Auxological and metabolic effects of long-term treatment with recombinant growth hormone in children born small for gestational age: a retrospective study.

RATIONALE: Children born small for gestational age (SGA) not showing catch-up during the first two years of life reportedly show an impaired growth rate and adult height, as well as a worse metabolic outcome, mainly in terms of glycemic and lipid profile, compared to general population. In SGA children with short stature, treatment with recombinant growth hormone (GH) is currently recommended until adolescence; therefore, it may last long-term. STUDY METHODS: The aim of the current study was to evaluate the auxological and metabolic effects and the safety of long-term recombinant GH treatment in SGA children. The study included 15 SGA children (5 F, 10 M; mean age: 6.78 yrs) treated with GH for at least 48 months. Growth and metabolic parameters, including glycemic and lipid profile, transaminases, and urycemia, were collected every six months. RESULTS: Compared to baseline, SGA children showed a significant improvement in height, weight, and growth rate after four yaers of treatment with GH (p ≤ 0.002), being already evident after six months of treatment (p < 0.001). Noteworthy, patients showed a constant, significant improvement in height throughout the treatment, as it was significantly higher at each follow-up compared to the previous one, until 42 months of treatment, except at 30 months of treatment (p < 0.001 T6VST12; p < 0.01 T12VST18, T18VST24; p < 0.05 T30VST36, T36VST42). Considering metabolic parameters, compared to baseline, a recurring increase in glycemia (p ≤ 0.028 vs T30, T36, and T48) and decrease in AST (p ≤ 0.035 vs T36, T42, and T48) and an occasional decrease in LDL cholesterol (p ≤ 0.04 vs T24 and T42) and triglycerides (p = 0.008 vs T18) and increase in urycemia (p = 0.034 vs T42). Considering safety profile, treatment was well tolerated, as the most frequently reported adverse event was poor compliance (20%); no hyperglycemia, hypercholesterolemia or hyperstransaminasemia occurred throughout the treatment, CONCLUSIONS: Long-term GH treatment showed to be effective in improving height and growth rate in SGA children, with a positive impact of metabolic profile and a safety profile, although glycemia should be carefully monitored over time.

Metabolic and Growth Outcome of Two-year Growth Hormone Treatment in Children Born Small for Gestational Age: A Retrospective Study.

BACKGROUND: Children born Small for Gestational Age (SGA) without early catch-up growth may show impaired growth rate, adult height, and metabolic profile [1]. Growth Hormone (GH) is recommended for their treatment, and it has been shown to have positive effects on growth and metabolic profile and good tolerability [2]. OBJECTIVE: The study aimed to evaluate the auxological and metabolic effects and safety of GH treatment in SGA children. METHODS: 34 SGA children (15 F, 19 M; mean age: 8.72 ± 2.48 yrs) treated with GH (starting dosage: 32.24 ± 2.88 mcg/kg/die) were evaluated every six months for 24 months with growth and metabolic parameters. RESULTS: After two years, SGA children showed a significant improvement in height, weight, and growth rate, already evident after six months (p < 0.001), with a constant, significant improvement in height throughout the treatment (p ≤ 0.03 T0 vs. T12, T12 vs. T24). Conversely, although significantly higher than baseline at each visit (p < 0.001), the growth rate significantly decreased from 6 to 18 months (p ≤ 0.015 T6 vs. T12, T12 vs. T18). During the follow-up, an increase in glycemia (p ≤ 0.042 vs. T12, T18) and urycemia (p ≤ 0.01 vs. T12, T18, and T24) and a decrease in AST (p ≤ 0.021 vs. T12, T18, and T24) and LDL cholesterol (p = 0.03 vs. T24) were observed. Overall, treatment was found to be well tolerated, with poor compliance being the most frequent adverse event (11.8%) and no reported hyperglycemia. CONCLUSION: In conclusion, GH can be considered an effective, safe treatment in SGA children, improving height and growth rate, although proper metabolic follow-up is required.

Growth alterations in rare forms of primary adrenal insufficiency: a neglected issue in paediatric endocrinology.

Primary adrenal insufficiency (PAI) is an endocrine disorder characterized by direct adrenal failure, with consequent glucocorticoid, and eventually mineralocorticoid, deficiency. In children, the main cause of PAI is congenital adrenal hyperplasia (CAH), due to a loss of function of adrenal steroidogenic enzymes, but also rarer forms, including autoimmune polyglandular syndrome, adrenoleucodistrophy, adrenal hypoplasia congenita, familial glucocorticoid deficiency, and Allgrove's Syndrome, may be observed. In PAI children, growth alterations represent a major issue, as both inadequate and excessive glucocorticoid replacement treatment may lead to reduced growth rate and adult height impairment. However, growth abnormalities are poorly studied in rare forms of paediatric PAI, and specific studies on growth rate in these children are currently lacking. In the present review, the currently available evidence on growth alterations in children with rare PAI forms will be summarized, with a major focus on comorbidities with a potential impact on patients' growth rate.

Co-occurrence of Beckwith-Wiedemann syndrome and pseudohypoparathyroidism type 1B: coincidence or common molecular mechanism?

Imprinting disorders are congenital diseases caused by dysregulation of genomic imprinting, affecting growth, neurocognitive development, metabolism and cancer predisposition. Overlapping clinical features are often observed among this group of diseases. In rare cases, two fully expressed imprinting disorders may coexist in the same patient. A dozen cases of this type have been reported so far. Most of them are represented by individuals affected by Beckwith-Wiedemann spectrum (BWSp) and Transient Neonatal Diabetes Mellitus (TNDM) or BWSp and Pseudo-hypoparathyroidism type 1B (PHP1B). All these patients displayed Multilocus imprinting disturbances (MLID). Here, we report the first case of co-occurrence of BWS and PHP1B in the same individual in absence of MLID. Genome-wide methylation and SNP-array analyses demonstrated loss of methylation of the KCNQ1OT1:TSS-DMR on chromosome 11p15.5 as molecular cause of BWSp, and upd(20)pat as cause of PHP1B. The absence of MLID and the heterodisomy of chromosome 20 suggests that BWSp and PHP1B arose through distinct and independent mechanism in our patient. However, we cannot exclude that the rare combination of the epigenetic defect on chromosome 11 and the UPD on chromosome 20 may originate from a common so far undetermined predisposing molecular lesion. A better comprehension of the molecular mechanisms underlying the co-occurrence of two imprinting disorders will improve genetic counselling and estimate of familial recurrence risk of these rare cases. Furthermore, our study also supports the importance of multilocus molecular testing for revealing MLID as well as complex cases of imprinting disorders.

De Novo Large Deletions in the PHEX Gene Caused X-Linked Hypophosphataemic Rickets in Two Italian Female Infants Successfully Treated with Burosumab.

Pathogenic variants in the PHEX gene cause rare and severe X-linked dominant hypophosphataemia (XLH), a form of heritable hypophosphatemic rickets (HR) characterized by renal phosphate wasting and elevated fibroblast growth factor 23 (FGF23) levels. Burosumab, the approved human monoclonal anti-FGF23 antibody, is the treatment of choice for XLH. The genetic and phenotypic heterogeneity of HR often delays XLH diagnoses, with critical effects on disease course and therapy. We herein report the clinical and genetic features of two Italian female infants with sporadic HR who successfully responded to burosumab. Their diagnoses were based on clinical and laboratory findings and physical examinations. Next-generation sequencing (NGS) of the genes associated with inherited HR and multiple ligation probe amplification (MLPA) analysis of the PHEX and FGF23 genes were performed. While a conventional analysis of the NGS data did not reveal pathogenic or likely pathogenic small nucleotide variants (SNVs) in the known HR-related genes, a quantitative analysis identified two different heterozygous de novo large intragenic deletions in PHEX, and this was confirmed by MLPA. Our molecular data indicated that deletions in the PHEX gene can be the cause of a significant fraction of XLH; hence, their presence should be evaluated in SNV-negative female patients. Our patients successfully responded to burosumab, demonstrating the efficacy of this drug in the treatment of XLH. In conclusion, the execution of a phenotype-oriented genetic test, guided by known types of variants, including the rarest ones, was crucial to reach the definitive diagnoses and ensure our patients of long-term therapy administration.

Diencephalic Syndrome Due to Optic Pathway Gliomas in Pediatric Patients: An Italian Multicenter Study.

Diencephalic syndrome (DS) is a rare pediatric condition associated with optic pathway gliomas (OPGs). Since they are slow-growing tumors, their diagnosis might be delayed, with consequences on long-term outcomes. We present a multicenter case series of nine children with DS associated with OPG, with the aim of providing relevant details about mortality and long-term sequelae. We retrospectively identified nine children (6 M) with DS (median age 14 months, range 3-26 months). Four patients had NF1-related OPGs. Children with NF1 were significantly older than sporadic cases (median (range) age in months: 21.2 (14-26) versus 10 (3-17); p = 0.015). Seven tumors were histologically confirmed as low-grade astrocytomas. All patients received upfront chemotherapy and nutritional support. Although no patient died, all of them experienced tumor progression within 5.67 years since diagnosis and were treated with several lines of chemotherapy and/or surgery. Long-term sequelae included visual, pituitary and neurological dysfunction. Despite an excellent overall survival, PFS rates are poor in OPGs with DS. These patients invariably present visual, neurological or endocrine sequelae. Therefore, functional outcomes and quality-of-life measures should be considered in prospective trials involving patients with OPGs, aiming to identify "high-risk" patients and to better individualize treatment.

Pretreatment Endocrine Disorders Due to Optic Pathway Gliomas in Pediatric Neurofibromatosis Type 1: Multicenter Study.

CONTEXT: Up to 20% of children with neurofibromatosis type 1 (NF1) develop low-grade optic pathway gliomas (OPGs) that can result in endocrine dysfunction. Data on prevalence and type of endocrine disorders in NF1-related OPGs are scarce. OBJECTIVES: The aim of the study was to determine the prevalence of endocrine dysfunctions in patients with NF1 and OPGs and to investigate predictive factors before oncological treatment. DESIGN: Multicenter retrospective study. SETTINGS AND PATIENTS: Records were reviewed for 116 children (64 females, 52 males) with NF1 and OPGs followed at 4 Italian centers. MAIN OUTCOME MEASURES: We evaluated endocrine function and reviewed brain imaging at the time of OPG diagnosis before radio- and chemotherapy and/or surgery. OPGs were classified according to the modified Dodge classification. RESULTS: Thirty-two children (27.6%) with a median age of 7.8 years had endocrine dysfunctions including central precocious puberty in 23 (71.9%), growth hormone deficiency in 3 (9.4%), diencephalic syndrome in 4 (12.5%), and growth hormone hypersecretion in 2 (6.2%). In a multivariate cox regression analysis, hypothalamic involvement was the only independent predictor of endocrine dysfunctions (hazard ratio 5.02 [1.802-13.983]; P = .002). CONCLUSIONS: Endocrine disorders were found in approximately one-third of patients with Neurofibromatosis type 1 and OPGs before any oncological treatment, central precocious puberty being the most prevalent. Sign of diencephalic syndrome and growth hormone hypersecretion, although rare, could be predictive of optic pathway gliomas in NF1. Tumor location was the most important predictor of endocrine disorders, particularly hypothalamic involvement.

Linear growth and intellectual outcome in children with long-term idiopathic subclinical hypothyroidism.

OBJECTIVE: The treatment of children with subclinical hypothyroidism (SH) is controversial for TSH values between 4.5 and 10 mU/l. The aim of this cross-sectional, controlled study was to evaluate growth and intellectual outcome in children with persistent SH who have never been treated with levothyroxine. DESIGN AND METHODS: Clinical and auxological parameters, thyroid function, and intellectual outcome were evaluated in 36 children with persistent SH at the age of 9.7±0.6 (range 4-18.0) years. Children had been followed longitudinally for 3.3±0.3 (range 2.0-9.3) years, from first diagnosis of SH until enrollment in the study. Thirty-six age- and sex-matched children were enrolled in the study as controls. RESULTS: At study entry, height (-0.8±0.2 SDS), bone age/chronological age (BA/CA ratio 0.92±0.6), and body mass index (BMI -0.1±0.2 SDS) in SH children were normal. Despite long-term duration of SH, none of these parameters showed a worsening with respect to height (-0.7±0.2 SDS), BA/CA (0.97±0.03), and BMI (-0.1±0.2) at the time of first SH detection. None of the children showed overt signs or symptoms of hypothyroidism during the follow-up. Verbal (99.1±2.2), performance (100.4±1.9), and full-scale (99.7±1.9) intelligence quotient (IQ) scores in SH children were normal and comparable to those of controls. No relationship was detected between IQ scores and the degree or duration of SH. CONCLUSIONS: Persistent SH in children is not associated with alterations in growth, bone maturation, BMI, and cognitive function or other complaints that could be ascribed to SH even after several years without therapeutic intervention.