Alport Sendromu Hastalarının Klinik ve Genetik Özellikleri ile Aile Bireylerinin Bulgularının Değerlendirilmesi

Atan, R., Evaluation of clinical and genetic characteristics of Alport syndrome patients and family members, Hacettepe University Faculty of Medicine, Department of Pediatrics, Speciality Thesis in Pediatrics, Ankara, 2020. Alport syndrome is a rare, progressive, genetic glomerular disease consisting of hereditary nephritis, sensorineural hearing loss and ocular abnormalities. This study aimed to evaluate the findings of patients and family members who were followed-up with AS and to compare them with the literature. 45 patients who were followed-up with the diagnosis of AS in our hospital were included in the study. The data of the patients were evaluated retrospectively from the archive and the electronic medical records. Family history of patients, hearing, vision, kidney findings at admission and follow-up, and distribution of the findings according to heredity patterns, biopsy and genetic analysis results and recent findings of family members were examined. 26 (57.8%) of the patients had X-linked, 15 (33.3%) of them AR, 4 (8.9%) of them AD inheritance pattern. There were consanguinity among the parents of 23 patients. 39 patients had a history of kidney disease in their relatives and 8 patients were diagnosed with this reason. 10 patients (22.2%) had nephrotic and 26 patients (57.7%) had nephritic proteinuria at the first assesment. It was found that CKD developed during follow-up in 6 patients. The development age of CKD was determined as 16.8 years. The development rate of CKD (33.3%) was significantly higher in AR patients than in other forms of inheritance patterns. There is a significant relationship between progression CKD and the levels of proteinuria at the first assesment. The development rate of CKD (33.3%) was significantly higher in AR patients than in other forms of inheritance patterns. 4 patients with AD had no CKD or hearing loss. Hearing loss rate of AR patients (86.7%) was found to be statistically higher than X-linked patients (30.8%). The diagnosis of retinal pigment epithelium in two patients, anterior lenticonus in one patient and keratoconus in one patient was observed. Biopsy was performed in 30 patients. 17 patients were diagnosed with AS through kidney biopsy and 1 patient was diagnosed with AS through skin biopsy. 12 patients who were not compatible with AS, as a result of pathology, were found to be diagnosed through genetic studies. Out of 17 mothers with X-linked heterozygous, 13 (76.4%) were found to have hematuria, 9 (53%) were found to have proteinuria accompanying hematuria, and one was found to be in the CKD process. No one in the process of CKD or with a history of hearing loss was found in parents of AR patients. When the parents of four AD patients were examined, two fathers of them were found to have renal transplant and hearing loss. A total of six fathers were on follow-up after kidney transplantation. Four of them were the fathers of the X-linked heterozygous carrier girls. The other two were fathers of AD patients. Hearing loss was detected in ten siblings and eight of them were AR patients, two of them were brothers of X-linked patients. Hematuria and proteinuria were found in 21 siblings, and only hematuria was found in 3 siblings. It was learned that 2 siblings were on follow-up after kidney transplantation, 1 was on dialysis and 1 was on follow-up in the CKD process. Siblings with transplant and CKD are siblings of patients with X-linked and AR, as in our patients. As a result, AS can be presented in a wide range from hematuria and / or proteinuria to ESRD. Genetic testing is important in terms of early diagnosis and treatment since it can be diagnosed without the development of biopsy findings. Kidney disease can also be serious in female carriers with X-linked inheritance pattern. It is possible to diagnose earlier if the family has a history of kidney disease or sensorineural hearing loss. Therefore, it is important to evaluate and follow up individuals with no symptoms in this regard.Atan, R., Alport sendromu hastalarının klinik ve genetik özellikleri ile aile bireylerinin bulgularının değerlendirilmesi, Hacettepe Üniversitesi Tıp Fakültesi, Çocuk Sağlığı ve Hastalıkları Anabilim Dalı, Uzmanlık Tezi, Ankara, 2020. Alport sendromu; herediter nefrit, sensörinöral işitme kaybı ve oküler anormalliklerden oluşan nadir, ilerleyici, genetik bir glomerüler hastalıktır. Bu çalışmada AS ile takipli hastaların ve aile bireylerinin bulgularının değerlendirilmesi, literatürle karşılaştırılması amaçlanmıştır. Çalışmaya hastanemizde AS tanısı ile takipli olan 45 hasta dahil edilmiştir. Hastaların verileri arşiv ve bilgisayar sisteminden retrospektif olarak değerlendirilmiştir. Hastaların aile öyküleri, başvuru ve takipteki işitme, görme, böbrek bulguları ve bulguların kalıtım şekillerine göre durumu, biyopsi ve genetik analiz sonuçları, aile bireylerinin son durumları incelenmiştir. Hastaların 26’sı (%57,8) X’e bağlı, 15’i (%33,3) OR, 4’ü (%8,9) OD kalıtım göstermektedir. 23'ünün annesi ile babası arasında akrabalık mevcuttur. 39 hastanın akrabasında böbrek hastalığı öyküsü olduğu, 8 hastanın bu nedenle tanı aldığı görülmüştür. Başvuruda 10 hastada (%22,2) nefrotik, 26 hastada (%57,7) nefrotik düzeyde olmayan proteinüri görülmüştür. İzlemde 6 hastada (%13,3) ortalama 16,8 yaşında KBH geliştiği görülmüştür. Başvurudaki proteinüri düzeyi ile KBH arasında anlamlı ilişki mevcuttur. OR hastalarda KBH gelişim oranı (%33,3) diğer kalıtım şekillerinden anlamlı yüksek saptanmıştır. OD olan 4 hastada KBH ve işitme kaybı görülmemiştir. OR hastaların işitme kaybı oranının (%86,7), X’e bağlı hastalara (%30,8) göre istatistiksel olarak daha yüksek olduğu görülmüştür. Hastaların 2’sinde retina pigment epitel değişikliği, 1’inde anterior lentikonus, 1’inde keratokonus tanısı mevcuttur. Otuz hastaya biyopsi yapıldığı ve 17’sinin böbrek, 1’inin cilt biyopsisi ile AS tanısı aldığı görülmektedir. Patoloji sonucu AS ile uyumlu olmayan 12 hastanın genetik çalışma ile tanı aldığı görülmüştür. X’e bağlı heterozigot 17 annenin 13’ünde (%76,4) hematüri, 9’unda (%53) hematüriye eşlik eden proteinüri, 1'inin KBH sürecinde olduğu görülmüştür. OR hastaların anne ve babalarında KBH sürecinde olan, işitme kaybı öyküsü olan görülmemiştir. OD dört hastanın ebeveynlerine bakıldığında 2 babanın renal transplant ve işitme kaybı olduğu görülmüştür. 4’ü X’e bağlı kız taşıyıcı, 2’si OD hastaların babası olmak üzere toplamda 6 baba böbrek nakli sonrası takiptedir. On kardeşte işitme kaybı saptanmıştır ve 8’inin OR hastaların, 2’sinin X’e bağlı olan hastaların erkek kardeşi olduğu görülmüştür. Kardeşlerin 21’inde hematüri ve proteinüri, 3’ünde sadece hematüri saptanmıştır. 2’sinin nakil sonrası, 1’inin diyaliz, 1’inin KBH sürecinde takipte olduğu öğrenilmiştir. Nakil ve KBH olan kardeşler hastalarımızda olduğu gibi X'e bağlı ve OR olan hastaların kardeşleridir. Sonuç olarak AS, hematüri ve/veya proteinüriden SDBH’ye kadar geniş bir yelpazede prezente olabilmektedir. Genetik inceleme; biyopsi bulguları gelişmeden de tanı konulabilmesi nedeniyle erken tanı ve tedavi açısından önemlidir. X’ e bağlı taşıyıcı bireylerde de böbrek hastalığı ciddi olabilmektedir. Ailede böbrek hastalığı, sensörinöral işitme kaybı öyküsü alındığı durumlarda daha erken tanı konulması mümkündür bu nedenle semptomu olmayan bireylerin bu açıdan değerlendirilmesi ve takibi önemlidir

The outcomes of renin-angiotensin-aldosterone system inhibition and immunosuppressive therapy in children with X-linked Alport syndrome

Background. Alport syndrome (AS) is characterized by progressive kidney disease. There is increasing evidence that renin-angiotensin-aldosterone system (RAAS) inhibition delays chronic kidney disease (CKD) while the effectiveness of immunosuppressive (IS) therapy in AS is still uncertain. In this study, we aimed to analyze the outcomes of pediatric patients with X-linked AS (XLAS) who received RAAS inhibitors and IS therapy. Methods. Seventy-four children with XLAS were included in this multicenter study. Demographic features, clinical and laboratory data, treatments, histopathological examinations, and genetic analyses were analyzed retrospectively. Results. Among 74 children, 52 (70.2%) received RAAS inhibitors, 11 (14.9%) received RAAS inhibitors and IS, and 11 (14.9%) were followed up without treatment. During follow-up, glomerular filtration rate (GFR) decreased <60 ml/min/1.73 m2 in 7 (9.5%) of 74 patients (M/F=6/1). In male patients with XLAS, kidney survival was not different between RAAS and RAAS+IS groups (p=0.42). The rate of progression to CKD was significantly higher in patients with nephrotic range proteinuria and nephrotic syndrome (NS), respectively (p=0.006, p=0.05). The median age at the onset of RAAS inhibitors was significantly higher in male patients who progressed to CKD (13.9 vs 8.1 years, p=0.003). Conclusions. RAAS inhibitors have beneficial effects on proteinuria and early initiation of therapy may delay the progression to CKD in children with XLAS. There was no significant difference between the RAAS and RAAS+IS groups in kidney survival. AS patients presenting with NS or nephrotic range proteinuria should be followed up more carefully considering the risk of early progression to CKD

Genomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency.

Biallelic inactivating mutations in IL21R causes a combined immunodeficiency that is often complicated by cryptosporidium infections. While eight IL-21R-deficient patients have been reported previously, the natural course, immune characteristics of disease, and response to hematopoietic stem cell transplantation (HSCT) remain to be comprehensively examined. In our study, we have collected clinical histories of 13 patients with IL-21R deficiency from eight families across seven centers worldwide, including five novel patients identified by exome or NGS panel sequencing. Eight unique mutations in IL21R were identified in these patients, including two novel mutations. Median age at disease onset was 2.5 years (0.5-7 years). The main clinical manifestations were recurrent bacterial (84.6%), fungal (46.2%), and viral (38.5%) infections; cryptosporidiosis-associated cholangitis (46.2%); and asthma (23.1%). Inflammatory skin diseases (15.3%) and recurrent anaphylaxis (7.9%) constitute novel phenotypes of this combined immunodeficiency. Most patients exhibited hypogammaglobulinemia and reduced proportions of memory B cells, circulating T follicular helper cells, MAIT cells and terminally differentiated NK cells. However, IgE levels were elevated in 50% of IL-21R-deficient patients. Overall survival following HSCT (6 patients, mean follow-up 1.8 year) was 33.3%, with pre-existing organ damage constituting a negative prognostic factor. Mortality of non-transplanted patients (n = 7) was 57.1%. Our detailed analysis of the largest cohort of IL-21R-deficient patients to date provides in-depth clinical, immunological and immunophenotypic features of these patients, thereby establishing critical non-redundant functions of IL-21/IL-21R signaling in lymphocyte differentiation, humoral immunity and host defense against infection, and mechanisms of disease pathogenesis due to IL-21R deficiency. Outcome following HSCT depends on prior chronic infections and organ damage, which should thus be considered as early as possible following molecular diagnosis