Growth hormone (GH) deficiency (GHD) in children is defined as impaired production of GH by the pituitary gland that results in growth failure. This disease might be congenital or acquired, and ...occurs in isolation or in the setting of multiple pituitary hormone deficiency. Isolated GHD has an estimated prevalence of 1 patient per 4000-10,000 live births and can be due to multiple causes, some of which are yet to be determined. Establishing the correct diagnosis remains key in children with short stature, as initiating treatment with recombinant human GH can help them attain their genetically determined adult height. During the past two decades, our understanding of the benefits of continuing GH therapy throughout the transition period from childhood to adulthood has increased. Improvements in transitional care will help alleviate the consequent physical and psychological problems that can arise from adult GHD, although the consequences of a lack of hormone replacement are less severe in adults than in children. In this Review, we discuss the differential diagnosis in children with GHD, including details of clinical presentation, neuroimaging and genetic testing. Furthermore, we highlight advances and issues in the management of GHD, including details of transitional care.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
The fecal microbiome of 55 obese children and adolescents (BMI-SDS 3.2 ± 0.7) and of 25 normal-weight subjects, matched both for age and sex (BMI-SDS - 0.3 ± 1.1) was analysed. Streptococcus, ...Acidaminococcus, Sutterella, Prevotella, Sutterella wadsworthensis, Streptococcus thermophilus, and Prevotella copri positively correlated with obesity. The inferred pathways strongly associated with obesity concern the biosynthesis pathways of tyrosine, phenylalanine, tryptophan and methionine pathways. Furthermore, polyamine biosynthesis virulence factors and pro-inflammatory lipopolysaccharide biosynthesis pathway showed higher abundances in obese samples, while the butanediol biosynthesis showed low abundance in obese subjects. Different taxa strongly linked with obesity have been related to an increased risk of multiple diseases involving metabolic pathways related to inflammation (polyamine and lipopolysaccharide biosynthesis). Cholesterol, LDL, and CRP positively correlated with specific clusters of microbial in obese patients. The Firmicutes/Bacteroidetes-ratio was lower in obese samples than in controls and differently from the literature we state that this ratio could not be a biomarker for obesity.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
We studied 45 patients with Wolfram syndrome 1 (WS1) to describe their clinical history and to search for possible genotype-phenotype correlations.
Clinical criteria contributing to WS1 diagnosis ...were analyzed. The patients were classified into three genotypic classes according to type of detected mutations.
WS1 prevalence in Italy is 0.74/1,000,000. All four manifestations of DIDMOAD were found in 46.7% of patients. Differently combined WS1 clinical features were detected in 53.3% of patients. We found 35 WFS1 different mutations and a novel missense mutation, c.1523A>G. WS1 patients were homozygotes or compound heterozygotes for WFS1 mutations except for 2 heterozygote patients (4.5%). Each genotypic group exhibited a different age onset of DM, D, and DI but not of OA. Genotypic Group 2 patients manifested a lower number of clinical manifestations compared to Groups 1 and 3. Moreover, genotypic Group 1 patients tended to have a shorter survival time than the other groups. No differences were found regarding type of clinical pictures.
Our study suggested that molecular WFS1 typing is a useful tool for early assessment of clinical history, follow-up, and prognosis of WS1.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract
Context
Primary adrenal insufficiency (PAI) is a rare and potentially life-threatening condition that is poorly characterized in children.
Objective
To describe causes, presentation, ...auxological outcome, frequency of adrenal crisis and mortality of a large cohort of children with PAI.
Patients and Methods
Data from 803 patients from 8 centers of Pediatric Endocrinology were retrospectively collected.
Results
The following etiologies were reported: 85% (n = 682) congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD); 3.1% (n = 25) X-linked adrenoleukodystrophy; 3.1% (n = 25) autoimmune polyglandular syndrome type 1; 2.5% (n = 20) autoimmune adrenal insufficiency; 2% (n = 16) adrenal hypoplasia congenital; 1.2% (n = 10) non-21-OHD CAH; 1% (n = 8) rare syndromes; 0.6% (n = 5) familial glucocorticoid deficiency; 0.4% (n = 3) acquired adrenal insufficiency; 9 patients (1%) did not receive diagnosis. Since 21-OHD CAH has been extensively characterized, it was not further reviewed. In 121 patients with a diagnosis other than 21-OHD CAH, the most frequent symptoms at diagnosis were fatigue (67%), hyperpigmentation (50.4%), dehydration (33%), and hypotension (31%). Elevated adrenocorticotropic hormone (96.4%) was the most common laboratory finding followed by hyponatremia (55%), hyperkalemia (32.7%), and hypoglycemia (33.7%). The median age at presentation was 6.5 ± 5.1 years (0.1-17.8 years) and the mean duration of symptoms before diagnosis was 5.6 ± 11.6 months (0-56 months) depending on etiology. Rate of adrenal crisis was 2.7 per 100 patient-years. Three patients died from the underlying disease. Adult height, evaluated in 70 patients, was −0.70 ± 1.20 standard deviation score.
Conclusions
We characterized one of the largest cohorts of children with PAI aiming to improve the knowledge on diagnosis of this rare condition.
Diabetes mellitus (DM) has been frequently associated with an impaired immune response against infectious agents, making affected patients at risk for more severe disease and sometimes causing worse ...outcomes. The recent COVID-19 pandemic has seriously affected patients with both diabetes, in particular those carrying comorbidities or with poor glycemic control. As regards pediatric diabetes mellitus, the availability of more accurate and technological tools for glycemic management and the improved markers of metabolic control might mitigate the negative impact of infections. Notably, good metabolic control of diabetes since its diagnosis reduces not only the risk of microangiopathic complications but also of impaired immune response to infectious diseases. Therefore, vaccinations are strongly recommended. Our paper aims to provide the most updated evidence regarding infectious diseases in type 1 pediatric DM.
Noonan syndrome (NS) is a genetic multisystem disorder characterised by variable clinical manifestations including dysmorphic facial features, short stature, congenital heart disease, renal ...anomalies, lymphatic malformations, chest deformities, cryptorchidism in males.
In this narrative review, we summarized the available data on puberty and gonadal function in NS subjects and the role of the RAS/mitogen-activated protein kinase (MAPK) signalling pathway in fertility. In addition, we have reported our personal experience on pubertal development and vertical transmission in NS.
According to the literature and to our experience, NS patients seem to have a delay in puberty onset compared to the physiological timing reported in healthy children. Males with NS seem to be at risk of gonadal dysfunction secondary not only to cryptorchidism but also to other underlying developmental factors including the MAP/MAPK pathway and genetics. Long-term data on a large cohort of males and females with NS are needed to better understand the impact of delayed puberty on adult height, metabolic profile and well-being. The role of genetic counselling and fertility related-issues is crucial.
Prader-Willi syndrome (PWS) is a rare and complex genetic disease, with numerous implications on metabolic, endocrine, neuropsychomotor systems, and with behavioural and intellectual disorders. Rare ...disease patient registries are important scientific tools (1) to collect clinical and epidemiologic data, (2) to assess the clinical management including the diagnostic delay, (3) to improve patients' care and (4) to foster research to identify new therapeutic solutions. The European Union has recommended the implementation and use of registries and databases. The main aims of this paper are to describe the process of setting up the Italian PWS register, and to illustrate our preliminary results.
The Italian PWS registry was established in 2019 with the aims (1) to describe the natural history of the disease, (2) to determine clinical effectiveness of health care services, (3) to measure and monitor quality of care of patients. Information from six different variables are included and collected into this registry: demographics, diagnosis and genetics, patient status, therapy, quality of life and mortality.
A total of 165 patients (50.3% female vs 49.7% male) were included into Italian PWS registry in 2019-2020 period. Average age at genetic diagnosis was 4.6 years; 45.4% of patients was less than 17 years old aged, while the 54.6% was in adult age (> 18 years old). Sixty-one percent of subjects had interstitial deletion of the proximal long arm of paternal chromosome 15, while 36.4% had uniparental maternal disomy for chromosome 15. Three patients presented an imprinting centre defect and one had a de novo translocation involving chromosome 15. A positive methylation test was demonstrated in the remaining 11 individuals but the underlying genetic defect was not identified. Compulsive food-seeking and hyperphagia was present in 63.6% of patients (prevalently in adults); 54.5% of patients developed morbid obesity. Altered glucose metabolism was present in 33.3% of patients. Central hypothyroidism was reported in 20% of patients; 94.7% of children and adolescents and 13.3% of adult patients is undergoing GH treatment.
The analyses of these six variables allowed to highlight important clinical aspects and natural history of PWS useful to inform future actions to be taken by national health care services and health professionals.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Congenital adrenal hyperplasia (CAH) consists of several autosomal recessive disorders that inhibit steroid biosynthesis. We describe a case report diagnosed with adrenal insufficiency due to low ...adrenal steroids and adrenocorticotropic hormone excess due to lack of cortisol negative feedback signaling to the pituary gland. Genetic work up revealed two missense variants, p.Thr204Arg and p.Leu260Arg in the
gene, inherited by both parents (non-consanguineous). The StAR protein supports CYP11A1 enzyme to cleave the side chain of cholesterol and synthesize pregnenolone which is metabolized to all steroid hormones. We used bioinformatics to predict the impact of the variants on StAR activity and then we performed functional tests to characterize the two novel variants. In a cell system we tested the ability of variants to support cholesterol conversion to pregnenolone and measured their mRNA and protein expression. For both variants, we observed loss of StAR function, reduced protein expression and categorized them as pathogenic variants according to guidelines of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. These results fit the phenotype of the girl during diagnosis. This study characterizes two novel variants and expands the list of missense variants that cause CAH.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Growth impairment is a common manifestation in Noonan syndrome (NS). Recombinant human GH (rhGH) treatment has been shown to increase growth and adult height (AH) in a few studies. We aimed to ...evaluate the growth trajectory towards the AH, and the effects of rhGH treatment in a large cohort of NS children.
Retrospective, multicenter, cohort study including subjects with genetic diagnosis of NS. A total of 228 NS patients, 154 with
mutations, 94 who reached AH, were recruited. Auxological data were collected at 2, 5, and 10 years, at pubertal onset, at AH. Sixty-eight NS subjects affected with GH deficiency (GHD) were treated with rhGH at a mean dose of 0.24 mg/kg per week until AH achievement.
ANOVA analysis showed a significant difference between birth length and height standard deviation scores (HSDS) at the different key ages (
), while no significant differences were found between HSDS measurements at 2, 5, and 10 years, at pubertal onset, and at AH. HSDS increased from -3.10 ± 0.84 to -2.31 ± 0.99 during rhGH treatment, with a total height gain of 0.79 ± 0.74, and no significant difference between untreated and treated NS at AH.
rhGH treatment at the standard dose used for children with GH idiopathic deficiency is effective in improving growth and AH in NS with GHD. Further studies are needed to assess genotype-specific response to rhGH treatment in the different pathogenic variants of
gene and in the less common genotypes.
Data on pubertal timing in Silver Russell syndrome (SRS) are limited.
Retrospective observational study including twenty-three SRS patients 11p15 loss of methylation, (11p15 LOM, n=10) and maternal ...uniparental disomy of chromosome 7 (mUPD7, n=13) and 21 small for gestational age (SGA). Clinical (thelarche in females; testis volume ≥ 4 ml in males; pubarche), BMI SD trend from the age of 5 to 9 years to the time of puberty, biochemical parameters of puberty onset Luteinizing hormone (LH), 17-β-estradiol, testosterone, and bone age progression were evaluated.
Pubertal onset and pubarche occurred significantly earlier in children with SRS than in SGA (p 0.03 and p 0.001, respectively) and clinical signs of puberty onset occurred earlier in mUPD7 than in 11p15LOM group (p 0.003). Five SRS children experienced central precocious puberty and LH, 17-β-estradiol, testosterone were detected earlier in SRS than in SGA (p 0.01; p 0.0001). Bone age delay in SRS children was followed by rapid advancement; the delta between bone age and chronological age in SRS group became significantly higher than in SGA group at the age of 9-11 years (p 0.007). 11p15LOM patients were underweight at the age of 5 years and showed a progressive normalization of BMI that was significantly higher than in mUPD7 (p 0.04) and SGA groups (p 0.03) at puberty onset.
Timing of puberty is affected in SRS and occurred earlier in mUPD7 compared to 11p15LOM. The impact of early puberty on adult height and metabolic status deserves long-term evaluation.
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