Clinical and Molecular Profiling in GNAO1 Permits Phenotype-Genotype Correlation.

BACKGROUND: Defects in GNAO1, the gene encoding the major neuronal G-protein Gαo, are related to neurodevelopmental disorders, epilepsy, and movement disorders. Nevertheless, there is a poor understanding of how molecular mechanisms explain the different phenotypes. OBJECTIVES: We aimed to analyze the clinical phenotype and the molecular characterization of GNAO1-related disorders. METHODS: Patients were recruited in collaboration with the Spanish GNAO1 Association. For patient phenotyping, direct clinical evaluation, analysis of homemade-videos, and an online questionnaire completed by families were analyzed. We studied Gαo cellular expression, the interactions of the partner proteins, and binding to guanosine triphosphate (GTP) and G-protein-coupled receptors (GPCRs). RESULTS: Eighteen patients with GNAO1 genetic defects had a complex neurodevelopmental disorder, epilepsy, central hypotonia, and movement disorders. Eleven patients showed neurological deterioration, recurrent hyperkinetic crisis with partial recovery, and secondary complications leading to death in three cases. Deep brain stimulation improved hyperkinetic crisis, but had inconsistent benefits in dystonia. The molecular defects caused by pathogenic Gαo were aberrant GTP binding and hydrolysis activities, an inability to interact with cellular binding partners, and reduced coupling to GPCRs. Decreased localization of Gαo in the plasma membrane was correlated with the phenotype of "developmental and epileptic encephalopathy 17." We observed a genotype-phenotype correlation, pathogenic variants in position 203 were related to developmental and epileptic encephalopathy, whereas those in position 209 were related to neurodevelopmental disorder with involuntary movements. Milder phenotypes were associated with other molecular defects such as del.16q12.2q21 and I344del. CONCLUSION: We highlight the complexity of the motor phenotype, which is characterized by fluctuations throughout the day, and hyperkinetic crisis with a distinct post-hyperkinetic crisis state. We confirm a molecular-based genotype-phenotype correlation for specific variants. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Ambiguous Genitalia: An Unexpected Diagnosis in a Newborn.

Alterations in gonad formation or function can lead to congenital conditions in which chromosomal, gonadal, or anatomical sex is atypical. These conditions are referred to as disorders of sex development (DSD) and have a heterogeneous etiology. The assessment of these children by a multidisciplinary team is crucial for an accurate diagnosis and should be initiated promptly due to the potentially life-threatening nature of congenital adrenal hyperplasia, a common cause of DSD. We present a neonate born at 39 weeks with a weak cry, slight hypotonia, poor suction reflex, peculiar facies, and ambiguous genitalia. From the study carried out, the abdominopelvic ultrasound revealed a nodular structure compatible with the left gonad. Aneuploidy screening confirmed the presence of the Y chromosome. Additionally, normal endocrinological studies and the karyotype showed a genotype compatible with cri-du-chat syndrome with partial trisomy of chromosome 3. Children with cri-du-chat syndrome characteristically exhibit a cat-like cry and distinctive facial features, along with developmental delay and intellectual disability. Duplication of 3p is a rare genetic disorder, usually associated with other chromosomal anomalies and congenital malformations, namely, of the genitals.

Clinical Role of Codon 87 of the CYFIP2 Gene in Early Infantile Epileptic Encephalopathy: A Clinical Case Description.

The diagnosis of early infantile epileptic encephalopathy (EIEE) remains challenging, and next-generation sequencing (NGS) techniques have played a key role in identifying genetic causes. Recent studies have shown an association between mutations in the CYFIP2 gene and EIEE, with 20 deleterious variants reported so far and a de novo mutational hotspot at codon 87.  A male infant presented with seizures since the age of four months as well as significant developmental delay and microcephaly. The seizures were of different types, frequent and refractory to treatment, including different anticonvulsant drugs. Metabolic studies showed no significant changes. The initial electroencephalogram revealed bilateral paroxysmal activity with hemispherical diffusion. Brain MRI showed no pathological changes. Analysis of a whole exome sequencing (WES) based multigene panel for epilepsy disclosed a heterozygous CYFIP2 gene variant [c.258_266del; p.(Trp86_Ser88del)] established as de novo. We describe the case of an infant with EIEE due to a de novo heterozygous in-frame deletion of three amino acids in CYFIP2: c.258_266del; p.(Trp86_Ser88del). This in-frame deletion eliminates codon 87, a mutational hotspot associated with a particularly severe EIEE phenotype. All previous reports had missense variants with a presumably gain-of-function mechanism. The clinical picture of our patient is very similar to the ones with deleterious variants affecting codon 87 reported in the literature. Our case report is the first to describe a disease-causing in-frame deletion in CYFIP2 and reiterates a consistent genotype-phenotype correlation.

Food Allergy in Preschoolers: Parents' Perception and Self-Reported Prevalence.

BACKGROUND: Food allergy is a potentially fatal condition (in the case of anaphylaxis, for example) and is characterized by an increasing prevalence. The main purpose of this study is to identify preschool children with parent-reported food allergies and characterize this population and type of allergy. METHODS: This is a cross-sectional study, based on questionnaires to parents/legal guardians. All children who attend daycare or preschool in an area of the city of Porto, Portugal, were included. RESULTS: A total of 740 questionnaires were distributed to nine schools, and responses were obtained from 363 (49.1%). Self-reported food reaction and/or allergy was related in 11.2% of children. The median age of the first reaction was 12 months and the most registered foods were milk, dry seed, and peanut. Cutaneous (48.7%) and gastrointestinal (35.9%) symptoms were the main manifestations. History of parents' and siblings' food allergies had statistically significant associations with food reactions and/or allergies of the child, with OR 3.05 (p=0.04, 95% CI 1.01-8.81) and OR 8.69 (p<0.01, 95% CI 2.11-35.79), respectively. Besides that, children's atopic dermatitis also had a statistically significant association with self-reported food reactions and/or allergies, with OR 2.30 (p<0.05, 95% CI 1.01-5.21). CONCLUSION: Food reactions and/or allergies were reported in 11.2% of children. The history of parents' and siblings' food allergies and children's atopic dermatitis had statistically significant associations with food reactions and/or allergies, which shows that it may be an important factor to consider.

Pediatric Thyroidectomy: Experience From a Portuguese Hospital.

Background and objective Pediatric thyroid disease requiring surgery is rare. Thyroid nodules are a frequent indication for surgery and are mostly benign. However, up to 25% of cases can be malignant. In this study, we aimed to describe our center's experience with regard to pediatric thyroid surgery. Methods This was a retrospective transverse study involving pediatric patients who underwent thyroid surgery at a tertiary hospital between January 2010 and December 2021. Results A total of 14 patients underwent 15 surgeries. The main reason for referral to pediatric endocrinology was thyroid nodules (n=10). Thirteen fine needle aspirations (FNAs) were performed, with follicular tumor (n=6) being the most common finding. The median age of patients at surgery was 15.9 years [interquartile range (IQR): 14.0-16.8]. The most common surgical indications were the presence of a follicular tumor on FNA (n=5) and thyroid nodule size causing symptoms (n=5). There was one case of prophylactic thyroidectomy due to the identification of a multiple endocrine neoplasia type 2A (MEN2A) mutation. The most frequently described histopathology results were follicular adenoma (n=6) and colloid nodular goiter (n=6). Three postoperative complications were observed in three different patients: bilateral lesion of the recurrent laryngeal nerve, cervical hematoma, and transient hypoparathyroidism with hypocalcemia. Conclusion In our study, the most frequent surgical indication was a follicular tumor. A good correlation was found between FNA cytology and final histopathology results, which is in accordance with previous studies. This reinforces the importance of FNA in diagnosis and surgical planning. The rate of complications in our study is comparable to that in larger single-center series in the literature.

Type 1 diabetes mellitus - Population characterization and metabolic control outcomes in a Portuguese patient sample.

AIMS: To characterize a cohort of T1D patients and to compare diabetes control between patients using different regimen of insulin therapy and glucose monitoring. METHODS: Were included all T1D patients followed at the Pediatric Endocrinology Unit, between April 1st and June 30th, 2021. Several clinical and demographic variables were analyzed. RESULTS: Our sample included 208 patients, 56.7 % males, mean age of 12.7 ± 4.6 years. The median HbA1c was 7.3 %. Most patients, 78.8% were treated with continuous subcutaneous insulin infusion (CSII) and 81.3 % used continuous glucose monitoring (CGM). CSII had a lower HbAc compared with multiple daily injections (MDI) users (7.1vs 8.1 %, p < 0.01). In the CSII group, those who used CGM had a lower HbAc (7.1 vs 7.5 %,p = 0.02). Analyzing the data of the ambulatory glucose report, the CSII users had a lower glucose management indicator, (7.2 % vs 7.6 %, p < 0.01), more time in range (58.0 % vs 52.4 %;p < 0.01) and less time above range > 250 mg/dL (12.4 % vs 20.5 %;p < 0.01) than MDI users. CONCLUSIONS: The median HbA1c was 7.3% very close to the recommended target. In Portugal, pediatric patients can access a CSII provided by the national health service and a CGM system due to an elevated reimbursement of their cost. This healthy policy allows us to achieve better goals without the risk of hypoglycemia.

Prevalence of pressure ulcers in a Brazilian hospital: results of a cross-sectional study.

Technological advances in recent decades have extended survival time of critically ill hospitalized patients but their unstable physiological state and limited mobility increase their risk for pressure ulcers. On two different days (June 16 and October 20, 2004), pressure ulcer prevalence in patients hospitalized at the São Paulo Hospital, Brazil was assessed. On study day 1, 43 of the 376 inpatients (prevalence, 11.4%) and on study day 2, 35 of 340 inpatients (prevalence, 10.3%) had pressure ulcers. No significant differences in patient or ulcer characteristics between the two study days were observed. Ulcer prevalence was highest among patients in the intensive care unit (average 32.7%). Most patients had one ulcer (61.5%), classified as Stage II (47%), located in the sacral area (47%), and were considered at high risk according to their Braden Scale scores (60% had a score ≤ 11). The results obtained were not unexpected and confirmed the need to improve quality of care by establishing pressure ulcer prevention protocols. Additional studies to optimize prevention efforts and improve the existing evidence-base are necessary, especially in patient care units with high pressure ulcer rates.