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

The Role of Registers in Increasing Knowledge and Improving Management of Children and Adolescents Affected by Familial Hypercholesterolemia: the LIPIGEN Pediatric Group

Pathology registers can be a useful tool to overcome obstacles in the identification and management of familial hypercholesterolemia since childhood. In 2018, the LIPIGEN pediatric group was constituted within the Italian LIPIGEN study to focus on FH subjects under 18 years. This work aimed at discussing its recent progress and early outcomes. Demographic, biochemical, and genetic baseline characteristics were collected, with an in-depth analysis of the genetic defects. The analysis was carried out on 1,602 children and adolescents (mean age at baseline 9.9 ± 4.0 years), and almost the whole cohort underwent the genetic test (93.3%). Overall, the untreated mean value of LDL-C was 220.0 ± 97.2 mg/dl, with an increasing gradient from subjects with a negative (N = 317; mean untreated LDL-C = 159.9 ± 47.7 mg/dl), inconclusive (N = 125; mean untreated LDL-C = 166.4 ± 56.5 mg/dl), or positive (N = 1,053; mean untreated LDL-C = 246.5 ± 102.1 mg/dl) genetic diagnosis of FH. In the latter group, the LDL-C values presented a great variability based on the number and the biological impact of involved causative variants. The LIPIGEN pediatric group represents one of the largest cohorts of children with FH, allowing the deepening of the characterization of their baseline and genetic features, providing the basis for further longitudinal investigations for complete details

“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

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