Introduction: Isolated SHOX haploinsufficiency is a common monogenic cause of short stature. Few studies compare untreated and rhGH-treated patients up to adult height(AH). Our study highlights a growth pattern from childhood to AH in patients with SHOX haploinsufficiency and analyzes the real-world effectiveness of rhGH alone or plus GnRHa or aromatase inhibitors (AI). Methods: Forty-seven patients (18 untreated and 29 rhGH-treated) with SHOX haploinsufficiency were included in a longitudinal retrospective study. Adult height was attained in 13 untreated and 18 rhGH-treated [rhGH alone (n=8) or plus GnRHa or AI (n=10)] patients. Results: The untreated group decreased height SDS from baseline to AH [-0.8 (-1.1; -0.4)], with an increase in the prevalence of short stature from 31% to 77%. Conversely, the rhGH-treated group had an improvement in height SDS from baseline to AH [0.6 (0.2;0.6); p<0.001)], with a reduction in the prevalence of short stature (from 61% to 28%). AH in the rhGH-treated patients was 1 SD (6.3 cm) taller than in untreated ones. Regarding the use of GnRHa or AI, the subgroups (rhGH alone or plus GnRHa/AI) attained similar AH, despite the higher prevalence of pubertal patients and worse AH prediction at the start of rhGH treatment in patients who used combined therapy. Conclusion: The use of rhGH treatment improves AH in patients with SHOX haploinsufficiency, preventing the loss of height potential during puberty. In peripubertal patients, the addition of GnRHa/AI to rhGH allows AH attainment similar to the AH of patients who start rhGH alone in the prepubertal age.

Introduction: Congenital hypogonadotropic hypogonadism (CHH) is a rare condition caused by GnRH deficiency. More than 40 genes have been associated with the pathogenesis of CHH, but most cases still remain without a molecular diagnosis. Mutations involving the same gene (e.g. FGFR1, PROK2/PROKR2, CHD7) were found to cause normosmic CHH and Kallmann syndrome, with and without associated phenotypes, illustrating the coexistence of CHH with signs of other complex syndromes. The Witteveen-Kolk syndrome (WITKOS), caused by defects of the SIN3A gene, is a heterogeneous disorder characterized by distinctive facial features, microcephaly, short stature, delayed cognitive and motor development. Although micropenis and cryptorchidism have been reported in this syndrome, WITKOS has not been formally associated with CHH so far. Patients and Methods: A man with Kallmann syndrome (KS) associated with mild syndromic features (S1) and a boy with global developmental delay, syndromic short stature, micropenis and cryptorchidism (S2), in whom common genetic defects associated with CHH and short stature had been previously excluded, were studied by either chromosomal microarray analysis (CMA) or whole exome sequencing (WES). Results: Rare SIN3A pathogenic variants were identified in these two unrelated patients with CHH phenotypic features. A 550 kb deletion at 15q24.1, including the whole SIN3A gene, was identified in S1, and a SIN3A nonsense rare variant (p.Arg471*) was detected in S2. Conclusion: These findings lead us to propose a link between SIN3A defects and CHH, especially in syndromic cases, based on these two patients with overlapping phenotypes of WITKOS and CHH.

Introduction: Pubertal delay is described as one of the clinical features in Noonan Syndrome (NS) and it may be one of the factors causing short adult height in those patients. The present study aims at characterizing pubertal development in NS and identifying pubertal delay predictors. Methods: We analyzed 133 individuals with a molecular diagnosis of NS and clinical puberty evaluation. We characterized delayed puberty as pubertal onset after 12 years in girls and 13.5 years in boys, according to parameters of the Brazilian population. To investigate its predictors, we correlated the age at onset of puberty with several characteristics and genotype in a multilevel regression model. For comprehending pubertal development in NS, we assessed age and anthropometric measures at each Tanner stage and adult age. Results: The mean age at puberty onset for girls was 11.9±1.9 years and for boys, 12.5±1.7 years, significantly later than the Brazilian population (p=0.025; p<0.001). Girls (49.1%) presented delayed puberty more frequently than boys (27.9%, p=0.031). BMI SDS and IGF1 SDS at puberty onset significantly predicted later puberty entry. Height gain from the onset of puberty to adult height was lower in children with pubertal delay. Conclusion: Pubertal delay is characteristically found in children with NS, more frequently in females. The low weight of patients with NS could modulate the age of puberty, just as the increase in overweight/obesity in the general population has shown an effect on reducing the age of onset of puberty.

<b><i>Context:</i></b> Treatment with growth hormone (GH) is considered effective in improving adult height (AH) in Turner syndrome (TS). However, there are few studies comparing AH between treated patients and a concurrent untreated group. <b><i>Objective:</i></b> To assess the efficacy of GH treatment in improving AH in TS and to review previous published studies with treated and untreated groups. <b><i>Participants and Methods:</i></b> We retrospectively analyzed clinical data and AH of a large cohort of GH-treated (<i>n</i> = 168) and untreated (<i>n</i> = 131) patients with TS. Data are shown as median and interquartile range (IQR). We assessed pretreatment variables related with AH and compared our results with 16 studies that also included an untreated group. <b><i>Results:</i></b> The GH-treated group was 6.2 cm taller than the untreated group (AH = 149 cm [IQR 144.5–152.5 cm] vs. 142.8 cm [IQR 139–148 cm], <i>p</i> &#x3c; 0.001) after 4.9 years of GH treatment with a dose of 0.35 mg/kg/week. AH SDS corrected for target height (TH) was 7.2 cm higher in GH-treated patients. AH SDS ≥−2 was more frequent in GH-treated patients (43%) than in untreated patients (16%, <i>p</i> &#x3c; 0.001). AH SDS was also more frequently within the TH range in the GH-treated group (52%) than in the untreated group (15%, <i>p</i> &#x3c; 0.001). Height SDS at start of GH therapy and TH SDS were positively correlated with AH (<i>p</i> &#x3c; 0.001; <i>R</i>² = 0.375). Considering the current result together with previous similar publications, a mean AH gain of 5.7 cm was observed in GH-treated (<i>n</i> = 696) versus untreated (<i>n</i> = 633) patients. <b><i>Conclusions:</i></b> Our study strengthens the evidence for efficacy of GH therapy in patients with TS from different populations.

Context: Overall, giant prolactinomas are rare tumors (4%), especially those larger than 60 mm (1%). Despite the predominance of macroadenoma documented in multiple endocrine neoplasia type 1 (MEN1)-related prolactinoma, only three giant prolactinoma cases were described so far (size > 40 mm and prolactin > 1,000 ng/mL). None of them was larger than 60 mm or presented hydrocephalus or intracranial hypertension (ICH) as initial manifestation of MEN1. Case Description: A 21-years-old man presented with ICH as the first clinical manifestation of MEN1. He harbored a MEN1 germline mutation but refused periodic vigilance after normal hormonal screening at age 14 years. During investigation, magnetic resonance imaging (MRI) of the skull showed an expansive sellar/parasellar lesion (75 × 44 × 36 mm) with moderate to severe supratentorial obstructive hydrocephalus and an extremely high serum prolactin (PRL) of 10,800 ng/mL, without combined hypersecretion of other pituitary hormones. He was diagnosed with giant prolactinoma, and cabergoline was initiated. The patient evolved with early improvement of clinical complaints for hydrocephalus and ICH and PRL reached normal values (11 ng/mL) in association with significant tumoral shrinkage after 18 months on cabergoline. After 2 months of cabergoline, cerebrospinal fluid leakage was diagnosed and corrective surgery was provided. The mean dose of cabergoline was 3 mg/week throughout treatment. Conclusion: We reported the first case with hydrocephalus and ICH as the initial clinical manifestation of a giant prolactinoma in MEN1. From our knowledge, this is the largest MEN1-related prolactinoma reported so far. Notably, all four MEN1-related giant prolactinomas cases reported were younger than 21 years strengthening the importance to routine MEN1 genetic testing for prolactinoma in this age group. Also, they all had initial effective response with dopamine agonist ensuring this drug as first-line treatment for MEN1-related giant prolactinoma. However, the scarce number of treated patients and progression of cabergoline resistance in two of them suggest strict surveillance.