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Adult subjects with isolated growth hormone deficiency (IGHD) due to a mutation in the growth hormone releasing hormone receptor gene exhibit higher values formant frequencies. In normal subjects, a significant negative association between the formant frequencies and the reduction of linear craniofacial measurements, especially of maxilla and mandible, has been reported. This suggests smaller pharyngeal width, despite low prevalence of obstructive sleep apnea syndrome. Here we evaluate their pharyngeal airway width, its correlation with vowel formant frequencies, and the correlation between them and the craniofacial measures. A two-step protocol was performed. In the first case-control experiment, aimed to assess the pharyngeal width, we compared nine adult IGHD and 36 normal statured controls. Both upper and lower pharyngeal widths were measured. The second step (assessment of pharyngeal width) was performed only in the IGHD group. Upper and lower pharyngeal widths were similar in IGHD and controls. In IGHD subjects, the lower pharyngeal width exhibited a negative correlation with F1 [a] and a positive correlation with mandibular length. There were negative correlations between F1 and F2 with linear and positive correlations with the angular measures. Pharyngeal airway width is not reduced in adults with congenital, untreated lifetime IGHD, contributing to the low prevalence of obstructive sleep apnea syndrome. The formant frequencies relate more with cephalometric measurements than with the pharyngeal airway width. These findings exemplify the consequences of lifetime IGHD on osseous and nonosseous growth. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Several acquired or congenital hypothalamic abnormalities may cause growth failure (GF). We described two of these congenital abnormalities. First, a case of CHARGE syndrome, an epigenetic disorder mostly caused by heterozygous mutations in the gene encoding CHD7, a chromatin remodeling protein, causing several malformations, some life-threatening, with additional secondary hypothalamus-hypophyseal dysfunction, including GF. Second, a cohort of individuals with genetic isolated severe GH deficiency (IGHD), due to a homozygous mutation in the GH-releasing hormone (GHRH) receptor gene described in Itabaianinha County, in northeast Brazil. In this IGHD, with marked reduction of serum concentrations of IGF-I, and an up regulation of IGF-II, GF is the principal finding in otherwise normal subjects, with normal quality of life and longevity. This IGHD may unveil the effects of GHRH, pituitary GH and IGF-I, IGF-II and local GH and growth factor on the size and function of body and several systems. For instance, anterior pituitary hypoplasia, and impairment of the non-REM sleep may be due to GHRH resistance. Proportionate short stature, doll facies, high-pitched pre-pubertal voice, and reduced muscle mass reflect the lack of the synergistic effect of pituitary GH and IGF-I in bones and muscles. Central adiposity may be due to a direct effect of the lack of GH. Brain, eyes and immune system may also involve IGF-II and local GH or growth factors. A concept of physiological hierarchy controlling body size and function by each component of the GH system may be drawn from this model. [ABSTRACT FROM AUTHOR]

Objective Ocular function is fundamental for environmental adaptation and survival capacity. Growth factors are necessary for a mature eyeball, needed for adequate vision. However, the consequences of the deficiency of circulating growth hormone (GH) and its effector insulin-like growth factor I (IGF-I) on the physical aspects of the human eye are still debated. A model of untreated isolated GH deficiency (IGHD), with low but measurable serum GH, may clarify this issue. The aim of this study was to assess the ocular aspects of adult IGHD individuals who have never received GH therapy. Design Cross sectional study. Methods Setting : University Hospital, Federal University of Sergipe, Brazil. Patients : Twenty-five adult (13 males, mean age 50.1 years, range 26 to 70 years old) IGHD subjects homozygous for a null mutation (c.57 + 1G > A) in the GHRH receptor gene, and 28 (15 males, mean age 51.1 years, range 26 to 67 years old) controls were submitted to an endocrine and ophthalmological assessment. Forty-six IGHD and 50 control eyes were studied. Main outcome measures : Visual acuity, intraocular pressure, refraction (spherical equivalent), ocular axial length (AL), anterior chamber depth (ACD), lens thickness (LT), vitreous depth (VD), mean corneal curvature (CC) and central corneal thickness (CCT). Results IGHD subjects exhibited unmeasurable serum IGF-I levels, similar visual acuity, intraocular pressure and LT, higher values of spherical equivalent and CC, and lower measures of AL, ACD, VD and CCT in comparison to controls, but within their respective normal ranges. While mean stature in IGHD group was 78% of the control group, mean head circumference was 92% and axial AL was 96%. Conclusions These observations suggest mild ocular effects in adult subjects with severe IGF-I deficiency due to non-treated IGHD. [ABSTRACT FROM AUTHOR]

Objective Experimental models demonstrate an important role of GH in retinal development. However, the interactions between GH and the neuro-vascularization of the human retina are still not clear. A model of untreated congenital isolated GH deficiency (IGHD) may clarify the actions of GH on the retina. The purpose of this work was to assess the retinal neuro-vascularization in untreated congenital IGHD (cIGHD). Design In a cross sectional study, we performed an endocrine and ophthalmological assessment of 25 adult cIGHD subjects, homozygous for a null mutation (c.57 + 1G > A) in the GHRH receptor gene and 28 matched controls. Intraocular pressure measurement, retinography (to assess the number of retinal vascular branching points and the optic disc and cup size), and optical coherence tomography (to assess the thickness of macula) were performed. Results cIGHD subjects presented a more significant reduction of vascular branching points in comparison to controls (91% vs. 53% [ p = 0.049]). The percentage of moderate reduction was higher in cIGHD than in controls ( p = 0.01). The percentage of individuals with increased optic disc was higher in cIGHD subjects in comparison to controls (92.9% vs. 57.1%). The same occurred for cup size (92.9% vs. 66.7%), p < 0.0001 in both cases. There was no difference in macula thickness. Conclusions Most cIGHD individuals present moderate reduction of vascular branching points, increase of optic disc and cup size, but have similar thickness of the macula. [ABSTRACT FROM AUTHOR]

Summary Objective To analyze the voice formants (F1, F2, F3, and F4 in Hz) of seven oral vowels, in Brazilian Portuguese, [a, ε, e, i, ɔ, o, and u] in adult individuals with congenital lifetime untreated isolated growth hormone deficiency (IGHD). Study Design This is a cross-sectional study. Methods Acoustic analysis of isolated vowels was performed in 33 individuals with IGHD, age 44.5 (17.6) years (16 women), and 29 controls, age 51.1 (17.6) years (15 women). Results Compared with controls, IGHD men showed higher values of F3 [i, e, and ε], P = 0.006, P = 0.022, and P = 0.006, respectively and F4 [i], P = 0.001 and lower values of F2 [u], P = 0.034; IGHD women presented higher values of F1 [i and e] P = 0.029 and P = 0.036; F2 [ɔ] P = 0.006; F4 [ɔ] P = 0.031 and lower values of F2 [i] P = 0.004. IGHD abolished most of the gender differences in formant frequencies present in controls. Conclusions Congenital, severe IGHD results in higher values of most formant frequencies, suggesting smaller oral and pharyngeal cavities. In addition, it causes a reduction in the effect of gender on the structure of the formants, maintaining a prepubertal acoustic prediction. [ABSTRACT FROM AUTHOR]

To understand the growth of teeth and mandibular and maxillary bones in subjects with isolated growth hormone deficiency (IGHD). Mesiodistal tooth width of 28 maxillary and mandibular dental models of 14 adult IGHD subjects (9 men) were digitalized and compared to 40 models of 20 normal-statured controls (11 men). The mean SDS of the maxillary and mandibular teeth were compared with height, cephalic perimeter, total anterior facial height, total maxillary and mandibular length, and maxillary and mandibular arches. All average mesiodistal dimensions in absolute values of the 14 dental pairs were reduced in the IGHD group. Eight of 28 (28.6%) mesiodistal dimensions in IGHD subjects of both sexes had an average SDS below −2, thirteen of them (46.4%) had mean SDS between −1 and − 2, and seven of them (25.0%) had SDS above −1. The highest SDS values were the upper lateral incisor (−0.32 in women), and the upper canine (−0.91 in men). The lowest SDS values were the 2nd upper molar (−3.51 in men), and the 2nd upper premolar (−2.64 in women). The ascending order of the mean SDS was height, total maxillary length, total mandibular length, total anterior height of the face, cephalic perimeter, the maxillary arches width, the mesiodistal width of the mandibular teeth, the mesiodistal width of the maxillary teeth and the mandibular arches width. Reduction in mesiodistal width is present in untreated IGHD adults with magnitude of tooth size reduction being lower than height, cephalic perimeter, total anterior facial height, and most jaw measurements. IGHD abolishes the sexual dimorphism in mesiodistal dental measures. • Mesiodistal dental width is the commonest measurement of the size of dental crowns. • Reduction in mesiodistal width was present in untreated adults with GH deficiency. • Isolated GH deficiency abolished the sexual dimorphism in mesiodistal dental width. • The magnitude of tooth size reduction was lower than several bone measurements. • Tooth growth seems mostly a prenatal process, partially independent from stature. [ABSTRACT FROM AUTHOR]

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. 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, 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. 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. • The growth of dental arches depends on GH and insulin-like growth factor 1. • The consequences of GH deficiency (GHD) on their growth are unclear. • This reflects different etiologies and severity of the GHD in most series. • We took advantage of a unique cohort with isolated congenital GHD (IGHD). • IGHD reduces maxillary arch to a greater degree than the mandibular arch. [ABSTRACT FROM AUTHOR]

Voice is produced by the vibration of the vocal folds expressed by its fundamental frequency (Hz), whereas the formants (F) are fundamental frequency multiples, indicating amplification zones of the vowels in the vocal tract. We have shown that lifetime isolated growth hormone deficiency (IGHD) causes high pitch voice, with higher values of most formant frequencies, maintaining a prepuberal acoustic prediction. The objectives of this work were to verify the effects of the therapy with a semi-occluded vocal tract (SOVTT) and choir training on voice in these subjects with IGHD. We speculated that acoustic vocal parameters can be improved by SOVTT or choir training. This is a prospective longitudinal study without control group. Acoustic analysis of isolated vowels was performed in 17 adults with IGHD before and after SOVTT (pre-SOVTT and post-SOVTT) and after choir training (post training), in a 30-day period. The first formant was higher in post training compared with the pre-SOVTT (P = 0.009). The second formant was higher in post-SOVTT than in pre-SOVTT (P = 0.045). There was a trend of reduction in shimmer in post-choir training in comparison with pre-SOVTT (P = 0.051), and a reduction in post-choir training in comparison with post-SOVTT (P = 0.047). SOVTT was relevant to the second formant, whereas choir training improved first formant and shimmer. Therefore, this speech therapy approach was able to improve acoustic parameters of the voice of individuals with congenital, untreated IGHD. This seems particularly important in a scenario in which few patients are submitted to growth hormone replacement therapy. [ABSTRACT FROM AUTHOR]

Summary: Objective: The aim of this study was to analyze the individual impact of short stature (SS) or untreated isolated growth hormone deficiency (IGHD) on voice quality and the influence of IGHD on voice aging. Methods: A cross-sectional study was carried out on 73 adults: 33 IGHD, 10 SS, and 30 normal controls (CO), by evaluating vocal perception using Voice-Related Quality-of-Life (V-RQOL) scores and fundamental frequency (ƒ 0). Analysis of variance with Bonferroni post-test was used to compare groups, and the Student t test was used to verify the influence of aging. Results: Stature of the SS and IGHD groups was similarly reduced in comparison to CO. Cephalic perimeter (CP) in SS males was larger than CO (P <0.05), and this was larger than in IGHD (P <0.0001). CP was similar in SS and CO females, and both were larger than in IGHD (P <0.0001). V-RQOL scores were lower in IGHD than in SS and CO. ƒ 0 (Hz) was similar in IGHD females and SS and higher than in CO (P <0.05). f 0 of IGHD males was higher than in SS (P =0.01) and CO (P =0.001). IGHD abolished the effect of aging on ƒ 0 exhibited by CO. Conclusions: Lower vocal perception and higher ƒ 0 were found in IGHD in comparison to CO in both genders; in comparison to SS, higher ƒ 0 was only found in IGHD males. Because SS males have higher CP than IGHD, this suggests that CP and craniofacial growth can influence voice in IGHD. Finally, IGHD seems to abolish the effects of aging on voice. [Copyright &y& Elsevier]

Summary: Impaired quality of life (QoL) is commonly described as being associated with growth hormone (GH) deficiency (GHD), and beneficial effects of GH replacement therapy on QoL have been reported. However, most studies examined heterogeneous cohorts of patients GHD of varying etiologies, severities and age of onset. Most of these patients miss other pituitary hormones, whose replacement can also influence QoL. We studied the QoL of a homogeneous cohort of 20 adults with isolated GH deficiency (IGHD) due to the same mutation in the GH-releasing hormone receptor gene (IGHD, 10 men) using the Life Satisfaction Hypopituitarism Module (QLS-H), and compared them with 20 matched controls residing in the same community (CO, 10 men). Additionally, the IGHD group was evaluated after 6 months of treatment with bi-monthly depot GH, and after 12 months from its interruption. There was no difference in the total score of QoL (TSQoL) or in any of the nine categories that composes the questionnaire between IGHD and CO. Similar results were obtained when data were analyzed by sex. GH treatment only increased satisfaction with physical endurance, but did not cause an increase in the TSQoL. We conclude that in this unique population congenital, untreated, lifetime IGHD does not reduce QoL, and treatment with GH for 6 months only causes improvement in satisfaction with physical resistance. [Copyright &y& Elsevier]