Neonatal Marfan Syndrome: Report of a Case with an Inherited Splicing Mutation outside the Neonatal Domain.
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SUBMITTER: Le Gloan L
PROVIDER: S-EPMC4802997 | biostudies-literature | 2016 Feb
REPOSITORIES: biostudies-literature
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Neonatal Marfan Syndrome: Report of a Case with an Inherited Splicing Mutation outside the Neonatal Domain.
Le Gloan Laurianne L Hauet Quentin Q David Albert A Hanna Nadine N Arfeuille Chloé C Arnaud Pauline P Boileau Catherine C Romefort Bénédicte B Benbrik Nadir N Gournay Véronique V Joram Nicolas N Baron Olivier O Isidor Bertrand B
Molecular syndromology 20160202 6
We report a child and her mother affected by Marfan syndrome. The child presented with a phenotype of neonatal Marfan syndrome, revealed by acute and refractory heart failure, finally leading to death within the first 4 months of life. Her mother had a common clinical presentation. Genetic analysis revealed an inherited FBN1 mutation. This intronic mutation (c.6163+3_6163+6del), undescribed to date, leads to exon 49 skipping, corresponding to in-frame deletion of 42 amino acids (p.Ile2014_Asp205 ...[more]
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Project description:RationaleMarfan syndrome (MFS) has been defined as a genetic disorder that affects various systems such as the musculoskeletal, orbital, and cardiovascular systems. Neonatal MFS is considered rare and the most severe form of MFS is characterized by rapidly progressive atrioventricular valve dysfunction, often leading to death during early childhood due to congestive heart failure.Patient concernsA newborn with neonatal MFS and severe cardiac involvement. He presented various severe clinical features such as arachnodactyly, camptodactyly, elbow and knee joint contracture, senile facial appearance, and deep settling with down-slanting palpebral fissure, hypoplastic ear cartilage, sagging mouth, brachycephaly, and ectopia lentis.DiagnosisGenetic analysis revealed a novel mutation at nucleotide 3964 (c.3964 + 1 G > T) in intron 32 of the fibrillin-1 gene. This mutation is identified to be in the so-called neonatal region of fibrillin-1 exon 24 to 32, as reported previously.InterventionsThe patient was managed medically for improving the low cardiac output according to severe mitral regurgitation and aortic regurgitation. Afterload reduction, full sedation, and use of diuretic were attempted to improve the oliguria and heart failure.OutcomesDespite the medical management, aortic regurgitation, mitral regurgitation, pulmonary hypertension, and cardiac contractility got worse. Surgical treatment is essential to prolong the patient's life, however, considerations for the grave progression of the disease make families decide to continue palliative care instead of surgical treatment. A few months after birth, he presented with rapidly progressive aortic regurgitation, mitral regurgitation, and congestive heart failure leading to death.ConclusionsThis review demonstrated the prominent characteristics of neonatal MFS mutations, it would be helpful for the recognition of novel neonatal MFS variants and valuable for the understanding of the genotype-phenotype correlations and using the plans for managements and counseling in neonatal MFS.
| S-EPMC10545169 | biostudies-literature
Project description:BackgroundMarfan syndrome (MFS) is a heritable disorder of connective tissue resulting from pathogenic variants of the fibrillin-1 gene (FBN1). Neonatal Marfan syndrome (nMFS) is rare and the most severe form of MFS, involving rapidly progressive cardiovascular dysfunction leading to death during early childhood. The constant enrichment of the nMFS mutation spectrum is helpful to improve our understanding of genotype-phenotype correlations in the disease. Herein, we report a novel dominant mutation in exon 26 of FBN1 (c.3331 T > C) in a sporadic case with nMFS.Case presentationAn 8-month-old Han Chinese girl presented with the classic nMFS phenotype, including prominent manifestations of bone overgrowth, aortic root dilatation, and multiple cardiac valve dysfunctions. Genetic analysis revealed that she was heterozygous for a de novo FBN1 missense mutation (c.3331 T > C). The mutation leads to the substitution of a highly conserved FBN1 cysteine residue (p.Cys1111Arg), which is likely to severely perturb the FBN1 structure because of an alteration of the disulfide bond pattern in the calcium-binding epidermal growth factor-like (cbEGF) 12 domain. This variant was absent in 208 ethnically matched controls, providing further evidence that it may be causative of nMFS. An analysis of nMFS-associated mutations from the UMD-FBN1 database indicates that those de novo mutations altering disulfide bonds or Ca(2+) binding sites of the cbEGF domains encoded by exons 25-33, and a lack of phenotypic heterogeneity may be associated with an increased risk for nMFS.ConclusionWe diagnosed an infant with rare nMFS showing rapidly progressive cardiovascular dysfunction and widely systemic features. As the only causal FBN1 mutation identified in the patient, the missense mutation c.3331 T > C (p.Cys1111Arg) was associated with the severe phenotype of MFS. However, the pathogenicity of the novel mutation needs further confirmation in other patients with nMFS. Our review of the prominent characteristics of nMFS mutations relative to classic or incomplete MFS-related mutations will be helpful for the recognition of novel nMFS-associated variants.
| S-EPMC4852411 | biostudies-literature
Project description:BackgroundPersistent neonatal hypoglycemia, owing to the possibility of severe neurodevelopmental consequences, is a leading cause of neonatal care admission. Hyperinsulinemic hypoglycemia is often resistant to dextrose infusion and needs rapid diagnosis and treatment. Several congenital conditions, from single gene defects to genetic syndromes should be considered in the diagnostic approach. Kabuki syndrome type 1 (MIM# 147920) and Kabuki syndrome type 2 (MIM# 300867), can be associated with neonatal hyperinsulinemic hypoglycemia.Patient presentationWe report a female Italian (Sicilian) child, born preterm at 35 weeks gestation, with persistent hypoglycemia. Peculiar facial dysmorphisms, neonatal hypotonia, and cerebellar vermis hypoplasia raised suspicion of Kabuki syndrome. Hyperinsulinemic hypoglycemia was confirmed with glucagon test and whole-exome sequencing (WES) found a novel heterozygous splicing-site mutation (c.674-1G > A) in KMT2D gene. Hyperinsulinemic hypoglycemia was successfully treated with diazoxide. At 3 months corrected age for prematurity, a mild global neurodevelopmental delay, postnatal weight and occipitofrontal circumference growth failure were reported.ConclusionsKabuki syndrome should be considered when facing neonatal persistent hypoglycemia. Diazoxide may help to improve hyperinsulinemic hypoglycemia. A multidisciplinary and individualized follow-up should be carried out for early diagnosis and treatment of severe pathological associated conditions.
| S-EPMC7499940 | biostudies-literature
Project description:Neonatal Marfan syndrome (nMFS) is considered to be on the most severe end of the spectrum of type I fibrillinopathies. The common features of nMFS include ascending aortic dilatation, severe mitral and/or tricuspid valve insufficiency, ectopia lentis, arachnodactyly, joint contractures, crumpled ear, loose skin, and pulmonary emphysema.We describe a newborn male diagnosed with nMFS. He presented several atypical features, such as diaphragmatic eventration, severe hydronephrosis with hydroureter, and dilated cisterna magna. Molecular analysis revealed a missense mutation at nucleotide 3217 (c.3217G>A) in exon 26 of the fibrillin-1 (FBN1) gene, resulting in the substitution of a glutamate for a lysine at codon 1073 (E1073K) in the 12th calcium binding epidermal growth factor-like domain of the FBN1 protein. Here we report a rare case of Nmfs with several combined atypical features, such as diaphragmatic eventration, severe hydronephrosis with hydroureter, and dilated cisterna magna. Our report is the first atypical nMFS case with p.Glu1073Lys mutation of FBN1 in Korea and may help clinicians with the diagnosis and follow-up of atypical nMFS.
| S-EPMC5143279 | biostudies-literature
Project description:BackgroundKabuki syndrome (KS) is an autosomal dominant inherited syndrome that involves multiple organs and systems. Gene mutation is the main cause of KS. The reported mutations in X-linked histone H3 lysine 4 methylase (KMT2D) and KDM6A genes are 2 relatively clear pathogenic pathways. In this paper, we report a case of KS with neonatal hypoglycemia and special features caused by KMT2D gene mutation confirmed by whole exome sequencing, it enriched the clinical phenotype spectrum and gene mutation spectrum of KS, which helps to improve the understanding of the disease.Case reportThrough whole exome sequencing, we performed gene diagnosis of a newborn child with special facial features and multiple malformations, which revealed heterozygous mutation of NM_003482.3:c.755dupA(p.His252Glnfs*21) in KMT2D gene. It is consistent with the pathogenesis of KS, an autosomal dominat genetic disease caused by KMT2D gene mutation. This pathogenic mutation has not been prebiously reported.DiscussionKS has strong clinical characteristics and biological heterogeneity. Genetic diagnosis can help identify mutant gene types. However, the relationship between genotype and phenotype has not been fully clarified. The molecular etiological mechanism still needs to be further explored and elucidated.
| S-EPMC10727567 | biostudies-literature
Project description:Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder caused by variants in the extracellular microfibril fibrillin (FBN1) gene. Here we report an FBN1 variant in a child with an unusual skin rash mimicking cutaneous vasculitis, and mild aortic root dilatation. The case was complicated by lack of typical skeletal MFS phenotype; and severe needle phobia preventing any blood testing for workup of suspected vasculitis. Therefore inflammatory markers, autoantibody profile and general hematology/biochemistry results were unknown. Diagnosis of MFS was made via genetic testing of a saliva sample alone using a next-generation sequencing (NGS) targeted gene panel designed to screen for monogenic forms of vasculitis and noninflammatory vasculopathic mimics. This revealed the patient was heterozygous for a pathogenic frameshift variant in FBN1; NM_000138, c.1211delC, p.(Pro404Hisfs*44), predicted to cause premature protein truncation leading to loss of function. The variant has not been detected in control populations and has previously been detected in individuals with MFS. This rapid diagnosis significantly impacted the patient management: avoidance of invasive investigations; avoidance of unnecessary immunosuppression; facilitating genetic counselling of the index case and family; and directly informing lifelong monitoring and ongoing treatment for aortic root involvement from MFS. This case further emphasizes the diagnostic utility of NGS early in the diagnostic workup of paediatric patients referred with suspected vasculitis, and we emphasize that MFS can present with cutaneous vasculitic-like features in the absence of the typical Marfanoid skeletal phenotype.
| S-EPMC10308279 | biostudies-literature
Project description:BackgroundNeonatal Marfan syndrome (nMFS), the most severe form of Marfan syndrome, is a rare condition that presents a clinical and treatment challenge. nMFS has high infant mortality related to progressive valvular dysfunction. Valve replacement in this setting improves long-term prognosis but carries high morbidity and mortality. Thus, sharing clinical experience in treating such patients is valuable.Case summaryA 2 year old with nMFS underwent tricuspid valve annuloplasty and prosthetic mitral valve replacement. Postoperative management was complicated by pulmonary hypertension, cardiogenic shock, and arrythmias. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) helped overcome these challenges but posed a high risk for prosthetic valve thrombosis (PVT). Despite decompression of the left atrium (LA) with an LA vent, the left ventricle (LV) was distended because of aortic regurgitation and no native cardiac output. We lowered the ECMO flow under echocardiographic guidance; used inodilators and pacing to encourage transmitral flow and reduce LV afterload. The patient completed a successful 6-day ECMO run with good end-organ perfusion. At last follow up, she was 6 years old, enjoying school, home-ventilated through the tracheostomy, and mobilizing with walking aids/wheelchair.DiscussionValve replacement can improve life quality and expectancy for patients with nMFS. Lowering ECMO flow under echocardiography guidance till the aortic valve is seen to open; coupled with inodilators, pacing and adequate anticoagulation can be a safe way to deliver VA-ECMO for cardiogenic shock after prosthetic valve replacement. Further research is needed to show if this strategy prevents prosthetic valve thrombosis and provides sufficient haemodynamic support and myocardial rest.
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Project description:RationaleKBG syndrome (KBGS, OMIM: 148050), a rare genetic disorder, is clinically characterized by megalodontia, short stature, skeletal abnormalities, and nervous system manifestations. In the study, we explore the clinical and genetic characteristics of one neonate suffering KBGS caused by ANKRD11 gene mutation.Patient concernsThe proband, a female, was born prematurely at 31 + 2 weeks. There were repeated infections and abdominal distension in the first month after birth, and the platelets could not rise to normal. Head ultrasound showed intracranial brain injury and intracranial hemorrhage.DiagnosesSequencing revealed that there was a heterozygous mutation in exon 9 of the ANKRD11 gene (NM_013275.5) for the child, c.1896_1897delTA (p.H632Qfs*30), which was a de novo mutation and has not been reported. Combining clinical features and genetic results, the proband was diagnosed as KBGS.Interventions and outcomesThe brain sonography on day 4 after birth showed brain injury and intracranial hemorrhage. Therefore, 140 mg of bovine lung surfactant was administered through endotracheal intubation in addition to ventilator-assisted ventilation. Antibiotic treatment was also given till the inflammatory indicators of the infant returned to normal levels. The following-up of 1-year-6-month showed that the language, motion and height of development is slight falling behind the children of the same age.LessonsThis is the first case of KBGS was diagnosed in the neonatal period, which provides a reference for the child to receive timely and correct treatment.
| S-EPMC10553122 | biostudies-literature
Project description:Marfan syndrome (MFS) is a genetic disorder of the connective tissue which rarely manifests in the neonatal period and has an ominous prognosis. A case of a first female offspring of healthy parents is described here. The pregnancy was uneventful and the mother had a term caesarean delivery. At birth, some dysmorphic signs became apparent, such as loose redundant skin, dolichocephaly, frontal bossing, deeply sunken eyes, micrognathia, contractures of the elbows, arachnodactyly and hip dysplasia. The echocardiogram showed a mitral and tricuspid valve regurgitation and a long aortic arch. The diagnosis of neonatal MFS came forward and genetic studies revealed a de novo mutation in the fibrillin 1 (FBN1) gene. At 6 months, due to a progressive worsening of the cardiac pathology, she was submitted to mitral valvuloplasty. She is now 2 years and 10 months old, which is a remarkable feat for a child suffering from this condition.
| S-EPMC4069814 | biostudies-literature
Project description:BackgroundMarfan syndrome (MFS) is an autosomal dominant multisystem connective tissue disorder with increased risk of aortopathy with a high risk of subsequent life-threatening aortic dissection. Diagnosing this condition is reliant on recognizing clinical features and genetic testing for confirming diagnosis, using the revised Ghent criteria.Case summaryWe identified a 49-year-old patient who presented with dyspnoea, with Marfan syndrome (MFS) and a previously unreported variant in the fibrillin-1 gene (FBN1), designated c.7016G>C. Prior to identifying the new gene variant, this patient did not meet the revised Ghent criteria for MFS diagnosis. We present clinical and molecular evidence supporting the likely pathogenic nature of this variant, leading to earlier therapy and intervention.DiscussionThe discovery of a new pathogenic gene will expand the current aortopathy and MFS database and may lead to more informed clinical management decisions for the timing and nature of interventions.
| S-EPMC8972828 | biostudies-literature