The clinical hallmarks of STAT5B deficiency are severe growth failure, complete growth hormone insensitivity, and immunodeficiency of variable severity [1].

Growth failure may be observed prenatally, but pregnancy and birth may also be uneventful [2] [3] [4]. With regards to the morphological features of STAT5B deficiency, a prominent forehead and saddle nose have repeatedly been described [3] [5]. Patients may have a high-pitched voice and present truncal obesity [3]. In case of mild immunodeficiency, these may be the only symptoms observed until puberty [4], although imaging studies carried out for unrelated reasons may reveal delayed bone maturation [6] [7]. Late manifestations of STAT5B deficiency include delayed puberty, small genitals, scarce body hair, and irregular menstruation or amenorrhea [4] [8].

Severe immunodeficiency may manifest shortly after birth, when neonates or infants present with respiratory difficulties. Although these difficulties may be overcome, recurrent respiratory infections are to be expected until therapy for STAT5B deficiency is initiated. Microbiological studies aiming at the identification of causal agents frequently demonstrate the presence of opportunistic pathogens typically found in immunocompromised patients, e.g., Streptococcus pyogenes and Pneumocystis jirovecii [3] [8]. The examination of lung biopsy specimens of individual patients revealed lymphoid interstitial pneumonia and idiopathic pulmonary fibrosis [3] [7].

Besides respiratory infections, patients with STAT5B deficiency may contract a broad spectrum of infections of the skin, eyes, gastrointestinal tract, and other organ systems [6]. Autoimmune thyroiditis has been diagnosed in at least one patient, and another one had juvenile idiopathic arthritis [2] [8]. Poor weight gain and failure to thrive may be attributed to a general developmental delay, but these conditions are often aggravated by recurrent infections and complications thereof.

• Recurrent Infection

  Recurrent infections may interfere with the general development of the child and provoke failure to thrive. [symptoma.com]

  Immunodeficiency is characterized by moderate lymphopenia which leads to recurrent infections of the skin and respiratory tract. [orpha.net]

  Here we describe a 16-year-old girl who suffered generalized eczema and recurrent infections of the skin and respiratory tract since birth. She also suffered severe chronic lung disease and multiple episodes of herpetic keratitis. [pediatrics.aappublications.org]

• Asymptomatic

  The ocular form is often found in adults, who show corneal tears and photophobia, but are otherwise asymptomatic. Early detection of the disease can significantly improve prognosis. [centogene.com]

  Nervous system disease H00957 Fleck corneal dystrophy Francois-Neetens speckled corneal dystrophy Fleck corneal dystrophy (FCD) is a rare corneal dystrophy characterized by multiple asymptomatic, non-progressive symmetric minute opacities disseminated [kegg.jp]

  A study of computer assisted tomography: The incidence of positive CAT scans in an asymptomatic group of patients. [tankonyvtar.hu]

• Abdominal Obesity

  A Back to top ABCD syndrome 1 0 Abdominal obesity-metabolic syndrome 1; AOMS1 Metabolic syndrome X 2 0 Abdominal obesity-metabolic syndrome 3; AOMS3 1 0 Abnormal pregnancies 1 0 Absence epilepsy early onset absence epilepsy 2 0 Acatalasemia acatalasia [guidetopharmacology.org]

  5 Obesity, Hyperphagia, And Developmental Delay 2 Obesity, Morbid, Due to Leptin Deficiency 8 Obesity, Morbid, Due to Leptin Receptor Deficiency 8 Obesity, susceptibility to, BMIQ14 1 Obesity, susceptibility to, BMIQ18 1 Obsessive-Compulsive Disorder [preventiongenetics.com]

• Weight Gain

  Poor weight gain and failure to thrive may be attributed to a general developmental delay, but these conditions are often aggravated by recurrent infections and complications thereof. [symptoma.com]

• Chills

  […] occurs due to the decreased amount of immunoglobulin G (IgG) levels in the infant during the three-month stage.[4] This is followed by viral infections such as pneumonitis, an inflammation of the lung which produces common symptoms such as cough, fever, chills [en.wikipedia.org]

• Respiratory Distress

  Severe chronic lung disease, chronic diarrhea, juvenile idiopathic arthritis (see these terms), generalized eczema, pulmonary infections and respiratory distress have already been described. [orpha.net]

  distress Kyphosis Deeply set eye Talipes equinovarus Frontal bossing Smooth philtrum Ptosis Anteverted nares Hypotrichosis Small hand Attention deficit hyperactivity disorder Macrocephaly Exocrine pancreatic insufficiency Short finger Thin vermilion [mendelian.co]

  Distress, And Dysphagia 5 Myopathy, Early-Onset, With Fatal Cardiomyopathy 3 Myopathy, isolated mitochondrial, autosomal dominant 1 Myopathy, Lactic Acidosis, And Sideroblastic Anemia 2 2 Myopathy, Mitochondrial Progressive, With Congenital Cataract, [preventiongenetics.com]

• Dyspnea

  […] administration Short fifth metatarsal Short 3rd metacarpal Subcutaneous calcification Abdominal symptom Hyperphosphatemia Short 4th metacarpal Spinal cord compression Hepatomegaly Joint hyperflexibility Paresthesia Underdeveloped nasal alae Anxiety Dyspnea [mendelian.co]

• Vomiting

  Intermittent hyperventilation Narrow palm Temperature instability Multiple pterygia Abnormality of the philtrum Excessive salivation Hyperinsulinemic hypoglycemia Misalignment of teeth Multicystic kidney dysplasia Flat occiput Pectus excavatum Mitral atresia Vomiting [mendelian.co]

• Severe Short Stature

  Similar articles Growth hormone insensitivity and severe short stature in siblings: a novel mutation at the exon 13-intron 13 junction of the STAT5b gene. [pubmed.ncbi.nlm.nih.gov]

  […] with short stature. [karger.com]

  "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 (5): 218–24. doi:10.1159/000101334. PMID 17389811. ^ "Increlex (mecasermin)". Centerwatch.com. [en.wikipedia.org]

  short stature Dwarfism Proportionate dwarfism Short stature, severe [ more ] 0003510 Truncal obesity 0001956 30%-79% of people have these symptoms Abnormality of the elbow Abnormality of the elbows 0009811 Brachydactyly Short fingers or toes 0001156 [rarediseases.info.nih.gov]

  The novel, predicted damaging homozygous mutation was identified in a child with severe short stature (−4.5 SDS) and IGFD (−4.1 SDS). [eje.bioscientifica.com]

• Long Arm

  STAT5B deficiency is the result of pathogenic mutations of the STAT5B gene, which is located on the long arm of chromosome 17. [symptoma.com]

  B Cell Primary Immunodeficiencies Hypogammaglobulinemia can be associated with chromosomal defects such as trisomy 18 and Jacobsen syndrome (hemizygous deletion of part of the long arm of chromosome 11). [accesspharmacy.mhmedical.com]

  "An infant with deletion of the distal long arm of chromosome 15 (q26. 1-qter) and loss of insulin-like growth factor 1 receptor gene". Am J Med Genet. 1991 ; 38 : 74–9. 28. Wood WI, Cachianes G, Henzel WJ, et al. [annsaudimed.net]

  Children with a deletion of the distal long-arm of chromosome 15, which includes the IGF1R gene, are short [27]. It was assumed that specific mutations/deletions of the IGF1R gene could result in growth retardation. [karger.com]

• Frontal Bossing

  Both had features of GHI as previously described (frontal bossing, mid-facial hypoplasia, height SDS: −3.7 and −4.3, and IGF-1 SDS: −2.8 and −3.4) (Fig. 1A and Supplementary Table 2) (10). [eje.bioscientifica.com]

  bossing Smooth philtrum Ptosis Anteverted nares Hypotrichosis Small hand Attention deficit hyperactivity disorder Macrocephaly Exocrine pancreatic insufficiency Short finger Thin vermilion border Thin skin Hypocalcemia Irritability Osteoporosis Cataract [mendelian.co]

  Their physical appearance was characterized by frontal bossing, depressed nasal bridge, a nasal quality to their speech, micropenis and a general appearance younger than their actual age. [annsaudimed.net]

• Areflexia

  Compton-North 5 Myopathy, Distal, 1 5 Myopathy, Distal, 2 4 Myopathy, Distal, 4 3 Myopathy, distal, 5 2 Myopathy, Distal, Tateyama Type 2 Myopathy, Distal, With Anterior Tibial Onset 4 Myopathy, distal, with rimmed vacuoles 2 Myopathy, Early-Onset, Areflexia [preventiongenetics.com]

The diagnosis of STAT5B deficiency is based on clinical data, the results of laboratory analyses of blood samples, and genetic studies. Concurrent dwarfism and immunodeficiency should raise suspicion as to a genetic disorder, particularly if accompanied by facial dysmorphism as described above [1]. Notwithstanding, clinical findings will rarely prompt anyone to set up straight-forward genetic analyses of the STAT5B gene. What's more, specific analyses of blood samples may be postponed until the patient proves resistant to growth hormone therapy [3] [4]. Standard analyses do not usually show any anomalies, but moderate lymphopenia and hypergammaglobulinemia have been reported [3] [5] [6] [8].

The measurement of serum levels of growth hormone, insulin-like growth factors, and growth hormone-binding protein, a soluble equivalent of the growth hormone receptor, will shed more light on possible causes of the disease: normal to high levels of growth hormone, decreased concentrations of insulin-like growth factors 1 (IGF1) and 2, insulin-like growth factor-binding protein-3 (IGFBP3), and the acid-labile subunit, and growth hormone-binding protein within the reference range point at a post-receptor defect in the growth hormone signaling cascade [9]. Prolactin levels may be elevated [4] [6] [8].

Finally, the diagnosis of STAT5B deficiency can be confirmed if the underlying mutation of the STAT5B gene is identified.

Information regarding the treatment of STAT5B deficiency is scarce. Patients are refractory to growth hormone therapy because the transduction of signals is interrupted downstream of binding to the growth hormone receptor. The administration of insulin-like growth factors may resolve this problem but is unlikely to cover the whole spectrum of growth hormone actions. Recombinant human IGF1 is approved for the treatment of primary IGF1 deficiency, including cases due post-receptor defects in the growth hormone signaling pathway [10]. There are no alternatives to recombinant human IGF1 in the management of STAT5B deficiency. The twice-daily application of 110 µg/kg body weight has been proposed. Unfortunately though, the response to the drug has been poor. It remains to be clarified whether refractoriness to IGF1 is inherent to STAT5B deficiency, or whether it has just been the unfortunate outcome in isolated cases [5].

Lung transplantation has been proposed as a last option in case of irreversible lung disease like pulmonary fibrosis. It has successfully been carried out in at least one patient [5] [8].

Bone marrow transplantation has been suggested as a possible option for cure, but the procedure has never been carried out in patients with STAT5B deficiency [5].

In the absence of IGF replacement therapy, recurrent infections will cause a progressive worsening of the lungs' and other organs' function [3] [6]. Therapy with IGF1 may improve the outcome, but long-term results have yet to be reported, and short-term effects have only been described in very few cases. They have been discouraging: significant improvements in growth velocity could not be observed [5].

STAT5B deficiency is the result of pathogenic mutations of the STAT5B gene, which is located on the long arm of chromosome 17. Distinct types of mutations have been related to growth hormone insensitivity with immunodeficiency, e.g., nonsense, missense, and frameshift mutations, as well as deletions. At least some of them affect the C-terminal SH2 domain of the protein [3] [4] [7] [8], which is required for the recruitment of STAT5B to the activated growth hormone receptor, for its dimerization and subsequent translocation to the nucleus, where it can fulfill its task as a transcription factor [4].

While complete growth hormone insensitivity with immune dysfunction is assumed to be inherited in an autosomal recessive manner, heterozygous carriers of STAT5B mutations are generally shorter than their wild-type relatives and may have reduced serum levels of IGF1 and IGFBP3 [11] [12].

To date, several patients with Laron-like dwarfism, increased concentrations of circulating growth hormone, reduced serum levels of IGF1, and normal activity of the growth hormone receptor have been described [3] [9] [13]. Only occasionally, immunodeficiency has been reported [3] [7]. It thus seems likely these people carried distinct mutations affecting growth hormone signaling [1]. Growth hormone insensitivity with immunodeficiency has not been related to STAT5B deficiency until 2003, so we are looking at a rather short period of time where epidemiological data on this disease could be collected. In the last 15 years, about ten case reports have been published [1] [14]. Both males and females may be affected, and several individuals diagnosed with STAT5B deficiency were born to consanguineous parents [2] [3] [6] [7].

The growth hormone - IGF1 signaling cascade may be interrupted at distinct points [1]:

• Binding of growth hormone to the growth hormone receptor
• Intracellular signal transduction
• Synthesis of insulin-like growth factors
• Transport/bioavailability of insulin-like growth factors
• Binding of insulin-like growth factors to their receptors

The pathogenetic mechanisms underlying STAT5B deficiency affect the intracellular signaling cascade activated upon binding of growth hormone to a functional receptor. Some effects of growth hormone may be exerted by means of MAP kinase, ERK1, and ERK2, PI3 kinase - PKB signaling, or the activation of other members of the STAT family of transcription factors, but STAT5B is considered the key mediator of growth hormone actions [1] [3]. Signal transduction via STAT5B induces the transcription of genes IGF1, IGFBP3, and IGFALS [2], which explains why the serum levels of the respective gene products are all diminished in patients with STAT5B deficiency.

Furthermore, STAT5B is implicated in immunological processes. In patients with STAT5B deficiency, moderate lymphopenia with lack of CD3+, CD4+, and CD8+ T cells, CD4+/CD25+ regulatory T cells, γδ T cells, and NK cells has been described [15]. Available T cells are functionally defective and poorly respond to stimulation via the T-cell receptor or interleukin-2 receptor. Additionally, STAT5B deficient T cells are chronically hyperactivated, and this condition has been associated with a predisposition for autoimmune diseases. It may be due to defective interleukin-2 signaling and cause autoimmune thyroiditis or juvenile idiopathic arthritis, among other disorders of peripheral tolerance [2] [6] [8].

Affected families may benefit from genetic counseling. But even in the absence of a positive family history, a genetic evaluation is recommended if children are small for their gestational age, and postnatal catch-up growth is not observed either, if those with a short stature present dysmorphic features or evidence of skeletal dysplasia, or if growth retardation is severe [1].

Laron syndrome is a rare genetic disorder caused by mutations of the GHR gene, which encodes for the growth hormone receptor. It has first been described by Laron et al. in 1966 and is also referred to as growth hormone insensitivity syndrome [16]. The clinical hallmark of Laron syndrome is dwarfism; additional features are blue sclerae, delayed bone maturation, midfacial hypoplasia, limited elbow extension, hip dysplasia, and truncal adiposity. In affected individuals, the production of growth hormone is unaltered, but due to functional deficits of the hormone's receptor, it cannot exert any effect, and the synthesis of IGF1 is not induced. Accordingly, the secretion of growth hormone by the pituitary gland is not inhibited, and the serum level of growth hormone is permanently increased [17].

In 1991, Buchanan and colleagues reported three siblings presenting symptoms characteristic of Laron syndrome [13]. The analyses of blood samples obtained from these children revealed high levels of growth hormone and reduced concentrations of IGF1. However, the activity of the growth hormone receptor was within reference ranges in all cases, which is in contrast to what had been described for classical Laron syndrome. These findings led the authors to suggest a related, yet different genetic disorder that interfered with the growth hormone - IGF1 signaling cascade at a downstream point.

Immunodeficiency has not been related to Laron-like dwarfism until Kofoed et al. described an adolescent girl with growth failure and recurrent respiratory infections [3]. The patient did not respond to growth hormone therapy and was subsequently found to be homozygous for a missense mutation of the STAT5B gene. Upon binding of growth hormone to its receptor, STAT5B should be activated and induce the transcription of the IGF1 gene, thereby initiating the transmission of negative feedback to the pituitary gland. Failure of this mechanism explains the anomalies in serum levels of growth hormone and IGF1, very much as in Laron syndrome. But STAT5B is a transcription factor involved in the regulation of several other processes, such as T-cell receptor signaling [14]. Therefore, affected individuals suffer from growth hormone insensitivity with immune dysfunction, a condition that is also known as Laron syndrome with immunodeficiency or STAT5B deficiency.

Laron syndrome with immunodeficiency is a rare genetic disorder. It may also be referred to as growth hormone insensitivity with immune dysfunction or STAT5B deficiency, whereby the latter term derives from the cause of the disease: Affected individuals carry mutations of the STAT5B gene, which encodes for a transcription factor involved in the transduction of growth hormone-mediated signals and in T-cell signaling. Accordingly, the clinical hallmarks of the disorder are growth failure and recurrent infections.

Growth failure may manifest before birth but certainly becomes apparent during childhood. Patients may present dysmorphic facial features, including a prominent forehead and saddle nose, and truncal obesity. They are prone to infections and frequently suffer from respiratory disorders. They may require hospitalization and entail irreversible lung damage. Some patients tend to develop generalized eczema due to skin infections, visual impairment due to infections of ocular tissues, or diarrhea as a result of infectious gastroenteritis. Recurrent infections may interfere with the general development of the child and provoke failure to thrive. Additional symptoms of STAT5B deficiency manifest during the second decade of life and consist in delayed puberty, small genitals, scarce body hair, and irregular menstruation or amenorrhea.

The diagnosis of STAT5B deficiency requires clinical suspicion, laboratory analyses of blood samples, and genetic studies. The disease is very rare - only ten cases have been described to date -, so that it is not usually put on the list of differential diagnoses. Notwithstanding, the measurement of serum levels of growth hormone and related mediators may point in the right direction. The identification of the underlying mutation of the STAT5B gene confirms the diagnosis.

Treatment options are very limited. Patients have been treated with recombinant insulin-like growth factor 1, a drug that may possibly fulfill part of the functions of growth hormone, but responses have been poor. There are no effective alternatives.

Data regarding the long-term outcome of Laron syndrome with immunodeficiency are not available.

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