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Background. Few data are available on quarterly 11.25 mg GnRH analog treatment in central precocious puberty (CPP). Aim. To assess the efficacy of triptorelin 11.25 mg in children with CPP. Patients. 17 patients (16 females) with CPP (7.9±0.9 years) were treated with triptorelin 11.25 mg/90 days. Methods. Gonadotropins, basal-, and GnRH-stimulated peak, gonadal steroids, and pubertal signs were assessed at preinclusion and at inclusion visit, 3 months, 6 months, and 12 months of treatment. Results. At 3, 6, and 12 months, all patients had suppressed LH peak (<3 IU/L after GnRH stimulation), as well as prepubertal oestradiol levels. Mean LH peak values after GnRH test significantly decreased from 25.7±16.5 IU/L at baseline to 0.9±0.5 IU/L at M3 (P<0.0001); they did not significantly changed at M6 and M12. Conclusions. Triptorelin 11.25 mg/90 days efficiently suppressed the pituitary-gonadal axis in children with CPP from first administration.

Complete androgen insensitivity syndrome (CAIS) represents a main disorder of sex development. Women with CAIS may have their gonads removed before, during or after adolescence, thus requiring hormonal replacement therapy to induce puberty and/or maintain secondary sexual characteristics, to optimize bone mass accrual, and to promote physical and social well-being. Usually estrogens are used for this purpose, but formulations and doses should be better defined in multicentric prospective studies. Some women started testostosterone as hormonal replacement therapy, but this practice remains anecdotal. Bone health remains a crucial aspect in the management of persons with CAIS, but few sound data are available to guide clinical practice.

Infantile anorexia nervosa (AN) is a specific eating disorder of prepubertal children. Poor data are available on growth hormone (GH)-insulin-like growth factor 1 (IGF-1) axis in this disorder. We report on a boy (4.5 years) with progressive growth impairment. At psychiatric assessment (DC: 0-3 R, AXIS I), he fulfilled all required criteria for diagnosis of infantile AN. Endocrine evaluation suggested impaired peripheral response to GH (high GH and low IGF-1 levels), likely related to energy deficiency. Auxological evaluation was shown as raw data and SDS using Italian reference values. GH secretion was assessed by arginine provocative test; IGFI generation test was done administering recombinant GH (0.05 mg/kg/day for four days). Psychiatric assessment was performed according to the DC:0-3R protocol. Impaired GH-IGF-1 axis may be involved in growth delay of children with infantile AN. A strict collaboration between endocrine pediatricians and child psychiatrists is advisable in the assessment of poor growing children without recognizable organic causes, showing normal/high GH levels and low IGF-1 values.

Background: Steroidogenic factor 1, encoded by the NR5A1 gene, is a key regulator of endocrine function within the hypothalamic-pituitary-steroidogenic axis. Both homozygous, compound heterozygous and heterozygous mutations in the NR5A1 gene may determine 46,XY disorders of sex development (DSD). Patients and Methods:NR5A1 gene sequencing was performed in a cohort of 6 patients with 46,XY DSD without specific diagnosis. Results: Heterozygous NR5A1 gene mutations were found in 2 girls, aged 0.5 years and 14 years. The older girl harbored the c.250C>T transition in exon 4 (p.Arg84Cys), previously reported in a Japanese girl. The younger girl presented a de novo novel exon 6 heterozygous frameshift mutation (c.1074dupG) in codon 359 associated with the p.Gly146Ala polymorphism the latter inherited from her father. This baby showed severe impairment of androgen secretion from the first months of life. Overt adrenal insufficiency did not occur, but the older girl showed subnormal cortisol peak after ACTH stimulation. Conclusions:NR5A1 gene mutations are a relatively frequent cause of 46,XY DSD in humans. Clear indications for management of these individuals remain elusive, mainly when diagnosis is made in infancy. Long-term monitoring of adrenal function should be recommended.

BACKGROUND: Mixed gonadal dysgenesis (MGD) is a rare disorder. Short stature is a well known feature of this condition. Although growth hormone (GH) treatment has been suggested to treat growth impairment, conflicting data surround this issue. CASE REPORT: We report on long-term growth hormone (GH) therapy at pharmacological doses (0.33 mg/kg/week) in a boy (age 4.6 years) with MGD [karyotype 45,X/46,X,idic(Yp)]. An untreated boy of similar karyotype and growth delay served as control. The treated boy showed a progressive improvement of stature during GH administration. His height completely normalized after 6.5 years of treatment and he reached his target height centile before puberty onset. In the untreated boy, no improvement of growth pattern was found. CONCLUSIONS: We conclude that short boys with MGD and 45,X/46,X,idic(Yp) karyotype may benefit from early GH therapy at pharmacological doses. Evaluation of larger patient samples and additional follow-up till final height are needed to reach definitive conclusions as to the optimal growth-promoting therapy for this disorder of sex development.

Abstract Background/Aim: In children with central precocious puberty (CPP), gonadotropin-releasing hormone (GnRH) analogue treatment has been associated with an increase in body mass index (BMI). We evaluated BMI and body composition in adolescents treated with GnRH analogue at their near final height to assess the long-term effects of therapy on these parameters. Patients and Methods: We studied 20 patients (14.8 ± 1.6 years; 17 females) previously treated with triptorelin depot for CPP (3.75 mg/28 days) from 8.1 ± 0.8 to 11.5 ± 0.8 years. 23 healthy adolescents with normal onset of puberty (14.7 ± 2.1 years, 19 females) were the controls. BMI and body composition (dual-energy x-ray absorptiometry) were assessed. Results: Patients reached their near adult height (–0.5 ± 1.1 standard deviation score (SDS)); the girls were menstruating and the majority (15/17) had regular cycles, the boys showed normal testicular function. BMI was unchanged from the start of GnRH analogue therapy (0.4 ± 1.0 SDS) to near adult height (0.2 ± 1.0 SDS, p = NS vs. 0). Total fat mass (TFM) was significantly increased (16,144 ± 8,065 g; controls 10,712.1 ± 4,120.4 g, p < 0.02); glucose homeostasis and lipid profile corresponded to reference ranges. Conclusions: GnRH analogue therapy did not show long-term detrimental effects on BMI, but it may increase TFM, suggesting that body composition should be monitored till adulthood.

BACKGROUNDShort stature represents one of the main features of children with Noonan syndrome. The reason for impaired growth remains largely unknown.OBJECTIVETo assess GH and IGF1 secretion in children with Noonan syndrome. Patients: 12 prepubertal children with Noonan syndrome due to mutations in the PTPN11 gene [7 males, 6 females; median age, years: 8.6 (range 5.1–13.4)] were studied; 12 prepubertal children with short stature (SS) [7 males, 5 females; median age, years: 8.1 (range 4.8–13.1)] served as the control group. Measurements: GH secretion after arginine stimulation test; IGF1 generation test by measurement of IGF1 levels before and after recombinant GH (rGH) administration (0.05 mg/kg/day for 4 days).RESULTSBaseline and stimulated peak values of GH were not significantly different between the two groups. At +120 minutes, GH levels remained significantly higher (p = 0.0121) in comparison with baseline values in children with Noonan syndrome. Baseline IGFI levels in patients and in SS controls were not significantly different, in contrast to values after the rGH generation test [205 ng/mL (interquartiles 138.2–252.5 ng/mL) and 284.5 ng/mL (inter-quartiles 172–476 ng/mL), respectively; p = 0.0248]. IGF1 values were significantly related to height (baseline: r = 773, p = 0.0320; peak: r = 0.591, p = 0.0428) in children with Noonan syndrome.CONCLUSIONSBlunted increase of IGF1 after the rGH generation test was present in children with Noonan syndrome due to mutations in the PTPN11 gene in comparison with SS children. This finding may be due to partial GH resistance in the former likely related to altered Ras-MAPK signaling pathway.

17β-hydroxysteroid dehydrogenase deficiency is a rare autosomal recessive inherited disorder of sex development, affecting only 46,XY individuals. It is due to mutations in the HSD17B3 gene, encoding the 17β-hydroxysteroid-dehydrogenase type 3 enzyme. Mutated enzymes lead to absent or reduced ability to convert Δ 4 -androstenedione to testosterone in the testis. Affected 46,XY individuals present with testes located in the inguinal canal and underdeveloped or hypoplastic Wolffian structures, but female or ambiguous external genitalia. Such individuals are usually raised as females, but show spontaneous virilization at puberty. Correct diagnosis is mandatory to optimize treatment and follow-up. The clinical and laboratory approach, as well as the follow-up of subjects with 17β-hydroxysteroid-dehydrogenase deficiency, are detailed in this review, and the genetic mutations characterized to date are summarized.

Hormonal treatment represents the principal aspect of clinical management of people with disorders of sex development (DSD) from adolescence onwards. In fact, individuals with DSD may require sex steroid replacement to induce secondary sex characteristics, to optimize bone mass accrual, and to promote physical and social well-being. Testosterone is the main hormone for treatment in males and estrogens in females. The optimal regimens for sex steroid substitutive therapy in subjects with DSD should be better defined in multi-center prospective studies. Bone health remains a crucial aspect in the management of these persons, but few sound data are available to guide clinical practice.

17β-hydroxysteroid dehydrogenase deficiency is a rare autosomal recessive inherited disorder of sex development, affecting only 46,XY individuals. It is due to mutations in the HSD17B3 gene, encoding the 17β-hydroxysteroid-dehydrogenase type 3 enzyme. Mutated enzymes lead to absent or reduced ability to convert Δ4-androstenedione to testosterone in the testis. Affected 46,XY individuals present with testes located in the inguinal canal and underdeveloped or hypoplastic Wolffian structures, but female or ambiguous external genitalia. Such individuals are usually raised as females, but show spontaneous virilization at puberty. Correct diagnosis is mandatory to optimize treatment and follow-up. The clinical and laboratory approach, as well as the follow-up of subjects with 17β-hydroxysteroid-dehydrogenase deficiency, are detailed in this review, and the genetic mutations characterized to date are summarized.