Rosario Ferrigno

Peripheral precocious puberty (PPP) is an endocrine disorder characterized by premature, autonomous gonadal or extragonadal sexual steroid secretion. Accounting for about 20% of cases of precocious puberty, PPP is usually caused by rare diseases, including congenital adrenal hyperplasias, hormone-secreting gonadal and adrenal tumours, and McCune-Albright Syndrome (MAS). MAS is a rare, genetic disorder, mainly characterized by bone dysplasia, skin hyperpigmentation, and endocrine, hyperfunctioning disorders, including, as reported, PPP. Being a rare disease, PPP management in MAS patients is currently anecdotically reported, and no systematic approach is granted. A four years and two months boy was admitted in our department due to precocious pubarche and recent growth acceleration. At physical examination, he showed cafè-au-lait skin macules on thorax, abdomen, and posterior neck, and at hormonal evaluation he showed evidence of PPP, confirmed at both baseline and stimulated gonadotropin and testosterone levels. Due to the clinical features, he was diagnosed with MAS, that was further confirmed by the evidence of bone skull and testicular lesions; a thyroid lesion was also reported, but its relationship with MAS was questioned. He therefore started combined treatment with androgen receptor blocker bicalutamide and aromatase inhibitor anastrazole, that were able to significantly reduce growth acceleration and to stop pubertal progression. He safely continued combined treatment for three years, showing good efficacy on growth and pubertal outcome. Combined treatment with bicalutamide and anastrozole is a safe and effective long-term therapeutic approach to PPP in MAS boys, although evidences on its use are scarce; therefore, wider studies including larger populations deriving from different centres should be performed to obtain general consensus.

Background: Turner syndrome (TS) is a chromosomal disorder characterized by specific clinical features, including cardiac and renal malformations and short stature. In these patients, recombinant growth hormone (GH) treatment is currently recommended, showing positive effects on growth rate, with good tolerability. However, height improvement and growth outcome in TS girls is reportedly impaired compared with other girls treated with GH due to other reason, including GH deficiency (GHD).Aim: The aim of the current study was to compare the growth outcome and the safety of 3‐years GH treatment in TS and GHD girls.Patients & Methods: The study included 20 girls, 10 with TS diagnosis (4 full complete monosomy of X chromosome, 40%; 6 partial monosomy (mosaic) of X chromosome, 60%) and 10 with isolated idiopathic GHD diagnosis, matched for age (range: 4.17–10.42 years; median: 6.8 ± 2.37) treated with GH (starting dosage: 33.08 ± 4.31 μg/kg/day in TS girls and 32.17 ± 2.51 μg/kg/day in GHD girls) for at least 36 months. Growth parameters, glycemic profile, and IGF‐1 levels were collected every 6 months.Results: Compared to baseline, both TS and GHD children showed a significant improvement in height, weight, and growth rate after 3 years of treatment with GH (p ≤ 0.01), already evident after 6 months of treatment (p ≤ 0.016). Noteworthy, patients in both groups showed a constant, significant improvement in height until 24 months of treatment, as a significantly increase was observed both after 12 months compared to 6 months of treatment (p ≤ 0.008) and after 24 months compared to 12 months of treatment (p ≤ 0.031), whereas only GHD girls showed a significant increase after 36 months compared to 30 months of treatment (p = 0.035). Comparing the two study groups, TS girls showed a lower height and a lower height increase throughout the study, but these differences reached statistical significance only after six and 12 months of treatment (T6: +0.42 ± 0.23 SDS in TS vs +0.74 ± 0.38 SDS in GHD, p = 0.045; T12: +0.59 ± 0.34 vs +0.93 ± 0.39 SDS in GHD, p = 0.034). Considering safety profile, treatment was well tolerated, as the most frequently reported adverse event was autoimmune thyroiditis (two TS girls, 10%); no hyperglycemia occurred throughout the treatment, whereas one TS girl (5%) and one GHD girl (5%) experience transient hypertransaminasemia and hypercholesterolemia, respectively.Conclusions: In conclusion, GH treatment in both TS and GHD girls is an effective, safe treatment for short stature, improving both height and growth rate, especially during the first year of treatment. Moreover, although growth outcomes were significantly better in GHD girls in the first year of treatment, over time no significant differences were observed between TS and GHD girls.

Defects of the adrenal gland in childhood comprise a broad spectrum of ae ologies, ranging from gene c variants resul ng in adrenal insufficiency 1 , autoimmune dysfunc on 1 , impaired s mula on by the hypothalamic-pituitary axis 1 , and adrenal tumours [2][3][4] , poten ally resul ng in autonomous neoplas c hypersecre on of both adrenal cor cal 3 and medullary steroids 4 . Adrenocor cal hypofunc on can be a life-threatening disorder requiring urgent diagnosis and replacement with glucocor coids 1 . In contrast, hypersecre on of cor sol as in Cushing syndrome leads to specific clinical features such as growth failure, obesity, hirsu sm and osteoporosis, which if undiagnosed can cause major morbidity and decrease in quality of life 3 . Adrenal tumours, including adrenocor cal carcinomas and phaeochromocytomas, may be isolated or a component of familial endocrine neoplas c syndromes, requiring urgent diagnosis, gene c characterisa on, and surgical removal [2][3][4] .In this collec on of ar cles, we describe the rare gene c causes of adrenal insufficiency, discussing the diagnosis, molecular characterisa on, and treatment of adrenal defects, comprising the variegate landscape of familial glucocor coid deficiency syndromes 5,6 . Autoimmune Addison's disease is also discussed and, although rare in childhood, may be isolated or a component of polyendocrine autoimmune dysfunc on in conjunc on with hypoparathyroidism and gonadal insufficiency 7 . The molecular features are also described 7 . The gene c origins of adrenoleukodystrophy are discussed together with the paediatric features, therapeu c approaches and long-term prognos c predic ons 8 .Finally, neoplas c disorders comprising adrenocor cal carcinoma 9 , Cushing syndrome [10][11][12] , and phaeochromocytoma 13 are discussed in detail. Adrenocor cal carcinomas are extremely rare in childhood, but associated with a poor prognosis 9 . Cushing syndrome may be ACTH-dependent, as in Cushing disease, which is the secre on of excess ACTH by a pituitary adenoma or ectopic ACTH syndrome 10,11 , or ACTH-independent as in the case of an adrenocor cal tumour or adrenocor cal hyperplasia, which may be isolated or part of the gene c complex of McCune-Albright syndrome or Carney Complex 11,12 . Guidelines for the management of paediatric phaeochromocytoma are described together with therapeu c recommenda ons for management of hypertension 13 .Our aim in bringing together this collec on of ar cles is to provide clinical and scien fic up-dates to inform and educate both paediatric and adult endocrinologists and their nursing support staff in the broad range of adrenal disorders, which although rare in childhood, can be life-threatening and, by defini serious. The collabora on between paediatric and adult endocrinology staff is emphasised, par cularly in disorders such as familial endocrine neoplasia and Cushing syndrome, where few have wide experience in the management of these disorders.

Children born small for gestational age (SGA) are defined as those having birth weight and/or length below -2 SD for gestational age. In approximately 90% of cases, SGA children experience catch-up growth in the first two years of life and a subsequent regular growth rate, reaching normal adult height. However, in the remaining 10% of cases, SGA children fail to have catch-up growth, showing persistent short stature and a constantly impaired growth rate, leading to decreased adult height compared with both general population and their mid-parental height. Therefore, in these children GH treatment may be indicated to improve growth outcome. As it can be started in most countries from the age of 4 years and is usually recommended until the completion of puberty, long-term GH treatment in SGA children (namely, longer than three years) showed a persistent improvement in height and an initial improvement in growth rate in the first year of treatment, followed by a stable, regular growth rate over time. In the present article, we systematically reviewed the currently available reports about efficacy of long-term GH treatment in SGA children, with a particular focus on growth rate over time and adult height.

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.

Adrenal insufficiency (AI) is a severe endocrine disorder characterized by insufficient glucocorticoid (GC) and/or mineralocorticoid (MC) secretion by the adrenal glands, due to impaired adrenal function (primary adrenal insufficiency, PAI) or to insufficient adrenal stimulation by pituitary ACTH (secondary adrenal insufficiency, SAI) or tertiary adrenal insufficiency due to hypothalamic dysfunction. In this review, we describe rare genetic causes of PAI with isolated GC or combined GC and MC deficiencies and we also describe rare syndromes of isolated MC deficiency. In children, the most frequent cause of PAI is congenital adrenal hyperplasia (CAH), a group of adrenal disorders related to steroidogenic enzyme deficiencies, which will not be included in this review. Less frequently, several rare diseases can cause PAI, either affecting exclusively the adrenal glands or with systemic involvement. The diagnosis of these diseases is often challenging, due to the heterogeneity of their clinical presentation and to their rarity. Therefore, the current review aims to provide an overview on these rare genetic forms of paediatric PAI, offering a review of genetic and clinical features and a summary of diagnostic and therapeutic approaches, promoting awareness among practitioners, and favoring early diagnosis and optimal clinical management in suspect cases.

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.

Cushing’s disease (CD) is rare in paediatric practice but requires prompt investigation, diagnosis and therapy to prevent long-term complications. Key presenting features are a change in facial appearance, weight gain, growth failure, virilization, disturbed puberty and psychological disturbance. Close consultation with an adult endocrinology department is recommended regarding diagnosis and therapy. The incidence of CD, a form of ACTH-dependent Cushing’s syndrome (CS), is equal to approximately 5% of that seen in adults. The majority of ACTH-secreting adenomas are monoclonal and sporadic, although recent studies of pituitary tumours have shown links to several deubiquitination gene defects. Diagnosis requires confirmation of hypercortisolism followed by demonstration of ACTH-dependence. Identification of the corticotroph adenoma by pituitary MRI and/or bilateral inferior petrosal sampling for ACTH may contribute to localisation before pituitary surgery. Transsphenoidal surgery (TSS) with selective microadenomectomy is first-line therapy, followed by external pituitary irradiation if surgery is not curative. Medical therapy to suppress adrenal steroid synthesis is effective in the short-term and bilateral adrenalectomy should be considered in cases unfit for TSS or radiotherapy or when urgent remission is needed after unsuccessful surgery. TSS induces remission of hypercortisolism and improvement of symptoms in 70–100% of cases, particularly when performed by a surgeon with experience in children. Post-TSS complications include pituitary hormone deficiencies, sub-optimal catch-up growth, and persisting excess of BMI. Recurrence of hypercortisolism following remission is recognised but infrequent, being less common than in adult CD patients. With experienced specialist medical and surgical care, the overall prognosis is good. Early referral to an experienced endocrine centre is advised.