Massive ribs fractures due to artriohepatic dysplasia (Alagille syndrome): a case report.

2018 ◽  
Author(s):  
Mohammed J Aboud
Keyword(s):  
De Novo ◽  
Alagille Syndrome ◽  
Pulmonary Artery Stenosis ◽  
De Novo Mutations ◽  
Stunted Growth ◽  
Notch Receptors ◽  
Chronic Cholestasis ◽  
The Family ◽  
Dominant Disease ◽  
History Of

Abstract   Alagille syndrome (ALGS) is a rare multisystem congenital disorder, with a minimum incidence of approximately 1:30,000 live births. It is an autosomal dominant disease that arises from mutations in the Jagged1 (JAG1) gene (approximately 60% of cases are caused by de novo mutations), which encodes a ligand for Notch receptors. The most common symptoms associated with this syndrome are cholestasis with the obstruction or slowing of biliary flow, congenital heart disease (pulmonary artery stenosis), and butterfly-shaped vertebrae, anterior chamber eye defects, and dysmorphic faces. Several of the characteristics of Alagille syndrome may result in patients having an especially high risk of fracture. The majority of patients suffer from chronic cholestasis, which can have a variety of adverse effects on bone metabolism. Case presentation; A 6-months-old girl admitted to pediatric surgery unit with jaundice since one month of age, progressive abdominal distention. She had been diagnosed with biliary atresia at the age of 1 month on the base of clinical diagnosis, she was malnourished with stunted growth. She had most of the features of Alagille syndrome. Chest radiographs showed generalized decreased in bone density with multiple ribs fractures on the left side, with pulmonary consolidation in the left middle and lower zone. Osteodystrophy (haptic cause) was enrolled based on the fact that there was no evidence or history of trauma (child abuse by the family was not considered). Our study is one of a few reports to document ribs fracture in children with AGLS. 

scholarly journals Chromosome 20p Partial De Novo Duplication Identified in a Female Paediatric Patient with Characteristic Facial Dysmorphism and Behavioural Anomalies

2020 ◽  
Vol 2020 ◽  
pp. 1-6
Author(s):  
Shahzaib Khattak ◽  
Meryam Jan ◽  
Sara Warsi ◽  
Sohail Khattak
Keyword(s):  
Scientific Literature ◽  
De Novo ◽  
Heart Defects ◽  
Self Regulation ◽  
Alagille Syndrome ◽  
Copy Number Variations ◽  
Facial Dysmorphism ◽  
Limited Data ◽  
Wide Range ◽  
History Of

Copy number variations (CNVs) involving the JAG1 gene are rare and infrequently reported in the scientific literature. Recently, a generally healthy young patient presenting with a history of behavioural concerns was referred to us. Herein, we discuss the patient, a 7-year-old female possessing a 0.797 Mb microduplication within the short arm of chromosome 20 at band 12.2. The patient generates considerable curiosity due to the rarity of her case, which includes a de novo partial duplication involving the JAG1 gene. The patient exhibits a wide range of symptoms including facial dysmorphism (dolichocephaly, round face, tented philtrum, anteverted nares, and micrognathia), clinodactyly, and an inborn congenital heart defect. She presented with behavioural concerns including ADHD-I, SPD, motor clumsiness, and poor self-regulation. Deletions in JAG1 are often linked to Alagille Syndrome; however, complete duplications have not been specifically identified as disease-causing. JAG1 mutations are reported alongside various clinical features including facial dysmorphology, heart defects, vertebral abnormalities, and ocular dysmorphic features (strabismus, epicanthal folds, and slanted palpebral fissures). This particular microduplication is rare, and thus, limited data exist regarding its significance. To our knowledge, most reported duplications are larger than 0.797 Mb. This may define a critical region causing phenotypical changes in some patient cases.

scholarly journals De novo arteriovenous malformation in a patient with hereditary hemorrhagic telangiectasia

2016 ◽  
Vol 17 (3) ◽  
pp. 330-335 ◽  
Author(s):  
Yusuke Shimoda ◽  
Toshiya Osanai ◽  
Naoki Nakayama ◽  
Satoshi Ushikoshi ◽  
Masaaki Hokari ◽  
...  
Keyword(s):  
Family History ◽  
Arteriovenous Malformation ◽  
Hereditary Hemorrhagic Telangiectasia ◽  
Arteriovenous Malformations ◽  
Autosomal Dominant ◽  
De Novo ◽  
The Family ◽  
Systemic Disorder ◽  
History Of ◽  
Cerebral Avms

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant systemic disorder characterized by the enlargement of capillaries, recurrent nosebleeds, and multiple arteriovenous malformations (AVMs). Although cerebral AVMs are traditionally considered to be congenital lesions, some reports have described de novo AVMs, which suggests that the authors believed them to be dynamic conditions. In this article, the authors describe the case of a 5-year-old boy with HHT in whom a de novo cerebral AVM was detected after a negative MRI result at 5 months. To the authors’ knowledge, this is the first report of a de novo AVM in a patient with HHT. In patients with a family history of HHT, de novo AVMs are possible, even when no lesions are detected at the first screening. Therefore, regular screenings need to be performed, and the family should be informed that AVMs could still develop despite normal MRI results.

scholarly journals Autism and attention-deficit/hyperactivity disorder among individuals with a family history of alcohol use disorders

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Jan Sundquist ◽  
Kristina Sundquist ◽  
Jianguang Ji
Keyword(s):  
Attention Deficit Hyperactivity Disorder ◽  
Family History ◽  
Alcohol Use ◽  
Attention Deficit ◽  
De Novo ◽  
Alcohol Use Disorders ◽  
De Novo Mutations ◽  
Parental History ◽  
Hyperactivity Disorder ◽  
History Of

Recent studies suggest de novo mutations may involve the pathogenesis of autism and attention-deficit/hyperactivity disorder (ADHD). Based on the evidence that excessive alcohol consumption may be associated with an increased rate of de novo mutations in germ cells (sperms or eggs), we examine here whether the risks of autism and ADHD are increased among individuals with a family history of alcohol use disorders (AUDs). The standardized incidence ratios (SIRs) of autism and ADHD among individuals with a biological parental history of AUDs were 1.39 (95% CI 1.34–1.44) and 2.19 (95% CI 2.15–2.23), respectively, compared to individuals without an affected parent. Among offspring whose parents were diagnosed with AUDs before their birth, the corresponding risks were 1.46 (95% CI 1.36–1.58) and 2.70 (95% CI 2.59–2.81), respectively. Our study calls for extra surveillance for children with a family history of AUDs, and further studies examining the underlying mechanisms are needed.

scholarly journals A variant in TAF1 is associated with a new syndrome with severe intellectual disability and characteristic dysmorphic features

2015 ◽  
Author(s):  
Jason O'Rawe ◽  
Yiyang Wu ◽  
Alan Rope ◽  
Laura T. Jimenez Barrón ◽  
Jeffrey Swensen ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
De Novo ◽  
Critical Role ◽  
False Negative ◽  
Disease Models ◽  
Sequencing Data ◽  
De Novo Mutations ◽  
Genetic Syndrome ◽  
Severe Intellectual Disability ◽  
The Family

We describe the discovery of a new genetic syndrome, RykDax syndrome, driven by a whole genome sequencing (WGS) study of one family from Utah with two affected male brothers, presenting with severe intellectual disability (ID), a characteristic intergluteal crease, and very distinctive facial features including a broad, upturned nose, sagging cheeks, downward sloping palpebral fissures, prominent periorbital ridges, deep-set eyes, relative hypertelorism, thin upper lip, a high-arched palate, prominent ears with thickened helices, and a pointed chin. This Caucasian family was recruited from Utah, USA. Illumina-based WGS was performed on 10 members of this family, with additional Complete Genomics-based WGS performed on the nuclear portion of the family (mother, father and the two affected males). Using WGS datasets from 10 members of this family, we can increase the reliability of the biological inferences with an integrative bioinformatic pipeline. In combination with insights from clinical evaluations and medical diagnostic analyses, these DNA sequencing data were used in the study of three plausible genetic disease models that might uncover genetic contribution to the syndrome. We found a 2 to 5-fold difference in the number of variants detected as being relevant for various disease models when using different sets of sequencing data and analysis pipelines. We derived greater accuracy when more pipelines were used in conjunction with data encompassing a larger portion of the family, with the number of putative de-novo mutations being reduced by 80%, due to false negative calls in the parents. The boys carry a maternally inherited missense variant in a X-chromosomal gene TAF1, which we consider as disease relevant. TAF1 is the largest subunit of the general transcription factor IID (TFIID) multi-protein complex, and our results implicate mutations in TAF1 as playing a critical role in the development of this new intellectual disability syndrome.

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.

Novel de novo BRCA1 mutation in a woman with early onset breast cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e22143-e22143
Author(s):  
E. Tang ◽  
A. Kwong ◽  
C. Wong ◽  
F. Law ◽  
C. Wong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Family History ◽  
Early Onset ◽  
De Novo ◽  
Family Members ◽  
Gene Sequencing ◽  
Large Deletion ◽  
Early Onset Breast Cancer ◽  
De Novo Mutations ◽  
History Of

e22143 Background: Germline mutations in BRCA1/2 account for a significant portion of hereditary breast/ovarian cancer. Mutation carriers usually have a family history of breast/ovarian cancer or early onset disease. Rarely, germline mutations are found only in the probands but not in any family members. Such de novo mutations have been reported in diseases such as hemophilia A, thalassaemia and familial adenomatous polyposis. De novo mutations in the BRCA1 or BRCA2 genes are rare and the few reported have been in BRCA2. Here, we describe de novo as well as novel mutation of the BRCA1 gene in a breast cancer patient. Methods: Blood DNA samples from a 30 year old Chinese woman with breast cancer and no family history of cancer was tested for a BRCA1/2 mutation by full gene sequencing and Multiple Ligation-dependent Probe Amplification (MLPA). Family members were analyzed for the same mutation. Paternity was determined by a set of highly polymorphic short tandem repeat (STR) markers. Results: Full gene sequencing found no deleterious mutation. MLPA revealed a large deletion of exons 1 to 12 of BRCA1 in the proband. MLPA performed on 5 family members: proband's mother and father (who were 1st degree relative- cousins), stepmother (mother's biological sister), 2 sisters (1, same parents; 1, same father and stepmother) found no similar deletion. By using a set of highly polymorphic STR markers, the proband's father and mother were confirmed to be her biological parents. Conclusions: We report a novel de novo BRCA1 deletion mutation encompassing exons 1 - 12 in a Chinese breast cancer patient of early onset with no family history. Identification of this large deletion confirms the importance of pursuing rearrangement testing if full gene sequencing fails to detect a point mutation or short insertion deletion. The mutation found in this study is de novo. This may simply be a random mutation event which occurred in the parents' germ cells during their lifetime which passed onto one of their offspring or maybe a result of gene inversion or splicing deficiency. The relations of such mutations with consanguineous marriage cannot be ruled out. Mutation screening is important in early onset breast cancer patients even if there is no family history. No significant financial relationships to disclose.

scholarly journals Analysis of De Novo Mutations in Sporadic Cardiomyopathies Emphasizes Their Clinical Relevance and Points to Novel Candidate Genes

2020 ◽  
Vol 9 (2) ◽  
pp. 370 ◽  
Author(s):  
Maria Franaszczyk ◽  
Grazyna Truszkowska ◽  
Przemyslaw Chmielewski ◽  
Malgorzata Rydzanicz ◽  
Joanna Kosinska ◽  
...  
Keyword(s):  
Candidate Genes ◽  
De Novo ◽  
Positive Family History ◽  
Disease Onset ◽  
De Novo Mutation ◽  
De Novo Mutations ◽  
Whole Exome ◽  
The Family ◽  
High Prevalence ◽  
Generation Sequencing

The vast majority of cardiomyopathies have an autosomal dominant inheritance; hence, genetic testing is typically offered to patients with a positive family history. A de novo mutation is a new germline mutation not inherited from either parent. The purpose of our study was to search for de novo mutations in patients with cardiomyopathy and no evidence of the disease in the family. Using next-generation sequencing, we analyzed cardiomyopathy genes in 12 probands. In 8 (66.7%), we found de novo variants in known cardiomyopathy genes (TTN, DSP, SCN5A, TNNC1, TPM1, CRYAB, MYH7). In the remaining probands, the analysis was extended to whole exome sequencing in a trio (proband and parents). We found de novo variants in genes that, so far, were not associated with any disease (TRIB3, SLC2A6), a possible disease-causing biallelic genotype (APOBEC gene family), and a de novo mosaic variant without strong evidence of pathogenicity (UNC45A). The high prevalence of de novo mutations emphasizes that genetic screening is also indicated in cases of sporadic cardiomyopathy. Moreover, we have identified novel cardiomyopathy candidate genes that are likely to affect immunological function and/or reaction to stress that could be especially relevant in patients with disease onset associated with infection/infestation.

scholarly journals Non-syndromic patients with infantile spasms and malformations of cortical development: absence of seizures in siblings

2015 ◽  
Author(s):  
Vijay N Tiwari ◽  
Harry T Chugani ◽  
William J Kupsky ◽  
AHM M Huq
Keyword(s):  
De Novo ◽  
Cortical Development ◽  
Recurrence Risk ◽  
Infantile Spasms ◽  
Pathological Diagnosis ◽  
Dysembryoplastic Neuroepithelial Tumor ◽  
De Novo Mutations ◽  
Migration Disorder ◽  
History Of ◽  
Sibling Recurrence Risk

Background: Parents of children with infantile spasms undergoing epilepsy surgery typically inquire about the risk of other children for a similar affliction.  Here, we determined whether non-syndromic patients with infantile spasms and malformation of cortical development (MCD) have a family history of seizures, particularly in siblings.Patients and methods: We selected 29 children with intractable infantile/epileptic spasms who underwent surgery (mean age at surgery:  4.4±3.8 years; 12 males, 17 females; age range 0.8-14.9 years). A pathological diagnosis of MCD was confirmed in all the patients. Family (including parents, and siblings) history of seizures was acquired in all patients through neurology chart review/telephonic interview.Results: Pathological diagnosis of migration disorder (16) and cortical dysplasia (9) was made in these patients.  Diagnosis of hemimegalencephaly, dysembryoplastic neuroepithelial tumor (DNET), lissencephaly type1 and porencephaly was also confirmed in 4 different patients. None of the siblings in any family (total number of siblings in the group = 30) were affected by infantile spasms or other types of seizures. The maternal aunt of one patient and mother of another patient had a history of childhood seizures for short durations.Conclusions: Our retrospective study showed that patients with infantile spasms with MCD who underwent resective surgery have low sibling recurrence risk for seizures.  Our study suggests that de novo mutations and non-genetic or epigenetic factors are major causes of infantile spasms due to MCD.

Neonatal Cyanosis Due to a Novel Fetal M-Hemoglobin: Hemoglobin F-M Circleville (Gγ63 His→Leu).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3806-3806
Author(s):  
Ferdane Kutlar ◽  
Richard Shell ◽  
Joan Atkin ◽  
Dedrey Elam ◽  
Leslie Holley ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
De Novo ◽  
Postnatal Period ◽  
De Novo Mutations ◽  
Reverse Phase Hplc ◽  
Hemoglobin F ◽  
The Family ◽  
Novel Variant ◽  
Hb S ◽  
Hemoglobin Variants

Abstract Neonatal cyanosis can result from a multitude of acquired and inherited causes. Cyanosis resulting from fetal M-Hemoglobin variants is a rare cause of this condition. In fact, to date, only two Gγ variants causing methemoglobinemia and cyanosis in the newborn have been reported. These are Hb F-M Osaka (Gγ63 His→Tyr) and Hb F-M Fort Ripley (Gγ92 His→Tyr). We report a novel fetal M-hemoglobin presenting with neonatal cyanosis. The propositus was a 1-day old Caucasian male admitted to the hospital because of cyanotic episodes. The patient had an O2 saturation of 85% on room air and required supplemental O2 during his 10-day hospitalization. The family history was significant for a 4-year old sister having a 5-day hospitalization after delivery for cyanosis. The sister required supplemental O2 for 4–5 months to maintain a satisfactory O2 saturation. Both parents were healthy and had no recollection of neonatal cyanosis or O2 requirement. The newborn screening for hemoglobinopathies reportedly showed Hb F, A, and a variant migrating between Hb S and Hb F. Cation exchange HPLC performed at 1-month of age revealed 68.4% Hb F; 17.5% Hb A, and 14.0% Hb X, eluting between Hb F and Hb A. Reverse phase HPLC showed only βA, αa, Gγ, and Aγ chains without any detectable abnormal chains. O2 affinity showed a P50 of 24.2mmHg (control 23.4mmHg). Sequencing of the PCR amplified Gγ gene revealed heterozygosity for a CAT→CTT mutation (His→Leu) at codon 63. (GenBank Acession # AY662983). This novel variant was named Hb F-Circleville [GγE7(63)His→Leu]. The M-hemoglobins arise from mutations in the conserved proximal (F8) or distal (E7) histidine residues, which are important heme contacts. Substitution of these residues lead to methemoglobinemia and cyanosis. Fetal Hb variants causing methemoglobinemia are rare causes of neonatal cyanosis. Hb F-Circleville is only the third fetal M-Hb reported to date. The prognosis of cyanosis is excellent in these cases, as Hb F declines post natally and is replaced by normal Hb A. Supplemental O2 may be required for several months during the postnatal period as was the case with this patient. Some fetal M-Hbs have been shown to arise as de novo mutations. In our case, an older sister and the mother were both proven to carry the Gγ63 His→Leu mutation consistent with autosomal dominant inheritance.

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