scholarly journals Congenital hypothalamic hypogonadism — a Kallmann syndrome in boys. Clinical cases

2021 ◽  
pp. 53-65
Author(s):  
E. V. Globa ◽  
N. B. Zelinska ◽  
V. A. Yengovatova ◽  
O. A. Horosha ◽  
N. L. Pogadayeva ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Wide Spectrum ◽  
Hypogonadotropic Hypogonadism ◽  
Genetic Diagnosis ◽  
Previous Treatment ◽  
Kallmann Syndrome ◽  
Positive Trend ◽  
Targeted Next Generation Sequencing ◽  
Pathogenic Variants ◽  
Different Response

Central hypogonadism (CH) is a rare disease that occurs with a frequency of 1 : 8000 in women and 1 : 4000 in men. In 60 % of cases of CH, it is caused by Kallmann syndrome (KS) — a disease in which hypogonadotropic hypogonadism is combined with olfactory disorders (hyposmia or anosmia).Aim — to study clinical features, principles of diagnosis of CH/KS and evaluation of the effectiveness of various treatment. Materials and methods. 4 cases with CH/KS from three families had been described. Laboratory and instrumental investigations were used to confirm the KS; genetic diagnosis was performed using targeted next-generation sequencing (tNGS hypogonadotropic panel).Results. Patients with CH/KS had a wide spectrum of genital disorders (micropenia, cryptorchidism, microorchidism), which appeared at different age. Extragenital pathology was found in three of four patients: namely disorders of kidney, eye, respiratory system, hypoparathyroidism, hypothyroidism and epilepsy. It should be noted that all patients had olfactory disorders, which appeared in two of them only during a detailed survey after receiving genetic testing. In all patients, the diagnosis of CH was confirmed by the test with triptorelin 0.1. Also, all patients who underwent densitometry were found to have significant osteoporosis. In three patients, genetic testing confirmed hemizygous pathogenic variants in ANOS1 gene, while in one patient a heterozygous variant in FGFR1 gene was confirmed. After treatment with chorionic gonadotropin (HCG), two patients responded positively, with a descent of the testicles into the scrotum and an increase of testosterone level and testicular volume. However, in the other two patients there was no positive trend in treatment with HCG, therefore, the use of recombinant human FSH (r-FSH) in the form of priming and then further — in combination with HCG may be considered. Although the presence of severe microorchidism, cryptorchidism, low levels of AMH, inhibin B, and an unsatisfactory response to the previous treatment with HCG indicates extremely unfavorable prognosis. Therefore, in order to achieve the fertility in some patients with CH/KS, the most likely attempt is the use of assisted reproductive technologies.Conclusions. The leading problem in the treatment of patients with KS is their different response to hormone therapy, including different manifestations of the disease.

scholarly journals Advances in Genetic Diagnosis of Kallmann Syndrome and Genetic Interruption

2021 ◽  
Author(s):  
Yujun Liu ◽  
Xu Zhi
Keyword(s):  
Prenatal Diagnosis ◽  
Genetic Testing ◽  
Early Stage ◽  
Hypogonadotropic Hypogonadism ◽  
Genetic Diagnosis ◽  
Kallmann Syndrome ◽  
Hereditary Diseases ◽  
Congenital Defects ◽  
Unilateral Renal Agenesis ◽  
Congenital Hypogonadotropic Hypogonadism

AbstractKallmann syndrome (KS) is a rare hereditary disease with high phenotypic and genetic heterogeneity. Congenital hypogonadotropic hypogonadism and hyposmia/anosmia are the two major characterized phenotypes of KS. Besides, mirror movements, dental agenesis, digital bone abnormalities, unilateral renal agenesis, midline facial defects, hearing loss, and eye movement abnormalities can also be observed in KS patients. Because of the phenotypic heterogeneity, genetic diagnosis become increasingly valuable to distinguish KS from other disorders including normosmic congenital hypogonadotropic hypogonadism, constitutional delay of growth and puberty, CHARGE syndrome, and functional hypogonadotropic hypogonadism. Application of next-generation sequencing has promoted the discovery of novel pathogenic genes in KS pedigrees. Prenatal diagnosis is an effective method in clinical settings to decrease birth defects and block transmission of genetic disorders. However, pregnant women may suffer from physical and psychological distress when fetuses are diagnosed with congenital defects. Preimplantation genetic testing (PGT) is a prospective approach during the in vitro fertilization process that helps to interrupt transmission of hereditary diseases to offspring at an early stage. Thus, genetic testing and counseling are recommended to KS patients with family histories, prenatal diagnosis and PGT are considered to be useful options.

Combined Muscle Biopsy and Comprehensive Electrophysiology in General Anesthesia is Valuable in Diagnosis of Neuromuscular Disease in Children

2021 ◽  
Author(s):  
Christina E. Hoei-Hansen ◽  
Marie L. B. Tygesen ◽  
Morten Dunø ◽  
John Vissing ◽  
Martin Ballegaard ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Muscle Biopsy ◽  
Neuromuscular Disease ◽  
Genetic Diagnosis ◽  
Congenital Myasthenic Syndrome ◽  
Diagnostic Quality ◽  
Pathogenic Variants ◽  
Combined Use ◽  
Myasthenic Syndrome ◽  
Size Variability

Abstract Aim The diagnostic workup in patients with delayed motor milestones suspected of having either myopathy or a congenital myasthenic syndrome is complex. Our hypothesis was that performance of a muscle biopsy and neurophysiology including stimulated single-fiber electromyography during an anesthetic procedure, combined with genetic testing has a high diagnostic quality. Materials and Methods Clinical and paraclinical data were retrospectively collected from 24 patients aged from 1 month to 10 years (median: 5.2 years). Results Neurophysiology examination was performed in all patients and was abnormal in 11 of 24. No patients had findings suggestive of a myasthenic syndrome. Muscle biopsy was performed in 21 of 24 and was normal in 16. Diagnostic findings included nemaline rods, inclusion bodies, fiber size variability, and type-II fiber atrophy. Genetic testing with either a gene panel or exome sequencing was performed in 18 of 24 patients, with pathogenic variants detected in ACTA1, NEB, SELENON, GRIN2B, SCN8A, and COMP genes. Conclusion Results supporting a neuromuscular abnormality were found in 15 of 24. In six patients (25%), we confirmed a genetic diagnosis and 12 had a clinical neuromuscular diagnosis. The study suggests that combined use of neurophysiology and muscle biopsy in cases where genetic testing does not provide a diagnosis can be useful in children with delayed motor milestones and clinical evidence of a neuromuscular disease.

Genetic Testing in Children with Epilepsy: Report of a Single-Center Experience

2020 ◽  
pp. 1-12
Author(s):  
So Lee ◽  
Natalya Karp ◽  
Eugenio Zapata-Aldana ◽  
Bekim Sadikovic ◽  
Ping Yang ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Diagnostic Yield ◽  
Single Gene ◽  
Medication Management ◽  
Genetic Diagnosis ◽  
Single Center Experience ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Gene Testing ◽  
Patients With Epilepsy

ABSTRACT: Background: Retrospective observational study to determine diagnostic yield and utility of genetic testing in children with epilepsy attending the Epilepsy Clinic at Children’s Hospital, London, Ontario, Canada. Methods: Children (birth–18 years) with epilepsy, who were seen in a 10-year period (January 1, 2008–March 31, 2018), were selected using defined inclusion criteria and by combining clinic datasets and laboratory records. Results: In total, 105 children (52.38% male and 47.61% female) with a variety of seizures were included in the analysis. Developmental delay was documented in the majority (83; 79.04%). Overall, a genetic diagnosis was established in 24 (22.85%) children. The diagnostic yield was highest for whole-exome sequencing (WES), at 35.71%. The yield from microarray was 8.33%. Yields of single-gene testing (18.60%) and targeted multigene panel testing (19.23%) were very similar. Several likely pathogenic and pathogenic variants not previously reported were identified and categorized using ACMG criteria. All diagnosed patients underwent a review of anti-seizure medication management and received counseling on natural history of their disease, possible complications, recurrence risks, and possibilities of preimplantation or prenatal genetic diagnosis. Conclusions: Our study confirms the multiple benefits of detecting a genetic etiology in children with epilepsy. Similar yields in single versus multigene testing underscore the importance of accurate clinical phenotyping. Patients with epilepsy and their caregivers in Ontario would undoubtedly benefit from repatriation of multigene panels and WES to the province.

scholarly journals Targeted broad-based genetic testing by next-generation sequencing informs diagnosis and facilitates management in patients with kidney diseases

2019 ◽  
Author(s):  
M Adela Mansilla ◽  
Ramakrishna R Sompallae ◽  
Carla J Nishimura ◽  
Anne E Kwitek ◽  
Mycah J Kimble ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Clinical Diagnosis ◽  
Kidney Diseases ◽  
Genetic Diagnosis ◽  
Copy Number Variant ◽  
Underlying Disease ◽  
Renal Diseases ◽  
Single Nucleotide Variants ◽  
Glomerular Diseases ◽  
Pathogenic Variants

Abstract Background The clinical diagnosis of genetic renal diseases may be limited by the overlapping spectrum of manifestations between diseases or by the advancement of disease where clues to the original process are absent. The objective of this study was to determine whether genetic testing informs diagnosis and facilitates management of kidney disease patients. Methods We developed a comprehensive genetic testing panel (KidneySeq) to evaluate patients with various phenotypes including cystic diseases, congenital anomalies of the kidney and urinary tract (CAKUT), tubulointerstitial diseases, transport disorders and glomerular diseases. We evaluated this panel in 127 consecutive patients ranging in age from newborns to 81 years who had samples sent in for genetic testing. Results The performance of the sequencing pipeline for single-nucleotide variants was validated using CEPH (Centre de’Etude du Polymorphism) controls and for indels using Genome-in-a-Bottle. To test the reliability of the copy number variant (CNV) analysis, positive samples were re-sequenced and analyzed. For patient samples, a multidisciplinary review board interpreted genetic results in the context of clinical data. A genetic diagnosis was made in 54 (43%) patients and ranged from 54% for CAKUT, 53% for ciliopathies/tubulointerstitial diseases, 45% for transport disorders to 33% for glomerulopathies. Pathogenic and likely pathogenic variants included 46% missense, 11% nonsense, 6% splice site variants, 23% insertion–deletions and 14% CNVs. In 13 cases, the genetic result changed the clinical diagnosis. Conclusion Broad genetic testing should be considered in the evaluation of renal patients as it complements other tests and provides insight into the underlying disease and its management.

scholarly journals Clinical and Genetic Characterization of 153 Patients with Persistent or Transient Congenital Hyperinsulinism

2020 ◽  
Vol 105 (4) ◽  
pp. e1686-e1694
Author(s):  
Jonna M E Männistö ◽  
Maleeha Maria ◽  
Joose Raivo ◽  
Teemu Kuulasmaa ◽  
Timo Otonkoski ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Katp Channel ◽  
Genetic Diagnosis ◽  
Cross Sectional Study ◽  
Congenital Hyperinsulinism ◽  
Inadequate Response ◽  
Phenotypic Data ◽  
Cross Sectional ◽  
Targeted Next Generation Sequencing ◽  
Pathogenic Variants

Abstract Context Major advances have been made in the genetics and classification of congenital hyperinsulinism (CHI). Objective To examine the genetics and clinical characteristics of patients with persistent and transient CHI. Design A cross-sectional study with the register data and targeted sequencing of 104 genes affecting glucose metabolism. Patients Genetic and phenotypic data were collected from 153 patients with persistent (n = 95) and transient (n = 58) CHI diagnosed between 1972 and 2015. Of these, 86 patients with persistent and 58 with transient CHI participated in the analysis of the selected 104 genes affecting glucose metabolism, including 10 CHI-associated genes, and 9 patients with persistent CHI were included because of their previously confirmed genetic diagnosis. Main outcome measures Targeted next-generation sequencing results and genotype–phenotype associations. Results Five novel and 21 previously reported pathogenic or likely pathogenic variants in ABCC8, KCNJ11, GLUD1, GCK, HNF4A, and SLC16A1 genes were found in 68% (n = 65) and 0% of the patients with persistent and transient CHI, respectively. KATP channel mutations explained 82% of the mutation positive cases. Conclusions The genetic variants found in this nationwide CHI cohort are in agreement with previous studies, mutations in the KATP channel genes being the major causes of the disease. Pathogenic CHI-associated variants were not identified in patients who were both diazoxide responsive and able to discontinue medication within the first 4 months. Therefore, our results support the notion that genetic testing should be focused on patients with inadequate response or prolonged need for medication.

scholarly journals Comprehensive screening shows that mutations in the known syndromic genes are rare in individuals presenting with hyperinsulinaemic hypoglycaemia

2018 ◽  
Author(s):  
Thomas W Laver ◽  
Matthew N Wakeling ◽  
Janet Hong Yeow Hua ◽  
Jayne AL Houghton ◽  
Khalid Hussain ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Clinical Diagnosis ◽  
Genome Sequencing ◽  
Clinical Data ◽  
Genetic Diagnosis ◽  
Kabuki Syndrome ◽  
Newly Diagnosed ◽  
Sequencing Data ◽  
Hyperinsulinaemic Hypoglycaemia ◽  
Pathogenic Variants

AbstractObjectiveHyperinsulinaemic hypoglycaemia (HH) can occur in isolation or more rarely feature as part of a syndrome. Screening for mutations in the ‘syndromic HH’ genes is guided by phenotype with genetic testing used to confirm the clinical diagnosis. As HH can be the presenting feature of a syndrome it is possible that mutations will be missed as these genes are not routinely screened in all newly diagnosed individuals. We investigated the frequency of pathogenic variants in syndromic genes in individuals with HH who had not been clinically diagnosed with a syndromic disorder at referral for genetic testing.DesignWe used genome sequencing data to assess the prevalence of mutations in syndromic HH genes in an international cohort of patients with HH of unknown genetic cause.MethodsWe undertook genome sequencing in 82 individuals with HH without a clinical diagnosis of a known syndrome at referral for genetic testing. Within this cohort we searched for the genetic aetiologies causing 20 different syndromes where HH had been reported as a feature.ResultsWe identified a pathogenic KMT2D variant in a patient with HH diagnosed at birth, confirming a genetic diagnosis of Kabuki syndrome. Clinical data received following the identification of the mutation highlighted additional features consistent with the genetic diagnosis. Pathogenic variants were not identified in the remainder of the cohort.ConclusionsPathogenic variants in the syndromic HH genes are rare but should be considered in newly diagnosed individuals as HH may be the presenting feature.

scholarly journals SOX10 Mutation Screening for 117 Patients with Kallmann Syndrome

2021 ◽  
Author(s):  
Hirohito Shima ◽  
Etsuro Tokuhiro ◽  
Shingo Okamoto ◽  
Mariko Nagamori ◽  
Tsutomu Ogata ◽  
...  
Keyword(s):  
Hypogonadotropic Hypogonadism ◽  
Mutation Screening ◽  
Hirschsprung Disease ◽  
Kallmann Syndrome ◽  
Dominant Negative ◽  
Negative Effects ◽  
Causative Gene ◽  
Pathogenic Variants ◽  
Medical Genomics

Abstract Introduction Kallmann syndrome (KS) is a genetically heterogeneous condition characterized by hypogonadotropic hypogonadism (HH) and olfactory dysfunction. Although SOX10, a causative gene for Waardenburg syndrome (WS) and peripheral demyelinating neuropathy, central demyelination, WS, and Hirschsprung disease (PCWH), has previously been implicated in KS, the clinical significance of SOX10 variants as the cause of KS remains uncertain. Patients and Methods A total of 117 patients with KS underwent mutation screening of SOX10 and 14 other causative genes for KS/HH. Rare SOX10 variants were subjected to in silico and in vitro analyses. We also examined clinical data of the patients and their parents with SOX10 variants. Results Sequence analysis identified two heterozygous variants of SOX10 (c.1225G>T, p.Gly409* and c.475C>T, p.Arg159Trp) in patients 1–3, as well as in the parents of patients 1 and 3. The variants were assessed as pathogenic/likely_pathogenic, according to the American College of Medical Genomics guidelines. Both variants lacked in vitro transactivating activity for the MITF promoter and exerted no dominant-negative effects. Patients 1–3 carried no pathogenic variants in other genes examined. The patients presented with typical KS, while such features were absent in the parents of patients 1 and 3. None of the five variant-positive individuals exhibited hypopigmentation, while one and two individuals exhibited complete and partial hearing loss, respectively. Conclusion These results provide evidence that SOX10 haploinsufficiency accounts for a few percent of KS cases. SOX10 haploinsufficiency is likely to be associated with a broad phenotypic spectrum which includes KS without other clinical features of WS/PCWH.

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