SOX2 heterozygous mutation causes multiple extra-ocular phenotypes in boys

2020 ◽  
Author(s):  
Yi Wang ◽  
LiJun Fan ◽  
Xiaoya Ren ◽  
Yanning Song ◽  
Beibei Zhang ◽  
...  
Keyword(s):  
Mental Retardation ◽  
De Novo ◽  
Hypogonadotropic Hypogonadism ◽  
Gene Mutations ◽  
Delayed Puberty ◽  
Heterozygous Mutation ◽  
Common Symptom ◽  
Causative Gene ◽  
Pathogenic Genes ◽  
The Central Nervous System

Abstract Background The SOX2 gene is widely expressed in the eyes and the central nervous system. Heterozygous mutations could cause eye malformations and hypopituitarism, and serve as the causative gene for syndromic and non-syndromic hypogonadotropic hypogonadism (HH). Our study reports three children with chromosome 46, XY, SRY (+), but SOX2 mutations.Methods Three children visited our endocrine clinic because of micropenis and/or cryptorchidism. Clinical data were collected, and one took PANEL sequencing and the others for whole exome sequencing. Then we summarized characteristics of the patients and compared with those mentioned in literature.Results Patient 1 manifested with micropenis, patient 2 with bilateral cryptorchidism and craniofacial deformities, both carrying the same reported SOX2 gene mutation (T232N), and both mutations from mothers with delayed puberty only. Patient 3 showed micropenis, mental retardation and craniofacial deformities, and the child carried a spontaneous truncation mutation (Y110X) of the SOX2 gene. This site has reported that a missense mutation caused adolescent adolescence without major eye signs. All three patients carried another gene mutations that affected hypothalamic-pituitary function: Patient 1, FGFR1: c.238C>T/p.R80C (uncertain) from father; Patient 2, CHD7: c.2656C>T/p.R886W (pathogenic) de novo; Patient 3, SEMA3A: c.1432G> A/p.E478K (uncertain) from mother. None had major ocular malformations, and all showed genitourinary tract malformations. Two patients had craniofacial deformities, and one patient had muscle anomality and intellectual disability. We summarized previous studies with SOX2 gene mutations and it showed: 71.2% of mutations are de novo, all patients reported whose variants inherit from parents, 15.1% parents (including mother 11.0% and father 4.1%) show completely normal phenotypes, 4.1% (3/73) variants inherit from mother with germinal mosaicism. Except for major ocular malformations (91.1%), the most common phenotype is developmental delay/mental retardation (DD/MR), accounting for 40.7%, followed by brain anomely (BA), accounting for 28.5%, male genital abnormalities (GA) for 20.3%, non-syndromic HH accounted for 4.9%, the younger the patients visit the doctor, the more common the retardation are. Conclusion SOX2 mutations could cause a broad phenotype spectrum from completely normal to severe ocular malformations, retardation and most mutations are de novo. Except for major ocular malformations and retardation, GA/HH is another common symptom. GA/HH may be the only symptom, and SOX2 may cooperate with another HH pathogenic genes to cause non-syndromic HH.

A De Novo BSCL2 Gene S90L Mutation in a Progressive Tetraparesis with Urinary Dysfunction and Corpus Callosum Involvement

2020 ◽  
Author(s):  
Joana Ramos-Lopes ◽  
Joana Ribeiro ◽  
Mário Laço ◽  
Cristina Alves ◽  
Anabela Matos ◽  
...  
Keyword(s):  
Corpus Callosum ◽  
De Novo ◽  
Spastic Paraparesis ◽  
Gene Mutations ◽  
Lower Limbs ◽  
Heterozygous Mutation ◽  
Incomplete Penetrance ◽  
Causative Gene ◽  
Small Hand ◽  
Silver Syndrome

AbstractA Silver syndrome is a rare autosomal dominant spastic paraparesis in which spasticity of the lower limbs is accompanied by amyotrophy of the small hand muscles. The causative gene is the Berardinelli-Seip congenital lipodystrophy 2 (BSCL2), which is related to a spectrum of neurological phenotypes. In the current study, we have presented a 14-year-old male with a slowly progressive spastic paraparesis with urinary incontinence that later on exhibited atrophy and weakness in the thenar and dorsal interosseous muscles. Magnetic resonance imaging (MRI) revealed discrete atrophy of the corpus callosum isthmus and an extended next-generation sequencing panel identified a de novo heterozygous mutation in BSCL2 gene, c.269C > T p.(S90L). Various clinical expression and incomplete penetrance of BSCL2 gene mutations complicate the establishment of a genetic etiology for these cases. Therefore, Silver syndrome should be included in the differential diagnosis if the initial presentation is a spastic paraparesis by urinary involvement with childhood-onset, even with MRI atypical findings. This report is the first Iberian Silver syndrome case carrying a de novo c.269C > T p. (S90L) BSCL2 gene mutation.

Clinical and molecular characterization of five Spanish kindreds with X-linked adrenal hypoplasia congenita: atypical findings and a novel mutation in NR0B1

2015 ◽  
Vol 28 (9-10) ◽  
Author(s):  
Amaia Rodríguez Estévez ◽  
Gustavo Pérez-Nanclares ◽  
Joaquin Fernández-Toral ◽  
Francisco Rivas-Crespo ◽  
Juan P. López-Siguero ◽  
...  
Keyword(s):  
Molecular Level ◽  
Novel Mutation ◽  
Hypogonadotropic Hypogonadism ◽  
Gene Mutations ◽  
Delayed Puberty ◽  
Salt Wasting ◽  
Adrenal Hypoplasia Congenita ◽  
Intrafamilial Variability ◽  
Adrenal Hypoplasia

AbstractX-linked adrenal hypoplasia congenita (AHC) is caused byTo characterize clinically and at the molecular level a cohort of Spanish patients with AHC.Nine boys (from five families) with AHC were screened forgene mutations were found in all analyzed patients, one of them being novel (p.Gln305*). One patient presented with preserved hypothalamic-pituitary-gonadal axis. Salt-wasting episodes, delayed puberty, and hypogonadotropic hypogonadism were common, although no association was observed between AHC phenotype and genetic mutations. None of the patients has had descendants.AHC phenotype cannot be predicted based on genetic results as there is no definite genotype-phenotype relationship, including intrafamilial variability. Nevertheless, genetic testing for

COL4A1 is a Novel Causative Gene Responsible for Congenital Hemolytic Anemia, Representing Characteristic Clinical Course in Infants

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 934-934
Author(s):  
Hiromi Ogura ◽  
Shouichi Ohga ◽  
Takako Aoki ◽  
Taiju Utsugisawa ◽  
Hidehiro Takahashi ◽  
...  
Keyword(s):  
Hemolytic Anemia ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Small Vessel Disease ◽  
Gene Mutations ◽  
Basement Membranes ◽  
Red Cell ◽  
Missense Mutations ◽  
Causative Gene ◽  
Congenital Hemolytic Anemia

Abstract We have been working on the differential diagnosis of congenital hemolytic anemia, but even with extensive analysis of hemoglobin, red cell membrane and enzymes, approximately 40% of patients remained to be diagnosed. In this study, we analyzed 17 undiagnosed hemolytic anemia subjects under the age of 1 by whole-exome sequencing, and identified COL4A1 gene mutations in 5 cases (29.4%). All patients were de novo cases without family histories and exhibited moderate to severe neonatal hemolytic anemia: Hgb, 5.2-9.3 g/dl; MCV, 90.0-126.9; MCHC, 29.9-32.7; and reticulocyte count, 9.2-33.0%. Either schizocytes or poikilocytes were observed in peripheral blood smears of 3 cases, suggesting that the microangiopathy was attributable to hemolysis. Previous reports showed that mutation of COL4A1 accounts for brain small-vessel disease characterized by stroke and eye abnormalities and the most characteristic complications of the present cases were congenital anomaly in the central nervous system, such as porencephaly, schizencephaly, congenital hydrocephalus, cataracts or paraventricular calcification, as reported previously. Hemolytic anemia became less severe within 2 months after birth, and all cases no longer required red cell transfusion after Day 50. COL4A1 encodes subtype 1 of type IV collagen, which is most abundantly expressed in basement membranes, including the vasculature. The COL4A1 gene mutations identified in the cases were all novel missense mutations except one, located in exons 26, 27, 37, 38 and 51. Although the pathophysiological significance of the mutations remains unclear, COL4A1 is the first identified causative gene responsible for congenital hemolytic anemia without intrinsic defects of red blood cells, and mutation of COL4A1 is the most prevalent cause of neonatal hemolytic anemia. Disclosures No relevant conflicts of interest to declare.

scholarly journals The Clinical and Genetic Characteristics of Chinese Male Pediatric Patients With Congenital Hypogonadotropic Hypogonadism

2021 ◽  
Author(s):  
Yi Wang ◽  
Miao Qin ◽  
Lijun Fan ◽  
Beibei Zhang ◽  
Chunxiu Gong
Keyword(s):  
Autosomal Recessive ◽  
Hypogonadotropic Hypogonadism ◽  
Positive Family History ◽  
Delayed Puberty ◽  
Genetic Characteristics ◽  
Cell Dysfunction ◽  
Congenital Hypogonadotropic Hypogonadism ◽  
Pathogenic Genes ◽  
Rare Phenotype ◽  
Chinese Male

Abstract BackgroundsCongenital hypogonadotropic hypogonadism (CHH) are invided into Kallmann Syndrome (KS) and normosmic HH(nHH). The clinical and genetic characteristics of CHH are more studied in adults, but less in pre-adults. MethodsMedical records of 126 patients with CHH at our hospital during 2008−2020 were evaluated. ResultsTotally, seven patients (5.6%) had hypospadias. Among 49 patients with positive family history, delayed puberty, KS/nHH and olfactory abnormalities accounted for 44.9%, 16.3%, and 12.2%, respectively. Sixty-five patients completed the hCG prolongation test, and T levels of 24 patients were lower than 100 ng/dl. 25 CHH-related genes were found in 78 patients, digenic mutations in 23 patients, and trigenic mutations in 3 patients. The most common pathogenic genes were FGFR1 (21.1%), PROKR2 ( 17.9%), ANOS1 (12.6%), and CHD7 (12.6%). The oligogenicity rate of common autosomal dominant heredity genes accounted for 50.0% (FGFR1, 10/20) and 33.3% (CHD7, 4/12), of autosomal recessive heredity gene PROKR2 accounted for 47.1% (8/17). ConclusionMicropenis and cryptorchidism are important cues for CHH in pre-adulthood; hypospadias is a rare phenotype of CHH. At least 22.9% of patients tested had testicular Leydig cell dysfunction (dual CHH). Oligogenic mutations were found in 27.4% of all patients with CHH.

scholarly journals Recurrent PAX 6 mutation in a Chinese family with congenital aniridia, progressive cataracts and mental retardation

2018 ◽  
Vol 30 (1) ◽  
pp. 181-188
Author(s):  
Dou-Dou Chen ◽  
Tao Yang ◽  
Si-Quan Zhu
Keyword(s):  
Mental Retardation ◽  
Family Members ◽  
Gene Mutations ◽  
Chinese Family ◽  
Heterozygous Mutation ◽  
Pathological Feature ◽  
Phosphate Backbone ◽  
Symptom Complex ◽  
Congenital Aniridia ◽  
And Control

Background: One prominent pathological feature of congenital aniridia is hypoplasia of the iris, often accompanied by other eye abnormalities. The objective of this study is to identify gene mutations responsible for autosomal dominance in a Chinese family with congenital aniridia, progressive cataracts and mental retardation. Methods: A total of 11 family members, including 6 affected and 5 unaffected individuals were recruited. Whole exome sequencing was performed on the proband and Sanger sequencing was applied to identify the causal mutation in the other family members and control samples. Results: A heterozygous mutation, c. 112delC (p. Arg38fs) in PAX 6, was identified in the family that was associated with congenital aniridia, progressive cataracts and mental retardation. The mutation was exclusively observed in all affected individuals but not in unaffected family members or unrelated healthy controls without aniridia recruited from Beijing Tongren Hospital. Bioinformatics analysis indicated that the mutation c. 112delC (p. Arg38fs) in PAX 6 affected sugar phosphate backbone construction, leading to half reduction of the full-length protein. Other symptoms such as lens opacity, keratitis, lens dislocation, ciliary body hypoplasia, foveal hypoplasia and mental development retardation were also observed in this family. Conclusion: These results provided a new insight into the effects of PAX 6 as a mutational hotspot, with a symptom complex that includes congenital aniridia, progressive cataracts and mental retardation. These findings suggested the cognitive treatment of PAX 6-mutated individuals could be considered earlier clinically, combined with medication or surgery of congenital aniridia and progressive cataracts.

scholarly journals A Novel c.91dupG JAG1 Gene Mutation Is Associated with Early Onset and Severe Alagille Syndrome

2018 ◽  
Vol 2018 ◽  
pp. 1-3 ◽  
Author(s):  
Alejandra del Pilar Reyes-de la Rosa ◽  
Gustavo Varela-Fascinetto ◽  
Constanza García-Delgado ◽  
Edgar Ricardo Vázquez-Martínez ◽  
Pedro Valencia-Mayoral ◽  
...  
Keyword(s):  
De Novo ◽  
Pulmonary Stenosis ◽  
Gene Mutations ◽  
Alagille Syndrome ◽  
Notch Signaling Pathway ◽  
Heterozygous Mutation ◽  
Sequencing Analysis ◽  
Autosomal Dominant Disorder ◽  
Intrahepatic Bile Ducts ◽  
Chronic Cholestasis

Alagille syndrome (MIM 118450) is an autosomal dominant disorder characterized by paucity of intrahepatic bile ducts, chronic cholestasis, pulmonary stenosis, butterfly-like vertebrae, posterior embryotoxon, and dysmorphic facial features. Most cases are caused by JAG1 gene mutations. We report the case of a 2-year-old Mexican mestizo patient with Alagille syndrome, having exhibited jaundice and cholestatic syndrome as of three weeks of age. Sequencing analysis of the JAG1 gene revealed the novel heterozygous mutation c.91dupG that originates a truncated protein and therefore a possibly diminished activation of the Notch signaling pathway. The latter may explain the severe phenotype of the patient. Since the mutation was not identified in the parents, it was considered a de novo event, highlighting the importance of molecular diagnosis and genetic counseling. In conclusion, this report widens the spectrum of JAG1 gene mutations associated with Alagille syndrome.

scholarly journals A novel heterozygous mutation of CHD7 gene in a Chinese patient with Kallmann syndrome: a case report

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Weiwei Xu ◽  
Weibin Zhou ◽  
Haiyang Lin ◽  
Dan Ye ◽  
Guoping Chen ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Hypogonadotropic Hypogonadism ◽  
Kallmann Syndrome ◽  
Delayed Puberty ◽  
Heterozygous Mutation ◽  
Human Menopausal Gonadotropin ◽  
Z Score ◽  
Idiopathic Hypogonadotropic Hypogonadism ◽  
Contrast Enhanced ◽  
Chd7 Gene

Abstract Background Variants of chromodomain helicase DNA binding protein 7 (CHD7) gene are commonly associated with Kallmann syndrome (KS) and account for 5–6% of idiopathic hypogonadotropic hypogonadism (IHH) cases. Here we report a novel mutation of CHD7 gene in a patient with KS, which may contribute to the better understanding of KS. Case presentation A 29-year-old male patient with KS and a chief complaint of delayed puberty for 13 years (Tanner B Stage< 4) was admitted to the Department of Endocrinology of the First Affiliated Hospital of Zhejiang University (Hangzhou, China) in September 2019. Dual-energy X-ray absorptiometry (DEXA) showed low bone density in both lumbar spine (L1 ~ L5 mean Z-score − 3.0) and femoral neck (Z-score − 2.7). Dynamic contrast-enhanced magnetic resonance imaging (MRI) of pituitary and contrast-enhanced computed tomography (CT) showed no abnormal findings. Ophthalmological evaluation showed that his both eyes showed exotropia, and no sight loss was noted. Heterozygous c.1619G > T mutation of TCD7 gene (p.G4856V) was detected, whereas none of his family members had this mutation. Human chorionic gonadotropin (HCG) and human menopausal gonadotropin (HMG) were injected for three times/week to treat idiopathic hypogonadotropic hypogonadism (IHH). After several months of therapy, the patient’s health condition improved. His testicles became larger, and his secondary sexual characteristics improved after treatment. Conclusion Exploration of the novel splice-site mutation of CHD7 may further our current understanding of KS.

scholarly journals Novel Perspectives of Super-High Dose Glybenclamide in an Infant With DEND Syndrome

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A453-A453
Author(s):  
Galia Barash ◽  
Haim Bassan ◽  
Livne Ayelet ◽  
Lilach Benyamini ◽  
Eli Heyman ◽  
...  
Keyword(s):  
Developmental Delay ◽  
De Novo ◽  
Glucose Monitoring ◽  
Gene Mutations ◽  
Missense Variant ◽  
Neonatal Diabetes ◽  
Heterozygous Mutation ◽  
High Dose ◽  
Kcnj11 Gene ◽  
High Doses

Abstract Mutations in KCNJ11 gene cause a variety of persistent neonatal diabetes mellitus syndromes (PNDM), with and without developmental delay and epilepsy presentations (developmental delay, epilepsy, and neonatal diabetes - DEND Syndrome). We report a heterozygous mutation for pathogenic KCNJ11 missense variant: c.190G&gt;A, p. (Val64Met), reported once so far, associated with severe epilepsy and neurological deterioration phenotype, responsive to a combination of super high doses of Glibenclamide (Sulfonylurea) and oral steroids. We had the patient attached to continuous glucose monitoring, performed electroencephalogramic tracings, magnetic resonance imaging and whole exome sequencing on parents and patient DNA and Sanger sequencing (SS) on candidate gene mutations. His phenotypic description and management during 18 months, demonstrates this mutation is responsive to super-high doses of SU combined with high dose 6 weeks steroids protocol. In conclusion, we have identified a de novo heterozygous missense mutation as the etiology for severe DEND syndrome in a one day old neonate, presenting with asymptomatic hyperglycemia, responsive to a novel management combination.

scholarly journals The Clinical and Genetic Characteristics of Chinese Male Pediatric Patients with Congenital Hypogonadotropic Hypogonadism

2021 ◽  
Author(s):  
Yi Wang ◽  
Miao Qin ◽  
Lijun Fan ◽  
Beibei Zhang ◽  
Chunxiu Gong
Keyword(s):  
Autosomal Recessive ◽  
Hypogonadotropic Hypogonadism ◽  
Positive Family History ◽  
Delayed Puberty ◽  
Genetic Characteristics ◽  
Cell Dysfunction ◽  
Congenital Hypogonadotropic Hypogonadism ◽  
Pathogenic Genes ◽  
Rare Phenotype ◽  
Chinese Male

Abstract Purpose：Congenital hypogonadotropic hypogonadism (CHH) are invided into Kallmann Syndrome (KS) and normosmic HH(nHH). The clinical and genetic characteristics of CHH are more studied in adults, but less in pre-adults. Methods: Medical records of 126 patients with CHH at our hospital during 2008−2020 were evaluated. Results: Totally, seven patients (5.6%) had hypospadias. Among 49 patients with positive family history, delayed puberty, KS/nHH and olfactory abnormalities accounted for 44.9%, 16.3%, and 12.2%, respectively. Sixty-five patients completed the hCG prolongation test, and T levels of 24 patients were lower than 100 ng/dl. 25 CHH-related genes were found in 78 patients, digenic mutations in 23 patients, and trigenic mutations in 3 patients. The most common pathogenic genes were FGFR1 (21.1%), PROKR2 (17.9%), ANOS1 (12.6%) and CHD7 (12.6%). The oligogenicity rate of common autosomal dominant heredity genes accounted for 50.0% (FGFR1, 10/20) and 33.3% (CHD7, 4/12), of autosomal recessive heredity gene PROKR2 accounted for 47.1% (8/17). And W178S accounted for 58.8% of all mutations in PROKRR2.Conclusion: Micropenis and cryptorchidism are important cues for CHH in pre-adulthood; hypospadias is a rare phenotype of CHH. At least 22.9% of patients tested had testicular Leydig cell dysfunction (dual CHH). Oligogenic mutations were found in 27.4% of all patients with CHH. W178S in PROKRR2 maybe a founder mutation in Chinese CHH crowds.

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