SIMPSON-GOLABI-BEHMEL syndrome type 1: How placental immunohistochemistry can rapidly Predict the diagnosis.

INTRODUCTION: Glypican-3 (GPC3) is an oncofetal protein involved in cellular signaling, strongly expressed in the placenta, absent or diminished in postnatal life, but often increased in human malignancies. Germline loss-of-function variants of GPC3 gene are associated with Simpson-Golabi-Behmel syndrome type 1 (SGBS1), a rare recessive X-linked overgrowth disease characterized by typical facial features, congenital abnormalities, and an increased risk of developing childhood cancers. METHODS: A clinical suspicion of SGBS1 was postulated for a newborn with prenatal history of overgrowth and polyhydramnios, presenting with neonatal weight and length >99th percentile, coarse facies, iris and retinal coloboma, supernumerary nipples, and splenomegaly. While waiting for whole-genome sequencing (WGS) results, we investigated placental GPC3 immunohistochemical expression in the proband, in three additional cases of SGBS1, and disorders commonly associated with fetal macrosomia and/or placentomegaly. RESULTS: WGS in the proband identified a likely pathogenic maternally inherited missense variant in GPC3: c.1645A > G, (p.Ile549Val), and GPC3 immunohistochemistry demonstrated full-thickness loss of stain of the placental parenchyma. The same pattern ("null") was also present in the placentas of three additional cases of SGBS1, but not in those of unaffected controls. DISCUSSION: Immunohistochemical expression of GPC3 in the placenta is highly reproducible. Our findings showed that a "null pattern" of staining is predictive of SGBS1 and represents a valuable aid in the differential diagnosis of fetal macrosomias, allowing targeted genetic testing and earlier diagnosis.

An Overview of The Role of Tumor Necrosis Factor-Alpha in Epileptogenesis and Its Terapeutic Implications.

The complex association between neuroinflammation and seizures has been widely investigated in recent years. As mediators of inflammatory response, cytokines like tumor necrosis factor- a (TNF-a) are potential therapeutic targets for epileptic disorders. TNF-a is a pleiotropic cytokine with a controversial role in epileptogenesis, seemingly capable to both favor the genesis of seizures and elicit neuromodulatory responses. Anti-TNF agents are a group of monoclonal antibodies engineered to inhibit the response to this cytokine for antinflammatory purposes. The clinical experience of the use of these drugs in neurological conditions like multiple sclerosis showed controversial results. Evidence in favor of the employment of anti-TNF agents for the treatment of epilepsy are still limited to certain forms of disorders, notably Rasmussen encephalitis, and in carefully selected patients.

A nationwide study on Sydenham's chorea: Clinical features, treatment and prognostic factors.

OBJECTIVES: Sydenham's Chorea (SC) is a neuropsychiatric disorder and a major manifestation of acute rheumatic fever. The erroneous assumption that SC is a benign and self-limiting disease, has led to a lack of high-quality scientific evidence of the therapeutical and prognostic features of SC. STUDY DESIGN: We retrospectively analyzed the medical records of patients <18-years old with SC in 17 Italian pediatric centers. Recorded data included clinical, instrumental and laboratory parameters. Prognostic risk factors including treatment regimens were assessed with univariate and multivariate sub-analysis. RESULTS: We included 171 patients with SC. 66% had generalized chorea, and 34% hemichorea. 81% had carditis (subclinical in 65%). Additional neurological symptoms were reported in 60% of the patients, mainly dysarthria and dysgraphia. 51% had neuropsychiatric symptoms at onset, which persisted after 12 months in 10%. Among psychiatric manifestations, the most common was anxiety disorder/depression (77%). Neurological remission was reached by 93% of the patients at 6 months; 9% relapsed. Patients were treated as follows: 11% penicillin alone, 37% immunomodulatory therapy, 16% symptomatic drugs (i.e. anti-seizure medication, dopamine antagonists) and 37% both symptomatic and immunomodulatory treatment. Neurological outcome did not differ between groups. Patients receiving symptomatic drugs had a higher risk of relapse on multivariate analysis (p = 0.045). CONCLUSIONS: Treatment of SC was largely heterogeneous. Based on our results, immunomodulatory therapy did not show higher efficacy at medium term, although it was associated to a slightly lower risk of relapse compared to symptomatic therapy. Longitudinal studies are needed to assess specific risk factors and best treatment options.

Gonosomal Mosaicism for a Novel COL5A1 Pathogenic Variant in Classic Ehlers-Danlos Syndrome.

(1) Background: Classic Ehlers-Danlos syndrome (cEDS) is a heritable connective tissue disorder characterized by joint hypermobility and skin hyperextensibility with atrophic scarring. Many cEDS individuals carry variants in either the COL5A1 or COL5A2 genes. Mosaicism is relatively common in heritable connective tissue disorders but is rare in EDS. In cEDS, a single example of presumed gonosomal mosaicism for a COL5A1 variant has been published to date. (2) Methods: An 8-year-old girl with cEDS was analyzed by next-generation sequencing (NGS). Segregation was performed by Sanger sequencing in her unaffected parents. In the father, the mosaicism of the variant was further analyzed by targeted NGS and droplet digital PCR (ddPCR) in the blood and by Sanger sequencing in other tissues. (3) Results: The NGS analysis revealed the novel germline heterozygous COL5A1 c.1369G>T, p.(Glu457*) variant in the proband. Sanger chromatogram of the father's blood specimen suggested the presence of a low-level mosaicism for the COL5A1 variant, which was confirmed by NGS and estimated to be 4.8% by ddPCR. The mosaicism was also confirmed by Sanger sequencing in the father's saliva, hair bulbs and nails. (4) Conclusions: We described the second case of cEDS caused by paternal gonosomal mosaicism in COL5A1. Parental mosaicism could be an issue in cEDS and, therefore, considered for appropriate genetic counseling.

Absence of lingual frenulum in children with Ehlers-Danlos Syndrome: a retrospective study of forty cases and literature review of a twenty years long debate.

BACKGROUND: Ehlers-Danlos syndrome (EDS) is part of connective tissue disorders and is characterized by skin hyperextensibility, joint hypermobility, easy bruising and other severe manifestations such as epilepsy, pneumothorax, arterial rupture and bowel perforation. In 2017 a new classification was published, indicating major and minor criteria for each form of EDS. Further reports in the past years tried to determine whether or not the absence of lingual frenulum should be included in minor criteria for the diagnosis of EDS, but a consensus has still not been reached. The aim of this study was to assess the clinical relevance of lingual frenulum absence, evaluating its prevalence in a cohort of EDS pediatric patients and comparing it to a group of controls. METHODS: Patients with Ehlers-Danlos syndrome were observed at our Department of Pediatrics of Policlinico S. Matteo in Pavia, Italy. Each patient underwent clinical examination of the oral cavity, and controls were chosen among patients referred to our Department. RESULTS: Thirty-three over 40 patients showed absence of lingual frenulum and 3 of them showed frenulum hypoplasia. Absence or hypoplasia of lingual frenulum showed a prevalence of 90% in our population, whereas only 3/170 controls (1.8%), had lingual frenulum absence. Overall, absence of the lingual frenulum showed a sensibility of 90% and a specificity of 98.2% in our population. CONCLUSIONS: In agreement with other authors, we believe that the absence of lingual frenulum should be included in the minor diagnostic criteria for Ehlers-Danlos Syndrome.

Timing, prevalence, and dynamics of thyroid disorders in children and adolescents affected with Down syndrome.

Objectives Limited data on the evolution of thyroid disorders (TD) in Down syndrome (DS) are available. We characterized the timing, prevalence, and dynamics of TD in patients with DS during a long-term follow-up. Methods We retrospectively evaluated 91 children and adolescents with DS (12.5 ± 8.3; follow-up 7.5 ± 6.2). Children were monitored at birth, 6, and 12 months of age and twice a year thereafter. Thyroid status and autoimmunity were periodically investigated. Results TD were detected in 73.6% of patients, in particular congenital hypothyroidism (CH), autoimmune thyroid diseases (ATD) and subclinical hypothyroidism (SH) were recorded in 16.4, 31.8, and 25.3%, respectively. CH was diagnosed at newborn screening in 86.7% of cases and in the first 6 months of life in the remaining 13.3%; the condition was persistent in 61.5% of patients. In more than 30% of CH cases, glandular hypoplasia was also revealed. In the ATD group, 63.1% of patients with Hashimoto's disease (HD, 82.6%) were treated with levothyroxine and subjects with Graves' Disease (GD, 17.4%) started therapy with methimazole. DS with SH were treated in 42.1% of cases. A thyroid hypogenic echopattern, without autoantibody positivity was identified in 27.6% of SH patients. Conclusions The high prevalence and evolution of TD in SD requires frequent monitoring starting in the first months of life. CH can be misdiagnosed at screening. In DS subjects, there is a high prevalence of ATD and non-autoimmune diseases with early antibody-negative phases should not be excluded.

Gender Differences at the Onset of Autoimmune Thyroid Diseases in Children and Adolescents.

Background: The incidence of autoimmune thyroid diseases (ATD) may vary with the beginning of reproductive function, although few reports differentiate the incidence before and during the onset of puberty, examining gender bias. We analyzed onset of ATD in a pediatric population to assess gender differences in onset age, disease subtype, pubertal status, autoimmune co-morbidity, family history and treatment, focusing on the interaction between gender and pubertal stage. Patients and methods: We retrospectively recorded 382 children and adolescents with ATD. In each patient physical examination was considered. The presence of other associated autoimmune diseases (AAD) and familial predisposition was also recorded. Results: Predominant prevalence was noted in females compared to males (p < 0.001), both in Hashimoto's diseases (HD or HT) and Graves' disease (GD) (p < 0.001). Mean age at diagnosis showed no significant difference between sexes (p > 0.05). A higher prevalence in pubertal subjects was noted compared to prepubertal (p < 0.001, particularly HT in early and GD in late pubertal stage), without sexes difference intra-(prepubertal vs. pubertal) and inter-puberty groups (prepubertal vs. early pubertal vs. late pubertal). Both in HT and in GD, the prevalence of autoimmune associated diseases (AAD) was higher in males compared to females (p = 0.04), with similar distribution according to the pubertal maturation. The familial predisposition was similarly distributed in both genders (p > 0.05) and into pubertal stages (p > 0.05). Conclusions: Females are more prone to develop ATD during puberty, earlier in HT than in GD. The effect of puberty is not different between genders, suggesting the role of additional factors other than hormones. The screening for detection of ATD is recommended in all patients with positive family history and other autoimmune diseases, mostly in males. Considerations of gender in pediatrics could be important to define pathogenic mechanisms of ATD and to help in early diagnosis and clinical management.

Adverse Effects of Ramadan Fasting in a Girl with Salt-Losing Congenital Adrenal Hyperplasia.

OBJECTIVE: Congenital adrenal hyperplasia (CAH) is the most common cause of adrenal insufficiency in pediatrics. Chronic glucocorticoid replacement is the mainstay of treatment in the classic forms of CAH, and mineralocorticoid replacement therapy is mandatory in the salt-wasting form. Fasting is a mild stressor, which can expose to dehydration, hypotension, hypoglycemia, and acute adrenal crisis in patients with adrenal insufficiency. CASE: We report the case of an adolescent affected by the classic form with salt-losing CAH, who observed Ramadan for 30 days, without individualized therapeutic management plan. After Ramadan, a dramatic increase of ACTH level (1081 pg/ml, n.v. 6-57), reduced cortisolemia, tendency to hypotension, and weight loss were recorded. She experienced insomnia, intense thirst, asthenia, and headache. The symptoms disappeared restarting the previous therapy schedule and increasing the total hydrocortisone daily dose with progressive restoring of hormonal control. CONCLUSION: Our case confirms that patients with CAH are vulnerable, especially during fasting in Ramadan, with a higher risk of acute adrenal crisis. CAH patients should reform and individualize their treatment plan and be submitted to careful monitoring.

Biotin-Thiamine Responsive Encephalopathy: Report of an Egyptian Family with a Novel SLC19A3 Mutation and Review of the Literature.

Biotin-thiamine responsive basal ganglia disease (BTRBGD) is an autosomal recessive neurometabolic disorder with poor genotype-phenotype correlation, caused by mutations in the SLC19A3 gene on chromosome 2q36.6. The disease is characterized by three stages: stage 1 is a sub-acute encephalopathy often triggered by febrile illness; stage 2 is an acute encephalopathy with seizures, loss of motor function, developmental regression, dystonia, external ophthalmoplegia, dysphagia, and dysarthria; stage 3 is represented by chronic or slowly progressive encephalopathy. Clinical and biochemical findings, as well as the magnetic resonance imaging (MRI) pattern, resemble those of Leigh's syndrome, so that BTRBGD can be misdiagnosed as a mitochondrial encephalopathy.Here we report the clinical and radiological phenotypes of two siblings diagnosed with BTRBGD in which a novel SLC19A3 mutation (NM_025243.3: c.548C > T; p.Ala183Val) was found by whole exome sequencing (WES) of the family members.

X-Linked Hypohidrotic Ectodermal Dysplasia: New Features and a Novel EDA Gene Mutation.

We described a 5-year-old male with hypodontia, hypohidrosis, and facial dysmorphisms characterized by a depressed nasal bridge, maxillary hypoplasia, and protuberant lips. Chromosomal analysis revealed a normal 46,XY male karyotype. Due to the presence of clinical features of hypohidrotic ectodermal dysplasia (HED), the EDA gene, located at Xq12q13.1, of the patient and his family was sequenced. Analysis of the proband's sequence revealed a missense mutation (T to A transversion) in hemizygosity state at nucleotide position 158 in exon 1 of the EDA gene, which changes codon 53 from leucine to histidine, while heterozygosity at this position was detected in the slightly affected mother; moreover, this mutation was not found in the publically available Human Gene Mutation Database. To date, our findings indicate that a novel mutation in EDA is associated with X-linked HED, adding it to the repertoire of EDA mutations.