Epidemiology, Clinical Features and Prognostic Factors of Pediatric SARS-CoV-2 Infection: Results From an Italian Multicenter Study

Background: Many aspects of SARS-CoV-2 infection in children and adolescents remain unclear and optimal treatment is debated. The objective of our study was to investigate epidemiological, clinical and therapeutic characteristics of pediatric SARS-CoV-2 infection, focusing on risk factors for complicated and critical disease. Methods: The present multicenter Italian study was promoted by the Italian Society of Pediatric Infectious Diseases, involving both pediatric hospitals and general pediatricians/family doctors. All subjects under 18 years of age with documented SARS-CoV-2 infection and referred to the coordinating center were enrolled from March 2020. Results: As of 15 September 2020, 759 children were enrolled (median age 7.2 years, IQR 1.4; 12.4). Among the 688 symptomatic children, fever was the most common symptom (81.9%). Barely 47% of children were hospitalized for COVID-19. Age was inversely related to hospital admission (p < 0.01) and linearly to length of stay (p = 0.014). One hundred forty-nine children (19.6%) developed complications. Comorbidities were risk factors for complications (p < 0.001). Viral coinfections, underlying clinical conditions, age 5\u20139 years and lymphopenia were statistically related to ICU admission (p < 0.05). Garazzino et al. SARS-CoV-2 in Children and Adolescents Conclusions: Complications of COVID-19 in children are related to comorbidities and increase with age. Viral co-infections are additional risk factors for disease progression and multisystem inflammatory syndrome temporarily related to COVID-19 (MIS-C) for ICU admission

Pediatric tuberculosis in Italian children: Epidemiological and clinical data from the Italian register of pediatric tuberculosis

Tuberculosis (TB) is one of the leading causes of death worldwide. Over the last decades, TB has also emerged in the pediatric population. Epidemiologic data of childhood TB are still limited and there is an urgent need of more data on very large cohorts. A multicenter study was conducted in 27 pediatric hospitals, pediatric wards, and public health centers in Italy using a standardized form, covering the period of time between 1 January 2010 and 31 December 2012. Children with active TB, latent TB, and those recently exposed to TB or recently adopted/immigrated from a high TB incidence country were enrolled. Overall, 4234 children were included; 554 (13.1%) children had active TB, 594 (14.0%) latent TB and 3086 (72.9%) were uninfected. Among children with active TB, 481 (86.8%) patients had pulmonary TB. The treatment of active TB cases was known for 96.4% (n = 534) of the cases. Overall, 210 (39.3%) out of these 534 children were treated with three and 216 (40.4%) with four first-line drugs. Second-line drugs where used in 87 (16.3%) children with active TB. Drug-resistant strains of Mycobacterium tuberculosis were reported in 39 (7%) children. Improving the surveillance of childhood TB is important for public health care workers and pediatricians. A non-negligible proportion of children had drug-resistant TB and was treated with second-line drugs, most of which are off-label in the pediatric age. Future efforts should concentrate on improving active surveillance, diagnostic tools, and the availability of antitubercular pediatric formulations, also in low-endemic countries

Cryptic chromosomal deletions detected by array-CGH in four cases affected by central precocious puberty and neurodevelopmental disorders

Background: Central precocious puberty (CPP) may be associated with CNS abnormalities including neurodevelopmental disorders (ND), epilepsy (E), CNS structural malformations and/or with dysmorphic features. In the literature, some chromosomal aberrations have been reported in patients with this association. Objective and hypotheses: The aim of this study was to detect cryptic chromosomal anomalies in patients affected by CPP and CNS disorders using the array CGH technique. Methods: We carried on the array-CGH analysis in 4 girls affected by CPP associated with one or more of following CNS anomalies: ND, E and structural abnormalities detected with MRI. The age at the onset of CPP ranged from 4 to 7.3 years. Results: Case 1. A de novo distal deletion of the chromosome 9 short arm [del(9)(p24.3-p23)] was found, as in the cases affected by 9p- syndrome. To our knowledge, this is the second reported case of precocious puberty associated to 9p distal deletion. Cases 2 and 3. A deletion of the chromosome 8 short arm was found: in the first case the deletion was localized in the region 8p23.2 and in the latter in the region 8p23.3.1. In both these cases the deletion determines the lost of the gene CSMD1, which is known to be particularly expressed in the ovary during the embryogenesis. Moreover, a duplication of CSMD1 has been found in a girl affected by delayed puberty [1]. Case 4. A deletion of chromosome 8p22 was detected, which is cited in the Database of Genomic Variants as a normal variant. However, this deletion may be related with the age at menarche in normal population. Conclusions: Our observations confirm the usefulness of the array-CGH analysis for detecting cryptic chromosomal aberrations in patients with CPP associated with CNS abnormalities and or dysmorphic features. Further studies are needed to identify genes responsible for this association

Coagulation-factor deficiencies and abnormal bleeding in Noonan’s syndrome

Background: Noonan syndrome (NS) is a congenital autosomal disorder, characterized by dysmorphic facies, congenital heart defects, short stature and other anomalies including coagulation abnormalities not fully studied so far. Objective and hypotheses: The aim of this study was to evaluate phenotypic features, gene mutations and coagulation parameters in a cohort of NS patients. Method: We studied 19 NS patients (10 M, 9 F), 12 probands and 7 first degree relatives, we found in 7/19 a mutation of PTPN11, in 8 of SOS1 and in 1 case of SOS1/RAF1, the remaining 3 cases were mutation-negative. Results: A positive history for abnormal bleeding was found in 9 patients (47%), a prolonged PTT in 5 cases (26%), coagulation factors deficiency in 9 patients (47%) and abnormal platelet aggregation in 8 cases (44%); the coagulation anomalies were found both in the 9 patients with a history of abnormal bleeding and in 6 cases (60%) without clinical evidence of bleeding disorders. The coagulation abnormalities were reported both in patients with or without a mutation and were not correlated with a mutation of a specific gene. Important differences in haemostatic status were found between probands and their relatives: the former showed coagulation abnormalities in the majority of the cases while the latter showed a history of bleeding diathesis, but normal laboratory hematological findings. The coagulation abnormalities were more frequent in patients with heart defects; however, a history of bleeding diathesis was detected in patients without cardiopathy. Conclusions: A high frequency of coagulation abnormalities was found in NS. These abnormalities do not seem to be related with the patients’ genotype. The heart defects should not to be the only cause of the haemostatic disorders. The bleeding disorders, as well as the other phenotypic NS features, tend to decrease with age. Our advice is to screen patients with NS for bleeding diathesis to avoid bleedings and post-operative complications

Abnormal growth in Noonan syndrome: correlation between growth parameters and genotype

Background: Noonan Syndrome (NS) is an autosomal dominant disorder characterized by short stature, dysmorphic features, congenital heart defects and other anomalies. Familial or de novo mutations in PTPN11, RAF1, SOS1, KRAS, and NRAS are detected in 60-75% of cases. Objective and hypotheses: The aim of this study was to find out a possible correlation between the linear growth, the GH secretion and the genotype in NS patients. Methods: A cohort of 34 patients affected by NS diagnosed by Van der Burgt criteria was studied: 13 had a PTPN11 mutation, 9 SOS1 (in one case associated with RAF1) and 12 were mutation negative. All of these patients underwent a clinical and auxological evaluation, GH secretion was evaluated in 29 patients. Results: Short stature was detected in 9/13 (69%) PTPN11+ patients, in 8/12 (67%) mutation negative and only in 2/9 (22%) of SOS1+ patients. The average H-SD was significantly higher in the SOS1+ group compared to PTPN11+ and to mutation negative groups, while no significant difference was found between the latter two groups. The average H-DS of PTPN11+ and of mutation negative groups was significantly lower (p<0,002) than their respective target height (TH) (-1,9±0,88 vs 0,43±1,26 and -2,18±1,4 vs -0,33±1,2, respectively) while it was close to TH in SOS1+ group (-0,63±0,49 vs -0,53±0,37). GH deficiency (GHD) was diagnosed in 4/9 (44%) PTPN11+, 2/8 (25%) SOS1+ and in 3/12 (25%) mutation negative. The final height reached from 5 patients SOS1+ was normal, while it was low in 2 cases PTPN11+. Conclusions: In this study short stature was more frequently seen in PTPN11+ and mutation negative patients than in those SOS1+. Short stature was rarely observed in SOS1+ patients, and when present, it was secondary to GHD. The SOS1+ patients reached a normal final height, suggesting that this mutation seems to preserve the linear growth in patients with NS

Pattern of inheritance and analysis of clinical and cerebral MRI features of familial cases of central precocious puberty

Background: Many clinical observations show that central precocious puberty (CPP) may be in some cases familial. However, the scientific support to this assumption remains sparse up to now. Objective and hypotheses: The aim of the present study was to define a pattern of inheritance of familial CPP, and to identify possible clinical differences between familial (FPP) and sporadic (SPP) forms of CPP. Methods: We studied 110 patients affected by CPP (104 F, 6 M). The family tree of each patient was analysed and all information regarding the age of puberty and of menarche, and the presence of CPP among first and second degree relatives was collected. Results: Forty-one cases (37.3%; 40 F, 1M) met the criteria for FPP and the remaining 69 cases (62.7%; 64 F, 5 M) were SPP. The FPP showed a pattern of inheritance that was autosomal dominant in 24 (58.5%) cases, autosomal dominant with incomplete sex-dependent penetrance in 16 (39%) girls and autosomal recessive in only 1 (2.5%) case. The age at onset and the age at diagnosis of CPP did not differ between FPP and SPP, the girls with FPP showed a higher BMI-SDS than girls with SPP (2.77 ± 2.28 SD vs 1.72 ± 1.71SD; P=0.0402) and a greater bone age acceleration (2.12yrs ± 1.28 SD vs 1.56yrs ± 1.32 SD; P=0.0275). MRI showed CNS anomalies in 14/69 (20%) children with SPP and in 7/41 (17%) children with FPP. Conclusions: A familial origin was found in 1/3 of cases with CPP. Girls with FPP have a higher BMI and bone age maturation than those with SPP. CNS abnormalities were found either in SPP either in FPP and do not allow to exclude the need of performing cerebral MRI in FPP. The high prevalence of FPP suggests a careful inquiry regarding precocious puberty in young siblings and first-degree cousins of a child diagnosed with CPP

Serum Anti-Müllerian Hormone (AMH) and Inhibin (IB) levels in girls with isolated premature thelarche and with central precocious puberty

Background: Inhibin B (IB) and Anti-Müllerian hormone (AMH) are produced by the granulosa cells in small antral follicles and are sensitive markers of ovarian follicular activity. Unlike the IB, the AMH production has never been evaluated in girls with sexual precocity. Objective and hypotheses: The aim of this study was to determine the IB and AMH production in girls with premature thelarche (PT) and with central precocious puberty (CPP) and to investigate whether the production of these two hormones is influenced by the Gn-RHa therapy. Method: Heighty-seven girls were enrolled in this study: 25 girls with PT (1.2-7.8 yrs) and 62 girls with CPP of whom 30 girls (1.4-9.1 yrs) before Gn- RHa therapy and 32 (5.9-12.4 yrs) during Gn-RHa therapy. The control group consisted of 26 healthy prepubertal age-matched girls. Results: Inhibin B levels were higher in girls with PT and with CPP than in controls; the IB concentrations decreased during GN-RHa therapy. Unlike IB, AMH levels were significantly (p=0.011) lower in girls with PT than in girls with CPP, during GnRH-a treatment the AMH concentrations didn’t show variation respect to pretreatment values. The AMH levels were significantly (p<0,005) higher in girls showing at ultrasound (US) examination a paucior multi-follicular ovarian pattern than in those with homogeneous pattern, no differences were found between IB levels and US ovarian morphology. A positive correlation was found between IB and FSH levels and between AMH and estradiol levels. Conclusions: AMH showed a different trend from IB in patients with PT and CPP. AMH levels better correlate than IB with the ovarian morphology and therefore seem to be more specific than IB in showing the presence of follicular activity. Unlike IB, AMH production didn’t decrease during Gn-RHa therapy, this suggests that other factors other than the gonadotropins may regulate the ovarian follicular activity