Multiple congenital contractures (MCC) comprise a number of rare, non-progressive conditions disp... more Multiple congenital contractures (MCC) comprise a number of rare, non-progressive conditions displaying marked phenotypic and etiologic heterogeneity. A genetic cause can be established in approximately half of the affected individuals, attributed to genetic defects in the formation and functioning of the central and peripheral nervous system, neuromuscular junctions, skeletal muscles, and connective tissue. USP14 encodes a major proteasome-associated deubiquitinating enzyme with an established dual role as an inhibitor and an activator of proteolysis, maintaining protein homeostasis. Usp14-deficient mice show a phenotype similar to lethal human MCC phenotypes, with callosal anomalies, muscle wasting, and early lethality, attributed to neuromuscular junction defects due to decreased monomeric ubiquitin pool. We describe a new, autosomal recessive MCC phenotype in three fetuses from two different branches of a consanguineous family, presenting with distal arthrogryposis, underdevelopment of the corpus callosum, and dysmorphic facial features. Exome sequencing identified a biallelic 4-bp deletion (c.233_236delTTCC;p.Leu78Glnfs*11, SCV002028347) in USP14, and sequencing of family members showed segregation with the phenotype. RT-qPCR experiment in an unaffected heterozygote revealed that mutant USP14 was expressed, indicating that abnormal transcript escapes nonsense-mediated mRNA decay. We propose that herein described fetuses represent the first human phenotype of USP14 loss, with callosal anomalies and/or cortical malformations, multiple contractures, and recognizable dysmorphic facial features. This article is protected by copyright. All rights reserved.
DOI : 10.26650/IUITFD.427250 Amac : Radiyal isin defektleri (RID) 1/30.000 prevalansi ile ust eks... more DOI : 10.26650/IUITFD.427250 Amac : Radiyal isin defektleri (RID) 1/30.000 prevalansi ile ust ekstremitenin en sik gozlenen konjenital anomalisidir. Olgularin yaklasik %30’unda RID izole olarak, %70’inde ek anomaliler veya sendromlar ile birlikte gozlenir. Bu nedenle, olgularda taninin kesinlesmesi, izlemi, ailelere ozgun genetik danisma verilmesi ve sonraki gebeliklerinde prenatal tani seceneginin sunulabilmesi icin onemlidir. Bu calisma ile RID olgularinin ayirici tanisinda yol gosterici olmasi, molekuler taniya katki saglamasi amaciyla yeni nesil dizileme (YND) gen-paneli olusturuldu ve panelin molekuler tanidaki etkinligi arastirildi. Gerec ve Yontem : Bu calismada, 2004-2014 yillari arasinda klinigimizde RID bulgusu ile degerlendirilen 37 aileden 48 etkilenmis olgunun klinik, molekuler ve sitogenetik bulgulari degerlendirildi. Karyotipi normal saptanan ve molekuler tanisi olmayan 31 ailenin indeks olgusunda 14 farkli fenotip ile iliskili 43 gen, RID icin tasarladigimiz hedefe ...
An 8-month-old male infant was brought to the outpatient clinic having experienced 5 days of feve... more An 8-month-old male infant was brought to the outpatient clinic having experienced 5 days of fever, coughing, and diarrhea following craniosynostosis surgery. In the prenatal period, he was monitored for right hydroureteronephrosis. He was born to nonconsanguineous healthy parents at 38 weeks of gestation with a weight of 3.6 kg, height of 51 cm, and head circumference of 37 cm. Postnatally, he was monitored in the neonatal intensive care unit (NICU) for extensive weight loss and acute kidney failure with a serum creatinine level of 3 mg/dL. He was found to have hyperkalemia (7.1 mmol/L) and hyperphosphatemia (10.1 mg/dL) during this period. A urinary ultrasonography (USG) showed bilateral small hyperechogenic kidneys, multiple millimetric punctuate, echogenic foci, decreased corticomedullary differentiation in renal parenchyma, right hydroureteronephrosis, and increased thickness of the bladder wall. Therefore, voiding cystourethrography (VCUG) was performed with the pre-diagnosis of posterior urethral valves (PUV), revealing enlarged posterior urethra and bladder wall irregularities, with no evidence of vesicoureteral reflux (VUR). He was diagnosed with type 1 PUV in the proceeding cystoscopy. After PUV ablation and 10 days of hospitalization, the creatinine values progressively improved (0.64 mg/dL). However, during the follow-up period, hypercalcemia developed (11.5 mg/dL) and hyperphosphatemia persisted. Before this admission, he had undergone a cranioplasty due to craniosynostosis and plagiocephaly. After the surgery, he had a persistent fever, cough, and diarrhea for 5 days. At the time of admission, he appeared to be in a good state of health. Body temperature was 38.5 °C, pulse 130 beats/min, blood pressure 95/50 mmHg, and respiratory rate 32 breaths/min. His body weight was 8 kg (41p), height 71 cm (17p), and head circumference 48.3 cm (95p). Scalp edema was present on the right frontal and parietal regions of the head; otherwise, the physical examination findings were normal. The laboratory work-up showed a leukocyte count of 13.700/mm3 with 41% polymorphonuclear leukocytes, hemoglobin 10.7 g/dL, serum creatinine 0.66 mg/dL, sodium 134 mmol/L (N 136–145 mmol/L), potassium 4.3 mmol/L (N 3.5–4.5 mmol/L), calcium 11.4 mg/dL (N 9.0–11.0), phosphorus 5.9 mg/dL (N 3.5–6.6), ALP 38 IU/L (N 83–469), CRP 43 mg/L (N < 4 mg/L), and procalcitonin 2.38 ng/mL (N < 2 ng/mL). The estimated glomerular filtration rate (eGFR) was calculated as 44 mL/min/1.73 m using the modified Schwartz formula. Additionally, the level of parathyroid hormone was 37 pg/ mL (N 15–65), 25-OH Vitamin D 65 ng/mL (mildly increased, N 20–50 ng/mL), and urinary calcium excretion 289 mg/g (N 30–810). Urinalysis and stool microscopy were normal. Apart from testing positive for rotavirus, the viral serologies were negative. After intravenous The answers to these questions can be found at https://doi.org/10.1007/ s00467-020-04666-5
Amaç: Sendromik (SCS) ve non-sendromik kraniyosinostozlu (NSCS) olgularda, kraniyosinostoz tipler... more Amaç: Sendromik (SCS) ve non-sendromik kraniyosinostozlu (NSCS) olgularda, kraniyosinostoz tipleriyle ilişkilendirilmiş genlerde (FGFR1-3, TWIST1, MSX2, POR, FREM1 ve RAB23) mutasyonların araştırılması ve moleküler genetik tanı için akılcı bir akış şeması oluşturulması. Gereç ve Yöntem: İstanbul Üniversitesi, İstanbul Tıp Fakültesi, Tıbbi Genetik AD'da kromozom anomalisi dışlanmış, altısı prenatal ve 34'ü postnatal tanı alan, dokuzu NSCS ve 31'i SCS toplam 40 olgu ile 34 sağlıklı ebeveyn çalışmamıza dahil edildi. SCS'li olguların dokuzu Pfeiffer (PS), altısı Crouzon (CRS), beşi Apert (AS), yedisi Saethre-Chotzen (SaCS) ve dördü Muenke (MUS)/Saethre Chotzen (SaCS) idi. Kraniyosinostoz tipine göre mutasyonların en sık gözlendiği gen/ekzon bölgelerinden başlanarak, tüm gen ve ilişkili diğer genler aşamalı olarak Sanger dizileme yöntemi ile incelendi. Mutasyon saptanmayan olgularda incelenen genlerdeki büyük delesyon ve duplikasyonlar Multiplex Ligation-depended Probe Amplification (MLPA) yöntemi ile araştırıldı. Bulgular: Olgularımızın %50'sinde dizi analizi ile ve %2,5'unda MLPA yöntemi ile klinik bulguları destekleyen moleküler genetik sonuçlara ulaşıldı. Moleküler tanı oranı SCS grubunda %64,5, NSCS grubunda %11,1 oldu. Sonuç: Sendromik olgularda moleküler tanı oranı seri ortalamasının üzerinde idi. Birinci basamakta FGFR2 geni ekzon 7-8'de olası mutasyonlar dışlandıktan sonra, ikinci basamaktaki hedef ekzonlara (3, 5, 11, 14-17) ekzon 12 ve 13'ün ilavesi PS'de mutasyon saptama oranını %33 arttırdı. Çalışmamız, moleküler tanı alan ailelere özgün genetik danışma olanağı sağladı. CS olgularında izlenen akış şemasında Sanger dizileme ile 1. ve 2. basamak testlerden sonra mutasyon saptanmayan olguların yeni nesil dizileme tekniği ile klinik ekzom ve yüksek çözünürlüklü mikroarray çalışmasına alınmasının uygun olacağına karar verildi.
The Journal of steroid biochemistry and molecular biology, 2018
Congenital adrenal hyperplasia (CAH) due to 11β-hydroxylase deficiency (11BOHD) is a rare autosom... more Congenital adrenal hyperplasia (CAH) due to 11β-hydroxylase deficiency (11BOHD) is a rare autosomal recessive disorder and the second most common form of CAH. To investigate genotype-phenotype correlation and to evaluate clinical characteristics and long-term outcomes of patients with 11BOHD. A total of 28 patients (n = 14, 46,XX; n = 14, 46,XY) with classical 11BOHD from 25 unrelated families were included in this study. Screening of CYP11B1 is performed by Sanger sequencing. Pathogenic features of novel variants are investigated by the use of multiple in silico prediction tools and with family based co-segregation studies. Protein simulations were investigated for two novel coding region alterations. The age at diagnosis ranged from 6 days to 12.5 years. Male patients received diagnose at older ages than female patients. The rate of consanguinity was high (71.4%). Five out of nine 46,XX patients were diagnosed late (age 2-8.7 years) and were assigned as male due to severe masculin...
Journal of clinical research in pediatric endocrinology, Jan 29, 2018
17-α-hydroxylase/17,20 lyase deficiency (17OHD) is a rare form of congenital adrenal hyperplasia ... more 17-α-hydroxylase/17,20 lyase deficiency (17OHD) is a rare form of congenital adrenal hyperplasia (CAH), characterized by hypertension and varying degrees of ambiguous genitalia and delayed pu-berty. The disease is associated with bi-allelic mutations in the gene located on chromosome 10q24.3. We aimed to present clinical and genetic findings and follow-up and treatment of 17-OHD patients. We evaluated six patients with 17OHD from five families at presentation and at follow up. Standard deviation score of all auxological measurements was calculated according to national data and karyotype status. gene sequence alterations were investigated in all of the patients. The mean age of patients at presentation was 14.6±4.2 years and mean follow-up time was 5.0±2.7 years. Five patients were referred to us because of delayed puberty and primary amenorrhea and four for hypertension. One novel single nucleotide insertion leading to frame shift and another ultra rare nucleotide alteration leadin...
Multiple congenital contractures (MCC) comprise a number of rare, non-progressive conditions disp... more Multiple congenital contractures (MCC) comprise a number of rare, non-progressive conditions displaying marked phenotypic and etiologic heterogeneity. A genetic cause can be established in approximately half of the affected individuals, attributed to genetic defects in the formation and functioning of the central and peripheral nervous system, neuromuscular junctions, skeletal muscles, and connective tissue. USP14 encodes a major proteasome-associated deubiquitinating enzyme with an established dual role as an inhibitor and an activator of proteolysis, maintaining protein homeostasis. Usp14-deficient mice show a phenotype similar to lethal human MCC phenotypes, with callosal anomalies, muscle wasting, and early lethality, attributed to neuromuscular junction defects due to decreased monomeric ubiquitin pool. We describe a new, autosomal recessive MCC phenotype in three fetuses from two different branches of a consanguineous family, presenting with distal arthrogryposis, underdevelopment of the corpus callosum, and dysmorphic facial features. Exome sequencing identified a biallelic 4-bp deletion (c.233_236delTTCC;p.Leu78Glnfs*11, SCV002028347) in USP14, and sequencing of family members showed segregation with the phenotype. RT-qPCR experiment in an unaffected heterozygote revealed that mutant USP14 was expressed, indicating that abnormal transcript escapes nonsense-mediated mRNA decay. We propose that herein described fetuses represent the first human phenotype of USP14 loss, with callosal anomalies and/or cortical malformations, multiple contractures, and recognizable dysmorphic facial features. This article is protected by copyright. All rights reserved.
DOI : 10.26650/IUITFD.427250 Amac : Radiyal isin defektleri (RID) 1/30.000 prevalansi ile ust eks... more DOI : 10.26650/IUITFD.427250 Amac : Radiyal isin defektleri (RID) 1/30.000 prevalansi ile ust ekstremitenin en sik gozlenen konjenital anomalisidir. Olgularin yaklasik %30’unda RID izole olarak, %70’inde ek anomaliler veya sendromlar ile birlikte gozlenir. Bu nedenle, olgularda taninin kesinlesmesi, izlemi, ailelere ozgun genetik danisma verilmesi ve sonraki gebeliklerinde prenatal tani seceneginin sunulabilmesi icin onemlidir. Bu calisma ile RID olgularinin ayirici tanisinda yol gosterici olmasi, molekuler taniya katki saglamasi amaciyla yeni nesil dizileme (YND) gen-paneli olusturuldu ve panelin molekuler tanidaki etkinligi arastirildi. Gerec ve Yontem : Bu calismada, 2004-2014 yillari arasinda klinigimizde RID bulgusu ile degerlendirilen 37 aileden 48 etkilenmis olgunun klinik, molekuler ve sitogenetik bulgulari degerlendirildi. Karyotipi normal saptanan ve molekuler tanisi olmayan 31 ailenin indeks olgusunda 14 farkli fenotip ile iliskili 43 gen, RID icin tasarladigimiz hedefe ...
An 8-month-old male infant was brought to the outpatient clinic having experienced 5 days of feve... more An 8-month-old male infant was brought to the outpatient clinic having experienced 5 days of fever, coughing, and diarrhea following craniosynostosis surgery. In the prenatal period, he was monitored for right hydroureteronephrosis. He was born to nonconsanguineous healthy parents at 38 weeks of gestation with a weight of 3.6 kg, height of 51 cm, and head circumference of 37 cm. Postnatally, he was monitored in the neonatal intensive care unit (NICU) for extensive weight loss and acute kidney failure with a serum creatinine level of 3 mg/dL. He was found to have hyperkalemia (7.1 mmol/L) and hyperphosphatemia (10.1 mg/dL) during this period. A urinary ultrasonography (USG) showed bilateral small hyperechogenic kidneys, multiple millimetric punctuate, echogenic foci, decreased corticomedullary differentiation in renal parenchyma, right hydroureteronephrosis, and increased thickness of the bladder wall. Therefore, voiding cystourethrography (VCUG) was performed with the pre-diagnosis of posterior urethral valves (PUV), revealing enlarged posterior urethra and bladder wall irregularities, with no evidence of vesicoureteral reflux (VUR). He was diagnosed with type 1 PUV in the proceeding cystoscopy. After PUV ablation and 10 days of hospitalization, the creatinine values progressively improved (0.64 mg/dL). However, during the follow-up period, hypercalcemia developed (11.5 mg/dL) and hyperphosphatemia persisted. Before this admission, he had undergone a cranioplasty due to craniosynostosis and plagiocephaly. After the surgery, he had a persistent fever, cough, and diarrhea for 5 days. At the time of admission, he appeared to be in a good state of health. Body temperature was 38.5 °C, pulse 130 beats/min, blood pressure 95/50 mmHg, and respiratory rate 32 breaths/min. His body weight was 8 kg (41p), height 71 cm (17p), and head circumference 48.3 cm (95p). Scalp edema was present on the right frontal and parietal regions of the head; otherwise, the physical examination findings were normal. The laboratory work-up showed a leukocyte count of 13.700/mm3 with 41% polymorphonuclear leukocytes, hemoglobin 10.7 g/dL, serum creatinine 0.66 mg/dL, sodium 134 mmol/L (N 136–145 mmol/L), potassium 4.3 mmol/L (N 3.5–4.5 mmol/L), calcium 11.4 mg/dL (N 9.0–11.0), phosphorus 5.9 mg/dL (N 3.5–6.6), ALP 38 IU/L (N 83–469), CRP 43 mg/L (N < 4 mg/L), and procalcitonin 2.38 ng/mL (N < 2 ng/mL). The estimated glomerular filtration rate (eGFR) was calculated as 44 mL/min/1.73 m using the modified Schwartz formula. Additionally, the level of parathyroid hormone was 37 pg/ mL (N 15–65), 25-OH Vitamin D 65 ng/mL (mildly increased, N 20–50 ng/mL), and urinary calcium excretion 289 mg/g (N 30–810). Urinalysis and stool microscopy were normal. Apart from testing positive for rotavirus, the viral serologies were negative. After intravenous The answers to these questions can be found at https://doi.org/10.1007/ s00467-020-04666-5
Amaç: Sendromik (SCS) ve non-sendromik kraniyosinostozlu (NSCS) olgularda, kraniyosinostoz tipler... more Amaç: Sendromik (SCS) ve non-sendromik kraniyosinostozlu (NSCS) olgularda, kraniyosinostoz tipleriyle ilişkilendirilmiş genlerde (FGFR1-3, TWIST1, MSX2, POR, FREM1 ve RAB23) mutasyonların araştırılması ve moleküler genetik tanı için akılcı bir akış şeması oluşturulması. Gereç ve Yöntem: İstanbul Üniversitesi, İstanbul Tıp Fakültesi, Tıbbi Genetik AD'da kromozom anomalisi dışlanmış, altısı prenatal ve 34'ü postnatal tanı alan, dokuzu NSCS ve 31'i SCS toplam 40 olgu ile 34 sağlıklı ebeveyn çalışmamıza dahil edildi. SCS'li olguların dokuzu Pfeiffer (PS), altısı Crouzon (CRS), beşi Apert (AS), yedisi Saethre-Chotzen (SaCS) ve dördü Muenke (MUS)/Saethre Chotzen (SaCS) idi. Kraniyosinostoz tipine göre mutasyonların en sık gözlendiği gen/ekzon bölgelerinden başlanarak, tüm gen ve ilişkili diğer genler aşamalı olarak Sanger dizileme yöntemi ile incelendi. Mutasyon saptanmayan olgularda incelenen genlerdeki büyük delesyon ve duplikasyonlar Multiplex Ligation-depended Probe Amplification (MLPA) yöntemi ile araştırıldı. Bulgular: Olgularımızın %50'sinde dizi analizi ile ve %2,5'unda MLPA yöntemi ile klinik bulguları destekleyen moleküler genetik sonuçlara ulaşıldı. Moleküler tanı oranı SCS grubunda %64,5, NSCS grubunda %11,1 oldu. Sonuç: Sendromik olgularda moleküler tanı oranı seri ortalamasının üzerinde idi. Birinci basamakta FGFR2 geni ekzon 7-8'de olası mutasyonlar dışlandıktan sonra, ikinci basamaktaki hedef ekzonlara (3, 5, 11, 14-17) ekzon 12 ve 13'ün ilavesi PS'de mutasyon saptama oranını %33 arttırdı. Çalışmamız, moleküler tanı alan ailelere özgün genetik danışma olanağı sağladı. CS olgularında izlenen akış şemasında Sanger dizileme ile 1. ve 2. basamak testlerden sonra mutasyon saptanmayan olguların yeni nesil dizileme tekniği ile klinik ekzom ve yüksek çözünürlüklü mikroarray çalışmasına alınmasının uygun olacağına karar verildi.
The Journal of steroid biochemistry and molecular biology, 2018
Congenital adrenal hyperplasia (CAH) due to 11β-hydroxylase deficiency (11BOHD) is a rare autosom... more Congenital adrenal hyperplasia (CAH) due to 11β-hydroxylase deficiency (11BOHD) is a rare autosomal recessive disorder and the second most common form of CAH. To investigate genotype-phenotype correlation and to evaluate clinical characteristics and long-term outcomes of patients with 11BOHD. A total of 28 patients (n = 14, 46,XX; n = 14, 46,XY) with classical 11BOHD from 25 unrelated families were included in this study. Screening of CYP11B1 is performed by Sanger sequencing. Pathogenic features of novel variants are investigated by the use of multiple in silico prediction tools and with family based co-segregation studies. Protein simulations were investigated for two novel coding region alterations. The age at diagnosis ranged from 6 days to 12.5 years. Male patients received diagnose at older ages than female patients. The rate of consanguinity was high (71.4%). Five out of nine 46,XX patients were diagnosed late (age 2-8.7 years) and were assigned as male due to severe masculin...
Journal of clinical research in pediatric endocrinology, Jan 29, 2018
17-α-hydroxylase/17,20 lyase deficiency (17OHD) is a rare form of congenital adrenal hyperplasia ... more 17-α-hydroxylase/17,20 lyase deficiency (17OHD) is a rare form of congenital adrenal hyperplasia (CAH), characterized by hypertension and varying degrees of ambiguous genitalia and delayed pu-berty. The disease is associated with bi-allelic mutations in the gene located on chromosome 10q24.3. We aimed to present clinical and genetic findings and follow-up and treatment of 17-OHD patients. We evaluated six patients with 17OHD from five families at presentation and at follow up. Standard deviation score of all auxological measurements was calculated according to national data and karyotype status. gene sequence alterations were investigated in all of the patients. The mean age of patients at presentation was 14.6±4.2 years and mean follow-up time was 5.0±2.7 years. Five patients were referred to us because of delayed puberty and primary amenorrhea and four for hypertension. One novel single nucleotide insertion leading to frame shift and another ultra rare nucleotide alteration leadin...
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