Stat3 loss in mesenchymal progenitors causes Job syndrome–like skeletal defects by reducing Wnt/β-catenin signaling

Job syndrome is a rare genetic disorder caused by STAT3 mutations and primarily characterized by immune dysfunction along with comorbid skeleton developmental abnormalities including osteopenia, recurrent fracture of long bones, and scoliosis. So far, there is no definitive cure for the skeletal defects in Job syndrome, and treatments are limited to management of clinical symptoms only. Here, we have investigated the molecular mechanism whereby Stat3 regulates skeletal development and osteoblast differentiation. We showed that removing Stat3 function in the developing limb mesenchyme or osteoprogenitor cells in mice resulted in shortened and bow limbs with multiple fractures in long bones that resembled the skeleton symptoms in the Job Syndrome. However, Stat3 loss did not alter chondrocyte differentiation and hypertrophy in embryonic development, while osteoblast differentiation was severely reduced. Genome-wide transcriptome analyses as well as biochemical and histological studies showed that Stat3 loss resulted in down-regulation of Wnt/β-catenin signaling. Restoration of Wnt/β-catenin signaling by injecting BIO, a small molecule inhibitor of GSK3, or crossing with a Lrp5 gain of function (GOF) allele, rescued the bone reduction phenotypes due to Stat3 loss to a great extent. These studies uncover the essential functions of Stat3 in maintaining Wnt/β-catenin signaling in early mesenchymal or osteoprogenitor cells and provide evidence that bone defects in the Job Syndrome are likely caused by Wnt/β-catenin signaling reduction due to reduced STAT3 activities in bone development. Enhancing Wnt/β-catenin signaling could be a therapeutic approach to reduce bone symptoms of Job syndrome patients.

Hyper IgE syndrome (Job syndrome) in Syria: a case report

ABSTRACT Hyper IgE syndrome (HIES) is a medical condition that can be sporadic or hereditary. It consists of multiple overlapping primary immunodeficiency conditions and is characterized by a classical triad of high immunoglobulin E (IgE) levels, recurrent pneumonia with pneumatocele and recurrent cold skin abscesses from staphylococcus infections. Eosinophilia is also common in HIES patients. HIES is often underdiagnosed in Syria as it cannot be confirmed without genetic testing, which is unavailable across Syria for HIES. We present the first case from Syria of a suspected child with HIES that has some additional distinct features. Other cases in a regional country carried atypical novel mutations, which may indicate that these mutations may exist in Syria as well. However, our case had findings that were not reported with other HIES cases. Determining these genes in the case presented was not possible, and future studies need to overcome this hurdle.

Pulmonary Artery Pseudoaneurysm in Hyper-IgE Syndrome: Rare Complication With Successful Endovascular Management

Hyper-IgE syndrome also known as Job syndrome is characterized by elevation of circulating immunoglobulin (IgE) levels and is usually associated with recurrent bacterial infections of the skin and sinopulmonary tract. Though bacterial pulmonary abscess and pneumatocele formation have been described, pulmonary artery pseudoaneurysm in Job syndrome has not been reported in literature. Our report describes a case of large pulmonary artery pseudoaneurysm in a child with Job syndrome, who presented with massive hemoptysis. Emergent endovascular management was performed with percutaneous coil occlusion of the feeding artery.

Immune Deficiency Diseases

Chapter 14 covers Chediak-Higashi Disease, Chronic Granulomatous Disease, Epidermodysplasia Verruciformis, Familial Mucocutaneous Candidiasis, Griscelli Syndrome Types 1, 2, and 3, Job Syndrome, Mucoepithelial Dysplasia, and Wiskott-Aldrich Syndrome. Each condition is discussed in detail, including dermatologic features, associated anomalies, histopathology, basic defect, treatment, mode of inheritance, prenatal diagnosis, and differential diagnosis.