Clin Endocrinol (Oxf). 2011 Nov 25;
Gorbenko Del Blanco D, de Graaff LC, Visser TJ, Hokken-Koelega AC

Objective:  Growth hormone insensitivity syndrome (GHIS) is characterized by extreme short stature and resistance to the actions of growth hormone. The heterogeneity ranges from the most severe form, known as Laron syndrome, to less severe phenotypes like idiopathic short stature and partial growth hormone insensitivity. Here, we aimed to identify and characterize the molecular cause of severe short stature in a patient with resistance to GH treatment. Patient:  We describe a male patient born small for gestational age (38 weeks gestation, length 38.5 cm; -7.8 SDS, weight 1350 g; -4.84 SDS). At the age of seven years (109.7 cm; -2.89 SD) he received GH treatment (1 mg/m(2) /day) for one year without any increase in height SDS, IGF-I or IGFBP-3 levels. Double-GH- dose treatment for another year did not result in any improvement of growth factor level either. The patient does not have the typical Laron craniofacial and somatic features. Results:  Analysis of GHR showed a heterozygous nonsense mutation (c.703C>T; p.Arg217X). Extensive mutation screening as well as copy number variation analysis of other candidate genes in the GH-IGF1 axis excluded any additional genetic defects. Analysis of the patient's fibroblasts showed that GHR mRNA expressed from the mutant allele was degraded by a mechanism called nonsense-mediated mRNA decay (NMD). Conclusions:  GHIS in this patient is due to a heterozygous nonsense mutation in GHR. Our study is the first to demonstrate that nonsense-mediated decay is involved in the phenotypic variability of GHIS caused by GHR mutations.

J Clin Endocrinol Metab. 2011 Nov; 96(11): E1896-904
Derr MA, Aisenberg J, Fang P, Tenenbaum-Rakover Y, Rosenfeld RG, Hwa V

GH insensitivity (GHI) is a condition characterized by pronounced IGF-I deficiency and severe short stature. We previously identified a novel compound heterozygous GH receptor (GHR) mutation, GHR:p.R229H/c.899dupC, in a patient presenting with GHI. The heterozygous p.R229H (prepeptide) variant was previously associated with GHI despite a lack of adequate functional studies. The novel heterozygous GHR:c.899dupC variant affects the critical JAK2-binding Box 1 region of the GHR intracellular domain; the duplication predicted a frameshift and early protein termination.The individual and synergistic effect(s) of the p.R229H and c.899dupC mutations on GHR function(s) were evaluated in reconstitution studies.The recombinant human GHR (hGHR):p.R229H variant was readily expressed, and unexpectedly, GH-induced signal transducer and activator of transcription 5b (STAT5b) phosphorylation was comparable to that induced by wild-type hGHR. The truncated, immunodetected hGHR:c.899dupC variant, in contrast, was unresponsive to GH. To mimic a compound heterozygous state, the two variants were coexpressed, and strikingly, the presence of the hGHR:c.899dupC effectively abolished the GH-induced STAT5b activities that were observed with hGHR:p.R229H alone. Furthermore, hGHR:c.899dupC dose-dependently reduced the GH-induced STAT5b activities associated with hGHR:p.R229H. This dominant negative effect was also observed when hGHR:c.899dupC was coexpressed with wild-type hGHR.The p.R229H variant, contrary to an earlier report, appeared to function like wild-type GHR and, therefore, is unlikely to cause GHI. The c.899dupC variant is a novel dominant negative mutation that disrupted normal GHR signaling and is the cause for the GHI phenotype of the reported patient.

Int J Obstet Anesth. 2011 Oct; 20(4): 344-6
Bhatia K, Cockerham R

We report a case of a parturient with Laron syndrome, a rare form of dwarfism which results from an inability to generate insulin-like growth factor 1. In addition to dwarfism these patients may have craniofacial abnormalities, atlantoaxial instability, spinal stenosis and metabolic, musculoskeletal and genitourinary abnormalities. The patient underwent an urgent caesarean section using combined spinal-epidural anaesthesia. Laron syndrome is reviewed and its anaesthetic implications discussed.

Am J Med Genet A. 2011 Sep; 155A(9): 2242-6
Gat-Yablonski G, Frumkin-Ben David R, Bar M, Potievsky O, Phillip M, Lazar L

Microdeletion syndromes include numerous syndromic phenotypes associated with intellectual disability and dysmorphic features. We report on a patient with a novel microdeletion of chromosomal region 3p11.2-p12.1 containing POU1F1, chromatin-modifying protein 2B (CHMP2B), and vestigial-like 3 (VGLL3) genes. Our patient was diagnosed as having a neonatal multiple pituitary hormone [growth hormone (GH), thyroid-stimulating hormone (TSH), and prolactin] deficiency. In addition to the typical findings associated with these hormonal deficiencies, she exhibited clinical features resembling those of Laron syndrome (frontal bossing, saddle nose, small chin, blue sclera, and acromicria), with moderate intellectual disability. She also displayed an unusual growth pattern characterized by unresponsiveness to high doses of GH replacement therapy during infancy and early childhood and an accelerated growth rate beginning at the age of 4.5 years. Insulin-like growth factor (IGF)-1 levels were consistently extremely low or undetectable. Extensive medical and genetic analysis ruled out primary and secondary GH insensitivity. The distinct phenotype and the peculiar growth pattern observed in this affected patient, not reported to have been observed in other cases with POU1F1 gene inactivity, suggest that the other two deleted genes play a possible role in the development of this syndrome. This hypothesis may be supported by the fact that both the CHMP2B and VGLL3 genes are expressed in the liver and the growth plate, the two main target organs of the GH/IGF-1 axis. The homozygous deletion of the CHMP2B gene, previously associated with frontotemporal dementia, may contribute to the intellectual disability observed in this patient.

AJNR Am J Neuroradiol. 2011 Sep; 32(8): 1560-2
Kornreich L, Konen O, Lilos P, Laron Z

Patients with LS have an inborn growth hormone resistance, resulting in failure to generate IGF-1. The purpose of this study was to evaluate the size of the eye and orbit in LS.We retrospectively reviewed the MR imaging of the brain in 9 patients with LS for the following parameters: axial diameter of the globe, interzygomatic distance, perpendicular distance from the interzygomatic line to margins of the globe, medial-to-lateral diameter of the orbit at the anterior orbital rim, distance from the anterior orbital rim to the anterior globe, maximal distance between the medial walls of the orbits, lateral orbital wall angle, lateral orbital wall length, and mediolateral thickness of the intraorbital fat in the most cranial image of the orbit. All measurements were made bilaterally. Twenty patients referred for MR imaging for unrelated reasons served as control subjects.Compared with the control group, the patients with LS had a significantly smaller maximal globe diameter and shallower but wider orbits due to a shorter lateral wall, a smaller medial distance between the orbits, and a larger angle of the orbit. The ratio between the most anterior orbital diameter and the globe was greater than that in controls. The position of the globe was more anterior in relation to the interzygomatic line.Shallow and wide orbits and small globes relative to orbital size are seen in LS and may be secondary to IGF-1 deficiency.

J Med Case Reports. 2011; 5: 301
Cotta OR, Santarpia L, Curtò L, Aimaretti G, Corneli G, Trimarchi F, Cannavò S

ABSTRACT:Primary growth hormone resistance or growth hormone insensitivity syndrome, also known as Laron syndrome, is a hereditary disease caused by deletions or different types of mutations in the growth hormone receptor gene or by post-receptor defects. This disorder is characterized by a clinical appearance of severe growth hormone deficiency with high levels of circulating growth hormone in contrast to low serum insulin-like growth factor 1 values.We report the case of a 15-year-old Caucasian girl who was diagnosed with Silver-Russell syndrome at the age of four and a half years. Recombinant growth hormone was administered for 18 months without an appropriate increase in growth velocity. At the age of seven years, her serum growth hormone levels were high, and an insulin-like growth factor 1 generation test did not increase insulin-like growth factor 1 levels (baseline insulin-like growth factor 1 levels, 52 μg/L; reference range, 75 μg/L to 365 μg/L; and peak, 76 μg/L and 50 μg/L after 12 and 84 hours, respectively, from baseline). The genetic analysis showed that the patient was homozygous for the R217X mutation in the growth hormone receptor gene, which is characteristic of Laron syndrome. On the basis of these results, the diagnosis of primary growth hormone insensitivity syndrome was made, and recombinant insulin-like growth factor 1 therapy was initiated. The patient's treatment was well tolerated, but unexplained central hypothyroidism occurred at the age of 12.9 years. At the age of 15 years, when the patient's sexual development was almost completed and her menstrual cycle occurred irregularly, her height was 129.8 cm, which is 4.71 standard deviations below the median for normal girls her age.The most important functional tests for the diagnosis of growth hormone insensitivity are the insulin-like growth factor 1 generation test and genetic analysis. Currently, the only effective treatment is daily administration of recombinant insulin-like growth factor 1 starting from early childhood. However, these patients show a dramatically impaired final height. In our case, unexplained central hypothyroidism occurred during treatment.

Eur Arch Otorhinolaryngol. 2012 Feb; 269(2): 461-6
Attias J, Zarchi O, Nageris BI, Laron Z

The aim of this prospective clinical study was to test auditory function in patients with Laron syndrome, either untreated or treated with insulin-like growth factor I (IGF-I). The study group consisted of 11 patients with Laron syndrome: 5 untreated adults, 5 children and young adults treated with replacement IGF-I starting at bone age <2 years, and 1 adolescent who started replacement therapy at bone age 4.6 years. The auditory evaluation included pure tone and speech audiometry, tympanometry and acoustic reflexes, otoacoustic emissions, loudness dynamics, auditory brain stem responses and a hyperacusis questionnaire. All untreated patients and the patient who started treatment late had various degrees of sensorineural hearing loss and auditory hypersensitivity; acoustic middle ear reflexes were absent in most of them. All treated children had normal hearing and no auditory hypersensitivity; most had recordable middle ear acoustic reflexes. In conclusion, auditory defects seem to be associated with Laron syndrome and may be prevented by starting treatment with IGF-I at an early developmental age.

Pediatr Endocrinol Rev. 2011 Mar; 8 Suppl 2: 290-4
De Sanctis V, Skordis N, Galati MC, Raiola G, Giovannini M, Candini G, Kaffe K, Savvides I, Christou S

In patients with b-thalassemia major (TM), the anterior pituitary gland is particularly sensitive to free radical stresses. It has been reported that the GH deficiency (GHD) may be secondary to either pituitary or hypothalamic dysfunction. The duration of the disease, the patient's age and the severity of iron overload are the most important factors responsible for the defect of growth hormone (GH) secretion. Recent reports have documented a frequency of severe growth hormone deficiency in 13%-32% of patients with b-thalassemia major. All of these patients underwent GH-releasing hormone (GH-RH) plus arginine (ARG) testing. We undertook the present study to evaluate the GH and adrenal response during glucagon stimulation test (GST) in patients with TM because the GH-RH plus ARG test in patients with hypothalamic GHD may be misleading. Thirty-three adult TM patients were recruited (mean age 36.6 years). Fifty four percent were included in the severe GHD group (GH peak below 3mg/l). The IGF-1 level in TM patients was consistently low (60.3 ± 35.3 mg/l) and 86.6% of patients with a normal GH response to GST had a low IGF-1 level. These findings are also indicative of a relative resistance to GH. In eight out of 18 TM patients (44.4%), the GHD was associated with hypogonadotropic hypogonadism. A positive correlation was found between GH peak after GST and IGF-1 level (r = 0.8, p: 0.003) and a negative correlation between the age of female TM patients and GH peak (r = 0.711, p: 0.007). All patients but one had no evidence of cardiac iron overload (mean T2* 30.4 ± 8.2 ms; range 14-44 ms). The mean LVEF (%) in TM patients was no different when compared to healthy controls. However, three patients with severe GHD and normal T2*were found to have reduced LVEF.One patient (4%) had a peak cortisol response to GST compatible to adrenal insufficiency. Nausea, headache and\or hypoglycemia occurred in 3 patients (12%) during GST. In conclusion, our study demonstrates that the presence of GHD is frequent in adult TM patients. According to the international guidelines for medical practice, we believe that before considering hormone replacement therapy, a second test to confirm the diagnosis of GHD and adrenal insufficiency is required.

Pediatr Endocrinol Rev. 2011 Mar; 8 Suppl 2: 284-9
Pincelli AI, Masera N, Tavecchia L, Perotti M, Perra S, Mariani R, Piperno A, Mancia G, Grassi G, Masera G

Endocrine complications in Β-thalassemia represent a prominent cause of morbidity. Above all, dysfunction of GH-IGF-1 axis is of a major concern because of its pathogenic role on cardiac and bone disease, frequently described in this clinical setting. The aim of this paper is to analyze GH-IGF-1 axis in a cohort of 25 adult patients affected by Β-thalassemia. We found that GH deficiency was present in only 8% of our patients if diagnosis was based on GH peak below 9μg/L to two GH provocative tests instead of only one, and was mainly related to iron overload. On the contrary, IGF-1 production was impaired in a higher percentage of patients (72%), without significant correlation with iron burden. Of note, patients with hepatitis C virus infection showed lower IGF-1 concentrations than uninfected subjects despite a normal GH reserve, suggesting that partial GH insensitivity at the post-receptor level may play a key role in IGF-1 deficiency described in thalassemic patients.

Nutr Metab (Lond). 2011; 8: 41
Melnik BC, John SM, Schmitz G

ABSTRACT: The insulin/insulin-like growth factor-1 (IGF-1) pathway drives an evolutionarily conserved network that regulates lifespan and longevity. Individuals with Laron syndrome who carry mutations in the growth hormone receptor (GHR) gene that lead to severe congenital IGF-1 deficiency with decreased insulin/IGF-1 signaling (IIS) exhibit reduced prevalence rates of acne, diabetes and cancer. Western diet with high intake of hyperglycemic carbohydrates and insulinotropic dairy over-stimulates IIS. The reduction of IIS in Laron subjects unmasks the potential role of persistent hyperactive IIS mediated by Western diet in the development of diseases of civilization and offers a rational perspective for dietary adjustments with less insulinotropic diets like the Paleolithic diet.

Endocr Rev. 2011 Aug; 32(4): 472-97
David A, Hwa V, Metherell LA, Netchine I, Camacho-Hübner C, Clark AJ, Rosenfeld RG, Savage MO

GH insensitivity (GHI) presents in childhood as growth failure and in its severe form is associated with dysmorphic and metabolic abnormalities. GHI may be caused by genetic defects in the GH-IGF-I axis or by acquired states such as chronic illness. This article discusses the former category. The field of GHI due to mutations affecting GH action has evolved considerably since the original description of the extreme phenotype related to homozygous GH receptor (GHR) mutations over 40 yr ago. A continuum of genetic, phenotypic, and biochemical abnormalities can be defined associated with clinically relevant defects in linear growth. The role and mechanisms of the GH-IGF-I axis in normal human growth is discussed, followed by descriptions of mutations in GHR, STAT5B, PTPN11, IGF1, IGFALS, IGF1R, and GH1 defects causing bioinactive GH or anti-GH antibodies. These defects are associated with a range of genetic, clinical, and hormonal characteristics. Genetic abnormalities causing growth failure that is less severe than the extreme phenotype are emphasized, together with an analysis of height and serum IGF-I across the spectrum of different types of GHR defects. An overall view of genotype and phenotype relationships is presented, together with an updated approach to the assessment of the patient with GHI, focusing on investigation of the GH-IGF-I axis and relevant molecular studies contributing to this diagnosis.

Best Pract Res Clin Endocrinol Metab. 2011 Feb; 25(1): 61-75
Hwa V, Nadeau K, Wit JM, Rosenfeld RG

Growth hormone (GH) regulates insulin-like growth factor (IGF)-I production primarily through activation of the GH receptor (GHR)-signal transducer and activator of transcription (STAT)-5b signaling cascade. One of four STAT proteins (STAT1, -3, -5a and -5b) activated by the GH-GHR system, the critical importance of STAT5b in IGF-I production became evident with the identification of homozygous, autosomal recessive STAT5b mutations in patients who presented with severe postnatal growth failure, growth hormone insensitivity syndrome (GHIS) and marked IGF-I deficiency. Unlike GHIS due to GHR mutations, patients carrying STAT5b mutations also presented with chronic pulmonary disease and evidence of perturbations of T-cell homeostasis. At present, no single treatment(s) is available to improve both poor statural growth and immune deficiency. Continued clinical evaluations of patients with STAT5b mutations and elucidating the impact of the mutation on STAT5b structure and function, are important to understanding the pathophysiology of this rare, complex, disease (MIM 245590).