Aicardi-Goutières Syndrome due to a SAMHD1 Mutation Presenting with Deep White Matter Cysts.

We report on the first Polish patient diagnosed with the Aicardi-Goutières syndrome 5 (AGS5). AGS is caused by mutations in one of 9 genes (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, IFIH, LSM11, RNU7-1) which stimulate the type I interferon response. The diagnosis was confirmed by identifying a compound heterozygous mutation p.(Phe165Ser)/p.(Gln235*) in the SAMHD1 gene using whole-exome sequencing. The cystic lesions in the temporal lobes are an uncommon finding in the presented patient carrying a SAMHD1 mutation. Reporting new cases expands the range of phenotypes and plays the crucial role in understanding the AGS pathogenesis and creates new therapy approaches.

Targeted Next-Generation Sequencing in Diagnostic Approach to Monogenic Cholestatic Liver Disorders-Single-Center Experience.

Objective: To evaluate the clinical utility of panel-based NGS in the diagnostic approach of monogenic cholestatic liver diseases. Study design: Patients with diagnosis of chronic cholestatic liver disease of an unknown etiology underwent NGS of targeted genes panel. Group 1 included five patients (prospectively recruited) hospitalized from January to December 2017 while group 2 included seventeen patients (retrospectively recruited) hospitalized from 2010 to 2017 presenting with low-GGT PFIC phenotype (group 2a, 11 patients) or indeterminant cholestatic liver cirrhosis (group 2b, 6 patients). Results: Among 22 patients enrolled into the study, 21 various pathogenic variants (including 11 novel) in 5 different genes (including ABCB11, ABCB4, TJP2, DGUOK, CYP27A1) were identified. The molecular confirmation was obtained in 15 out of 22 patients (68%). In group 1, two out of five patients presented with low-GGT cholestasis, and were diagnosed with BSEP deficiency. Out of three patients presenting with high-GGT cholestasis, one patient was diagnosed with PFIC-3, and the remaining two were not molecularly diagnosed. In group 2a, seven out of eleven patients, were diagnosed with BSEP deficiency and two with TJP-2 deficiency. In group 2b, three out of six patients were molecularly diagnosed; one with PFIC-3, one with CYP27A1 deficiency, and one with DGUOK deficiency. Conclusions: Panel-based NGS appears to be a very useful tool in diagnosis of monogenic cholestatic liver disorders in cases when extrahepatic causes have been primarily excluded. NGS presented the highest diagnosis rate to identify the molecular background of cholestatic liver diseases presenting with a low-GGT PFIC phenotype.

Mild Zellweger syndrome due to functionally confirmed novel PEX1 variants.

Zellweger spectrum disorders (ZSD) constitute a group of rare autosomal recessive disorders characterized by a defect in peroxisome biogenesis due to mutations in one of 13 PEX genes. The broad clinical heterogeneity especially in late-onset presenting patients and a mild phenotype complicates and delays the diagnostic process. Here, we report a case of mild ZSD, due to novel PEX1 variants. The patient presented with an early hearing loss, bilateral cataracts, and leukodystrophy on magnetic resonance (MR) images. Normal results of serum very-long-chain fatty acids (VLCFA) and phytanic acid were found. Molecular diagnostics were performed to uncover the etiology of the clinical phenotype. Using whole exome sequencing, there have been found two variants in the PEX1 gene-c.3450T>A (p.Cys1150*) and c.1769T>C (p.Leu590Pro). VLCFA measurement in skin fibroblasts and C26:0-lysoPC in dried blood spot therefore was performed. Both results were in line with the diagnosis of ZSD. To conclude, normal results of routine serum VLCFA and branched-chain fatty acid measurement do not exclude mild forms of ZSD. The investigation of C26:0-lysoPC should be included in the diagnostic work-up in patients with cataract, hearing loss, and leukodystrophy on MR images suspected to suffer from ZSD.

Premature ovarian insufficiency as a variable feature of blepharophimosis, ptosis, and epicanthus inversus syndrome associated with c.223C > T p.(Leu75Phe) FOXL2 mutation: a case report.

BACKGROUND: FOXL2 gene mutations cause blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) and may be associated with premature ovarian insufficiency (POI). Two types of BPES were described in the literature. BPES type 2 is a simple association of inherited developmental defects of the eyelid area, while in type 1 female patients additionally suffer from POI. The following case study is the first report of endocrine impairments typical for menopausal transition in young female with NG_012454.1:g.138665342G > A, c.223C > T p.(Leu75Phe), mutation in FOXL2 gene. This mutation has been reported in the literature before, however until now, it was never linked to BPES type 1. CASE PRESENTATION: An 18-year-old nulliparous woman suspected of secondary amenorrhea was referred to our Endocrinology Outpatient Clinic. Blood tests revealed decreased levels of AMH (anti-Mullerian hormone) and increased levels of gonadotropins, suggesting menopausal transition. Her past medical history was remarkable for several ophthalmic defects that has required surgical interventions. BPES syndrome had not been suspected before, although the patient had reported a similar phenotype occurring in her father, sister and half-sister. Venous blood samples were collected from the female proband and from her three family members. Whole-exome sequencing and deep amplicon sequencing were performed. A potential pathogenic variant in the FOXL2 gene was revealed. Namely, the c.223C > T p.(Leu75Phe) missense variant was detected. CONCLUSIONS: The authors found mutations, c.223C > T p.(Leu75Phe) in the FOXL2 gene in a young woman with hormonal disorders suggesting menopausal transition. These results indicate that the possibility of different phenotypes should be considered in patients with a similar genetic mutation.