Massive pericardial effusion in an infant with Aymé-Gripp syndrome: A case report and review of the literature.

Aymé-Gripp syndrome (AYGRPS) is a multisystemic disorder caused by a subset of pathogenic variants in the MAF gene. Major clinical features include bilateral early cataracts, sensorineural hearing loss (SNHL), and a characteristic facial appearance along with variable neurodevelopmental delay. Pericarditis resulting in pericardial effusion of varying degree has been observed in a subset of affected individuals and could represent a severe feature in neonatal or infantile age. Here, we describe a syndromic infant with massive pericardial effusion and craniofacial features that oriented toward the suspicion of AYGRPS, which was subsequently confirmed by the molecular analysis of MAF. Pericardial effusion was first observed prenatally and documented to be recurrent, progressive, and severe in the first months of life, thus requiring pericardiocentesis and surgical procedures. In this report, we provide further delineation of the minor clinical characteristics, particularly focusing on cardiac features of AYGRPS. A dedicated cardiac surveillance of these findings may help reduce the morbidity and mortality of this rare condition.

Neonatal diagnosis of ACTA2-related disease: A case report and review of literature.

Multisystemic smooth muscle dysfunction syndrome (MSMDS, OMIM # 613834) is a rare autosomal dominant condition caused by pathogenetic variants of ACTA2 gene that result in impaired muscle contraction. MSMDS is characterized by an increased susceptibility to aneurismal dilatations and dissections, patent ductus arteriosus, early onset coronary artery disease, congenital mydriasis, chronic interstitial lung disease, hypoperistalsis, hydrops of gall bladder, and hypotonic bladder. Here, we report an early diagnosis of a MSMDS related to ACTA2 p.Arg179His (R179H) mutation in a newborn and performed a review of the literature. An early diagnosis of MSMDS is extremely important, because of the severe involvement of cardiovascular system in the MSMDS. Multidisciplinary care and surveillance and timely management of symptoms are important to reduce the risk of complications.

8p23.1 deletion: Look out for left ventricular hypertrabeculation and not only congenital heart diseases. Single-center experience and literature revision.

Deletions involving the distal portion of the short arm of chromosome 8(8p23.1) show a high phenotypic variability. Congenital heart diseases (CHD) are often described. GATA4 when mutated or deleted is reported to be involved in cardiac morphogenesis. Only twice, left ventricular non compaction (LVNC) was reported in literature in association with 8p23.1 deletion. The present cohort includes five new patients with 8p23.1 deletions including GATA4. The spectrum of CHD is variable. Moreover, in four patients, LV hypertrabeculation was detected and in the fifth LVNC was recognized. Literature revision identified 45 patients with 8p23.1 deletions (encompassing GATA4) and heart involvement. It included wide spectrum of CHD including: heterotaxy spectrum 7/45 (15, 6%), atrioventricular canal 14/45 (balanced 3/45 including two of them with hypoplastic aortic arch; unbalanced 4/45, Fallot-AVC 1/45, partial AVC 3/45, unspecified 3/45), predominant major left heart lesions included 2/45 (4, 4%): interrupted aortic arch and hypoplastic left heart syndrome. Left ventricular hypertrabeculation might be potentially underestimated in patients with 8p23.1 deletion. These might suggest the importance of including microarray analysis in this group of patients. Moreover, 8p23.1 microdeletion or GATA4 variants can be considered in heterotaxy genetic panels.

Clinical and molecular characterizations of 11 new patients with type 1 Feingold syndrome: Proposal for selecting diagnostic criteria and further genetic testing in patients with severe phenotype.

Feingold Syndrome type 1 (FS1) is an autosomal dominant disorder due to a loss of function mutations in the MYCN gene. FS1 is generally clinically characterized by mild learning disability, microcephaly, short palpebral fissures, short stature, brachymesophalangy, hypoplastic thumbs, as well as syndactyly of toes, variably associated with organ abnormalities, the most common being gastrointestinal atresia. In current literature, more than 120 FS1 patients have been described, but diagnostic criteria are not well agreed upon, likewise the genotype-phenotype correlations are not well understood. Here, we describe 11 FS1 patients, belonging to six distinct families, where we have identified three novel MYCN mutations along with three pathogenetic variants, the latter which have already been reported. Several patients presented a mild phenotype of the condition and they have been diagnosed as being affected only after segregation analyses of the MYCN mutation identified in the propositus. We also describe here the first ever FS1 patient with severe intellectual disability having a maternally inherited MYCN variant together with an additional GNAO1 mutation inherited paternally. Mutations in the GNAO1 gene are associated with a specific form of intellectual disability and epilepsy, thus the finding of two different rare diseases in the same patient could explain his severe phenotype. Therein, a thorough investigation is merited into the possibility that additional variants in patients with a MYCN mutation and severe phenotype do exist. Finally, in order to guarantee a more reliable diagnosis of FS1, we suggest using both major and minor clinical-molecular diagnostic criteria.

Delayed appearance of 3-methylglutaconic aciduria in neonates with early onset metabolic cardiomyopathies: A potential pitfall for the diagnosis.

Infantile onset cardiomyopathies are highly heterogeneous with several phenocopies compared with adult cardiomyopathies. Multidisciplinary management is essential in determining the underlying etiology in children's cardiomyopathy. Elevated urinary excretion of 3-methylglutaconic acid (3-MGA) is a useful tool in identifying the etiology in some metabolic cardiomyopathy. Here, we report the delayed appearance of 3-MGA-uria, between 6 and 18 months in three patients (out of 100 childhood onset cardiomyopathy) with neonatal onset cardiomyopathy, secondary to TMEM70 mutations and TAZ mutations (Barth syndrome), in whom extensive metabolic investigations, performed in the first weeks of life, did not display 3-MGA-uria. Serial retrospective evaluations showed full characteristic features of TMEM70 and TAZ mutations (Barth syndrome) in these three patients, including a clearly abnormal monolysocardiolipin/cardiolipin ratio in the two Barth syndrome patients. Serially repeated metabolic investigations finally discovered the 3-MGA-uria biomarker in all three patients between the age of 6 and 18 months. Our observation provides novel insights into the temporal appearance of 3-MGA-uria in TMEM70 and TAZ mutations (Barth syndrome) and focus the importance of multidisciplinary management and careful evaluation of family history and red flag signs for phenocopies in infantile onset cardiomyopathies.

Familial aggregation of "apple peel" intestinal atresia and cardiac left-sided obstructive lesions: A possible causal relationship with NOTCH1 gene mutations.

"Apple peel" intestinal atresia is a rare form of small bowel atresia, in which the duodenum or proximal jejunum ends in a blind pouch and the distal small bowel wraps around its vascular supply, in a spiral resembling an apple peel. The etiology of "apple peel" intestinal atresia is presently unknown, although a congenital or acquired intestinal vascular accident can have a role in the pathogenesis. We report a family in which the proband affected by "apple peel" intestinal atresia, had a sibling (an interrupted pregnancy), and a paternal cousin with cardiac left-sided obstructive lesions. Molecular testing for NOTCH1 gene was carried out in the proband, because pathogenic mutations in this gene have been associated with familial and sporadic cardiac left-sided obstructive lesions and vascular anomalies, both isolated or within the spectrum of the Adams-Oliver syndrome (AOS). The heterozygous c.2734C>T (p.Arg912Trp) NOTCH1 variant was found in the proband with "apple peel" intestinal atresia and in his father. This result argues for a possible causal relationship between NOTCH1 gene mutations and some forms of intestinal defects, through a vascular mechanism. The spectrum of NOTCH1-associated malformations is widened. Genetic counseling should take into account intrafamilial variable clinical expression and incomplete penetrance.

First evidence of maternally inherited mosaicism in TGFBR1 and subtle primary myocardial changes in Loeys-Dietz syndrome: a case report.

BACKGROUND: Loeys-Dietz syndrome (LDS) is a rare multisystemic disorder characterized by vascular and skeletal abnormalities, with considerable intra- and interfamilial variability. CASE PRESENTATION: We report the case of an 8-year-old male with clinical features of two distinct genetic disorders, namely LDS, manifesting in the first months by progressive aortic root dilatation, arterial tortuosity, bifid uvula, and inguinal hernias and oculocutaneous albinism (OCA) manifesting by white hair and skin that does not tan, nystagmus, reduced iris pigment with iris translucency, and reduced retinal pigment). We identified previously reported, homozygous mutations of TYR, c.1A > G (p.Met1Val) and heterozygous, missense mutation of TGFBR1, c.1460G > A (p.Arg487Gln). Family history revealed that his mother underwent multiple surgical repairs for recurrent hemorrhage originating from the buccal artery. Molecular studies confirmed a maternally inherited low grade TGFBR1 mutation somatic mosaicism (18% in peripheral blood leukocytes, 18% in buccal cells and 10% in hair root cells). Maternal cardiac investigations revealed peculiar cardiovascular features: mild tortuosity at the aortic arch, dilatation of the proximal abdominal aorta, multiple deep left ventricular myocardial crypts, and dysplastic mitral valve. TGFBR2 germline mosaicism has been described in three fathers of children carrying TGFBR2 mutations but, to the best of our knowledge, no case of maternally inherited TGFBR1 mutation mosaicism has been reported so far. CONCLUSIONS: This case report suggests that individuals with somatic mosaicism might be at risk for mild and unusual forms of LDS but germline mosaicism can lead to full blown picture of the disease in offspring.

Small 4p16.3 deletions: Three additional patients and review of the literature.

Wolf-Hirschhorn syndrome is a well-defined disorder due to 4p16.3 deletion, characterized by distinct facial features, intellectual disability, prenatal and postnatal growth retardation, and seizures. Genotype-phenotype correlations based on differently sized deletions have been attempted, and some candidate genes have been suggested. We report on clinical characteristics of three patients with pure interstitial submicroscopic 4p16.3 deletions, ranging in size from 68 to 166 kb, involving WHSCR1 and/or part of WHSCR2, and review published cases with overlapping 4p16.3 losses. The present study highlights a major role of NSD2 gene in the pathogenesis of the WHS main features and predicts that loss-of-function mutations affecting NSD2 gene could result in microcephaly, prenatal and postnatal growth retardation, psychomotor and language delay, and craniofacial features. Absent seizures in all subjects corroborate the suggestion that this specific feature is causally linked with at least one additional causative gene. Finally, we suggest that mir-943 could play a role in the pathogenesis of CHD in some of these patients.

Structural, Functional, and Clinical Characterization of a Novel PTPN11 Mutation Cluster Underlying Noonan Syndrome.

Germline mutations in PTPN11, the gene encoding the Src-homology 2 (SH2) domain-containing protein tyrosine phosphatase (SHP2), cause Noonan syndrome (NS), a relatively common, clinically variable, multisystem disorder. Here, we report on the identification of five different PTPN11 missense changes affecting residues Leu261 , Leu262 , and Arg265 in 16 unrelated individuals with clinical diagnosis of NS or with features suggestive for this disorder, specifying a novel disease-causing mutation cluster. Expression of the mutant proteins in HEK293T cells documented their activating role on MAPK signaling. Structural data predicted a gain-of-function role of substitutions at residues Leu262 and Arg265 exerted by disruption of the N-SH2/PTP autoinhibitory interaction. Molecular dynamics simulations suggested a more complex behavior for changes affecting Leu261 , with possible impact on SHP2's catalytic activity/selectivity and proper interaction of the PTP domain with the regulatory SH2 domains. Consistent with that, biochemical data indicated that substitutions at codons 262 and 265 increased the catalytic activity of the phosphatase, while those affecting codon 261 were only moderately activating but impacted substrate specificity. Remarkably, these mutations underlie a relatively mild form of NS characterized by low prevalence of cardiac defects, short stature, and cognitive and behavioral issues, as well as less evident typical facial features.

Myoclonic status and central fever in Angelman syndrome due to paternal uniparental disomy.

Myoclonic status in nonprogressive encephalopathy (MSNE) is an early-onset, drug-resistant epileptic syndrome characterized by occurrence of continuous diffuse epileptiform abnormalities, associated with positive and/or negative phenomena and accompanied by transient and recurring motor, cognitive, and behavioral impairment. MSNE has been reported in Angelman syndrome (AS) secondary to 15q11-13 deletions or UBE3A mutations but not to paternal uniparental disomy (UPD). We describe the case of a male patient with AS caused by UPD who developed a myoclonic status (MS) associated with long-lasting fever of central origin, both promptly regressed with introduction of levetiracetam. Only three descriptions of thermal dysregulation in AS exist, and none of the previously reported cases were associated with MS or with UPD. Association of MS and central fever expands the spectrum of epileptic and non-epileptic features in UPD-related AS and provides a further evidence of hypothalamus involvement in the pathogenesis of this neurodevelopmental disorder.

Partial atrioventricular canal defect and aortic coarctation associated with variants in GDF1 and NOTCH1 genes: A case report.

BACKGROUND: A peculiar subgroup of patients with partial or complete atrioventricular canal defect exhibits a spectrum of left-sided obstructions including right ventricular dominance and aortic coarctation. The association of atrioventricular canal defect with left-sided obstructions is found in several genetic syndromes; however, the molecular basis of nonsyndromic atrioventricular canal defect with aortic coarctation is still poorly understood. Although some candidate genes for nonsyndromic atrioventricular canal defect are known, a complex oligogenic inheritance determined in some cases by the co-occurrence of multiple variants has also been hypothesized. CASE REPORT: We describe a nonsyndromic infant with mesocardia with viscero-atrial situs solitus, partial atrioventricular canal defect, mild right ventricular dominance, and coarctation of the aorta. Next generation sequencing genetic testing revealed variants in two genes, GDF1 and NOTCH1, previously reported in association with atrioventricular canal defect and left-sided obstructive lesions, respectively. CONCLUSION: The present report could support the hypothesis that the co-occurrence of cumulative variants may be considered as genetic predisposing risk factor for specific congenital heart defects.

A novel mutation in GAS8 gene associated with chronic rhinosinusitis with nasal polyposis in a case of primary ciliary dyskinesia: a case report.

Background: Primary ciliary dyskinesia (PCD) is considered a rare cause of chronic rhinosinusitis with nasal polyposis (CRSwNP), which is reported in 6% of children with PCD. The forms of PCD associated with the variants of the GAS8 gene identified so far seem to be linked to recurrent respiratory infections (sinusitis, otitis, and bronchiectasis) without situs inversus. Case presentation: We report a case of an 11-year-old girl with recurrent otitis media, productive cough, and chronic rhinosinusitis with nasal polyposis with homozygosity for a novel nonsense mutation in the GAS8. Conclusion: Children with CRSwNP should be treated in a multidisciplinary manner (ENT, pulmonologist, allergist, pathologist, pediatrician, and geneticist) because nasal polyposis often hides etiologies that must be recognized.

Biallelic NEXN variants and fetal onset dilated cardiomyopathy: two independent case reports and revision of literature.

BACKGROUND: Dilated cardiomyopathy (DCM) is an etiologically heterogeneous group of diseases of the myocardium. With the rapid evolution in laboratory investigations, genetic background is increasingly determined including many genes with variable penetrance and expressivity. Biallelic NEXN variants are rare in humans and associated with poor prognosis: fetal and perinatal death or severe DCMs in infants. CASE PRESENTATION: We describe two male infants with prenatal diagnosis of dilated cardiomyopathy with impaired ventricular contractility. One of the patients showed hydrops and polyhydramnios. Postnatally, a DCM with severely reduced systolic function was confirmed and required medical treatment. In patient 1, Whole Exome Sequencing (WES) revealed a homozygous NEXN variant: c.1156dup (p.Met386fs) while in patient 2 a custom Next Generation Sequencing (NGS) panel revealed the homozygous NEXN variant c.1579_1584delp. (Glu527_Glu528del). These NEXN variants have not been previously described. Unlike the unfavorable prognosis described for biallelic NEXN variants, we observed in both our patients a favorable clinical course over time. CONCLUSION: This report might help to broaden the present knowledge regarding NEXN biallelic variants and their clinical expression. It might be worthy to consider the inclusion of the NEXN gene sequencing in the investigation of pediatric patients with DCM.

Defining the epsilon-sarcoglycan (SGCE) gene phenotypic signature in myoclonus-dystonia: a reappraisal of genetic testing criteria.

Mutations or exon deletions of the epsilon-sarcoglycan (SGCE) gene cause myoclonus-dystonia (M-D), but a subset of M-D patients are mutation-negative and the sensitivity and specificity of current genetic testing criteria are unknown. We screened 46 newly enrolled M-D patients for SGCE mutations and deletions; moreover, 24 subjects previously testing negative for SGCE mutations underwent gene dosage analysis. In our combined cohorts, we calculated sensitivity, specificity, positive and negative predictive values, and area under the curve of 2 published sets of M-D diagnostic criteria. A stepwise logistic regression was used to assess which patients' characteristics best discriminated mutation carriers and to calculate a new mutation predictive score ("new score"), which we validated in previously published cohorts. Nine of 46 (19.5%) patients of the new cohort carried SCGE mutations, including 5 novel point mutations and 1 whole-gene deletion; in the old cohort, 1 patient with a complex phenotype carried a 5.9-Mb deletion encompassing SGCE. Current diagnostic criteria had a poor ability to discriminate SGCE-positive from SGCE-negative patients in our cohort; conversely, age of onset, especially if associated with psychiatric features (as included in the new score), showed the best discriminatory power to individuate SGCE mutation carriers, both in our cohort and in the validation cohort. Our results suggest that young age at onset of motor symptoms, especially in association with psychiatric disturbance, are strongly predictive for SGCE positivity. We suggest performing gene dosage analysis by multiple ligation-dependent probe amplification (MLPA) to individuate large SGCE deletions that can be responsible for complex phenotypes.

Prenatal CFAP53-related laterality defect: case report and review of the literature.

Laterality defects include morphological anomalies with impaired left-right asymmetry induction, such as dextrocardia, situs inversus abdominis, situs inversus totalis and situs ambiguus. The different arrangement of major organs is called heterotaxy. We describe for the first time a fetus with situs viscerum inversus and azygos continuation of the inferior vena cava, due to previously unreported variants in compound heterozygosity in the CFAP53 gene, whose product is implied in cilial motility. Prenatal trio exome sequencing was performed with turn-around time during the pregnancy. The fetuses with laterality defects are suitable candidates for prenatal exome sequencing due to the emerging high diagnostic rate of this group of morphological anomalies. A timely molecular diagnosis plays a fundamental role in genetic counseling, regarding couple decisions on the ongoing pregnancy, providing recurrence risks, and in predicting possible respiratory complications due to ciliary dyskinesia.

Novel Variant in the USP9X Gene Is Associated with Congenital Heart Disease in a Male Patient: A Case Report and Literature Review.

Introduction: The X-chromosomal USP9X gene encodes a deubiquitylating enzyme involved in protein turnover and TGF-ß signaling during fetal and neuronal development. USP9X variants in females are primarily associated with complete loss-of-function (LOF) alleles, leading to neurodevelopmental delay and intellectual disability, as well as a wide range of congenital anomalies. In contrast, USP9X missense variants in males often result in partial rather than complete LOF, specifically affecting neuronal migration and development. USP9X variants in males are associated with intellectual disability, behavioral disorders, global developmental delay, speech delay, and structural CNS defects. Facial dysmorphisms are found in almost all patients. Case Presentation: We report the case of an Italian boy presenting dysmorphism, intellectual disability, structural brain anomalies, and congenital heart disease. Using next-generation sequencing analysis, we identified a hemizygous de novo variant in the USP9X gene (c.5470A>G, p.Met1824Val) that was never reported in the literature. Conclusion: We provide an overview of the available literature on USP9X variants in males, in order to further expand the genotypic and phenotypic landscape of male-restricted X-linked mental retardation syndrome. Our findings confirm the involvement of USP9X variants in neuronal development and corroborate the possible association between the novel USP9X variant and congenital heart malformation.

Biallelic truncating variants in children with titinopathy represent a recognizable condition with distinctive muscular and cardiac characteristics: a report on five patients.

Background: Monoallelic and biallelic TTN truncating variants (TTNtv) may be responsible for a wide spectrum of musculoskeletal and cardiac disorders with different age at onset. Although the prevalence of heterozygous TTNtv is relatively high in the general population, cardiac phenotyping (mainly cardiomyopathies, CMPs) in biallelic titinopathy has rarely been described in children. Methods: We reviewed the medical records of pediatric patients with biallelic TTNtv and cardiac involvement. Clinical exome sequencing excluded pathogenic/likely pathogenic variants in major CMP genes. Results: Five pediatric patients (four male) with biallelic TTNtv were included. Major arthrogryposis multiplex was observed in four patients; no patient showed intellectual disability. At a cardiac level, congenital heart defects (atrial and ventricular septal defects, n = 3) and left ventricular non-compaction (n = 1) were reported. All patients had dilated cardiomyopathy (DCM) diagnosed at birth in one patient and at the age of 10, 13, 14, and 17 years in the other four patients. Heart rhythm monitoring showed tachyarrhythmias (premature ventricular contractions, n = 2; non-sustained ventricular tachycardia, n = 2) and nocturnal first-degree atrio-ventricular block (n = 2). Cardiac magnetic resonance (CMR) imaging was performed in all patients and revealed a peculiar late gadolinium enhancement distribution in three patients. HyperCKemia was present in two patients and end-stage heart failure in four. End-organ damage requiring heart transplantation (HT) was indicated in two patients, who were operated on successfully. Conclusion: Biallelic TTNtv should be considered when evaluating children with severe and early-onset DCM, particularly if skeletal and muscular abnormalities are present, e.g., arthrogryposis multiplex and congenital progressive myopathy. End-stage heart failure is common and may require HT.

FOXI3 pathogenic variants cause one form of craniofacial microsomia.

Craniofacial microsomia (CFM; also known as Goldenhar syndrome), is a craniofacial developmental disorder of variable expressivity and severity with a recognizable set of abnormalities. These birth defects are associated with structures derived from the first and second pharyngeal arches, can occur unilaterally and include ear dysplasia, microtia, preauricular tags and pits, facial asymmetry and other malformations. The inheritance pattern is controversial, and the molecular etiology of this syndrome is largely unknown. A total of 670 patients belonging to unrelated pedigrees with European and Chinese ancestry with CFM, are investigated. We identify 18 likely pathogenic variants in 21 probands (3.1%) in FOXI3. Biochemical experiments on transcriptional activity and subcellular localization of the likely pathogenic FOXI3 variants, and knock-in mouse studies strongly support the involvement of FOXI3 in CFM. Our findings indicate autosomal dominant inheritance with reduced penetrance, and/or autosomal recessive inheritance. The phenotypic expression of the FOXI3 variants is variable. The penetrance of the likely pathogenic variants in the seemingly dominant form is reduced, since a considerable number of such variants in affected individuals were inherited from non-affected parents. Here we provide suggestive evidence that common variation in the FOXI3 allele in trans with the pathogenic variant could modify the phenotypic severity and accounts for the incomplete penetrance.

ATM gene alterations in chronic lymphocytic leukemia patients induce a distinct gene expression profile and predict disease progression.

BACKGROUND: The genetic characterization of chronic lymphocytic leukemia cells correlates with the behavior, progression and response to treatment of the disease. DESIGN AND METHODS: Our aim was to investigate the role of ATM gene alterations, their biological consequences and their value in predicting disease progression. The ATM gene was analyzed by denaturing high performance liquid chromatography and multiplex ligation probe amplification in a series of patients at diagnosis. The results were correlated with immunoglobulin gene mutations, cytogenetic abnormalities, ZAP-70 and CD38 expression, TP53 mutations, gene expression profile and treatment-free interval. RESULTS: Mutational screening of the ATM gene identified point mutations in 8/57 cases (14%). Multiplex ligation probe amplification analysis identified six patients with 11q deletion: all of them had at least 20% of deleted cells, analyzed by fluorescent in situ hybridization. Overall, ATM point mutations and deletions were detected in 14/57 (24.6%) cases at presentation, representing the most common unfavorable genetic anomalies in chronic lymphocytic leukemia, also in stage A patients. Patients with deleted or mutated ATM had a significantly shorter treatment-free interval compared to patients without ATM alterations. ATM-mutated cases had a peculiar gene expression profile characterized by the deregulation of genes involved in apoptosis and DNA repair. Finally, definition of the structure of the ATM-mutated protein led to a hypothesis that functional abnormalities are responsible for the unfavorable clinical course of patients carrying these point mutations. CONCLUSIONS: ATM alterations are present at diagnosis in about 25% of individuals with chronic lymphocytic leukemia; these alterations are associated with a peculiar gene expression pattern and a shorter treatment-free interval.