Alternative titles; symbols
ORPHA: 220465; DO: 0080836;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17q21.2 | Growth hormone insensitivity with immune dysregulation 1, autosomal recessive | 245590 | Autosomal recessive | 3 | STAT5B | 604260 |
A number sign (#) is used with this entry because of evidence that autosomal recessive growth hormone insensitivity syndrome with immune dysregulation-1 (GHISID1) is caused by homozygous mutation in the STAT5B gene (604260) on chromosome 17q21.
Heterozygous mutation in the STAT5B gene causes a similar disorder with milder immune defects (GHISID2; 618985).
Autosomal recessive growth hormone insensitivity syndrome with immune dysregulation-1 (GHISID1) is a congenital disorder characterized by short stature due to insensitivity to growth hormone (GH1; 139250). Affected individuals usually have failure to thrive, delayed bone age, and delayed puberty associated with decreased serum IGF1 (147440), IGFBP3 (146732), and ALS (601489). Some patients may have dysmorphic features. Most, but not all, patients have features of immune dysregulation, including chronic pulmonary disease, interstitial pneumonitis, recurrent or severe infections, eczema, and autoimmune arthritis. The immune features are highly variable (summary by Kofoed et al., 2003; Vidarsdottir et al., 2006).
See 262500 for a form of growth hormone insensitivity caused by mutation in the growth hormone receptor gene (GHR; 600946).
Laron et al. (1966) reported a form of genetic dwarfism (262500) associated with high circulating growth hormone. Originally, they assumed a faulty GH molecule, but subsequent investigations established defective GH receptor (GHR; 600946), which precluded the binding of GH as the cause. The defect in feedback on the pituitary, causing the extensive GH oversecretion, was thought to be related to the lack of IGF1 (147440), the synthetic product of GH-receptor interaction. The defect in the growth hormone receptor was reflected by the deficiency of serum growth hormone binding protein (GHBP), which is encoded by the GHR gene. Buchanan et al. (1991) reported children in families originating from Pakistan or India who showed typical features of Laron syndrome but had normal levels of serum GHBP.
Laron et al. (1993) reported the cases of 3 sibs, born of first-cousin Palestinian Arab parents, with Laron syndrome and normal serum GHBP who underwent long-term treatment with biosynthetic IGF1 with results indicating a post-GH receptor defect. Basal serum levels of growth hormone were high and IGF1 low, but, in contradistinction to the classic form of Laron syndrome, serum GHBP and insulin-like growth factor-binding protein-3 (IGFBP3; 146732) were normal in these patients. Laron et al. (1993) concluded from the results of short-term treatment with human growth hormone and short- and long-term IGF1 administration that the GH receptor and the signal transmission for IGFBP-3 synthesis were normal but that a defect existed in the post-GH receptor mechanism for the generation of IGF1. Treatment with IGF1 for 1 year increased the growth velocity by 47 to 96% in the 2 older children. The sibs showed the typical clinical features of Laron syndrome: they were very short and obese, had acromicria, small genitalia (in the boys), and a high-pitched voice. A prominent forehead was demonstrated in 1 patient. It is perhaps significant that females on both sides of the family, aunts of the 3 sibs, and the paternal grandmother were very short, being less than 2 standard deviations below the mean. This may represent heterozygous manifestation.
Kofoed et al. (2003) described a 16.5-year-old Argentinian girl, born of first-cousin parents, who required care in a neonatal unit at birth due to respiratory difficulties. She had poor weight gain and growth failure during the first 3 years of life, and at 7 years of age, her height and weight were below the 5th percentile. Continued respiratory difficulties with increasing oxygen requirements led to lung biopsy, which showed lymphoid interstitial pneumonia. At age 8 years, she presented with severe hemorrhagic varicella, and she subsequently had several episodes of herpes zoster. Progressive worsening of her pulmonary function resulted in a second lung biopsy at the age of 10 years from which Pneumocystis carinii was isolated. A 12-month trial of growth hormone therapy resulted in no improvement in growth rate. At age 16.5 years, her height was 117.8 cm (7.5 SD below the mean for age), with normal body proportions and delayed secondary sex characteristics (Tanner stage III pubertal development). She had a prominent forehead, a saddle nose, and a high-pitched voice. There was no family history of growth failure, and 2 unaffected sisters had normal stature.
Cohen et al. (2006) studied the then-20-year-old Argentinian patient originally reported by Kofoed et al. (2003) and observed immune dysregulation with decreased numbers of regulatory CD4+ (186940)/CD25 (IL2RA; 147730)-high T cells (Tregs). The patient's Tregs showed low expression of FOXP3 (300292) and were impaired in their ability to suppress proliferation of or to kill CD4+/CD25- cells. CD25 expression was also reduced after IL2 (147680) stimulation, although IL2-mediated upregulation of IL2RG (308380), perforin (PRF1; 170280), and CD154 (CD40LG; 300386) was normal. The immunologic phenotype of the patient's heterozygous parents tended to be normal or intermediate.
Bernasconi et al. (2006) described a 16-year-old girl, born to nonconsanguineous parents, who had generalized eczema and recurrent infections of the skin and respiratory tract since birth, chronic diarrhea from 2 years of age, and multiple episodes of herpetic keratitis beginning at 10 years of age, with progressive loss of visual acuity. When hospitalized at age 16 due to respiratory distress, she had evidence of severe chronic hypoxemic lung disease as well as clinical features of congenital GH deficiency, including prominent forehead, saddle nose, and high-pitched voice, with no signs of pubertal onset. She had a normal serum GH level with undetectable IGF1 or IGFB3, and prolactin (176760) levels were persistently high. Immunologic analysis revealed moderate T-cell lymphopenia, normal CD4/CD8 ratio, and very low numbers of natural killer and gamma-delta T cells (see 186970), and the T cells showed a chronically hyperactivated phenotype. In vitro T-cell proliferation and IL2 signaling were impaired, and CD4+/CD25+ regulatory T cells (Tregs) were significantly diminished.
Freeth et al. (1997) identified 4 girls from 2 families with the Laron syndrome phenotype but normal GHBP levels. No GHR gene mutations were identified in 1 family. In the other family, the affected sibs, an unaffected brother, and the father were heterozygous for a point mutation (D152H; 600946.0021) within exon 6 of the GHR gene. In addition, use of intron-9 polymorphisms to determine linkage to the GHR gene implied inheritance of different maternal GHR alleles in the 2 affected girls of this family. It is unlikely, therefore, that the D152H substitution alone could account for the Laron syndrome phenotype. To identify the defect, endpoints of GH action, DNA synthesis, IGFBP3 mRNA, and peptide production were examined in skin fibroblast cultures established from 3 of the patients and 4 normal children. Whereas normal fibroblasts incorporated [3H]thymidine dose dependently in response to increments of GH, the patients' fibroblasts failed to respond significantly above basal levels (P less than 0.01). In normal fibroblasts, IGFBP3 mRNA and peptide increased maximally at 48 hours in response to GH, as determined by ribonuclease protection assay, Western ligand blotting, and radioimmunoassay. In comparison, the patients' fibroblasts produced significantly less IGFBP3 peptide than normal fibroblasts in response to GH, whereas IGFBP3 mRNA failed to increase above basal levels. The findings suggested that GH insensitivity in these children was not caused exclusively by GHR mutations, and was probably caused by dysfunctional GHR signaling.
In a 16.5-year-old Argentinian girl with the clinical and biochemical characteristics of GH insensitivity and immunodeficiency, Kofoed et al. (2003) analyzed the GHR gene and protein but found no mutations and normal serum GHBP levels. Noting that signal transduction involving the GHR occurs by means of at least 3 well-established pathways, including signal transducers and activators of transcription (STATs), phosphatidylinositol-3 kinase (see PIK3R1; 171833), and mitogen-activated protein kinase (see MAPK1; 176948) pathways, the authors analyzed the STAT5B gene (604260) in this patient and identified homozygosity for a missense mutation (A630P; 604260.0001). Kofoed et al. (2003) concluded that the combined phenotype of growth hormone insensitivity and immunodeficiency was consistent with the presence of a defect in the JAK/STAT signaling system.
Hwa et al. (2005) reported a 16.4-year-old Turkish girl, born of second-cousin parents, who had severe postnatal short stature and normal to high levels of GH, normal GHBP levels, and extremely low serum IGF1, which remained low after administration of GH. She also had a history of pruritic skin lesions and recurrent pulmonary infections; CT scan of the chest revealed primary idiopathic pulmonary fibrosis with diffuse lung involvement, but biopsy was not performed because of a bleeding diathesis due to defective thrombocyte aggregation. Evaluation at 15 years of age revealed that gross T cells, B cells, and natural killer cells were within normal limits, as was the lymphoproliferative response. Noting phenotypic similarities to the patient described by Kofoed et al. (2003), Hwa et al. (2005) analyzed the STAT5B gene and identified homozygosity for a 1-bp insertion (604260.0002) predicted to severely truncate the protein with loss of the C terminus.
Vidarsdottir et al. (2006) described a 30-year-old man, born in the Dutch Antilles of nonconsanguineous parents, who was diagnosed with congenital ichthyosis (see 242300) at birth and had hemorrhagic varicella at 16 years of age that was treated with acyclovir. He also had short stature and delayed puberty with normal GH and GHBP levels, an elevated plasma prolactin level, and extremely low levels of IGF1, IGFBP3, and acid-labile subunit (ALS; 601489). Sequence analysis of the STAT5B gene revealed homozygosity for a frameshift mutation (604260.0003). The authors stated that unlike 2 previously reported patients with STAT5B mutations (Kofoed et al., 2003; Hwa et al., 2005), this patient had no history of pulmonary or immunologic problems.
In a 16-year-old girl with severe GH insensitivity and immunodeficiency, Bernasconi et al. (2006) identified homozygosity for a nonsense mutation in the STAT5B gene (604260.0004).
Hwa et al. (2007) reported 2 Kuwaiti sisters, born of consanguineous parents, who had severe postnatal growth retardation with normal GH and GHBP levels but abnormally low IGF1, IGFBP3, and ALS. Sequencing of the GHR gene revealed no mutations, but both sibs were found to be homozygous for a 1-bp deletion in the STAT5B gene (604260.0005). The older sister, who was 3.9 years old, had been diagnosed with bronchiectasis and interstitial pneumonitis; and her 2-year-old sister had been diagnosed with idiopathic juvenile arthritis.
Bernasconi, A., Marino, R., Ribas, A., Rossi, J., Ciaccio, M., Oleastro, M., Ornani, A., Paz, R., Rivarola, M. A., Zelazko, M., Belgorosky, A. Characterization of immunodeficiency in a patient with growth hormone insensitivity secondary to a novel STAT5b gene mutation. Pediatrics 118: e1584, 2006. Note: Electronic Article. [PubMed: 17030597] [Full Text: https://doi.org/10.1542/peds.2005-2882]
Buchanan, C. R., Maheshwari, H. G., Norman, M. R., Morrell, D. J., Preece, M. A. Laron-type dwarfism with apparently normal high affinity serum growth hormone-binding protein. Clin. Endocr. 35: 179-185, 1991. [PubMed: 1934534] [Full Text: https://doi.org/10.1111/j.1365-2265.1991.tb03518.x]
Cohen, A. C., Nadeau, K. C., Tu, W., Hwa, V., Dionis, K., Bezrodnik, L., Teper, A., Gaillard, M., Heinrich, J., Krensky, A. M., Rosenfeld, R. G., Lewis, D. B. Decreased accumulation and regulatory function of CD4+CD25(high) T cells in human STAT5b deficiency. J. Immun. 177: 2770-2774, 2006. [PubMed: 16920911] [Full Text: https://doi.org/10.4049/jimmunol.177.5.2770]
Freeth, J. S., Ayling, R. M., Whatmore, A. J., Towner, P., Price, D. A., Norman, M. R., Clayton, P. E. Human skin fibroblasts as a model of growth hormone (GH) action in GH receptor-positive Laron's syndrome. Endocrinology 138: 55-61, 1997. [PubMed: 8977385] [Full Text: https://doi.org/10.1210/endo.138.1.4853]
Hwa, V., Camacho-Hubner, C., Little, B. M., David, A., Metherell, L. A., El-Khatib, N., Savage, M. O., Rosenfeld, R. G. Growth hormone insensitivity and severe short stature in siblings: a novel mutation at the exon 13-intron 13 junction of the STAT5b gene. Horm. Res. 68: 218-224, 2007. [PubMed: 17389811] [Full Text: https://doi.org/10.1159/000101334]
Hwa, V., Little, B., Adiyaman, P., Kofoed, E. M., Pratt, K. L., Ocal, G., Berberoglu, M., Rosenfeld, R. G. Severe growth hormone insensitivity resulting from total absence of signal transducer and activator of transcription 5b. J. Clin. Endocr. Metab. 90: 4260-4266, 2005. [PubMed: 15827093] [Full Text: https://doi.org/10.1210/jc.2005-0515]
Kofoed, E. M., Hwa, V., Little, B., Woods, K. A., Buckway, C. K., Tsubaki, J., Pratt, K. L., Bezrodnik, L., Jasper, H., Tepper, A., Heinrich, J. J., Rosenfeld, R. G. Growth hormone insensitivity associated with a STAT5b mutation. New Eng. J. Med. 349: 1139-1147, 2003. [PubMed: 13679528] [Full Text: https://doi.org/10.1056/NEJMoa022926]
Laron, Z., Klinger, B., Eshet, R., Kaneti, H., Karasik, A., Silbergeld, A. Laron syndrome due to a post-receptor defect: response to IGF-1 treatment. Isr. J. Med. Sci. 29: 757-763, 1993. [PubMed: 8300382]
Laron, Z., Pertzelan, A., Mannheimer, S. Genetic pituitary dwarfism with high serum concentration of growth hormone: a new inborn error of metabolism? Isr. J. Med. Sci. 2: 152-155, 1966. [PubMed: 5916640]
Vidarsdottir, S., Walenkamp, M. J. E., Pereira, A. M., Karperien, M., van Doorn, J., van Duyvenvoorde, H. A., White, S., Bruening, M. H., Roelfsema, F., Kruithof, M. F., van Dissel, J., Janssen, R., Wit, J. M., Romijn, J. A. Clinical and biochemical characteristics of a male patient with a novel homozygous STAT5b mutation. J. Clin. Endocr. Metab. 91: 3482-3485, 2006. [PubMed: 16787985] [Full Text: https://doi.org/10.1210/jc.2006-0368]