPH5 gene are typical for patients with non-specific epidermolysis bullosa (autosomal recessive type). Mutation in the TGM1 gene that is described in patients with congenital ichthyosis (autosomal recessive type), pathogenic mutations in KRT74 gene typical for ectodermal dysplasia, hypotrichosis and uncombable hair syndrome, and mutations in the KRT86 gene typical for monilethrix were also revealed. Medical history taking and histological examination as well as clinical data evaluating are crucial for correct diagnosis. They allow to understand the absence of the such manifestations in relatives and reveal various pathological processes in the epidermis. Molecular genetic testing with new generation sequencing (NGS) helps to finally establish the diagnosis and determine the further tactics for patient management.Conclusion. Multidisciplinary approach and use of high-technology methods of examination and treatment (such as molecular genetic testing and biological therapy) are required for final diagnosis in severe forms of chronic dermatosis resistant to treatment and for decision on correct tactics for the further management of such patients.

A Case of Dubin-Johnson Syndrome Presenting as Neonatal Cholestasis With Paucity of Interlobular Bile Ducts

2021 ◽  
pp. 109352662098057
Author(s):  
Kara L Chan ◽  
Natasha Varughese ◽  
Patricia M Jones ◽  
David L Zwick ◽  
Veena Rajaram ◽  
...  
Keyword(s):  
Bile Ducts ◽  
Autosomal Recessive ◽  
Molecular Genetic ◽  
Autosomal Recessive Disorder ◽  
Neonatal Cholestasis ◽  
Molecular Genetic Testing ◽  
Biopsy Tissue ◽  
Johnson Syndrome ◽  
Clinicopathologic Findings ◽  
Conjugated Hyperbilirubinemia

Dubin-Johnson syndrome (DJS) is a rare autosomal recessive disorder that typically manifests in young adulthood as jaundice with conjugated hyperbilirubinemia. We report a case presenting as neonatal cholestasis with the unexpected histologic finding of paucity of interlobular bile ducts, a feature that is not typically seen in DJS. The diagnosis was confirmed by absent canalicular multidrug-resistance-associated protein 2 (MRP2) immunohistochemical staining on liver biopsy tissue and molecular genetic testing that demonstrated heterozygous mutations in the ATP-Binding Cassette Subfamily C Member 2 ( ABCC2) gene, including a novel missense mutation. This report describes a case of DJS with atypical clinicopathologic findings and suggests that DJS should be considered in patients with neonatal cholestasis and bile duct paucity.

scholarly journals Clinical and Genetic Characteristics of Autosomal Recessive Polycystic Kidney Disease in Oman

2020 ◽  
Author(s):  
Intisar Al Alawi ◽  
Elisa Molinari ◽  
Issa Al Salmi ◽  
Fatma Al Rahbi ◽  
Adhra Al Mawali ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Clinical Diagnosis ◽  
Autosomal Recessive ◽  
Molecular Genetic ◽  
Genetic Diagnosis ◽  
Pcr Analysis ◽  
Genetic Profile ◽  
Polycystic Kidney ◽  
Genetic Characteristics

Abstract Background There is a high prevalence of rare genetic disorders in the Middle East, and their study provides unique clinical and genetic insights. Autosomal recessive polycystic kidney disease (ARPKD) is one of the leading causes of kidney and liver-associated morbidity and mortality in Oman. We describe the clinical and genetic profile of cohort of ARPKD patients.Methods We studied patients with a clinical diagnosis of ARPKD ( n =40) and their relatives [parents ( n =24) and unaffected siblings ( n =10)] from 32 apparently unrelated families, who were referred to the National Genetic Centre in Oman between January 2015 and December 2018. Genetic analysis of PKHD1 was performed through next generation sequencing (NGS) and Sanger sequencing.Results A clinical diagnosis of ARPKD was made prenatally in 8 patients, 21 were diagnosed during infancy (0-1 year), 9 during early childhood (2-8 years) and 2 at later ages (9-13 years). Clinical phenotypes included polycystic kidneys, hypertension, hepatic fibrosis and splenomegaly. 24 patients had documented chronic kidney disease. 24 out of the 32 families had a family history suggesting an autosomal recessive pattern of inherited kidney disease, and there was known consanguinity in 21 families (66%). A molecular genetic diagnosis with biallelic PKHD1 mutations was confirmed in 38 patients from 30 different families, giving a detection rate of 94%. Two unrelated patients remained genetically unsolved. In all of the solved cases, only four different PKHD1 missense pathogenic variants were identified: c.107C>T, p.(Thr36Met); c.406A>G, p.(Thr136Ala); c.4870C>T, p.(Arg1624Trp) and c.9370C>T, p.(His3124Tyr) located in exons 3, 6, 32 and 58, respectively. The c.406A>G, p.(Thr136Ala) missense mutation was detected homozygously in one family and heterozygously with a c.107C>T, p.(Thr36Met) allele in 5 other families. Overall, the most commonly detected pathogenic allele was c.107C>T; (Thr36Met), which was seen in 24 families.Conclusion Molecular genetic screening of PKHD1 in clinically suspected ARPKD cases produced a high diagnostic rate. The four PKHD1 missense variants identified suggest there may be common founder alleles in the Omani population. Cost effective targeted PCR analysis of these specific alleles can be a useful diagnostic tool for future cases of suspected ARPKD in Oman.

scholarly journals Clinical and Genetic Characteristics of Autosomal Recessive Polycystic Kidney Disease in Oman

2020 ◽  
Author(s):  
Intisar Al Alawi ◽  
Elisa Molinari ◽  
Issa Al Salmi ◽  
Fatma Al Rahbi ◽  
Adhra Al Mawali ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Clinical Diagnosis ◽  
Autosomal Recessive ◽  
Molecular Genetic ◽  
Genetic Diagnosis ◽  
Pcr Analysis ◽  
Genetic Profile ◽  
Polycystic Kidney ◽  
Genetic Characteristics

Abstract Background: There is a high prevalence of rare genetic disorders in the Middle East, and their study provides unique clinical and genetic insights. Autosomal recessive polycystic kidney disease (ARPKD) is one of the leading causes of kidney and liver-associated morbidity and mortality in Oman. We describe the clinical and genetic profile of cohort of ARPKD patients. Methods: We studied patients with a clinical diagnosis of ARPKD (n=40) and their relatives (parents (n=24) and unaffected siblings (n=10)) from 32 apparently unrelated families, who were referred to the National Genetic Centre in Oman between January 2015 and December 2018. Genetic analysis of PKHD1 if not previously known was performed using targeted exon PCR of known disease alleles and Sanger sequencing. Results: A clinical diagnosis of ARPKD was made prenatally in 8 patients, 21 were diagnosed during infancy (0-1 year), 9 during early childhood (2-8 years) and 2 at later ages (9-13 years). Clinical phenotypes included polycystic kidneys, hypertension, hepatic fibrosis and splenomegaly. 24 patients had documented chronic kidney disease (median age 3 years). 24 out of the 32 families had a family history suggesting an autosomal recessive pattern of inherited kidney disease, and there was known consanguinity in 21 families (66%). A molecular genetic diagnosis with biallelic PKHD1 mutations was known in 18 patients and newly identified in 20 other patients, totalling 38 patients from 30 different families. Two unrelated patients remained genetically unsolved. The different PKHD1 missense pathogenic variants were: c.107C>T, p.(Thr36Met); c.406A>G, p.(Thr136Ala); c.4870C>T, p.(Arg1624Trp) and c.9370C>T, p.(His3124Tyr) located in exons 3, 6, 32 and 58, respectively. The c.406A>G, p.(Thr136Ala) missense mutation was detected homozygously in one family and heterozygously with a c.107C>T, p.(Thr36Met) allele in 5 other families. Overall, the most commonly detected pathogenic allele was c.107C>T; (Thr36Met), which was seen in 24 families. Conclusions: Molecular genetic screening of PKHD1 in clinically suspected ARPKD cases produced a high diagnostic rate. The limited number of PKHD1 missense variants identified in ARPKD cases suggests these may be common founder alleles in the Omani population. Cost effective targeted PCR analysis of these specific alleles can be a useful diagnostic tool for future cases of suspected ARPKD in Oman.

scholarly journals Mucopolysaccharidosis-Plus Syndrome

2020 ◽  
Vol 21 (2) ◽  
pp. 421
Author(s):  
Filipp Vasilev ◽  
Aitalina Sukhomyasova ◽  
Takanobu Otomo
Keyword(s):  
Skin Fibroblast ◽  
Autosomal Recessive ◽  
Heart Defects ◽  
Molecular Genetic ◽  
Symptomatic Treatment ◽  
Molecular Genetic Testing ◽  
Multisystem Disorder ◽  
Specific Therapy ◽  
Yakut Population ◽  
Hematopoietic Disorders

Previously, we reported a novel disease of impaired glycosaminoglycans (GAGs) metabolism without deficiency of known lysosomal enzymes—mucopolysaccharidosis-plus syndrome (MPSPS). MPSPS, whose pathophysiology is not elucidated, is an autosomal recessive multisystem disorder caused by a specific mutation p.R498W in the VPS33A gene. VPS33A functions in endocytic and autophagic pathways, but p.R498W mutation did not affect both of these pathways in the patient’s skin fibroblast. Nineteen patients with MPSPS have been identified: seventeen patients were found among the Yakut population (Russia) and two patients from Turkey. Clinical features of MPSPS patients are similar to conventional mucopolysaccharidoses (MPS). In addition to typical symptoms for conventional MPS, MPSPS patients developed other features such as congenital heart defects, renal and hematopoietic disorders. Diagnosis generally requires evidence of clinical picture similar to MPS and molecular genetic testing. Disease is very severe, prognosis is unfavorable and most of patients died at age of 10–20 months. Currently there is no specific therapy for this disease and clinical management is limited to supportive and symptomatic treatment.

scholarly journals Clinical and Genetic Characteristics of Autosomal Recessive Polycystic Kidney Disease in Oman

2020 ◽  
Author(s):  
Intisar Al Alawi ◽  
Elisa Molinari ◽  
Issa Al Salmi ◽  
Fatma Al Rahbi ◽  
Adhra Al Mawali ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Clinical Diagnosis ◽  
Autosomal Recessive ◽  
Molecular Genetic ◽  
Genetic Diagnosis ◽  
Pcr Analysis ◽  
Genetic Profile ◽  
Polycystic Kidney ◽  
Genetic Characteristics

Abstract Introduction There is a high prevalence of rare genetic disorders in the Middle East, and their study provides unique clinical and genetic insights. Autosomal recessive polycystic kidney disease (ARPKD) is one of the leading causes of kidney and liver-associated morbidity and mortality in Oman. We describe the clinical and genetic profile of cohort of ARPKD patients. Methods We studied patients with a clinical diagnosis of ARPKD ( n =40) and their relatives [parents ( n =24) and unaffected siblings ( n =10)] from 32 apparently unrelated families, who were referred to the National Genetic Centre in Oman between January 2015 and December 2018. Genetic analysis of PKHD1 was performed through next generation sequencing (NGS) and Sanger sequencing. Results A clinical diagnosis of ARPKD was made prenatally in 8 patients, 21 were diagnosed during infancy (0-1 year), 9 during early childhood (2-8 years) and 2 at later ages (9-13 years). Clinical phenotypes included polycystic kidneys, hypertension, hepatic fibrosis and splenomegaly. 24 patients had documented chronic kidney disease. 24 out of the 32 families had a family history suggesting an autosomal recessive pattern of inherited kidney disease, and there was known consanguinity in 21 families (66%). A molecular genetic diagnosis with biallelic PKHD1 mutations was confirmed in 38 patients from 30 different families, giving a detection rate of 94%. Two unrelated patients remained genetically unsolved. In all of the solved cases, only four different PKHD1 missense pathogenic variants were identified: c.107C>T, p.(Thr36Met); c.406A>G, p.(Thr136Ala); c.4870C>T, p.(Arg1624Trp) and c.9370C>T, p.(His3124Tyr) located in exons 3, 6, 32 and 58, respectively. The c.406A>G, p.(Thr136Ala) missense mutation was detected homozygously in one family and heterozygously with a c.107C>T, p.(Thr36Met) allele in 5 other families. Overall, the most commonly detected pathogenic allele was c.107C>T; (Thr36Met), which was seen in 24 families. Conclusion Molecular genetic screening of PKHD1 in clinically suspected ARPKD cases produced a high diagnostic rate. The four PKHD1 missense variants identified suggest there may be common founder alleles in the Omani population. Cost effective targeted PCR analysis of these specific alleles can be a useful diagnostic tool for future cases of suspected ARPKD in Oman.

A novel keratin 10 gene mutation causing epidermolytic hyperkeratosis (bullous congenital ichthyosiform erythroderma) in a term neonate

2017 ◽  
Vol 6 (1) ◽  
Author(s):  
Satyaranjan Pegu ◽  
Jaya. P. Bodani ◽  
Edmond G. Lemire ◽  
Karen I. Holfeld
Keyword(s):  
Genetic Testing ◽  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
Molecular Genetic ◽  
Autosomal Recessive Inheritance ◽  
Skin Condition ◽  
Molecular Genetic Testing ◽  
Epidermolytic Hyperkeratosis ◽  
Autosomal Dominant Fashion ◽  
Congenital Ichthyosiform Erythroderma

Abstract Epidermolytic hyperkeratosis (EHK) is a rare skin condition characterized by erythroderma and blistering at birth, leading to generalized hyperkeratosis of varying severity in adulthood. EHK is frequently mistaken for staphylococcal scalded skin syndrome (SSSS) or epidermolysis bullosa. EHK is usually inherited in an autosomal dominant fashion, but very rare autosomal recessive families have been reported. Molecular genetic testing in this patient identified a novel homozygous keratin-10 gene (KRT10) mutation consistent with autosomal recessive inheritance. Furthermore, diagnosis was achieved by molecular genetic testing circumventing the need to perform a skin biopsy.

scholarly journals Extending the phenotypic spectrum of PRPF8, PRPH2, RP1 and RPGR, and the genotypic spectrum of early-onset severe retinal dystrophy

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Michalis Georgiou ◽  
Naser Ali ◽  
Elizabeth Yang ◽  
Parampal S. Grewal ◽  
Tryfon Rotsos ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Early Onset ◽  
Molecular Genetic ◽  
Disease Onset ◽  
Retinal Dystrophy ◽  
Genetic Diagnosis ◽  
Retinal Imaging ◽  
Molecular Genetic Testing ◽  
Phenotypic Spectrum ◽  
Novel Variant

Abstract Purpose To present the detailed retinal phenotype of patients with Leber Congenital Amaurosis/Early-Onset Severe Retinal Dystrophy (LCA/EOSRD) caused by sequence variants in four genes, either not (n = 1) or very rarely (n = 3) previously associated with the disease. Methods Retrospective case series of LCA/EOSRD from four pedigrees. Chart review of clinical notes, multimodal retinal imaging, electrophysiology, and molecular genetic testing at a single tertiary referral center (Moorfields Eye Hospital, London, UK). Results The mean age of presentation was 3 months of age, with disease onset in the first year of life in all cases. Molecular genetic testing revealed the following disease-causing variants: PRPF8 (heterozygous c.5804G > A), PRPH2 (homozygous c.620_627delinsTA, novel variant), RP1 (homozygous c.4147_4151delGGATT, novel variant) and RPGR (heterozygous c.1894_1897delGACA). PRPF8, PRPH2, and RP1 variants have very rarely been reported, either as unique cases or case reports, with limited clinical data presented. RPGR variants have not previously been associated with LCA/EOSRD. Clinical history and detailed retinal imaging are presented. Conclusions The reported cases extend the phenotypic spectrum of PRPF8-, PRPH2-, RP1-, and RPGR-associated disease, and the genotypic spectrum of LCA/EOSRD. The study highlights the importance of retinal and functional phenotyping, and the importance of specific genetic diagnosis to potential future therapy.

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