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Growth hormone (GH) promotes postnatal human growth primarily by regulating insulin-like growth factor (IGF)-I production through activation of the GH receptor (GHR)-JAK2-signal transducer and activator of transcription (STAT)-5B signaling pathway. Inactivating STAT5B mutations, both autosomal recessive (AR) and dominant-negative (DN), are causal of a spectrum of GH insensitivity (GHI) syndrome, IGF-I deficiency and postnatal growth failure. Only AR STAT5B defects, however, confer additional characteristics of immune dysfunction which can manifest as chronic, potentially fatal, pulmonary disease. Somatic activating STAT5B and JAK2 mutations are associated with a plethora of immune abnormalities but appear not to impact human linear growth. In this review, molecular defects associated with STAT5B deficiency is highlighted and insights towards understanding human growth and immunity is emphasized., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Shwachman-Diamond syndrome is a rare congenital disorder of unknown etiology. Characteristic abnormalities of this disease include pancreatic insufficiency, skeletal anomalies, growth retardation, recurrent infections, and hematologic abnormalities. Significant morbidity and mortality in these patients result from respiratory infections, which are not well explained on the basis of neutrophil defects. We have had the opportunity to perform an in-depth clinical immunologic and endocrinologic evaluation of a patient with this syndrome with recurrent respiratory tract infections. She was found to have profound humoral immunologic defects, and serum thymulin was absent. In addition, endocrinologic evaluation for growth retardation revealed growth hormone deficiency. The patient responded to treatment with supplemental growth hormone and intravenous gammaglobulin with accelerated growth and cessation of infections. This case is unique in that it links growth hormone deficiency and hypogammaglobulinemia in a non-X-linked manner and may provide the basis for treatment of other patients with this rare syndrome.

In 34 children with idiopathic short stature (ISS) we studied parameters of humoral and cellular immunity before and during growth hormone (GH) therapy. The patients were treated with recombinant human GH 3.0 or 4.5 IU/m2 body surface/day, 6 times/week. Leucocyte and lymphocyte counts, percentages of neutrophils, eosinophils, basophils and monocytes were available up to 4 years of therapy (n = 34) and lymphocyte subsets and serum immunoglobulins during the first year of treatment (n = 16). Differences between the measurements at the start and during therapy were tested by a mixed model ANOVA to repeated measurements. Before the start of GH therapy all parameters of immunity were within the normal range in these children. During the first months of treatment the leucocyte and lymphocyte counts decreased and at 6 months were significantly lower than at the start (p = 0.003 and p = 0.006, respectively). Thereafter leucocyte numbers no longer differed from baseline. Lymphocytes were again lower at 36 months (p = 0.001). The percentages of neutrophils, eosinophils, basophils, monocytes and lymphocyte subsets did not change during therapy. Serum IgA concentrations showed a transient decrease at 3 and 6 months of GH therapy (p = 0.01 and p = 0.02). The observed changes were not related to GH dosage or height velocity. We conclude that GH treatment in children with ISS induced a small decrease in leucocyte and lymphocyte counts and serum IgA concentrations.

Thirty-seven prepubertal children evaluated for severe growth retardation were studied by assessment of total granulocyte, monocyte and lymphocyte count, lymphocyte subsets CD3+, CD3+Dr+, CD3+Dr-, CD4+, CD8+, CD8+CD57+, CD8+CD57-, CD16+, CD20+ and CD23+, serum immunoglobulin concentrations, and phagocytic activity of circulating neutrophils and monocytes (by a flow cytometric assay). Idiopathic GH deficiency was diagnosed in 21 of 37 patients; the remaining 16 healthy subjects served as controls. Fourteen patients received biosynthetic GH (rhGH), and their immune parameters were assessed at baseline and after 6 months of therapy. Phagocytic function mediated by both polymorphonuclears and monocytes was significantly impaired in GH-deficient subjects compared to controls (p < 0.003 for neutrophils, p < 0.007 for monocytes), while a significant increase of phagocytic activity was obtained during long-term rhGH replacement therapy (p < 0.02 for neutrophils, p < 0.001 for monocytes), thus suggesting that GH may affect the functional activity of circulating phagocyte cells. No significant differences were found in total granulocyte, monocyte and lymphocyte counts, T- and B-lymphocyte subsets and immunoglobulin levels, between GH-deficient patients and controls, and between values observed before and during rhGH substitution treatment.

Growth hormone deficiency associated with hypogammaglobulinemia has been reported only in a few publications. Our patient was a male with recurrent episodes of infections. Serum immunoglobulin (Ig) G was extremely low although IgM concentration was much greater than the normal limit. Growth hormone responses to insulin, 1-Dopa and growth hormone-releasing hormone were low. The mean growth hormone concentration during sleep was less than the normal limit. These results are consistent with hyper-IgM immunodeficiency associated with growth hormone deficiency. The mode of transmission appears to be autosomal dominant. This combination has not been reported previously.

Objective: The aim was to investigate the long-term evolution of circulating growth hormone antibodies (GH-AB) during and after treatment with methionyl-recombinant human growth hormone (met-rhGH)., Design and Patients: The investigation was performed on serum samples of 46 growth hormone deficient children, treated for at least 12 months with met-rhGH. Twenty patients had never been treated with hGH (previously untreated patients, Group I). Twenty-six subjects were previously treated with pituitary extracted hGH (treated patients, Group II)., Measurements: Serum levels of GH-AB were measured by radioimmunoassay using charcoal precipitation of free ligand., Results: Fifteen patients (75%) of Group I and three patients (12%) of Group II developed GH-AB. In 15 GH-AB positive patients the antibodies became detectable during the first year of treatment with met-rhGH. In three patients, however, the GH-AB appeared during the second year. Once present, the GH-AB remained detectable throughout the period of treatment with met-rhGH. In six patients in whom treatment with met-rhGH was stopped, GH-AB levels decreased rapidly. In nine patients in whom treatment with met-rhGH was changed to rhGH, the levels of GH-AB decreased and ultimately became undetectable. In two patients GH-AB remained present during administration of rhGH. No effect of GH-AB on the growth-promoting effect of met-rhGH could be documented, either during the first or during the second year of treatment., Conclusions: This study confirms the high immunogenicity of met-rhGH, especially in patients not treated earlier with hGH. Once present, the GH-AB remain detectable throughout the period of treatment with met-rhGH. After stopping met-rhGH treatment or changing to rhGH the GH-AB disappear rapidly in most patients. No effect of GH-AB on the growth-promoting effect of rhGH could be documented.

Small stature is associated with low growth hormone secretion, but in most cases the reason is unknown. The commonest cause of hormone insufficiency is autoimmunity, and autoantibodies to hormones are often found where there is autoimmune disease of the corresponding gland. Displaceable growth hormone binding by the sera of 125 short (< 3rd centile) but otherwise normal school entrants was significantly higher (P < 0.05) than by the sera of 100 age-matched children of normal height (10th-90th centile), and binding in 21 (17%) of the small children exceeded the upper limit of 95% of the normal population. Furthermore, urinary growth hormone excretion was significantly lower in the small children (total overnight output 0.6-1.7 ng) compared with controls (1.5-3.7 ng) (P < 0.05) even when corrected for body surface area. Thus, growth hormone binding and growth hormone excretion discriminated between two groups of children selected only on the basis of height. The assay used for growth hormone binding was specific for IgG, suggesting that the binding factor was antibody. Autoimmunity merits further investigation as a basis for poor growth.

Immune functions, including cell surface markers, interleukin-2 receptor levels and responses of lymphocytes to mitogenic stimulation were evaluated in seven growth hormone deficient children ages 4-15 years, during treatment with biosynthetically derived human growth hormone. Treatment resulted in a decrease in % B cells and in % T total cells and also decreases in most individual patients' mitogen responses and interleukin-2 receptor levels. Most of the changes noted were transient and similar to those previously demonstrated during pituitary-derived human growth hormone treatment. Although not resulting in overt clinical manifestations in our patients, we think that potential interactions between growth hormone and immune functions need to be considered by physicians treating children with growth hormone.

Conflicting data regarding the immune function in growth hormone (GH) -deficient children or changes in immune parameters during substitutive GH therapy have been reported. We have studied the immune function in 13 patients with GH deficiency before and during treatment with biosynthetic GH (12 IU/m2 body surface/week) after 6 and 12 months of therapy. We found that the absolute number of total T lymphocytes and T-cell subsets (using monoclonal Ab as markers), Natural Killer cell activity (target K562) and response of lymphocytes to polyclonal mitogens (PHA, ConA, PWM) were all in the normal range and remained so after 6 and 12 months of therapy. The absolute number of B lymphocytes was in the normal range before treatment and after 6 months of therapy but dropped significantly after 12 months of treatment. Serum immunoglobulins (IgG, IgA, IgM) did not show a parallel drop and remained normal throughout the whole study. Our GH-deficient patients did not show any undue susceptibility to infections and our data thus seem to confirm that the immune function is basically intact in these children and that it is not suppressed by GH treatment. Although a drop in B lymphocytes was observed, the normal level of immunoglobulins and the normal functional response to PWM seem to demonstrate the maintenance of a normal humoral immune response.

GH influences the immune response. The mechanism is not known; however, the presence of receptors for GH on human lymphocytes as well as its ability to influence and modulate immune responses in animals suggest an association between GH and immune function in man. We evaluated the effect of recombinantly derived natural sequence human GH (hGH) on lymphocyte surface antigen expression, response to mitogenic stimulation, expression of interleukin-1 receptors, and production of anti-hGH antibodies in GH-deficient children. The only observed changes were a decrease in the percentage of B-cells and a transient increased reactivity to phytohemagglutinin stimulation. It appears from the results of our studies that the administration of hGH has a selective effect on lymphocyte immune function; however, we cannot eliminate a role for hGH in the initiation or regulation of antigen-mediated immune responses.

Natural killer (NK) cell activity was assessed in the peripheral blood of 20 patients with growth hormone (GH) deficiency due to a hypothalamic deficit of GH-releasing hormone (GHRH). All patients failed to respond to at least two provocative tests of GH secretion (GH below 7 ng/ml) but responded to a single GHRH iv bolus injection (1 microgram/kg body wt). In 14 of the 20 patients (20 determinations), lymphocyte subsets were also measured; in all patients the distribution of lymphocyte subsets was within the normal range. More importantly, NK cell activity in the 20 patients was significantly lower than in controls (P less than 0.01). To assess the in vivo effect of GH and GHRH on NK activity and lymphocyte subset distribution, immunologic tests were performed (i) before and after a single iv bolus injection of GHRH (1 microgram/kg body wt) in six patients; (ii) before and after 3 weeks of GHRH treatment (3-9 micrograms/kg body wt, one to four times daily) in five patients; and (iii) after 6 weeks of GH treatment (5 IU sc every alternate day) in one patient. Neither NK activity nor the distribution of lymphocyte subsets was altered during short-term GHRH administration. In conclusion, low NK activity is found in GH-deficient patients, and short-term administration of GH or GHRH fails to restore this immunological abnormality. This result suggests that the hypothalamus may be a regulator of NK activity in the human and that patients with hypothalamic deficiencies should be monitored for the development of discrete immunodeficiencies.

A 10-year-old child with idiopathic growth hormone deficiency was treated with recombinant methionyl human growth hormone (m-hGH, Somatonorm) at a dose of 14 IU/week. Height increased from 122.3 to 126.5 cm during the first 9 months of treatment (5.6 cm/y), but only from 126.5 to 126.6 cm during the next 3 month of treatment (0.4 cm/y). Anti-hGH antibody was detected at 2 months of treatment, reached its maximum at the end of 9 months with a titer of 10(6) and a binding capacity of 2.0 mg/L. After switching from m-hGH to pituitary extracted hGH (p-hGH) treatment, his height increased again from 126.6 to 132.2 cm during the next 12 months of p-hGH treatment (5.6 cm/y). The cause of growth attenuation during m-hGH treatment was concluded to be the high titer of anti-hGH antibody. This is the first case in Japan and one of only three cases in which growth attenuation occurred during m-hGH treatment.

To delineate the role of growth hormone (GH) in the development and function of the immune system, immunological parameters including quantitative immunoglobulins, T and B lymphocytes, phytohemagglutinin lymphoproliferative response and delayed hypersensitivity skin tests were studied in nine GH-deficient children prior to GH therapy and at 2 months and 9 to 12 months following therapy. The phytohemagglutinin response (74.1 +/- 37.6, mean +/- SD), and the T rosette (58.3% +/- 9.4), B rosette (21.1% +/- 6.1), IgG (810 +/- 241 mg/dl), (IgA 140 +/- 85), and IgM (176 +/- 70) levels in GH-deficient children were comparable to age adjusted values in normal children. Following GH therapy the phytohemagglutinin response increased significantly at 9 to 12 months post-therapy, 123.2 +/- 51.9 versus 74.1 +/- 37.6, p less than 0.05. T and B rosettes, immunoglobulin concentrations, and hypersensitivity skin tests were not affected by GH therapy. Although an effect of GH was not demonstrable by these studies, a positive role of GH cannot be entirely excluded since total GH deficiency did not exist in all children.

The growth of 26 short normal prepubertal children (mean age 8.4, height velocity standard deviation score for chronological age between +0.4 and -0.8) was studied for two years. Sixteen children were treated with somatrem (methionyl growth hormone) during the second year, and the remaining 10 children served as controls. During one year of treatment the height velocity standard deviation score for chronological age increased from the pretreatment mean of -0.44 (SD 0.33) to +2.20 (1.03). These values represented a change in height velocity from a pretreatment mean of 5.3 cm/year (range 4.6-6.9) to 7.4 cm/year (range 5.7-9.9). In the control group the height velocity standard deviation score was unchanged. Bone age advanced by 0.75 (0.33) years in the treated group compared with 0.70 (0.18) years in the control group. There was a significant increase in the height standard deviation score for bone age (0.63 (0.55] in the treated group. Multiple regression analysis of predictive factors contributing to the change in height velocity standard deviation score over the first year of treatment showed that the dose of growth hormone and pretreatment height velocity standard deviation score were important, together yielding a regression correlation coefficient of 0.80. The only metabolic side effect of treatment was an increase in fasting insulin concentration, which may be an important mediator of the anabolic effects of growth hormone. Treatment had no effect on thyroid function, blood pressure, or glucose tolerance. At the end of the treatment year seven of the 16 treated children had developed antibodies to growth hormone, but they were present in low titre with low binding capacity and in no child was growth attenuated. Biosynthetic growth hormone improved the height velocity of children growing along or parallel to the third height centile, but the effects on height prognosis need to be assessed over a longer period.

Using restriction endonuclease analysis of genomic DNA hybridized to a human chorionic somatomammotropin (hCS) complementary (c)DNA probe, we studied four young Jewish patients with isolated growth hormone deficiency (IGHD), and 15 family members. One family originated in Iraq, two in Yemen and one in Iran. Each patient was homozygous for a deletion of approximately 7.5 kilobases, which included the hGH-N gene. Three of the deletions were associated with the same restriction fragment length polymorphism haplotype, while the deletion in the child of Iranian descent was associated with a different haplotype. All the patients were treated with three injections per week of pituitary human growth hormone (hGH) for periods of 2 1/2 to 14 1/2 years. All had a good growth response. Three reached normal and one almost normal height. Repeated serum analyses revealed absence of anti-hGH antibodies. Thus, the presently described patients differ from those previously reported from Switzerland, Argentina and Japan, all of whom developed anti-hGH antibodies during treatment, with resultant slowing or arresting of growth. Expression of heterozygosity in family members was variable with regard to stature, hGH reserve and insulin-like growth factor I (IGF-I) levels. It is hypothesized that hGH-N gene deletion is not the sole determinant of immune response during hGH treatment, and that the difference between the current series and other cases needs further investigation.

In a multicentre clinical trial 54 children aged 4.0 to 17.3 years, who had growth hormone deficiency that had not previously been treated, were given biosynthetic methionyl growth hormone (somatrem) 4 units three times a week by subcutaneous or intramuscular injection for one year. Height was measured every three months for at least one year before and during treatment. Forty two patients responded to treatment with an increase in growth of greater than 1.5 cm/year. The remaining 12 who grew more slowly were less obviously short and had a higher pretreatment growth than those who responded. The three who responded and the one who did not had undergone therapeutic spinal irradiation before starting the drug. If a whole year's pretreatment growth rate of less than 5 cm/year had been used as a diagnostic criterion the prediction of those who responded would have slightly improved. About two thirds of the patients developed antibodies against growth hormone and Escherichia coli protein; these were, however, of low and fluctuating titre and binding capacity, and did not influence the response to treatment. No adverse side effects were encountered. We conclude that somatrem is a safe and effective alternative to pituitary growth hormone.