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OBJECTIVE: To establish the influence of overweight/obesity, medicated hypothyroidism, and medicated non-syndromic hypogrowth on maxillary and mandibular growth. MATERIALS AND METHODS: The relation between 10 craniofacial anthropometric measurements and hypothyroidism (n = 216), overweight/obesity (n = 108), and non-syndromic hypogrowth (n = 250) were evaluated in patients aged 1-19 years and a control group of healthy patients (n = 587). A subgroup analysis was performed at the peak growth in all groups. RESULTS: Patients with overweight/obesity and hypothyroidism showed increased craniofacial growth, while hypogrowth patients showed differences in zygomatic width and nasal base growth. Females with hypothyroidism and non-syndromic hypogrowth showed decreased head circumference at peak growth. Several anthropometric measurements were increased in patients with overweight/obesity, including head circumference. When all age groups were analyzed, overweight/obese and hypothyroidism patients showed increased zygomatic width while decreased hypogrowth. Overall, most craniofacial anthropometric measurements in overweight/obese patients were increased. Finally, the peak growth in males with hypothyroidism and subjects with non-syndromic hypogrowth was delayed compared to the control group (p < 0.05). CONCLUSIONS: Children and adolescents with overweight/obesity and endocrine disorders showed alterations in craniofacial growth. Clinicians must be aware that the growth peak in these patients may be delayed when planning maxillary and mandibular orthopedic treatment.

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ABSTRACT Objective: Congenital hypopituitarism (CH) is a rare disease characterized by one or more hormone deficiencies of the pituitary gland. To date, many genes have been associated with CH. In this study, we identified the allelic variant spectrum of 11 causative genes in Turkish patients with CH. Materials and methods: This study included 47 patients [21 girls (44.6%) and 26 boys (55.4%)] from 45 families. To identify the genetic etiology, we screened 11 candidate genes associated with CH using next-generation sequencing. To confirm and detect the status of the specific familial variant in relatives, Sanger sequencing was also performed. Results: We identified 12 possible pathogenic variants in GHRHR, GH1, GLI2, PROP-1, POU1F1, and LHX4 in 11 patients (23.4%), of which six were novel variants: two in GHRHR, two in POU1F1, one in GLI2, and one in LHX4. In all patients, these variants were most frequently found in GLI2, followed by PROP-1 and GHRHR. Conclusion: Genetic causes were determined in only 23.4% of all patients with CH and 63% of molecularly diagnosed patients (7/11) from consanguineous families. Despite advances in genetics, we were unable to identify the genetic etiology of most patients with CH, suggesting the effect of unknown genes or environmental factors. More genetic studies are necessary to understand the etiology of CH.

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Hypopituitarism, or the failure to secrete hormones produced by the anterior pituitary (adenohypophysis) and/or to release hormones from the posterior pituitary (neurohypophysis), can be congenital or acquired. When more than one pituitary hormone axis is impaired, the condition is known as combined pituitary hormone deficiency (CPHD). The deficiency may be primarily due to a hypothalamic or to a pituitary disorder, or concomitantly both, and has a negative impact on target organ function. This review focuses on the pathophysiology, diagnosis and management of anterior pituitary hormone deficiency in the pediatric age. Congenital hypopituitarism is generally due to genetic disorders and requires early medical attention. Exposure to toxicants or intrauterine infections should also be considered as potential etiologies. The molecular mechanisms underlying the fetal development of the hypothalamus and the pituitary are well characterized, and variants in the genes involved therein may explain the pathophysiology of congenital hypopituitarism: mutations in the genes expressed in the earliest stages are usually associated with syndromic forms whereas variants in genes involved in later stages of pituitary development result in non-syndromic forms with more specific hormone deficiencies. Tumors or lesions of the (peri)sellar region, cranial radiation therapy, traumatic brain injury and, more rarely, other inflammatory or infectious lesions represent the etiologies of acquired hypopituitarism. Hormone replacement is the general strategy, with critical periods of postnatal life requiring specific attention.

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Objective: Congenital hypopituitarism (CH) is a rare disease characterized by one or more hormone deficiencies of the pituitary gland. To date, many genes have been associated with CH. In this study, we identified the allelic variant spectrum of 11 causative genes in Turkish patients with CH. Materials and methods: This study included 47 patients [21 girls (44.6%) and 26 boys (55.4%)] from 45 families. To identify the genetic etiology, we screened 11 candidate genes associated with CH using next-generation sequencing. To confirm and detect the status of the specific familial variant in relatives, Sanger sequencing was also performed. Results: We identified 12 possible pathogenic variants in GHRHR, GH1, GLI2, PROP-1, POU1F1, and LHX4 in 11 patients (23.4%), of which six were novel variants: two in GHRHR, two in POU1F1, one in GLI2, and one in LHX4. In all patients, these variants were most frequently found in GLI2, followed by PROP-1 and GHRHR. Conclusion: Genetic causes were determined in only 23.4% of all patients with CH and 63% of molecularly diagnosed patients (7/11) from consanguineous families. Despite advances in genetics, we were unable to identify the genetic etiology of most patients with CH, suggesting the effect of unknown genes or environmental factors. More genetic studies are necessary to understand the etiology of CH.

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Objective: Isolated childhood growth hormone deficiency (GHD) can persist into adulthood, and re-testing at the transition period is needed to determine whether continued growth hormone therapy is indicated. Here, our objective was to identify predictors of permanent GHD. Design: Retrospective single-centre study of patients with childhood-onset GHD who were re-tested after adult height attainment. Methods: Auxological, clinical, laboratory, and MRI data throughout follow-up were collected. Results: We included 101 patients. At GH treatment initiation, age was 8.1 ± 0.4 years, height -2.25 ± 0.8, and BMI -0.27 ± 0.1 SDS. The 29 (28.7%) patients with persistent GHD had lower height SDS (-2.57 ± 0.1 vs. -2.11 ± 0.1, p<0.001) and mean GH peaks (8.4 ± 1.0 vs.13.2 ± 0.5 mIU/L, p<0.001) at GHD diagnosis; at adult height, they had lower IGF1 (232 ± 19.9 vs. 331 ± 9.1 ng/mL, p<0.001) and higher BMI SDS (-0.15 ± 0.27 vs. -0.73 ± 0.13, p<0.005). By multivariate analysis, the best predictive model included height and BMI SDS, both GH peaks, and MRI findings at diagnosis. Patients with height at diagnosis <-3 SDS had a 7.7 (95% IC 1.4-43.1, p=0.02) fold higher risk of persistent GHD after adjustment on BMI SDS. An abnormal pituitary region by MRI was the strongest single predictor (7.2 times, 95% CI 2.7-19.8) and after multivariate analysis adjustment for GH peaks and height SDS at diagnosis, the risk increased to 10.6 (1.8 - 61.3) times. Conclusions: Height <-3 SDS at GHD diagnosis and pituitary MRI abnormalities should lead to a high index of suspicion for persistent GHD.

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ABSTRACT Objective: Test if the MRI FAST1.2 protocol can detect extra-pituitary midline structural brain abnormalities in patients with ectopic posterior pituitary (EPP), and highlighting their radiological-laboratory correlations. Subjects and methods: Cross-sectional study of patients with EPP and control group. All individuals were submitted to FAST1.2, which combines the FAST1 protocol developed by our group with 3D T2DRIVE imaging. Results: We evaluated 36 individuals with EPP and 78 as control group. Pituitary stalk (PS) was identified in 7/36 patients in EPP group by FAST1, and in 24/36 patients in FAST1.2 (p < 0.001). FAST1 failed to detect PS in one individual in the control group, while the FAST1.2 defined the PS in all individuals. In EPP group, eleven had interhypothalamic adhesion (IHA), three septo-optic dysplasia, and one cerebellar malformation. We didn't observe higher frequency of panhypopituitarism or developmental delay in patients with IHA. In control group, three had pars intermedia cysts, one hydrocephalus, and one hypothalamic hamartoma. Conclusions: FAST1.2 allows confident recognition of midline structural abnormalities, including the pituitary stalk and IHA, thereby making MRI acquisition faster and with no need for contrast administration. IHA could be associated with defects in neuronal migration, as occur in patients with EPP, with no clinical significance.

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ABSTRACT In the late 19th century, José Dantas de Souza Leite, a physician born in Sergipe, published the first detailed clinical description of acromegaly under the guidance of the French neurologist Pierre Marie. In 2014, the Brazilian Society of Endocrinology and Metabolism created the "José Dantas de Souza Leite Award", which is granted every two years to a Brazilian researcher who has contributed to the development of endocrinology. In 2022, the award was given to another physician from Sergipe, Manuel Hermínio de Aguiar Oliveira, from the Federal University of Sergipe for the description of "Itabaianinha syndrome" in a cohort of individuals with isolated GH deficiency due to a homozygous inactivating mutation in the GH-releasing hormone receptor gene. This research, which was carried out over almost 30 years, was performed in partnership with Roberto Salvatori from Johns Hopkins University and in collaboration with other researchers around the world. This review article tells the story of Souza Leite, some milestones in the history of GH, and summarizes the description of Itabaianinha syndrome.

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In the late 19th century, José Dantas de Souza Leite, a physician born in Sergipe, published the first detailed clinical description of acromegaly under the guidance of the French neurologist Pierre Marie. In 2014, the Brazilian Society of Endocrinology and Metabolism created the "José Dantas de Souza Leite Award", which is granted every two years to a Brazilian researcher who has contributed to the development of endocrinology. In 2022, the award was given to another physician from Sergipe, Manuel Hermínio de Aguiar Oliveira, from the Federal University of Sergipe for the description of "Itabaianinha syndrome" in a cohort of individuals with isolated GH deficiency due to a homozygous inactivating mutation in the GH-releasing hormone receptor gene. This research, which was carried out over almost 30 years, was performed in partnership with Roberto Salvatori from Johns Hopkins University and in collaboration with other researchers around the world. This review article tells the story of Souza Leite, some milestones in the history of GH, and summarizes the description of Itabaianinha syndrome.

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Objective: Test if the MRI FAST1.2 protocol can detect extra-pituitary midline structural brain abnormalities in patients with ectopic posterior pituitary (EPP), and highlighting their radiological-laboratory correlations. Subjects and methods: Cross-sectional study of patients with EPP and control group. All individuals were submitted to FAST1.2, which combines the FAST1 protocol developed by our group with 3D T2DRIVE imaging. Results: We evaluated 36 individuals with EPP and 78 as control group. Pituitary stalk (PS) was identified in 7/36 patients in EPP group by FAST1, and in 24/36 patients in FAST1.2 (p < 0.001). FAST1 failed to detect PS in one individual in the control group, while the FAST1.2 defined the PS in all individuals. In EPP group, eleven had interhypothalamic adhesion (IHA), three septo-optic dysplasia, and one cerebellar malformation. We didn't observe higher frequency of panhypopituitarism or developmental delay in patients with IHA. In control group, three had pars intermedia cysts, one hydrocephalus, and one hypothalamic hamartoma. Conclusion: FAST1.2 allows confident recognition of midline structural abnormalities, including the pituitary stalk and IHA, thereby making MRI acquisition faster and with no need for contrast administration. IHA could be associated with defects in neuronal migration, as occur in patients with EPP, with no clinical significance.

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Several complications associated with active Cushing's disease may persist even years after complete and successful therapeutic remission of hypercortisolism. Growth hormone deficiency (GHD) shares many clinical features seen in patients with Cushing's disease, and its presence after disease remission (GHD-CR) might negatively influence and potentially worsen the systemic complications caused by previous hypercortisolism. GHD-CR is more prevalent in women, and compared to other causes of GHD, patients are younger at the onset of the pituitary disease, at diagnosis of GHD-CR and at start of GH therapy; prevalence of pituitary macroadenomas and visual abnormalities are lower, while prevalence of diabetes, hypertension, low bone mass, fractures, and worst quality of life, are higher. Serum IGF-1 levels are not useful for the diagnosis of GHD-CR and the application of GH stimulating tests requires some special attention in addition to the general recommendations for detecting GHD from other etiologies. In patients with active hypercortisolism, GH secretion is completely suppressed, but it may spontaneously and progressively recover over the years following successful therapy, meaning that GH testing may be performed at an appropriate time after remission for the correct diagnosis. Moreover, if the patient presents concomitant adrenal insufficiency, GH testing should only be carried out under adequate cortisol replacement therapy. GH therapy in children with GHD-CR improves adult height in the majority of patients, while GH therapy in adults has been associated with improvements in body composition, lipid profile and quality of life, but also with worsening of glucose metabolism.

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INTRODUCTION: Ectopic posterior pituitary (EPP) is a malformation of the hypothalamic-pituitary region presented as a spectrum from isolated growth hormone deficiency (GHD) to multiple pituitary hormone deficiencies (MPHDs). Our goal was to establish whether the FAST1.2 protocol, which combines the FAST1 protocol with 3D-T2 DRIVE images, could identify the pituitary stalk (PS) and the regional anatomy more accurately. METHODS: A retrospective study of 36 individuals with EPP and hypopituitarism and a control group of 78 individuals with eutopic posterior pituitary was conducted. All individuals were submitted to FAST1.2. The position and size of the pituitary lobes were described, and the presence/absence of the PS was confirmed. RESULTS: FAST1 identified the PS in 19% of individuals with EPP, while FAST1.2 identified the PS in 67% (p < 0.001). In the FAST1.2 protocol, the PS was visible in all control individuals. All EPP patients with isolated GHD had visible PS in FAST1.2, while only 58.6% of MPHD cases had visible PS. The size of the anterior lobe and the anteroposterior length of the posterior pituitary were smaller in the EPP group versus controls (p < 0.001). We noticed a reduced anterior pituitary lobe in both diameters in MPHD patients (p < 0.05). Six patients acquired new pituitary hormone deficiencies not recognized at the time of MRI; in this group, only 1 patient had a PS not visible in FAST1.2. DISCUSSION/CONCLUSION: The FAST1.2 protocol could prevent the misdiagnosis of idiopathic GHD in patients with short stature and could also be important in the progression to MPHD. The PS could be considered a predictor of hypopituitarism, but its use as an isolated indicator for the progression to MPHD is not recommended. Our results reinforce the use of the size of the anterior lobe as a predictor of hypopituitarism and a possible predictor of the degree of pituitary insufficiency. The FAST1.2 protocol could be used as an alternative to gadolinium administration, as a cheaper and faster method, while eliminating the potential risks associated with the administration of contrast media.

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OBJECTIVES: The growth of the dental arches depends on GH and insulin-like growth factor type 1 (IGF1), but the consequences of GH deficiency (GHD) on their growth are still unclear, probably due to the acquired etiology of GHD in most described series, often associated with additional pituitary deficits (thyrotrophic, corticotrophic and gonadotrophic hormones), and imperfections of related replacement therapies, which may affect the dental arch growth. To avoid these limitations, we took advantage of a unique cohort of subjects with isolated GH deficiency (IGHD) due the same mutation in the GH releasing hormone receptor gene, living with very low serum GH and low to undetectable circulating IGF1 levels. Our purpose was to analyze the dimensions of maxillary and mandibular dental arches. METHODS: 22 adult IGHD (15 untreated and 7 previously partially treated with GH) and 33 controls were enrolled in a cross-sectional study using the Ortho Insight 3D and MeshMixer software, RESULTS: In untreated IGHD subjects all maxillary arch measures were smaller than controls, while among mandibular arches, only the mandibular canine width and the mandibular arch length were reduced. In partially GH treated subjects only the palate depth, the maxillary canine width, the maxillary and mandibular arch lengths remained smaller than controls. CONCLUSIONS: IGHD reduces the growth of maxillary arch to a greater degree than the mandibular arch, suggesting different control of superior and inferior dental arches. GH treatment increases some of these measures.

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INTRODUCTION: Standard-of-care treatment for growth hormone deficiency consists of daily subcutaneous injections of recombinant human growth hormone, also known as somatropin. Although somatropin treatment is well established, the burden of daily injections can lead to poor adherence and quality of life. In this regard, a TransCon human growth hormone (lonapegsomatropin-tcgd) technology was developed to optimize the therapeutic effect of daily somatropin for the treatment of children with growth hormone deficiency. AREAS COVERED: The authors reviewed the effects of lonapegsomatropin-tcgd in children with growth hormone deficiency. EXPERT OPINION: Lonapegsomatropin-tcgd was found to be non-inferior to and superior to daily somatropin for annualized height velocity. In addition, the safety was comparable between them. As a result, the convenient dosing of lonapegsomatropin-tcgd has the potential to improve patient adherence, leading to increased efficacy and quality of life. Medication adherence, quality of life, long-term safety, and cost-effectiveness studies comparing lonapegsomatropin-tcgd and daily somatropin are required to confirm these possible benefits.

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Hormone resistances have been described in association with growth disorders, the majority involving the growth hormone (GH)/insulin-like growth factor 1(IGF-1) axis or hormones with specific paracrine-autocrine actions in the growth plate. Defects in hormone receptors or in proteins involved in intracellular signal transduction (post-receptor defects) are the main mechanisms of hormone resistance leading to short stature. The characteristic phenotypes of each of these hormonal resistances are very distinct and bring with them important insights into the role of each hormone and its signaling pathway. In this review, we discuss the molecular and clinical aspects of the main hormone resistances associated with short stature in humans.

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RESUMEN Fundamento: la talla baja supone un motivo de preocupación para los padres y es una causa muy frecuente de consulta en Pediatría y en Endocrinología Pediátrica. Objetivo: presentar el caso de un adolescente con baja talla por déficit de hormona del crecimiento. Presentación del caso: paciente adolescente de 12 años de edad que acude a consulta de Endocrinología por baja talla con examen físico normal y dosificaciones de hormona del crecimiento bajas en dos estudios de estimulación (test de clonidina e hipoglucemia inducida por insulina). Conclusiones: la baja talla por déficit de hormona del crecimiento es una de las causas corregibles de este trastorno.

ABSTRACT Background: short stature is a common cause of preoccupation in parents and it's a frequent shift complaint at Pediatric Endocrinology. Objective: to show the case of a teenager who had short stature due to loss growth hormone. Case report: a 12 years-old male teenager who came to Endocrinologist because of a short stature. Physical exam was normal meanwhile hormonal lab test shown loss growth hormone on two stimulated test (clonidine test and insulin-induced hypoglycemia). Conclusions: short stature due to loss growth hormone is a latent corrigible cause of that disorder.

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Individuals surviving cancer and brain tumors may experience growth hormone (GH) deficiency as a result of tumor growth, surgical resection and/or radiotherapy involving the hypothalamic-pituitary region. Given the pro-mitogenic and anti-apoptotic properties of GH and insulin-like growth factor-I, the safety of GH replacement in this population has raised hypothetical safety concerns that have been debated for decades. Data from multicenter studies with extended follow-up have generally not found significant associations between GH replacement and cancer recurrence or mortality from cancer among childhood cancer survivors. Potential associations with secondary neoplasms, especially solid tumors, have been reported, although this risk appears to decline with longer follow-up. Data from survivors of pediatric or adult cancers who are treated with GH during adulthood are scarce, and the risk versus benefit profile of GH replacement of this population remains unclear. Studies pertaining to the safety of GH replacement in individuals treated for nonmalignant brain tumors, including craniopharyngioma and non-functioning pituitary adenoma, have generally been reassuring with regards to the risk of tumor recurrence. The present review offers a summary of the most current medical literature regarding GH treatment of patients who have survived cancer and brain tumors, with the emphasis on areas where active research is required and where consensus on clinical practice is lacking.

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Langerhans cell histiocytosis (LCH) is a disorder of the mononuclear phagocyte system that can affect almost any organ and system. The most common central nervous system (CNS) manifestation in LCH is the infiltration of the hypothalamic-pituitary region leading to destruction and neurodegeneration of CNS tissue. The latter causes the most frequent endocrinological manifestation, that is, central diabetes insipidus (CDI), and less often anterior pituitary hormone deficiency (APD). The reported incidence of CDI is estimated between 11.5 and 24% and is considered a risk factor for neurodegenerative disease and APD. Three risk factors for development of CDI are recognized in the majority of the studies: (1) multisystem disease, (2) the occurrence of reactivations or active disease for a prolonged period, and (3) the presence of craniofacial bone lesions. Since CDI may occur as the first manifestation of LCH, differential diagnosis of malignant diseases like germ cell tumours must be made. APD is almost always associated with CDI and can appear several years after the diagnosis of CDI. Growth hormone is the most commonly affected anterior pituitary hormone. Despite significant advances in the knowledge of LCH in recent years, little progress has been made in preventing long-term sequelae such as those affecting the hypothalamic-pituitary system.

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The metabolic actions of growth hormone (GH) last a lifetime and involve several physiological functions associated with the control of body composition, energy metabolism, water regulation, immune response, cardiovascular performance, physical and mental work. Adult patients with GH deficiency (GHD) present a constellation of clinical findings, which include increased total and visceral body fat, low bone and muscle mass, reduced muscle strength, impaired anaerobic physical capacity, unfavorable cardiovascular profile, and poor quality of life. Recombinant human GH (rhGH) therapy has been proved to reverse or improve many abnormalities associated with GHD in adult life, but the therapeutic response is highly variable among patients and influenced by multiple factors, which are the main focus of this narrative review. Given the individual sensitivity of adult GHD patients to rhGH replacement, dose regimens evolved from weight-based to individualized dose-titration strategies, which improved efficacy and reduced the frequency of adverse events. Individual tailoring and maintenance doses of rhGH are mainly influenced by age, age at GHD onset, sex, body mass index, baseline GH status, quality of life and other pituitary hormone replacements. In addition, genetic background and poor adherence due to patient or product-related factors might play a role in the responsiveness to rhGH therapy. There have been attempts to develop predictive mathematical models to distinguish good and poor responders to rhGH therapy, but thus far none of them have been prospectively tested and validated in a large cohort of adult GHD individuals.

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Growth hormone deficiency (GHD) is a rare but treatable cause of short stature. The diagnosis requires a careful evaluation of clinical history, physical examination and appropriate interpretation of longitudinal growth, with specific features for each period of life. Other clinical findings, in addition to growth failure, may be present and can be related to the etiology and to associated hormone deficiencies. Despite more than 50 years since the first reports of provocative tests of growth hormone (GH) secretion for the diagnosis of GHD, the interpretation of the results remains a matter of debate. When GHD is confirmed, GH treatment is recommended. Treatment is effective and safe, but requires daily injections during many years, which can affect adherence. At the end of longitudinal growth, during the transition phase, it might be necessary to re-evaluate GH secretion. This review summarizes and updates the recent information related to GHD in children, as well the recommendations for treatment.

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BACKGROUND: The utility of insulin-like growth factor type 1 (IGF-1) is well established in the diagnosis of growth hormone deficiency (GHD), whereas IGF-binding protein type 3 (IGFBP-3) has a more controversial role. Most studies evaluated the value of these peptides by assessing their sensitivity and specificity but not considering the low prevalence of GHD among short children (<2%). OBJECTIVE: To evaluate the utility of basal IGF-1 and IGFBP-3 values in the GHD diagnosis process with a Bayesian approach, based on pre- and post-test probability. METHODS: We determined ROC curves, sensitivity, specificity, and positive and negative predictive values for IGF-1 and IGFBP-3 obtained from patients with GHD (n = 48) and GH-sufficient children (n = 175). The data were also analyzed by classifying the children into early childhood and late childhood (girls and boys younger and older than 8 and 9 years, respectively). RESULTS: The area under the curve (AUC) of the receiver operating characteristic curve of IGF-1-SDS (standard deviation score) was greater than that of IGFBP-3-SDS (AUC 0.886 and 0.786, respectively, p = 0.001). In early childhood, the AUC of IGFBP-3-SDS was significantly improved (0.866) and similar to IGF-1-SDS (0.898). IGF-1-SDS, in comparison to IGFBP-3-SDS, had a greater sensitivity (92 vs. 45.8%, respectively), lower specificity (69 vs. 93.8%, respectively), and lower positive predictive value (5.7 vs. 13.1%, respectively), with similar negative predictive values. CONCLUSION: IGF-1-SDS is a useful screening tool in the diagnosis of GHD. Although IGFBP-3-SDS lacks sensitivity, its high specificity supports the role to confirm GHD in short children, especially in early childhood. This strategy could simplify and reduce the necessity of a second laborious and expensive GH stimulation test to confirm the diagnosis of GHD.

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