Compound heterozygous LPIN2 pathogenic variants in a patient with Majeed syndrome with recurrent fever and severe neutropenia: case report

Abstract Background Majeed syndrome is a rare, autosomal recessive autoinflammatory disorder first described in 1989. The syndrome starts during infancy with recurrent relapses of osteomyelitis typically associated with fever, congenital dyserythropoietic anemia (CDA), and often neutrophilic dermatosis. Mutations in the LPIN2 gene located on the short arm of chromosome 18 have been identified as being responsible for Majeed syndrome. Case presentation We report an 8-month-old boy, who presented with recurrent fever, mild to moderate anemia, and severe neutropenia. Erythrocyte sedimentation rate and C-reactive protein were elevated. Molecular testing identified a paternal splicing donor site variant c.2327 + 1G > C and a maternal frameshift variant c.1691_1694delGAGA (Arg564Lysfs*3) in LPIN2. Conclusions Only a few cases with LPIN2 mutation have been reported, mainly in the Middle East with homozygous variants. Our patient exhibited a mild clinical phenotype and severe neutropenia, different from previous reports.

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Compound heterozygous LPIN2 pathogenic variants in a patient with Majeed syndrome with recurrent fever and severe neutropenia: case report

10.21203/rs.2.11655/v3 ◽

2019 ◽

Author(s):

jun liu ◽

Xu-Yun Hu ◽

Zhi-Peng Zhao ◽

Ruo-Lan Guo ◽

Jun Guo ◽

...

Keyword(s):

Donor Site ◽

Severe Neutropenia ◽

Recurrent Fever ◽

Neutrophilic Dermatosis ◽

Molecular Testing ◽

Compound Heterozygous ◽

Case Presentation ◽

Reactive Protein ◽

Pathogenic Variants ◽

Moderate Anemia

Abstract Background: Majeed syndrome is a rare, autosomal recessive autoinflammatory disorder first described in 1989. The syndrome starts during infancy with recurrent relapses of osteomyelitis typically associated with fever, congenital dyserythropoietic anemia (CDA), and often neutrophilic dermatosis. Mutations in the LPIN2 gene located on the short arm of chromosome 18 have been identified as being responsible for Majeed syndrome. Case presentation: We report an 8-month-old boy, who presented with recurrent fever, mild to moderate anemia, and severe neutropenia. Erythrocyte sedimentation rate and C-reactive protein were elevated. Molecular testing identified a paternal splicing donor site variant c.2327+1G>C and a maternal frameshift variant c.1691_1694delGAGA (Arg564Lysfs*3) in LPIN2. Conclusions: Only a few cases with LPIN2 mutation have been reported, mainly in the Middle East with homozygous variants. Our patient exhibited a mild clinical phenotype and severe neutropenia, different from previous reports.

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Compound heterozygous LPIN2 pathogenic variants in a Majeed Syndrome patient with recurrent fever and severe neutropenia: case report

10.21203/rs.2.11655/v1 ◽

2019 ◽

Author(s):

jun liu ◽

Xu-Yun Hu ◽

Zhi-Peng Zhao ◽

Ruo-Lan Guo ◽

Jun Guo ◽

...

Keyword(s):

Donor Site ◽

Severe Neutropenia ◽

Recurrent Fever ◽

Neutrophilic Dermatosis ◽

Compound Heterozygous ◽

Case Presentation ◽

Reactive Protein ◽

Pathogenic Variants ◽

Moderate Anemia ◽

Mild Clinical Phenotype

Abstract Background Majeed syndrome is a rare, autosomal recessive autoinflammatory disorder first described in 1989. The syndrome starts during infancy with recurrent relapses of osteomyelitis typically associated with fever, congenital dyserythropoietic anemia (CDA) and often neutrophilic dermatosis. Mutations in the LPIN2 gene located on the short arm of chromosome 18 have been identified as being responsible for the Majeed syndrome. Case presentation We report a 8-month old boy, who presented with recurrent fever, mild to moderate anemia and severe neutropenia. Erythrocyte sedimentation rate and C-reactive protein were elevated. Molecular studies identified a paternal splicing donor site variant c.2327+1G>C and a maternal frameshift variant c.1691_1694delGAGA (Arg564Lysfs*3)in LPIN2. Conclusions Up to now, only a few cases with LPIN2 mutation have been reported, mainly in the Middle East with homozygous variants. Our patient exhibited a mild clinical phenotype and severe neutropenia, distinct from previously reported.

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A man with recurrent fever, arthritis, and rashes-brucellosis? A case report

BMC Infectious Diseases ◽

10.1186/s12879-019-4746-0 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Wen Wang ◽

Xu Lu ◽

Chengbo Li ◽

Myong Jun Ri ◽

Wei Cui

Keyword(s):

Infectious Disease ◽

Bone Marrow ◽

Case Report ◽

Myelodysplastic Syndrome ◽

Skin Biopsy ◽

Rare Case ◽

Glucocorticoid Therapy ◽

Recurrent Fever ◽

Neutrophilic Dermatosis ◽

Case Presentation

Abstract Background We report a rare case of chronic brucellosis accompanied with myelodysplastic syndrome and neutrophilic dermatosis, which to the best of our knowledge, has never been reported. Case presentation A young man was admitted to our hospital complaining of recurrent fever, arthritis, rashes and anemia. He had been diagnosed with brucellosis 6 years prior and treated with multiple courses of antibiotics. He was diagnosed with myelodysplastic syndrome and neutrophilic dermatosis following bone marrow puncture and skin biopsy. After anti-brucellosis treatment and glucocorticoid therapy, the symptoms improved. Conclusions Clinicians should consider noninfectious diseases when a patient who has been diagnosed with an infectious disease exhibits changing symptoms.

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A novel USH2A variant in a patient with hearing loss and prenatal diagnosis of a familial fetus: a case report

BMC Medical Genomics ◽

10.1186/s12920-021-01052-4 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Cong Zhou ◽

Yuanyuan Xiao ◽

Hanbing Xie ◽

Shanling Liu ◽

Jing Wang

Keyword(s):

Hearing Loss ◽

Prenatal Diagnosis ◽

Usher Syndrome ◽

Chinese Patient ◽

Compound Heterozygous ◽

Case Presentation ◽

Pathogenic Variants ◽

Compound Heterozygous Variants ◽

Gene Panels

Abstract Background Usher syndrome (USH) is the most common cause of inherited deaf-blindness. The current study aimed to identify pathogenic variants in a Chinese patient with hearing loss and to report the identification of a novel p.(Phe1583Leufs*10) variant in USH2A, which met the needs of prenatal diagnosis of the patient's mother. Case presentation Genomic DNA obtained from a five-year-old girl with hearing loss was analyzed via the hearing loss-targeted gene panels. We identified the compound heterozygous variants c.8559-2A>G and c.4749delT in Usher syndrome type 2A (USH2A) gene as the underlying cause of the patient; the former variation has been reported in the literature, but not the latter. The parents of the girl were heterozygous carriers. The two variants were classified as pathogenic. Based on these findings, amniotic fluid samples were used for prenatal diagnosis of the couple's fetus, which was found to carry c.4749delT but not c.8559-2A>G variation. During the follow-up period of more than 9 months after the birth of the fetus, it was confirmed that the infant was healthy. Conclusions The results of the present study identified two compound heterozygous USH2A variants in a patient with hearing loss and reported a novel USH2A variant which expands the spectrum of USH2A variants in USH.

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Spectrum of MEFV Variants and Genotypes among Clinically Diagnosed FMF Patients from Southern Lebanon

Medical Sciences ◽

10.3390/medsci8030035 ◽

2020 ◽

Vol 8 (3) ◽

pp. 35

Author(s):

Ali El Roz ◽

Ghassan Ghssein ◽

Batoul Khalaf ◽

Taher Fardoun ◽

José-Noel Ibrahim

Keyword(s):

Autosomal Recessive ◽

Mefv Gene ◽

Allele Frequencies ◽

Molecular Testing ◽

Compound Heterozygous ◽

Pathogenic Variants ◽

South Lebanon ◽

Auto Inflammatory Disease ◽

Mediterranean Fever ◽

The Mean

Background: Familial Mediterranean Fever (FMF) is an autosomal recessive auto-inflammatory disease characterized by pathogenic variants in the MEFV gene, with allele frequencies greatly varying between countries, populations and ethnic groups. Materials and methods: In order to analyze the spectrum of MEFV variants and genotypes among clinically diagnosed FMF patients from South Lebanon, data were collected from 332 participants and 23 MEFV variants were screened using a Real-Time PCR Kit. Results: The mean age at symptom onset was 17.31 ± 13.82 years. The most prevalent symptoms were abdominal pain, fever and myalgia. MEFV molecular analysis showed that 111 patients (63.79%) were heterozygous, 16 (9.20%) were homozygous, and 47 (27.01%) carried two variants or more. E148Q was the most encountered variant among heterozygous subjects. E148Q/M694V was the most frequent in the compound heterozygous/complex genotype group, while M694I was the most common among homozygous patients. Regarding allele frequencies, M694V was the most common variant (20.7%), followed by E148Q (17.1%), V726A (15.7%) and M694I (13.2%). Conclusion: The high percentage of heterozygous patients clinically diagnosed as FMF highlights the pseudo-dominant transmission of the disease in Lebanon and emphasizes the importance of molecular testing for a more accurate diagnosis and better management and treatment of FMF.

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Infantile fever-triggered acute liver failure caused by novel neuroblastoma amplified sequence mutations: a case report

BMC Gastroenterology ◽

10.1186/s12876-020-01451-4 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Weiran Li ◽

Yu Zhu ◽

Qin Guo ◽

Chaomin Wan

Keyword(s):

Liver Failure ◽

Acute Liver Failure ◽

Complete Recovery ◽

Recurrent Fever ◽

Compound Heterozygous ◽

Intravenous Glucose ◽

Case Presentation ◽

Genetic Sequencing ◽

Chinese Girl ◽

Antipyretic Treatment

Abstract Background Infantile liver failure syndrome-2 (ILFS2) is caused by neuroblastoma amplified sequence (NBAS) mutation. The disease is characterized by recurrent episodes of acute liver failure (ALF) or by liver crisis triggered by recurrent episodes of fever and complete recovery. Case presentation Here, we describe the case of a Chinese girl with typical clinical manifestation of ILFS2 without exhibition of extrahepatic involvement. The patient harbored novel compound heterozygous mutations in the NBAS region (c.3386C > T (p.Ser1129Phe), c.1A > C (p.Met1Leu) and c.875G > A (p.Gly292Glu)), mutations which have not been previously reported. After administration of antipyretics and intravenous glucose and electrolyte administration, the patient recovered fully. Conclusion Through the present study, we recommend that ILFS2 should be taken into consideration during the differential diagnosis of children with recurrent, fever-triggered ALF. While the definitive diagnosis of ILFS2 remains dependent on genetic sequencing and discovery of NBAS, early antipyretic treatment is recommended to prevent liver crisis.

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Case Report: Compound Heterozygous Variants of SLC13A3 Identified in a Chinese Patient With Acute Reversible Leukoencephalopathy and α-Ketoglutarate Accumulation

Frontiers in Pediatrics ◽

10.3389/fped.2021.801719 ◽

2021 ◽

Vol 9 ◽

Author(s):

Qingyun Kang ◽

Liming Yang ◽

Hongmei Liao ◽

Sai Yang ◽

Haiyang Yang ◽

...

Keyword(s):

Plasma Membrane ◽

Case Report ◽

Chinese Patient ◽

Compound Heterozygous ◽

Genetic Studies ◽

Case Presentation ◽

Pathogenic Variants ◽

Chinese Girl ◽

Febrile Episodes ◽

Compound Heterozygous Variants

Background:SLC13A3 gene encodes the Na+/dicarboxylate cotransporter 3 (NaDC3), which locates on the plasma membrane and is mainly expressed in kidney, astrocytes and the choroid plexus. It imports four to six carbon dicarboxylates together with three Na+ ions into the cytosol. Nowadays, pathogenic variants of SLC13A3 gene were found to cause acute reversible leukoencephalopathy and α-ketoglutarate accumulation (ARLIAK) in patients. Here, we report two novel SLC13A3 variants c.185C>T (p.T62M) and c.331C>T (p.R111*) identified in a Chinese patient with ARLIAK.Case Presentation: The patient was a Chinese girl aged 13 years and 7 months old, who had acute, recurrent neurological deterioration during two febrile episodes. She presented with reversible leukoencephalopathy and increased urinary excretion of α-ketoglutarate. Genetic studies revealed compound heterozygous variants (c.185C>T, p.T62M, and c.331C>T, p.R111*) in SLC13A3, which had not been reported previously.Conclusions: These findings expand the variant spectrum of SLC13A3, providing the basis for the further study of this rare disease.

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Prenatal findings of cataract and arthrogryposis: recurrence of cerebro-oculo-facio-skeletal syndrome and review of differential diagnosis

BMC Medical Genomics ◽

10.1186/s12920-021-00939-6 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Fabio Sirchia ◽

Ilaria Fantasia ◽

Agnese Feresin ◽

Elisa Giorgio ◽

Flavio Faletra ◽

...

Keyword(s):

Differential Diagnosis ◽

Growth Failure ◽

Recurrence Risk ◽

Flow Chart ◽

Molecular Testing ◽

Compound Heterozygous ◽

Genetic Investigation ◽

Diagnostic Features ◽

Case Presentation ◽

First Case

Abstract Background Cerebro-oculo-facio-skeletal syndrome (COFS) is a severe and progressive neurologic condition characterized by prenatal onset of arthrogryposis, cataract, microcephaly and growth failure. The aim of this study was to present a case of recurrence of the COFS syndrome and to propose a differential diagnosis flow-chart in case of prenatal findings of arthrogryposis and cataract. Case presentation We report a case of recurrence of COFS3 syndrome within the same family, with similar diagnostic features. In the first case the COFS syndrome remained undiagnosed, while in the second case, due to prenatal findings of arthrogryposis and cataract, genetic investigation focusing on responsible genes of COFS (ERCC5, ERCC6 and FKTN genes) was carried out. The fetus was found to be compound heterozygous for two different ERCC5 mutations, confirming the clinical suspect of COFS syndrome. A review of the literature on possible causative genes of prenatal cataract and arthrogryposis was performed and we present a flow-chart to guide differential diagnosis and possible genetic testing in case of these findings. Conclusion COFS syndrome is a rare autosomic recessive condition. However, it can be suspected and diagnosed prenatally. The flow-chart illustrates a pathway to guide differential diagnosis according to the prenatal findings. Main syndromes, key testing and specific genes are included. Targeted molecular testing should be offered to the couple in order to reach a diagnosis and assess the recurrence risk for future pregnancies.

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Bi-allelic variants in MTMR5/SBF1 cause Charcot-Marie-Tooth type 4B3 featuring mitochondrial dysfunction

BMC Medical Genomics ◽

10.1186/s12920-021-01001-1 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Beatrice Berti ◽

Giovanna Longo ◽

Francesco Mari ◽

Stefano Doccini ◽

Ilaria Piccolo ◽

...

Keyword(s):

Intellectual Disability ◽

Mitochondrial Dysfunction ◽

Early Onset ◽

Integrated Approach ◽

Compound Heterozygous ◽

Charcot Marie Tooth ◽

Charcot Marie Tooth Disease ◽

Pathogenic Variants ◽

First Case ◽

Spine Mri

Abstract Background Charcot-Marie-Tooth disease (CMT) type 4B3 (CMT4B3) is a rare form of genetic neuropathy associated with variants in the MTMR5/SBF1 gene. MTMR5/SBF1 is a pseudophosphatase predicted to regulate endo-lysosomal trafficking in tandem with other MTMRs. Although almost ubiquitously expressed, pathogenic variants primarily impact on the peripheral nervous system, corroborating the involvement of MTMR5/SBF1 and its molecular partners in Schwann cells-mediated myelinization. Case presentation We report a case of severe CMT4B3 characterized by early-onset motor and axonal polyneuropathy in an Italian child in absence of any evidence of brain and spine MRI abnormalities or intellectual disability and with a biochemical profile suggestive of mitochondrial disease. Using an integrated approach combining both NGS gene panels and WES analysis, we identified two novel compound heterozygous missense variants in MTMR5/SBF1 gene, p.R763H (c.2291G > A) and p.G1064E (c.3194G > A). Studies in muscle identified partial defects of oxidative metabolism. Conclusion We describe the first case of an early onset severe polyneuropathy with motor and axonal involvement, due to recessive variants in the MTMR5/SBF1 gene, with no evidence of brain and spine MRI abnormalities, intellectual disability, no clinical and neurophysiological evidences of distal sensory impairment, and rapid neuromuscular deterioration. This report suggests that MTMR5/SBF1 should be considered in cases of infantile-onset CMT with secondary mitochondrial dysfunction.

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