Rare Frequency of Mutations in Pituitary Transcription Factor Genes in Combined Pituitary Hormone or Isolated Growth Hormone Deficiencies in Korea.

PURPOSE: Congenital hypopituitarism is caused by mutations in pituitary transcription factors involved in the development of the hypothalamic-pituitary axis. Mutation frequencies of genes involved in congenital hypopituitarism are extremely low and vary substantially between ethnicities. This study was undertaken to compare the clinical, endocrinological, and radiological features of patients with an isolated growth hormone deficiency (IGHD) or combined pituitary hormone deficiency (CPHD). MATERIALS AND METHODS: This study included 27 patients with sporadic IGHD and CPHD. A mutation analysis of the POU1F1, PROP1, LHX3, LHX4, and HESX1 genes was performed using genomic DNA from peripheral blood leukocytes. RESULTS: IGHD and CPHD were observed in 4 and 23 patients, respectively. Mean age at diagnosis was 8.28±7.25 years for IGHD and 13.48±10.46 years for CPHD (p=0.37). Serum insulin-like growth factor-1 and peak growth hormone (GH) levels following GH stimulation tests were significantly lower in patients with CPHD than in those with IGHD (p<0.05). Sellar MRI findings revealed structural abnormalities in 3 patients with IGHD (75%) and 21 patients with CPHD (91.3%) (p=0.62). A mutation analysis identified homozygous p.R109Q mutations in HESX1 in a patient with CPHD. Patients with CPHD had more severe GHD than those with IGHD. CONCLUSION: The frequency of defects in the genes encoding pituitary transcription factors was extremely low in Korean patients with congenital hypopituitarism. Environmental factors and the impact of other causative genes may contribute to this clinical phenotype.

Abnormal vascular and neural retinal morphology in congenital lifetime isolated growth hormone deficiency.

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.

GPR101 Mutations are not a Frequent Cause of Congenital Isolated Growth Hormone Deficiency.

Patients with Xq26.3 microduplication present with X-linked acrogigantism (X-LAG) syndrome, an early-childhood form of gigantism due to marked growth hormone (GH) hypersecretion from mixed GH-PRL adenomas and hyperplasia. The microduplication includes GPR101, which is upregulated in patients' tumor tissue. The GPR101 gene codes for an orphan G protein coupled receptor that is normally highly expressed in the hypothalamus. Our aim was to determine whether GPR101 loss of function mutations or deletions could be involved in patients with congenital isolated GH deficiency (GHD). Taking advantage of the cohort of patients from the GENHYPOPIT network, we studied 41 patients with unexplained isolated GHD. All patients had Sanger sequencing of the GPR101 gene and array comparative genome hybridization (aCGH) to look for deletions. Functional studies (cell culture with GH secretion measurements, cAMP response) were performed. One novel GPR101 variant, c.589 G>T (p.V197L), was seen in the heterozygous state in a patient with isolated GHD. In silico analysis suggested that this variant could be deleterious. Functional studies did not show any significant difference in comparison with wild type for GH secretion and cAMP response. No truncating, frameshift, or small insertion-deletion (indel) GPR101 mutations were seen in the 41 patients. No deletion or other copy number variation at chromosome Xq26.3 was found on aCGH. We found a novel GPR101 variant of unknown significance, in a patient with isolated GH deficiency. Our study did not identify GPR101 abnormalities as a frequent cause of GH deficiency.

Growth hormone and early treatment.

Growth hormone (GH) treatment is approved by the US Food and Drug Administration (FDA) not only for GH deficiency (GHD) but also for other childhood growth disorders with growth failure and/or short stature. GHD is the most frequent endocrine disorder presenting with short stature in childhood. During neonatal period, metabolic effects due to congenital GHD require a prompt replacement therapy to avoid possible life-threatening complications. In childhood and adolescence, growth impairment is the most evident effect of GHD and early treatment has the aim of restore normal growth and to reach normal adult height. We reassume in this review the conditions causing GHD and the diagnostic challenge to reach an early diagnosis, and an early treatment, necessary to obtain the best results. Finally, we summarize results obtained in clinical studies about pediatric patients with GHD treated at an early age, in which a marked early catch-up growth and a normalization of adult height were obtained.

Increased visceral adiposity and cortisol to cortisone ratio in adults with congenital lifetime isolated GH deficiency.

CONTEXT: Adult-onset GH deficiency (GHD) increases visceral adiposity and the activity of the enzyme 11ß-hydroxysteroid dehydrogenase, which converts cortisone (E) to cortisol (F), both linked to insulin resistance and increased cardiovascular risk. Conversely, we reported that adults with congenital isolated GHD (IGHD) have increased insulin sensitivity. OBJECTIVE: To assess the type of fat distribution and the amount of visceral and sc fat and to correlate them to the F/E ratio in adults with untreated IGHD due to a mutation in the GHRH receptor gene. METHODS: Body composition was assessed by dual-energy x-ray absorptiometry, thickness of sc and visceral fat was measured by sonography, and serum F and E were measured in 23 IGHD subjects and 21 age-matched controls. RESULTS: Waist/hip ratio (WHR), trunk fat, and trunk/extremity fat (TR/EXT) ratio were higher in IGHD subjects. Visceral fat index (VFI) (but not sc fat index [SFI]) was higher in IGHD. F and F/E ratio were also higher in IGHD. In all 44 individuals, WHR correlated with TR/EXT ratio, thickness of visceral fat, VFI/SFI ratio, F, and F/E ratio. TR/EXT ratio correlated with visceral fat thickness, VFI/SFI ratio, and F. Age had a significant effect on VFI and on F/E ratio. Body mass index SD score and WHR have a similar significant effect on TR/EXT ratio and on F/E ratio. CONCLUSIONS: Lifetime congenital untreated IGHD causes increased visceral adiposity with a high F/E ratio. However, the increased insulin sensitivity suggests that visceral adiposity needs a minimal GH secretion to translate into increased insulin resistance.

Biphasic response of subscapular skinfold thickness to hGH or IGF-1 administration to patients with congenital IGHD, congenital MPHD and Laron syndrome.

OBJECTIVE: To evaluate changes in adiposity in congenital GH/IGF-1 deficient children during hGH or IGF-1 treatment. SUBJECTS AND METHODS: 27 children with congenital isolated growth hormone deficiency (cIGHD) treated with hGH for 2.5-€“15.2 years (mean 10.0 ± 3.4), 18 children with congenital multiple pituitary hormone deficiency (cMPHD), treated with hGH for 2.3-€“17.9 years (mean 6.1 ± 4.3), and 14 children with Laron syndrome (LS) treated with IGF-1 for 1.2-12 years (mean 5.5 ± 3.7) were studied. Changes in the degree of adiposity were evaluated by subscapular skinfold thickness (SSFT), before, during and up to 2 years after treatment. All the children had various degrees of obesity. RESULTS: During the pretreatment period, cIGHD patients showed little changes in SSFT (P = 0.45), cMPHD and LS patients showed an increase in SSFT (P = 0.01, P = 0.06 respectively). During the initial 0.6-1.1 years of hGH/IGF-1 treatment, the SSFT decreased in all 3 groups (P < 0.001), while during subsequent years a significant increase in SSFT (P < 0.001) was observed, in all types of patients, notably in females. Only the cIGHD patients demonstrated a significant correlation between the degree of SSFT decrease and height SDS gain (R = -ˆ’0.56, P = 0.002) in the first period of treatment. CONCLUSIONS: Short term replacement therapy of 0.6-€“1.1 years with either hGH or IGF-1, induced a reduction in subscapular subcutaneous fat whereas prolongation of therapy led to an increase in the subcutaneous fat.

Periodontal disease in adults with untreated congenital growth hormone deficiency: a case-control study.

AIM: The aim of this study was to investigate the possible associations between isolated growth hormone deficiency (IGHD) and periodontal attachment loss (PAL) in adults affected by congenital IGHD. MATERIALS AND METHODS: Forty-five previously identified IGHD subjects were eligible for this study. The final study sample comprised 32 cases (gender:20M/12F; age:44.8 ± 17.5) matched for age, gender, diabetes, smoking status and income to 32 controls (non-IGHD subjects). Participants were submitted to a full-mouth clinical examination of six sites per tooth and were interviewed using a structured, written questionnaire. Periodontitis was defined as proximal PAL≥5 mm affecting ≥30% of teeth. RESULTS: No significant differences were observed in the percentage of sites with visible plaque between IGHD and non-IGHD subjects (59.4% versus 46.9%, p=0.32). IGHD subjects had significant less supragingival calculus (31.3% versus 59.4%, p=0.02) and more bleeding on probing (71.9% versus 18.8%, p<0.01) than controls. PAL≥5 mm was significantly more prevalent (100% versus 71.9%, p<0.01) and affected more teeth (30.5% versus 6.7%, p<0.01) in cases than in controls. After adjusting for supragingival calculus, IGHD cases had a higher likelihood of having periodontitis than controls (OR=17.4-17.8, 95% CI=2.3-134.9, p=0.004-0.005). CONCLUSION: Congenital IGHD subjects have a greater chance of having PAL.

Cephalometric features in isolated growth hormone deficiency.

OBJECTIVE: To analyze cephalometric features in adults with isolated growth hormone (GH) deficiency (IGHD). MATERIALS AND METHODS: Nine adult IGHD individuals (7 males and 2 females; mean age, 37.8 ± 13.8 years) underwent a cross-sectional cephalometric study, including 9 linear and 5 angular measurements. Posterior facial height/anterior facial height and lower-anterior facial height/anterior facial height ratios were calculated. To pool cephalometric measurements in both genders, results were normalized by standard deviation scores (SDS), using the population means from an atlas of the normal Brazilian population. RESULTS: All linear measurements were reduced in IGHD subjects. Total maxillary length was the most reduced parameter (-6.5 ± 1.7), followed by a cluster of six measurements: posterior cranial base length (-4.9 ± 1.1), total mandibular length (-4.4 ± 0.7), total posterior facial height (-4.4 ± 1.1), total anterior facial height (-4.3 ± 0.9), mandibular corpus length (-4.2 ± 0.8), and anterior cranial base length (-4.1 ± 1.7). Less affected measurements were lower-anterior facial height (-2.7 ± 0.7) and mandibular ramus height (-2.5 ± 1.5). SDS angular measurements were in the normal range, except for increased gonial angle (+2.5 ± 1.1). Posterior facial height/anterior facial height and lower-anterior facial height/anterior facial height ratios were not different from those of the reference group. CONCLUSIONS: Congenital, untreated IGHD causes reduction of all linear measurements of craniofacial growth, particularly total maxillary length. Angular measurements and facial height ratios are less affected, suggesting that lGHD causes proportional blunting of craniofacial growth.

Quality of life in congenital, untreated, lifetime isolated growth hormone deficiency.

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.

Long-term effects of growth hormone replacement therapy on thyroid function in adults with growth hormone deficiency.

BACKGROUND: Clinical studies on the effect of growth hormone (GH) on thyroid function in patients with GH deficiency are contradictory. Further, the majority of published observations are limited to the first 6-12 months of GH replacement therapy. The aim of our study was to estimate the incidence of clinically relevant hypothyroidism in a cohort of patients with adult GH deficiency (AGHD) during long-term therapy with recombinant human GH (rhGH). METHODS: The study was designed as a retrospective collection of data on thyroid function in 49 AGHD patients of whom 44 (90%) had multiple hormone deficiency. Thirty-seven patients (76%) were on stable levothyroxine (LT4) replacement therapy (HYPO), and 12 (24%) were euthyroid (EUT). Therapy with rhGH was started at a dose of 3.5 microg/kg body weight and adjusted according to insulin-like growth factor-I (IGF-I) levels. At baseline, 6 months, 12 months, and yearly thereafter we measured free triiodothyronine (fT3), free thyroxine (fT4), thyroid-stimulating hormone, and IGF-I. Study outcome was fT4 level below the normal range (9 pmol/L), irrespectively of fT3 or thyroid-stimulating hormone levels. RESULTS: During a follow-up of 115 patient-years, mean fT4 level decreased significantly, although remaining within the normal range (p = 0.0242; month 48 vs. baseline). The largest decrease was between baseline and month 6, when fT4 decreased of 1.43 pmol/L (95% confidence interval, 0.33-2.53) per 1 unit (microg/kg body weight) increase in rhGH dose. The incidence of hypothyroidism was 1.2 (HYPO group) and 6.7 (EUT group) events per 100 patient-years. CONCLUSION: We confirm that in patients with AGHD, rhGH therapy is associated with a small, although significant, decrement of fT4 in the first 6 months of replacement therapy. However, the incidence of hypothyroidism is low. Monitoring of thyroid function during rhGH therapy is advisable, particularly in the first year of therapy when the largest decrease in fT4 occurs.

Congenital hyposomatotropism in a domestic shorthair cat presenting with congenital corneal oedema.

A six-month-old, female, domestic shorthair cat was presented with a history of failure to grow and bilateral corneal opacity caused by corneal oedema. Congenital hyposomatotropism and possible secondary hypothyroidism were diagnosed on the basis of fasting serum levels of insulin-like growth factor-1 and thyroxine levels, respectively. These endocrinopathies are rare in the cat and have not been reported to cause ocular signs. The cat died during investigation of these diseases, and histopathological examination of the eyes showed significantly reduced corneal endothelial cell density and number of corneal epithelial cell layers when compared with age-matched healthy control corneas. These changes were implicated in the development of the corneal oedema.

A novel splicing mutation in exon 4 (456G>A) of the GH1 gene in a patient with congenital isolated growth hormone deficiency.

Isolated Growth Hormone Deficiency (IGHD) due to GH1 gene defects has a variable inheritance pattern: autosomal recessive, autosomal dominant, and X-linked. the autosomal dominantly inherited form, IGHD II, is mainly caused by heterozygous mutations of splicing around the exon 3/IVs3 boundary region of the GH1 gene resulting in exon 3 skipping of transcripts. We have previously reported findings on GH1 gene mutations in 28 russian patients with severe congenital IGHD (-3.22+/-1.2 height sDs at the age of 1yr); five heterozygous dominant negative splice site mutations in intron 2, intron 3, and exon 4 of the GH1 gene were identified in 32.1% of the cohort. In the present report we describe a novel 456G>A heterozygous mutation of splicing of the last base of the 3'-acceptor splice site of exon 4 within the GH1 in a 4.2-year old, extremely short (-5.32 height sDs) girl with congenital IGHD. the mutation involves a highly conserved GGGgtg sequence of the exon 4/IVs4 boundary region of the GH1 gene. the predicted effect of the 456 G>A mutation is perturbed splicing with possible skipping of exon 4 of the GH1 gene. the novel heterozygous 456 G>A mutation in exon 4 expands the spectrum of dominant negative splicing defects within the GH1 gene, responsible for congenital IGHD.

Moebius syndrome associated with pituitary dwarfism and hypoplastic optic disc.

A 17 year old male patient with Moebius syndrome with pituitary dwarfism and unilateral hypoplastic optic disc is presented. Although there have been several reports of an association of Moebius syndrome and pituitary dysfunction, growth hormone deficiency has not been reported previously. These associations may give some insight into the pathogenesis of Moebius syndrome.

[Laron-type dwarfism: heterogeneity of the biochemical abnormality in 3 children and their parents]. / Nanisme de type Laron: hétérogénéité de l'anomalie biochimique chez trois enfants et leurs parents.

The authors report three cases of Laron-type dwarfism (LTD) having clinical features similar to those of congenital growth hormone (GH) deficiency, but with high levels of plasma GH and a lack of effect of exogenous GH on their growth. The main plasma growth hormone binding protein (GHBP), recently identified and considered as being identical to the extracellular part of the cell receptor to GH, was absent in two of the three patients, and lower than normal in their parents, suggesting a defect of the cell GH receptor. The third patient and his parents had a normal level of GHBP, suggesting a defect limited to the intracellular domain of the receptor or lying beyond the receptor. The conclusion is that there are two different biochemical abnormalities corresponding to LTD.

[Study on testicular tissue in animals with congenital hormone deficiency].

Of 3 kinds of animals with congenital hormone deficiency, i.e., mouse with Snell pituitary dwarfism (dw) in which hypoplasia of the pituitary anterior lobe is seen from embryonal stage and which almost lacks in growth hormone (GH), prolactin (PRL), thyroid stimulating hormone (TSH) and adrenocorticotrophic hormone (ACTH); mouse with little dwarfism lacking only in GH (lit); and mouse with congenital primary hypothyroidism in which the thyroidal gland shows hypoplasia, thyroxine (T4) in blood is not measurable and, conversely, TSH level is abnormally high (hyt), the males of dw/dw and hyt/hyt have been proved to be infertile, but it is little known about lit/lit. After performing early recovery experiment by administering GH + T4 to dw/dw, GH to lit/lit and T4 to hyt/hyt from birth, the testicles of 40-day-old mice were investigated morphologically in the normal control group, non-treated group and treated group in order to clarify the relation between hormones and the sperm-generating potency. The total number of sperm-generating cells, which consist of spermatogonia, spermatocytes, spermatids and sperms, showed remarkable decreases, compared with each control group, and the decrease in total cell number was improved favorably by treatment with hormone. In comparison with the control groups, significant decreases were showed in the spermatid number for the dw/dw group, sperm number for the lit/lit group, and spermatid and sperm numbers for the hyt/hyt group. These results indicate that GH and T4 have a potential effect on sperm-generating function.