Endocrine features of Prader-Willi syndrome: a narrative review focusing on genotype-phenotype correlation.

Prader-Willi syndrome (PWS) is a complex genetic disorder caused by three different types of molecular genetic abnormalities. The most common defect is a deletion on the paternal 15q11-q13 chromosome, which is seen in about 60% of individuals. The next most common abnormality is maternal disomy 15, found in around 35% of cases, and a defect in the imprinting center that controls the activity of certain genes on chromosome 15, seen in 1-3% of cases. Individuals with PWS typically experience issues with the hypothalamic-pituitary axis, leading to excessive hunger (hyperphagia), severe obesity, various endocrine disorders, and intellectual disability. Differences in physical and behavioral characteristics between patients with PWS due to deletion versus those with maternal disomy are discussed in literature. Patients with maternal disomy tend to have more frequent neurodevelopmental problems, such as autistic traits and behavioral issues, and generally have higher IQ levels compared to those with deletion of the critical PWS region. This has led us to review the pertinent literature to investigate the possibility of establishing connections between the genetic abnormalities and the endocrine disorders experienced by PWS patients, in order to develop more targeted diagnostic and treatment protocols. In this review, we will review the current state of clinical studies focusing on endocrine disorders in individuals with PWS patients, with a specific focus on the various genetic causes. We will look at topics such as neonatal anthropometry, thyroid issues, adrenal problems, hypogonadism, bone metabolism abnormalities, metabolic syndrome resulting from severe obesity caused by hyperphagia, deficiencies in the GH/IGF-1 axis, and the corresponding responses to treatment.

Impact of 12-SNP and 6-SNP Polygenic Scores on Predisposition to High LDL-Cholesterol Levels in Patients with Familial Hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) comprises high LDL-cholesterol (LDL-c) levels and high cardiovascular disease risk. In the absence of pathogenic variants in causative genes, a polygenic basis was hypothesized. METHODS: In a population of 418 patients (excluding homozygotes) with clinical suspicion of FH, the FH-causative genes and the regions of single nucleotide polymorphisms (SNPs) included in 12-SNP and 6-SNP scores were sequenced by next-generation sequencing, allowing for the detection of pathogenic variants (V+) in 220 patients. To make a comparison, only patients without uncertain significance variants (V-/USV-) were considered (n = 162). RESULTS: Higher values of both scores were observed in V+ than in V-. Considering a cut-off leading to 80% of V-/USV- as score-positive, a lower prevalence of patients positive for both 12-SNP and 6-SNP scores was observed in V+ (p = 0.010 and 0.033, respectively). Mainly for the 12-SNP score, among V+ patients, higher LDL-c levels were observed in score-positive (223 mg/dL -IQR 187-279) than in negative patients (212 mg/dL -IQR 162-240; p = 0.006). Multivariate analysis confirmed the association of scores and LDL-c levels independently of age, sex, and presence of pathogenic variants and revealed a greater association in children. CONCLUSIONS: The 12-SNP and 6-SNP polygenic scores could explain hypercholesterolemia in patients without pathogenic variants as well as the variability of LDL-c levels among patients with FH-causative variants.

Simplified Criteria for Identification of Familial Hypercholesterolemia in Children: Application in Real Life.

BACKGROUND: The diagnosis of familial hypercholesterolemia (FH) in children is primarily based on main criteria including low-density lipoprotein cholesterol (LDL-C) levels, increased in the proband and relatives, and its inheritance. Two other relevant parameters are symptoms, rarely occurring in children, as rare are the FH homozygous patients, and the mutation detection of related genes. The latter allows the final diagnosis, although it is not commonly available. Moreover, the application of diagnostic scores, useful in adults, is poorly applied in children. The aim of this study was to compare the reliability of criteria here applied with different scores, apart from genetic analysis, for FH diagnosis. The latter was then confirmed by genetic analysis. METHODS: n. 180 hypercholesterolemic children (age 10.2 ± 4.6 years) showing LDL-C levels ≥95th percentile (age- and sex-related), the dominant inheritance pattern of hypercholesterolemia (including LDL-C ≥95th percentile in one parent), were considered potentially affected by FH and included in the study. The molecular analysis of the LDLR, APOB and PCSK9 genes was applied to verify the diagnostic accuracy. Biochemical and family history data were also retrospectively categorized according to European Atherosclerosis Society (EAS), Simon Broome Register (SBR), Pediatric group of the Italian LIPIGEN (LIPIGEN-FH-PED) and Dutch Lipid Clinic Network (DLCN) criteria. Detailed kindred biochemical and clinical assessments were extended to three generations. The lipid profile was detected by standard laboratory kits, and gene analysis was performed by traditional sequencing or Next-Generation Sequencing (NGS). RESULTS: Among 180 hypercholesterolemic subjects, FH suspected based on the above criteria, 164/180 had the diagnosis confirmed, showing causative mutations. The mutation detection rate (MDR) was 91.1%. The scoring criteria proposed by the EAS, SBR and LIPIGEN-FH-PED (resulting in high probable, possible-defined and probable-defined, respectively) showed high sensitivity (~90%), low specificity (~6%) and high MDR (~91%). It is noteworthy that their application, as a discriminant for the execution of the molecular investigation, would lead to a loss of 9.1%, 9.8% and 9.1%, respectively, of FH-affected patients, as confirmed by the genetic analysis. DLCN criteria, for which LDL-C cut-offs are not specific for childhood, would lead to a loss of 53% of patients with mutations. CONCLUSIONS: In the pediatric population, the combination of LDL-C ≥95th percentile in the proband and the dominant inheritance pattern of hypercholesterolemia, with LDL-C ≥95th percentile in one parent, is a simple, useful and effective diagnostic criterion, showing high MDR. This pattern is crucial for early FH diagnosis. EAS, SBR and LIPIGEN-FH-PED criteria can underestimate the real number of patients with gene mutations and cannot be considered strictly discriminant for the execution of molecular analysis.

The treatment of obesity in children and adolescents: consensus position statement of the Italian society of pediatric endocrinology and diabetology, Italian Society of Pediatrics and Italian Society of Pediatric Surgery.

This Position Statement updates the different components of the therapy of obesity (lifestyle intervention, drugs, and surgery) in children and adolescents, previously reported in the consensus position statement on pediatric obesity of the Italian Society of Pediatric Endocrinology and Diabetology and the Italian Society of Pediatrics. Lifestyle intervention is the first step of treatment. In children older than 12 years, pharmacotherapy is the second step, and bariatric surgery is the third one, in selected cases. Novelties are available in the field of the medical treatment of obesity. In particular, new drugs demonstrated their efficacy and safety and have been approved in adolescents. Moreover, several randomized control trials with other drugs are in process and it is likely that some of them will become available in the future. The increase of the portfolio of treatment options for obesity in children and adolescents is promising for a more effective treatment of this disorder.

Pediatric Myxedema Due to Autoimmune Hypothyroidism: A Rare Complication of a Common Disorder.

In children, hypothyroidism usually presents non-specific symptoms; symptoms can emerge gradually, compromising a timely diagnosis. We report the case of a 13-year-old male, who was admitted to the hospital due to swelling of the torso and neck. Besides these symptoms, the child was healthy, except for a significant growth delay. Ultrasound evaluation and blood tests led to the diagnosis of myxedema secondary to severe hypothyroidism, which was due to autoimmune thyroiditis. Further investigations revealed pericardial effusion and pituitary hyperplasia, with hyper-prolactinemia. Treatment with levothyroxine led to edema regression and clinical, hemato-chemical and radiological improvement. After 6 months, growth velocity increased, although the recovery of growth already lost was not guaranteed. Brain MRI showed regression of pituitary hyperplasia. The diagnostic delay in this case was probably due to the patient's apparent good health, and the underestimation of growth restriction. This report underlines the importance of growth monitoring in adolescence, a critical period for identifying endocrine conditions; if undiagnosed, these conditions can lead to serious complications, such as myxedema in hypothyroidism, with potential effects beyond growth on multiple organs.

Menorrhagia as main presentation sign of severe hypothyroidism in a pediatric patient: a case report.

BACKGROUND: The relative high frequency of menstrual irregularities in the first two-three years after menarche may lead to the risk of underestimation of associated pathological conditions, which are always to be accurately researched with careful examination and anamnesis. The association between menstrual irregularities and hypothyroidism is described in literature but the available data are scarce and mainly based on adult case series. It is described that low plasma levels of thyroid hormone can shift the hemostatic system towards a hypocoagulable and hyperfibrinolytic state and seem to lead to an increased bleeding risk. CASE PRESENTATION: This case report describes the case of a thirteen years old girl who presented to our Emergency Department complaining of menorrhagia for the last fifteen days, leading to severe anemia. The objective examination revealed clinical signs of hypothyroidism and a severe short stature, lower than mid-parental height, with stunting of growth and a significant bone age delay. Blood exams and thyroid ultrasound were consistent with the diagnosis of severe hypothyroidism in autoimmune thyroiditis with acquired von Willebrand syndrome, growth hormone deficiency. Magnetic resonance showed pituitary functional hyperplasia. The substitutive therapy with levothyroxine led to the resolution of heavy bleeding after five days and following normalization of coagulative parameters and pituitary hyperplasia. CONCLUSIONS: Hypothyroidism usually presents with unspecific symptoms, with consequent risk of diagnostic delay. It can influence the coagulation system and it seems to be associated to increased risk of menstrual irregularities. We underline the importance of a regular follow up of the pubertal development, including height measurements, thyroid palpation and menstrual anamnesis to intercept red flags findings for hypothyroidism.

Mediterranean Dietary Treatment in Hyperlipidemic Children: Should It Be an Option?

BACKGROUND: Diet is considered the cornerstone of lipid management in hyperlipidemic children but evidence to demonstrate the effects of nutrient benefits on the lipid profile is limited. AIM: The aim of this study is to evaluate the impact of the Mediterranean diet on low-density lipoprotein (LDL-C) and non-high density lipoprotein (HDL-C) decrease in primary hyperlipidemia affected children and in the achievement of therapeutical target levels. METHODS: A retrospective cohort study was used, recruiting n = 223 children (10.05 ± 3.26 mean age years) with familial hypercholesterolemia (FH) (n = 61, 27%) and polygenic hypercholesterolemia (PH) (n =162, 73%). Secondary hyperlipidemias were excluded. Based on LDL-C and non-HDL-C decrease, participants were divided into two groups, named the Responder Group and Non-Responder Group. Participants and their families underwent dietary education by an expert nutritionist and were asked to fill in a weekly diary to be delivered at visits. Dietary indications were in line with daily caloric requirement, daily food quality and quantity intakes typical of the Mediterranean diet. These include carbohydrates, extra virgin olive oil, yoghurt and milk derivatives, fish and vegetable proteins, fresh seasonal vegetables and fresh fruits. Nuts or almonds were also recommended. The advice to limit intakes of meat, in particular red meat, and caution against junk food and sugar added food and beverages was provided. At medical visits, carried out at baseline (T0) and 6 months later (T1), children underwent anthropometric measurements and blood collection. Standard kits and methods were applied for lipid analysis. Statistical methods were performed by SAS version 9.4 (SAS Institute, Cary, NC, USA). Signed informed consent was given by parents according to the Declaration of Helsinki and the study was approved by the Local Committee. RESULTS: The Responder Group (n = 156/223, 70%) included 45 FH and 111 PH children, while the Non-Responder Group (n = 67/223, 30%) included 16 FH and 51 PH children. The Responder Group showed total cholesterol (TC), LDL-C and non-HDL-C median percentage decreases of 9.45, 13.51 and 10.90, respectively. These statistically significant changes (p ≤ 0.0001) were similar in the FH and PH subgroups but just PH subjects reached the LDL-C and non-HDL-C target, which fell below 130 mg/dL and 145 mg/dL, respectively. Saturated fatty acids (SFAs) were the main dietary parameter that distinguished between the Responder Group and the Non-Responder Group (p = 0.014). Positive correlations were found at T1 between dietary total lipids, SFAs and cholesterol with serum LDL-C, non-HDL-C and TC variations. These latter serum parameters had an inverse correlation with dietary carbohydrate at T1. Among macronutrients, SFAs were finally demonstrated to be the predictor of serum lipids variation at T1. CONCLUSIONS: The dietary intervention with a Mediterranean diet in children with primary hyperlipidemia significantly improves the lipid profile both in FH and PH subgroups and allows target levels of LDL-C and non-HDL-C in PH subjects to be reached. Responsiveness benefits should be primarily attributed to the reduction in SFAs, but changes in dietary lipids, cholesterol and carbohydrate intake may also play a role. In contrast, the Non-Responder Group showed a worsening of lipid profile regarding the unchanged diet.

Oestrogenic Activity in Girls with Signs of Precocious Puberty as Exposure Biomarker to Endocrine Disrupting Chemicals: A Pilot Study.

The relationship between endocrine disrupting chemical (EDC) exposure and Precocious Puberty (PP) was investigated in this pilot study, involving girls with signs of PP (P) and pre-pubertal girls (C). Risk factors for PP were assessed through questionnaires, while 17ß-oestradiol (E2) levels and oestrogenic activity were quantified on sera. The oestrogenic activity, expressed as E2 equivalent concentration (EEQ), was applied as EDC exposure biomarker. Questionnaires showed a low EDC knowledge, a high EDC exposure, and a potential relationship between some habits at risk for EDC exposure and PP. EEQs were similar between C and P; however, they were significantly higher in girls living in an urban environment than in girls living in a rural environment, suggesting a potential higher EDC exposure in cities. The results of this pilot study highlighted the need to raise awareness on EDCs and can be considered a starting point to clarify the relationship between EDC exposure and PP.

Multidisciplinary Approach for Hypothalamic Obesity in Children and Adolescents: A Preliminary Study.

Hypothalamic obesity (HO) is delineated by an inexorable weight gain in subjects with hypothalamic disorder (congenital or acquired). The aim of the present study was to evaluate the effect of a multidisciplinary approach on weight trend and metabolic outcome in children and adolescents with hypothalamic disease who were overweight or obese. Thirteen patients (aged 8.1-16.1 years) received a personalized diet, accelerometer-based activity monitoring, and psychological assessment. Height, weight, body mass index (BMI), and serum metabolic parameters were assessed at baseline (T0) and after six months (T1). Metformin was introduced at T1 in four subjects who were then re-evaluated after six months (T2). At T1, weight gain was significantly reduced compared with T0 (0.29 ± 0.79 kg/month vs. 0.84 ± 0.55 kg/month, p = 0.03), and weight standard deviation score (SDS) and BMI SDS did not change significantly, as serum metabolic parameters. The four subjects treated with metformin showed a reduction of weight SDS and BMI SDS at T2. In conclusion, patients treated with our multidisciplinary approach showed, after 6 months, favorable results characterized by decreased weight gain and stabilization of weight SDS and BMI SDS in a condition usually characterized by inexorable weight gain. However, further analysis, larger cohorts, and longer follow-up are needed to confirm these preliminary data.

"Primary Hyperparathyroidism (PHPT) in Children: Two Case Reports and Review of the Literature".

Primary hyperparathyroidism (PHPT) is a rare disorder in children and adolescents. Typical biochemical features are hypercalcemia and hypophosphatemia, but the clinical features can be heterogeneous, and in some cases, symptoms are vague and nonspecific, leading to misdiagnosis or late diagnosis. Herein, we report two cases of PHPT in pediatric age with different presenting symptoms, pain in the foot, and progressive alteration of the gait in the first case and recurrent abdominal pain with emotional lability in the second. Biochemical and radiological assessment confirmed PHPT. Both cases were treated surgically as definitive treatment, but in the second case, previous medical treatment with cinacalcet, a calcimimetic agent, was required to reduce serum PTH and calcium levels. After surgery, despite conventional treatment with calcium and calcitriol, case 1 developed a hungry bone syndrome. The analysis of the MEN-1 (Multiple Endocrine Neoplasia) gene was negative in both cases. A diagnosis of PHPT should be considered when children or adolescents present bone pain with radiological imaging of osteolytic lesion and biochemical feature of hypercalcemia associated with hypophosphatemia. In PHPT, the gold standard treatment is represented by surgery followed by strict postoperative endocrine monitoring to maintain adequate homeostasis of calcium and bone metabolism.

Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy in Two Siblings: Same Mutations but Very Different Phenotypes.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), caused by mutations in the AIRE gene, is mainly characterized by the triad of hypoparathyroidism, primary adrenocortical insufficiency and chronic mucocutaneous candidiasis, but can include many other manifestations, with no currently clear genotype-phenotype correlation. We present the clinical features of two siblings, a male and a female, with the same mutations in the AIRE gene associated with two very different phenotypes. Interestingly, the brother recently experienced COVID-19 infection with pneumonia, complicated by hypertension, hypokalemia and hypercalcemia. Although APECED is a monogenic disease, its expressiveness can be extremely different. In addition to the genetic basis, epigenetic and environmental factors might influence the phenotypic expression, although their exact role remains to be elucidated.

SHOX deficiency in children with growth impairment: evaluation of known and new auxological and radiological indicators.

BACKGROUND: The phenotypic features of SHOX deficiency (SHOX-D) are highly variable and can be very mild, especially in young children. The aim of this retrospective study was to evaluate auxological and radiological indicators that could be predictive of SHOX-D in children. METHODS: Molecular analysis of the SHOX gene was performed in 296 subjects with growth impairment or skeletal disproportion, without alternative diagnosis. Auxological variables and radiographs of the hand, wrist and forearm were evaluated. RESULTS: SHOX mutations (88% inherited, 12% de novo) were identified in 52 subjects. The most predictive auxological indicators of SHOX-D were an increased sitting height/height ratio and a decreased arm span/height ratio. The convexity of distal radial metaphysis at X-ray, not yet reported in literature, was also found to be predictive of SHOX-D. In young children, stratification of data by bone age also highlighted ulnar tilt, lucency of the ulnar border of the distal radius and enlarged radius as the radiological signs most related to SHOX-D . CONCLUSIONS: In this study, the analysis of auxological and radiological indicators in SHOX-D children allowed to identify an additional early radiological sign and underlines the importance of family auxological evaluation.

Cardiovascular risk factors in children and adolescents with type 1 diabetes in Italy: a multicentric observational study.

AIMS: To assess the prevalence of cardiovascular risk factors (CVRFs) and to identify the variables associated with CVRFs in a cohort of children and adolescents with Type 1 Diabetes. METHODS: 2021 subjects, 2-18 year-old, were recruited in 17 Italian Pediatric Diabetes Centers. Anthropometric, blood pressure, biochemical (HbA1c, lipid profile, ACR), insulin therapy, physical activity level, smoking and family socio-economic status data were collected. CVRFs prevalence and their distribution were analyzed according to age and binary logistic regression was performed with positivity for at least one major CVRF (BMI-SDS > +2SD, blood pressure > 90th percentile, LDL cholesterol>100 mg/dL) as dependent variable and age, duration of illness, gender, HbA1c and physical activity, as independent variables. RESULTS: The prevalence of CVFRs not at the recommended target was respectively: 32.5% one CVRF, 6.7% two CVRFs and 0.6% three CVRFs, with no significant differences across the 3 age groups (2-10, 10-15, 15-18 years). In the total sample, HbA1c and inadequate physical activity were associated with a higher probability of having at least one major CVRF. This probability was associated with physical activity in the 2-10-year-old group, with physical activity and HbA1c in the 10-15-year-old group and with HbA1c only in subjects older than 15 years. CONCLUSIONS: More than 30% of subjects had at least a major CVRF. Early detection of CVRFs may be useful to enforce the therapeutic intervention in this subgroup, in order to reduce the risk to develop cardiovascular complications.

Jaffe-Campanacci syndrome or neurofibromatosis type 1: a case report of phenotypic overlap with detection of NF1 gene mutation in non-ossifying fibroma.

BACKGROUND: Jaffe-Campanacci syndrome is characterized by multiple non-ossifying fibromas, café-au-lait macules and giant cell granulomas of the jaw. Even if the association between all these peculiar features and neurofibromatosis type 1 have been described, it has not yet been clarified whether Jaffe-Campanacci syndrome represents a distinct entity or it can be regarded as a neurofibromatosis type 1 subtype. CASE PRESENTATION: The patient here described is a young boy, who fulfilled the clinical diagnostic criteria for both syndromes. He had a complex clinical history with café-au-lait macules, axillary and inguinal freckling, multiple non-ossifying fibromas, giant-cell granuloma of the jaw, neurofibromas, plexiform fibroma, ocular Lisch nodules, optic chiasmatic- hypothalamic glioma, pseudarthrosis, scoliosis, short stature, vascular anomalies, seizures. Molecular analysis of the NF1 gene both on blood cells and non-ossifying fibroma's biopsy tissue allowed the detection of a novel variant within the coding region, NM_000267.3:c.2789_2791delATC(p.Tyr930_Pro931delinsSer), with loss of heterozygosity (second hit mutation) in the non-ossifying fibroma. CONCLUSION: This result indicates that every patient with clinical features of Jaffe-Campanacci syndrome should be further evaluated to detect features related to neurofibromatosis type 1 and genetically investigated for mutations in the NF1 gene, since this could lead to a definite diagnosis, but also could clarify and quantify the real genotype-phenotype overlap between neurofibromatosis type 1 and Jaffe-Campanacci syndrome.

Teriparatide (rhPTH 1-34) treatment in the pediatric age: long-term efficacy and safety data in a cohort with genetic hypoparathyroidism.

BACKGROUND: Hypoparathyroidism is characterized by the absence or inadequately low circulating concentrations of the parathyroid hormone, resulting in hypocalcemia, hyperphosphatemia, and elevated fractional excretion of calcium in the urine. The use of activated vitamin D analogs and calcium supplements represent conventional therapy. Subcutaneous recombinant human parathormone [rhPTH(1-34)] has been proposed as a substitutive treatment, even to avoid side effects of vitamin D and calcium. OBJECTIVE: To assess the long-term safety and efficacy of rhPTH(1-34) in a pediatric cohort of patients with genetic hypoparathyroidism. METHODS: The study is a 9.2-year self-controlled study of six pediatric patients (four males and two females, aged 9.4 ± 5.2) with DiGeorge, hypoparathyroidism-deafness-renal dysplasia (HDR) or autoimmune-candidiasis-polyendocrinopathy-ectodermal-dysplasia (APECED) syndrome, associated with autoimmune intestinal malabsorption in a patient. The presence of clinical signs of hypocalcemia and biochemical parameters, such as calcium, phosphate, alkaline phosphatase in the blood and calcium-creatinine ratio in urine, were compared during conventional treatment and rhPTH(1-34) (teriparatide, 12.5 µg twice daily). RESULTS: The rhPTH(1-34) treatment allowed a reduction, although not always a complete suspension, of calcium supplementation and a slight reduction of calcitriol therapy. The number of tetanic episodes was reduced in four patients during the rhPTH(1-34) treatment. Mean blood calcium, alkaline phosphatase, and phosphate did not significantly change, while a significant reduction of the urinary calcium-to-creatinine ratio (0.55 ± 0.32 vs 0.16 ± 0.09, p = 0.03) was obtained. Renal ultrasound examination showed a worsening in three patients, while it did not change in the remaining three subjects during the follow-up. CONCLUSIONS: In children with syndromic hypoparathyroidism presented here, replacement therapy with rhPTH(1-34) allowed to maintain adequate levels of the calcium and phosphate in the blood, normalize urinary calcium excretion, and reduce tetanic episodes. In patients with low compliance to conventional therapy or intestinal malabsorption, the use of rhPTH(1-34) could be considered, also to reduce the side effects of treatment with vitamin D and calcium.