Ihsan Turan

Complete Idiopathic Hypogonadotropic Hypogonadism due to Homozygous GNRH1 Mutations in the Mutational Hot Spots in the Region Encoding the Decapeptide

Introduction: Mutations of the human GNRH1 gene are an extremely rare cause of normosmic idiopathic hypogonadotropic hypogonadism (nIHH), with only 6 mutations so far described. Patients: As part of a larger study, families with IHH were screened for mutations in genes known to be associated with IHH. In family 1, a 15-year and 9-month-old boy first presented during infancy with micropenis and bilateral cryptorchidism. His pubic and axillary hair is at stage 4 and 2, respectively. His testes are 1 ml bilaterally, and his stretched penile length is 3.6 cm. In family 2, a 19-year and 2-month-old man was referred because of absence of secondary sexual characteristics. His 13-year and 8-month-old sister did not have any breast development. Results: In 3 patients from 2 independent families we identified GNRH1 mutations. In the proband from family 1, a homozygous 1-base deletion (c.87delA) leading to a frameshift mutation (p.G29GfsX12) was identified. In family 2, the affected siblings had a novel homozygous mutation of c.G92A leading to p.R31H. Conclusion: Both mutations in these families are located in the region encoding the decapeptide and in the loci where the mutations have been described before. Therefore, these areas can be considered as mutational hot spots, indicating priority for routine diagnostic gene mutation analysis.

CCDC141 Mutations in Idiopathic Hypogonadotropic Hypogonadism

Context Gonadotropin-releasing hormone neurons originate outside the central nervous system in the olfactory placode and migrate into the central nervous system, becoming integral components of the hypothalamic-pituitary-gonadal axis. Failure of this migration can lead to idiopathic hypogonadotropic hypogonadism (IHH)/Kallmann syndrome (KS). We have previously shown that CCDC141 knockdown leads to impaired migration of GnRH neurons but not of olfactory receptor neurons. Objective The aim of this study was to further describe the phenotype and prevalence of CCDC141 mutations in IHH/KS. Design Using autozygosity mapping, candidate gene screening, whole-exome sequencing, and Sanger sequencing, those individuals carrying deleterious CDCD141 variants and their phenotypes were determined in a cohort of 120 IHH/KS families. Patients and Interventions No interventions were made. Results Our studies revealed nine affected individuals from four independent families in which IHH/KS is associated with inactivating CCDC141 variants, revealing a prevalence of 3.3%. Affected individuals (with the exception of those from family 1 who concomitantly have FEZF1 mutations) have normal olfactory function and anatomically normal olfactory bulbs. Four affected individuals show evidence of clinical reversibility. In three of the families, there was at least one more potentially deleterious variant in other known puberty genes with evidence of allelic heterogeneity within respective pedigrees. Conclusions These studies confirm that inactivating CCDC141 variants cause normosmic IHH but not KS. This is consistent with our previous in vitro experiments showing exclusively impaired embryonic migration of GnRH neurons upon CCDC141 knockdown. These studies expand the clinical and genetic spectrum of IHH and also attest to the complexity of phenotype and genotype in IHH.

Idiopathic Hypogonadotropic Hypogonadism Caused by Inactivating Mutations in SRA1.

Objective: What initiates the pubertal process in humans and other mammals is still unknown. We hypothesized that gene(s) taking roles in triggering human puberty may be identified by studying a cohort of idiopathic hypogonadotropic hypogonadism (IHH). Methods: A cohort of IHH cases was studied based on autozygosity mapping coupled with whole exome sequencing. Results: Our studies revealed three independent families in which IHH/delayed puberty is associated with inactivating SRA1 variants. SRA1 was the first gene to be identified to function through its protein as well as noncoding functional ribonucleic acid products. These products act as co-regulators of nuclear receptors including sex steroid receptors as well as SF-1 and LRH-1, the master regulators of steroidogenesis. Functional studies with a mutant SRA1 construct showed a reduced co-activation of ligand-dependent activity of the estrogen receptor alpha, as assessed by luciferase reporter assay in HeLa cells. Conclusion: Our findings strongly suggest that SRA1 gene function is required for initiation of puberty in humans. Furthermore, SRA1 with its alternative products and functionality may provide a potential explanation for the versatility and complexity of the pubertal process.

Molecular genetic studies in a case series of isolated hypoaldosteronism due to biosynthesis defects or aldosterone resistance

Hypoaldosteronism is associated with either insufficient aldosterone production or aldosterone resistance (pseudohypoaldosteronism). Patients with aldosterone defects typically present with similar symptoms and findings, which include failure to thrive, vomiting, hyponatremia, hyperkalemia and metabolic acidosis. Accurate diagnosis of these clinical conditions therefore can be challenging. Molecular genetic analyses can help to greatly clarify this complexity. The aim of this study was to obtain an overview of the clinical and genetic characteristics of patients with aldosterone defects due to biosynthesis defects or aldosterone resistance.

The Authors' Reply: In systemic pseudohypoaldosteronism type 1 skin manifestations are not rare and the disease is not transient

We appreciate the valuable comments on our article by Hanukoglu and Hanukoglu. With regard to cutaneous involvement in systemic pseudohypoaldosteronism (sysPHA), we agree with Hanukoglu and Hanukoglu in that these co-occurrences are not rare. Indeed, in our study, three of four patients with sysPHA1 showed skin manifestations. This article is protected by copyright. All rights reserved.

Urolithiasis Frequency and Risk Factors in Home Ventilated Patients with Tracheostomy

©Telif Hakkı 2017 Çocuk Acil Tıp ve Yoğun Bakım Derneği Çocuk Acil ve Yoğun Bakım Dergisi, Galenos Yayınevi tarafından basılmıştır. Yazışma Adresi/Address for Correspondence: Dr. İlknur Tolunay, Çukurova Üniversitesi Tıp Fakültesi, Çocuk Yoğun Bakım Bilim Dalı, Adana, Türkiye E-posta: ilknurtolunay@gmail.com ORCID ID: orcid.org/0000-0002-3454-8483 Geliş Tarihi/Received: 30.07.2017 Kabul Tarihi/Accepted: 14.09.2017 Giriş: Bu çalışmada, ev tipi ventilatör ile izlenen trakeostomili hastalarda ürolitiazis sıklığı ve risk faktörlerinin değerlendirilmesi amaçlanmıştır. Yöntemler: Ocak 2014 ve Aralık 2015 tarihleri arasında çocuk yoğun bakım ünitemize yatırılan ve ev tipi ventilatörü olan trakeostomili 30 hasta geriye dönük olarak değerlendirilmiştir. Hastalara ait yaş, cinsiyet, altta yatan hastalık, kullanmakta olduğu ilaçlar, beslenme şekli, beslenme ürünü, kan biyokimyası, parathormon, 25(OH) vitamin D düzeyi, spot idrarda kalsiyum/kreatin, üriner sistem ultrasonografisi bilgileri hastaların arşiv dosyaları ve bilgisayar sisteminden elde edilmiştir. Bulgular: Hastaların %30’u (9/30) kız, %70’i (21/30) erkek olup yaş ortanca 70 ay (15-197 ay) idi. Motor fonksiyon sınıflama sistemine göre hastaların %33,3’ü (10/30) skor 4, %66,7’si (20/30) skor 5 olup tamamı immobil hastalar idi. Üriner sistem ultrasonografisi ile hastaların %30’unda (9/30) üst üriner sistem taşı saptandı. Hastaların %56,7’sinde (17/30) spot idrar kalsiyum/kreatin 0,21’in üzerinde bulundu. Yaşa göre spot idrar kalsiyum/kreatin hastaların %66,6’sında (20/30) yüksek saptandı. Hastaların günlük kalsiyum alımı 541±182 (336-1200) mg/gün; vitamin D alımı 25,9±10,6 (7,8-51,4) μg/gün idi. Hastaların tamamında kan kalsiyum düzeyi normal sınırlarda (8,5-10,5 mg/dL) olup kan 25(OH) vitamin D düzeyi 8 hastada >30 ng/mL, 13 hastada 20-30 ng/mL ve 9 hastada <20 ng/mL idi. Sonuç: Ev tipi ventilatör ile izlenen trakeostomili hastalarda immobilizasyon ürolitiazis açısından önemli bir risk faktörü olup bu hastaların eşlik eden metabolik bozukluklar açısından düzenli olarak takip edilmesi gerekmektedir. Anahtar Kelimeler: Çocuk, immobilizasyon, ürolitiazis, ev tipi ventilatör hastas

Idiopathic Hypogonadothropic Hypogonadism Due To Novel FGFR1 Mutations.

Objective: The underlying genetic etiology of hypogonadotropic hypogonadism (HH) is heterogeneous. Fibroblast growth factor signaling is pivotal in the ontogeny of gonadotropin-releasing hormone neurons. Loss-of-function mutations in FGFR1 gene cause variable HH phenotypes encompassing pubertal delay to idiopathic HH (IHH) or Kallmann syndrome (KS). As FGFR1 mutations are common, recognizing mutations and associated phenotypes may enhance clinical management. Methods: Using a candidate gene approach, we screened 52 IHH/KS patients. Results: We identified three novel (IVS3-1G>C and p.W2X, p.R209C) FGFR1 gene mutations. Despite predictive null protein function, patients from the novel mutation families had normosmic IHH without non-reproductive phenotype. Conclusion: These findings further emphasize the great variability of FGFR1 mutation phenotypes in IHH/KS.