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Maria Cristina Digilio

Publications and source records attributed to Maria Cristina Digilio.

At least 19 recordsLinked to original sources
PubMed2025

Neonatal diabetes-associated missense PDX1 variant disrupts chromatin association and protein-protein interaction.

PDX1 mutations are associated with multiple forms of diabetes, including syndromic, neonatal, mature onset diabetes of the young (MODY), and type 2 diabetes. Two PDX1 missense mutations (Thr151Met and Asn196Thr) were identified in a pediatric female patient that cause permanent neonatal diabetes, pancreas hypoplasia, and a malformed gallbladder. We found that the mouse Pdx1 Asn197Thr variant (homologous to human PDX1 Asn196Thr), but not Pdx1 Thr152Met (homologous to human PDX1 Thr151Met), altered its nuclear localization and disrupted the PDX1-ONECUT1 interaction. Neither variant substantially affected PDX1 protein stability, but both reduced PDX1 binding to the Pdx1 gene promoter. Importantly, the Pdx1 Asn197Thr variant caused pancreas agenesis and reduced enteroendocrine cells in the duodenum in genetically engineered mice, due at least in part to reduced Pdx1 promoter binding and disrupted PDX1-ONECUT1 interaction.

Homeodomain Proteins↗
PubMed2025

AUTS2-related syndrome: Insights from a large European cohort.

PURPOSE: AUTS2-related syndrome is characterized by developmental delay, autism spectrum disorder, and intellectual disability. From alternative promoters, AUTS2 encodes 2 distinct long and short isoforms encoding a putative transcriptional activator. METHODS: Through a European collaborative study, we collected clinical and genotype data on the largest AUTS2-related syndrome cohort of 58 patients harboring genomic rearrangements or single-nucleotide variants (SNVs). RESULTS: Pathogenic SNVs were recurrently found in individuals from different countries, suggesting mutational hotspots. Independent of the underlying defect at the AUTS2 locus, we observed that autistic behavior, hyperactivity, learning difficulties, and speech delay are common features of AUTS2-related syndrome. Among patients with SNVs, individuals carrying pathogenic variants affecting both longer and shorter AUTS2 transcripts showed a recognizable phenotype with microcephaly, brachycephaly, microretrognathia, broad nasal base, and anteverted nares. Behavioral disorders were more common in patients with variants affecting only the longer isoform. Arthrogryposis and stiff movements were only observed in patients with SNVs. CONCLUSION: This study provides a comprehensive clinical characterization of AUTS2-related syndrome, reveals few genotype-phenotype correlations, and suggests that the disruption of the 2 distinct AUTS2 transcripts has a different impact on the clinical phenotype.

Humans↗
PubMed2007

Thyroid morphology and subclinical hypothyroidism in children and adolescents with Williams syndrome.

OBJECTIVE: To verify the prevalence of morpho-volumetric and functional thyroid abnormalities in young patients with Williams syndrome (WS). STUDY DESIGN: Ninety-two patients with WS (49 boys and 43 girls, 0.2-17.2 years of age) underwent evaluation of thyroid function by means of thyroid-stimulating hormone (TSH), fT3, and fT4 measurement. Thyroid ultrasonography was performed in 37 patients. Thyroid antibodies (thyroid peroxidase and thyroglobulin) were measured in all patients with abnormal thyroid function tests. RESULTS: None of our patients had overt hypothyroidism; 29 patients (31.5%) had subclinical hypothyroidism. Thyroid antibodies were absent in all patients. The prevalence of patients with subclinical hypothyroidism was significantly higher in the younger patients. Ultrasonography revealed morphological or volumetric abnormalities of the thyroid gland in 67.5% of patients; these abnormalities were more frequently observed in the older children. CONCLUSIONS: Subclinical hypothyroidism is a frequent but stable finding in young children with WS. The great majority of patients with WS >10 years, either with normal or hypoplastic thyroid, have normal thyroid function. Therefore, we suggest yearly monitoring of thyroid function and sonographic studies at least once in patients with WS. Treatment should be reserved for the patients with overt hypothyroidism or for those whose thyroid function shows signs of progressive deterioration.

Adolescent↗
PubMed2006

Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome.

Noonan syndrome is a developmental disorder characterized by short stature, facial dysmorphia, congenital heart defects and skeletal anomalies. Increased RAS-mitogen-activated protein kinase (MAPK) signaling due to PTPN11 and KRAS mutations causes 50% of cases of Noonan syndrome. Here, we report that 22 of 129 individuals with Noonan syndrome without PTPN11 or KRAS mutation have missense mutations in SOS1, which encodes a RAS-specific guanine nucleotide exchange factor. SOS1 mutations cluster at codons encoding residues implicated in the maintenance of SOS1 in its autoinhibited form. In addition, ectopic expression of two Noonan syndrome-associated mutants induces enhanced RAS and ERK activation. The phenotype associated with SOS1 defects lies within the Noonan syndrome spectrum but is distinctive, with a high prevalence of ectodermal abnormalities but generally normal development and linear growth. Our findings implicate gain-of-function mutations in a RAS guanine nucleotide exchange factor in disease for the first time and define a new mechanism by which upregulation of the RAS pathway can profoundly change human development.

Animals↗
PubMed2006

Genetic heterogeneity and phenotypic anomalies in children with atrioventricular canal defect and tetralogy of Fallot.

Tetralogy of Fallot associated with the atrioventricular canal defect has been usually reported in association with Down syndrome. The aim of the present study was to describe the cardiac aspects and the genetic anomalies in children with this association of heart defects. We identified 64 patients with atrioventricular canal defect tetralogy of Fallot. All children underwent complete cardiovascular, clinical phenotypic and genetic evaluation. A genetic syndrome or extracardiac anomalies were found in 56 patients (87.5%). Down syndrome (43 patients, 67.2%) was the most frequent genetic diagnosis. Other syndromes were 8p deletion, trisomy 13, duplication 5p, cranio-cerebello-cardiac syndrome, Cantrell syndrome, CHARGE association, VACTERL association, and DiGeorge syndrome related to maternal diabetes. No patients in our series had 22q11 deletion. Tetralogy of Fallot with extreme dextroposition of the aorta was found in seven patients (only one with Down syndrome). Additional cardiac malformations were present in 23 patients (only 11 with Down syndrome). The association between atrioventricular canal defect and tetralogy of Fallot represents a cardiac phenotype with strong genetic characteristics. For this reason, a careful genetic examination is required. Our study confirms the high prevalence of Down syndrome, but also reveals a significant genetic heterogeneity. Additional cardiac defects are prevalent in patients without Down syndrome.

Adolescent↗
PubMed2006

Concordant familial segregation of atrial septal defect and Axenfeld-Rieger anomaly in father and son.

The association of congenital heart defect and ocular malformations is involved in several genetic syndromes, metabolic diseases and environmental entities. We report here on father and son, both presenting with the combination of atrial septal defect and congenital ocular anomalies in Axenfeld-Rieger anomaly. The son had anterior iridotrabecular dysgenesis and posterior embryotoxon bilaterally, corneal leucoma and marked iridial vascularization at right. The father had bilateral anterior iridotrabecular dysgenesis, posterior embryotoxon and nystagmus, and corneal leucoma at left. No additional malformations were noted in these patients. The Axenfeld-Rieger syndrome seems to be a spectrum of developmental disorders. The present report confirms the existence of a specific Axenfeld-Rieger phenotype associated with congenital heart defect. Atrial septal defect is the anatomic type of congenital heart defect linked to this condition.

Abnormalities, Multiple↗
PubMed2006

22q11 deletion syndrome: a review of some developmental biology aspects of the cardiovascular system.

The morphology and molecular genetics of the 22q11 deletion syndrome cardiovascular anomalies are reviewed. Special emphasis is given to TBX1, recently identified and considered to be the potential key gene for this clinical syndrome. The TBX1 downstream molecular pathways modulating the normal development of the pharyngeal apparatus are also discussed, and emphasis is given to the possible, equally fundamental role of downstream molecular pathway disruption in causing the clinical 22q11 deletion phenotype features.

Animals↗
PubMed2005

NF1 gene mutations represent the major molecular event underlying neurofibromatosis-Noonan syndrome.

Neurofibromatosis type 1 (NF1) demonstrates phenotypic overlap with Noonan syndrome (NS) in some patients, which results in the so-called neurofibromatosis-Noonan syndrome (NFNS). From a genetic point of view, NFNS is a poorly understood condition, and controversy remains as to whether it represents a variable manifestation of either NF1 or NS or is a distinct clinical entity. To answer this question, we screened a cohort with clinically well-characterized NFNS for mutations in the entire coding sequence of the NF1 and PTPN11 genes. Heterozygous NF1 defects were identified in 16 of the 17 unrelated subjects included in the study, which provides evidence that mutations in NF1 represent the major molecular event underlying this condition. Lesions included nonsense mutations, out-of-frame deletions, missense changes, small inframe deletions, and one large multiexon deletion. Remarkably, a high prevalence of inframe defects affecting exons 24 and 25, which encode a portion of the GAP-related domain of the protein, was observed. On the other hand, no defect in PTPN11 was observed, and no lesion affecting exons 11-27 of the NF1 gene was identified in 100 PTPN11 mutation-negative subjects with NS, which provides further evidence that NFNS and NS are genetically distinct disorders. These results support the view that NFNS represents a variant of NF1 and is caused by mutations of the NF1 gene, some of which have been demonstrated to cause classic NF1 in other individuals.

Child↗
PubMed2005

A new observation of acro-cardio-facial syndrome substantiates interindividual clinical variability.

We report on a baby presenting with ectrodactyly, heart defects, and mild facial dysmorphisms, an association recognized as acro-cardio-facial syndrome (ACFS). Based on the first three observations, the acronym CCGE, cleft palate, cardiac defect, genital anomalies, and ectrodactyly had been proposed to embrace the most consistent features of this syndrome. A subsequent report and the present patient point to an obvious interindividual and intrafamilial variability of this autosomal recessive disorder in which ectrodactyly was the sole characteristic shared by all affected individuals.

Abnormalities, Multiple↗
PubMed2005

ZFPM2/FOG2 and HEY2 genes analysis in nonsyndromic tricuspid atresia.

Tricuspid atresia (TriAt), the third most common cyanotic congenital heart defect (CHD), consists of complete lack of tricuspid valve formation, with no connection between the right atrium and the right ventricle. To date, the genetic mechanism responsible of TriAt is still obscure. However, animal models have suggested a role of cardiogenic Zfpm2/Fog2 and Hey2 genes in the pathogenesis of TriAt. Therefore, we screened 40 individuals affected by nonsyndromic TriAt for ZFPM2/FOG2 and HEY2 gene mutations. No pathogenetic mutation has been identified, thus failing to demonstrate a major role of ZFPM2/FOG2 and HEY2 genes in the pathogenesis of human TriAt.

Adolescent↗
PubMed2004

KBG syndrome in a cohort of Italian patients.

KBG syndrome comprises a distinct facial phenotype, macrodontia, short stature, and skeletal anomalies. So far, it has been reported in 29 individuals. Recently, diagnostic criteria were outlined. Here, we describe eight new patients whose clinical and radiological findings fit the diagnostic criteria of KBG syndrome. While most patients were sporadic in occurrence, in two families the disorder was transmitted from mildly affected mothers to their affected children. The phenotype of KBG syndrome has been reviewed based on published and present patients. EEG anomalies with or without seizures, mixed hearing loss, palatal anomalies with secondary speech disorder, distinct age-related behavior, and cryptorchidism are possible additional characteristics. Less common manisfestations were posterior fossa malformations, eye defects, and congenital heart defects.

Abnormalities, Multiple↗
PubMed2004

Conotruncal heart defects: impact of genetic syndromes on immediate operative mortality.

BACKGROUND: The surgical outcome of conotruncal heart defects in patients with genetic syndromes has been poorly studied. The aim of this prospective 5-year multicenter study was to elucidate the post-surgical death rate of children with conotruncal heart defects in relation to the presence of associated genetic syndromes. METHODS: Two institutions enrolled 350 consecutive inpatients with conotruncal heart defects, aged between 1 day and 60 months, who were submitted to surgery; all patients were evaluated by a clinical geneticist and had a standard metaphase chromosome analysis and a fluorescent in situ hybridization study searching for deletion of chromosome 22q11 (del22q11). RESULTS: No genetic syndrome was diagnosed in 289 patients; among the other 61 patients, 27 had DiGeorge velocardiofacial syndrome (del22q11), 16 patients had Down syndrome, and 18 presented with other genetic syndromes. The overall post-surgical death rate was higher in syndromic patients (18%) than in non-syndromic ones (10.7%) with a relative risk of 1.9 (p = 0.06). However, children with del22q11 showed a higher risk for surgical mortality (25.9 vs 10.7%; relative risk 2.4, p = 0.03). Del22q11 was identified as a risk factor for immediate surgical mortality in patients with pulmonary atresia and ventricular septal defect and in patients with interrupted aortic arch. CONCLUSIONS: Down syndrome is not a risk factor for surgery in children with conotruncal heart defects. The presence of a del22q11 may influence the surgical results in children with pulmonary atresia and ventricular septal defect and in those with interrupted aortic arch. Patients with genetic syndromes other than del22q11 and Down syndrome have a higher surgical mortality compared to that observed in non-syndromic patients. These data may be useful for preoperative counseling and for the elaboration of specific protocols of perioperative treatment.

Child, Preschool↗