Skin assessment in congenital untreated isolated GH deficiency.

PURPOSE: The separation between the inside and outside through the skin was fundamental for the evolution of prevertebrates, which grow through extrapituitary circuits, to vertebrates, which grow through the somatotrophic axis, namely pituitary growth hormone (GH). and circulating IGF1.Individuals with untreated isolated growth hormone (GH) deficiency (IGHD) due to a mutation in the GH-releasing hormone receptor (GHRH) gene, residing in Itabaianinha, Brazil, are vulnerable to skin cancer and have reduced sweating. However other aspects of their skin physiology are still unknown. Our objectives were to evaluate the number of skin cancers, skin aging, and functional aspects of the skin in this IGHD cohort. METHODS: Twenty-six IGHD individuals and 26 controls matched by age, sex, ethnicity, and occupation were submitted to a biochemical, dermatological and a functional skin assessment by the Multi Probe Adapter Cutometer® MPA 580. RESULTS: There was no difference in the number of skin cancers and in the degrees of photodamage between the groups. The melanin content in the forearm was similar between the groups but was lower in the buttocks (p = 0.005), as well as skin resistance (p < 0.0001) and elasticity (p = 0.003), lower in the IGHD. There was no difference in hydration and sebum content between the two groups. CONCLUSION: IGHD is apparently associated with a neutral profile in terms of skin cancer and photodamage, with similar melanin on the forearm and lower buttocks, lower skin resistance and elasticity, with hydration and sebum similar to controls.

Cognitive performance during senescence in untreated congenital isolated GH deficiency.

Individuals with untreated isolated GH deficiency (IGHD) due to a mutation in the GHRH receptor gene from Itabaianinha Brazil have increased insulin sensitivity, normal life expectancy, and an extended health span, i.e. the period of life free from disabilities. We hypothesize that their prolonged health span is accompanied by a delayed cognitive decline in senescence. To test this hypothesis, we have administered the Literacy-Independent Cognitive Assessment (LICA) to 15 IGHD individuals aged over 50 years and 15 controls matched by age, sex, years of education, and percentage of illiteracy. All individuals were negative for HIV and syphilis serology, and there were no differences in serum levels of folate, vitamin B12 and TSH between the two groups, while free T4 was higher in the IGHD group. IGHD subjects had a higher total LICA score than controls, 215 (22.7) vs 204.2 (18.1), without reaching statistical significance. Scores of memory, visuoconstruction, language and calculation were similar between the two groups, with better attention (9.5 (1.4) vs 8.3 (1.1), P = 0.01) and executive function (38.3 (4.8) vs 35.1 (2.5), P = 0.03) scores in IGHD. MANCOVA revealed that group (but no age) had a significant effect on the LICA variables (partial eta squared of 0.455, power of 0.812, P = 0.02). This effect is verified on attention (partial eta squared 0.216, power of 0.749, P = 0.01) and executive function (partial eta squared 0.154, power of 0.570, P = 0.03. In conclusion, IGHD in senescence is associated with similar total cognitive performance but better attention and executive function than controls.

Function and form of the shoulder in congenital and untreated growth hormone deficiency.

OBJECTIVES: The shoulder is the most mobile joint in the entire human body. During arm elevation, it requires the integrity of a set of muscles, bones, and tendons. Individuals with short stature often need to raise their arms above the shoulder girdle and may have functional restriction or shoulder injuries. The impact of isolated GH deficiency (IGHD) on joints remains not well defined. The purpose of this work is to evaluate the function and structure of the shoulder in short-statured adult individuals with untreated IGHD due to the same homozygous mutation in the GHRH receptor gene. METHODS: A cross-sectional study (evidence 3) was carried out in 20 GH-naive IGHD subjects and 20 age-matched controls. They completed the disabilities of the arm, shoulder, and hand (DASH) questionnaire and shoulder ultrasound (US). Thickness of the anterior, medial, and posterior portions of the supraspinatus tendon and of subacromial space was measured, and the number of individuals with tendinosis or tearing of the supraspinatus tendon was registered. RESULTS: DASH score was similar between IGHD and controls, but IGHD subjects complained less of symptoms (p = 0.002). The number of individual with tears was higher in the controls (p = 0.02). As expected, the absolute US measurements were lower in IGHD, but the magnitude of the reduction was most pronounced in the thickness of the anterior portion of the supraspinatus tendon. CONCLUSION: Adults with lifetime IGHD do not have functional shoulder restrictions, complain less of problems in performing upper extremity activities, and have fewer tendinous injuries than controls.

Quantitative measures of the vascular and neural components of the retina in adult individuals with congenital and untreated growth hormone deficiency.

BACKGROUND: The somatotrophic axis, including hypothalamic growth hormone (GH)-releasing hormone (GHRH), pituitary GH and circulating IGF-I, is critical for body size. However, the local production of GH/IGF-I (and IGF-II) and other peptides is relevant for other body functions, such as vascular, brain, and retinal function. The consequences of GH deficiency (GHD) on the retinal structure are still unclear, possibly reflecting the heterogeneity of patients and the different types of assessment in previous publications. Our purpose was to assess quantitative measures of the vascular and neural components of the retina in subjects with severe congenital isolated GHD (IGHD). METHODS: A cross-sectional study was carried out in 25 adult IGHD subjects and 25 age- and gender-matched controls. Interview, physical examination, laboratory data, optical coherence tomography (OCT) and OCT angiography (OCTA) were performed. RESULTS: OCT revealed no difference in the areas of the nerve fiber layer average, nor in the areas of superior, inferior, or nasal quadrants, between the two groups. However, areas of the temporal quadrant (p = 0.041), the optical disc (p = 0.042), the cup (p < 0.0001), as well as the cup/disc ratio (p < 0.0001), were higher in IGHD subjects than controls. The rim area was smaller (p = 0.002), although still normal. In OCTA, there was no difference in the minimum foveal thickness, central fovea, foveal avascular zone, and retinal density in any assessed area. CONCLUSIONS: In conclusion, congenital IGHD does not affect quantitative measures of the vascular and neural retina, and it is associated with increased optical disc in this genetically homogeneous cohort.

Individuals with isolated congenital GH deficiency due to a GHRH receptor gene mutation appear to cope better with SARS-CoV-2 infection than controls.

PURPOSE: Several interactions exist between the GH/IGF axis and the immune system, including effects on innate immunity and humoral and cellular response. Acquired GH deficiency (GHD) has been recently proposed as a risk factor for severity of COVID-19 infections. However, acquired GHD is often associated to other factors, including pituitary tumors, surgery, radiotherapy, and additional pituitary hormones deficits and their replacements, which, together, may hinder an accurate analysis of the relationship between GHD and COVID-19. Therefore, we decided to assess the seroprevalence of SARS-CoV-2 antibodies and the frequency of symptomatic cases of COVID-19 in adults subjects with untreated isolated GHD (IGHD) due to a homozygous null mutation in the GHRH receptor gene. METHODS: A cross-sectional study was carried out in 27 adult IGHD subjects and 27 age- and gender-matched local controls. Interview, physical examination, bio-impedance, hematological and SARS-CoV-2 IgM and IgG antibodies were analyzed. RESULTS: There was no difference in the prevalence of positivity of anti-SARS-CoV-2 IgM and IgG antibodies between the two groups. Conversely, no IGHD individual had a previous clinical diagnosis of COVID-19 infection, while 6 control subjects did (p = 0.023). CONCLUSION: The production of anti-SARS-CoV-2 antibodies was similar between IGHD subjects due to a GHRH receptor gene mutation and controls, but the evolution to symptomatic stages of the infection and the frequency of confirmed cases was lower in IGHD subjects than in GH sufficient individuals.

Reduced fibroblast growth factor 21 and ß-Klotho secretion in untreated congenital isolated GH deficiency.

PURPOSES: Increasing evidence suggests that the FGF-Klotho endocrine system and the somatotropic system (pituitary and extra-pituitary GH) may have important metabolic and immune relationships, thus contributing to the pathophysiology of aging-related disorders, including diabetes, atherosclerosis, and cancer. The status of these interactions in isolated GH deficiency (IGHD) is unknown. The objective of this study was to assess the response of both FGF21 and ß-Klotho levels to a standard meal in a homogeneous group of adults with congenital untreated IGHD due to a homozygous mutation in the GHRH receptor gene. METHODS: In a cross-sectional study, we measured the levels of FGF21 and ß-Klotho, before and 30, 60, 120, and 180 min after a standardized test meal in 20 (11 males) IGHD and 20 (11 males) age-matched controls. Areas under the curves (AUC) of FGF21 and ß-Klotho were calculated. RESULTS: Baseline levels of FGF21 were similar, but baseline levels of ß-Klotho were lower in IGHD subjects. The IGHD individuals exhibited lower AUC for FGF21 and ß-Klotho levels than control subjects. There was a positive correlation between IGF1 and ß-Klotho levels in the pooled groups. No correlation was found between IGF1 and FGF21 levels. CONCLUSIONS: Subjects with lifetime, untreated IGHD exhibit reduced FGF21 and ß-Klotho levels response to a mixed meal. This difference may have consequences on metabolism and aging.

Cerebral vasoreactivity, a surrogate marker of cerebrovascular disease, is not impaired in subjects with lifetime, untreated, congenital isolated GH deficiency.

OBJECTIVES: Cerebrovascular disease (CeVD) is a major cause of death and disability. The role of the GH/IGF-I axis on CeVD risk is controversial. Patients with GH deficiency (GHD) in the setting of hypopituitarism often exhibit CeVD predisposing factors, like low nitric oxide generation, endothelial dysfunction, increased visceral fat mass, increased levels of LDL cholesterol, and increased intima-media thickness, a surrogate marker of atherosclerosis. However, several confounders such as the primary hypothalamic-pituitary lesion, hormonal replacement therapies, consequences of surgery and radiotherapy, may influence this relationship. Therefore, we decided to assess cerebral vasoreactivity, a surrogate marker of CeVD, in adult subjects with untreated isolated GHD (IGHD) due to the same homozygous null mutation in the GHRH receptor gene. METHODS: A cross-sectional study was carried out in 25 adult IGHD subjects and 25 age- and gender-matched controls. Interview, physical examination, laboratory data, intima-media thickness measurement, and transcranial Doppler were performed. The intracranial hemodynamics (mean flow velocity, pulsatility and resistance indexes) were measured, and the response to the vasodilatory stimulus by breath-holding maneuver (breath-holding index) was calculated. RESULTS: IGHD and control groups were similar in Framingham risk score and intima-media thickness. Similarly, there was no difference in mean flow velocity, pulsatility, resistance, and breath-holding index. CONCLUSIONS: Lifetime, untreated IGHD does not cause impaired cerebral vasoreactivity.

Sweat and vitamin D status in congenital, lifetime, untreated GH deficiency.

PURPOSE: A reciprocal relationship exists between the skin and the GH/IGF-I axis. Skin produces both IGF- I and vitamin D, and GH and IGF-I exert several actions in the skin. Reduced sweating and altered phosphor-calcium homeostasis are occasionally reported in subjects with GH deficiency (GHD), mostly in the setting of hypopituitarism, therefore associated to other hormonal deficiencies. It is unclear whether these findings are due to GHD. The aim of this study was to assess skin function in subjects with isolated GHD (IGHD) due to a mutation in the GHRH receptor gene. METHODS: In a cross-sectional study we enrolled 20 IGHD and 20 local controls. Sweating (volume, conductivity and chloride content) was assessed by a 30 min pilocarpine iontophoresis test, using the Macroduct® Sweat Collection System. IGF-I, Insulin, PTH, 25-hydroxyvitamin D, C-reactive protein (CRP), CPK, glucose, calcium, phosphate, alkaline phosphatase, total proteins and fractions, urinary calcium, and insulin were measured. HOMA-IR was calculated. RESULTS: IGHD presented lower sweating, but normal vitamin D and phosphor-calcium homeostasis. Additionally, IGHD subjects presented lower HOMA-IR, higher CRP and reduced CPK. CONCLUSION: Untreated IGHD cause reduction in sweating, but does not affect phosphor-calcium homeostasis.

Enteroendocrine Connections in Congenital Isolated GH Deficiency Due to a GHRH Receptor Gene Mutation.

CONTEXT: GH and IGF-1 are crucial for attainment of normal body size and regulation of food intake, nutrient storage, and insulin sensitivity. Enteroendocrine connections exist between the GH-IGF-1 axis and insulin, ghrelin, and glucagon-like peptide 1 (GLP-1). The status of these connections in GH deficiency (GHD) is unknown. OBJECTIVE: To study the enteroendocrine connections before and after a standard meal test in a homogeneous population of adults with congenital untreated isolated GHD (IGHD) due to a mutation in the GHRH receptor gene. DESIGN: In a cross-sectional study of 20 individuals with IGHD and 20 control subjects, we measured glucose, insulin, ghrelin, and GLP-1 before and 30, 60, 120, and 180 minutes after a standardized test meal. Homeostasis model assessment index of insulin resistance (HOMA-IR) and homeostasis model assessment (HOMA)-ß were calculated. Participants scored feelings of hunger, fullness, and prospective food consumption on a visual analog scale. MAIN OUTCOME MEASURES: Area under the curve (AUC) values of glucose, insulin, ghrelin, GLP-1, hunger, fullness, and prospective food consumption. RESULTS: Fasting HOMA-IR and HOMA-ß were lower in individuals with IGHD than in control subjects (P = 0.002 and P = 0.023, respectively). AUC was higher for hunger (P < 0.0001), glucose (P = 0.0157), ghrelin (P < 0.0001), and GLP-1 (P < 0.0001) and smaller for fullness (P < 0.0001) in individuals with IGHD compared with control subjects. There was no difference in AUC for prospective food consumption or insulin. CONCLUSIONS: Untreated IGHD is associated with increased GLP-1 secretion and reduced postprandial ghrelin and hunger attenuation in response to a mixed meal. These enteroendocrine connections can result in a favorable outcome in terms of environmental adaptation and guaranteeing appropriate food intake and can confer metabolic benefits.

Occurrence of neoplasms in individuals with congenital, severe GH deficiency from the Itabaianinha kindred.

Growth hormone (GH) and the insulin-like growth factor I (IGF-I) have cell proliferative and differentiation properties. Whether these hormones have a role in mutagenesis is unknown. Nevertheless, severe IGF-I deficiency seems to confer protection against the development of neoplasms. Here, we report five cases of adult patients with severe and congenital isolated GH deficiency (IGHD) due to the c.57+1G>A mutation in the GHRH receptor gene, who developed tumors. Four GH-naïve subjects presented skin tumors: a 42-year-old man with a fibroepithelial polyp, a 53-year-old woman and two men (59 and 56 years old) with epidermoid skin cancers. One of these died from it after three surgeries and radiotherapy. The fifth patient was a 25-year-old woman, who had intermittently received GH replacement therapy (GHRT) from age 11 to 18, who developed an ependymoma extending from the fourth ventricle to the end of the thoracic spine. She underwent three surgical procedures, without obvious evidence of tumor recurrence during the six years follow up. These observations suggest that severe IGHD does not protect completely from development of tumors.