Hyper-IgE Recurrent Infection syndrome

What is Hyper-IgE Recurrent Infection syndrome?

Once known as Job syndrome, this rare disease can affect multiple systems and parts of the body, but mainly affects the immune system. This triggers recurrent infections in affected individuals. Inflammation and pneumonia being the most common medical conditions triggered by a compromised immune system. Frequent infections can have an impact on other parts and systems of the body too, triggering other health conditions.

To date it is believed to occur in less than 1 million people globally, making it very rare.

This syndrome is also known as:
Buckley syndrome Hies, Autosomal Dominant Hyper IgE syndrome Hyper-ige Syndrome, Autosomal Dominant Job Syndrome

What gene changes cause Hyper-IgE Recurrent Infection syndrome?

Changes in the STAT3 gene are responsible for most of the cases of this syndrome. It is inherited in an autosomal dominant pattern.

In the case of autosomal dominant inheritance just one parent is the carrier of the gene mutation, and they have a 50% chance of passing it onto each of their children. Syndromes inherited in an autosomal dominant inheritance are caused by just one copy of the gene mutation.

The following genes IL6R, IL6ST, DOCK8 and ZNF341 are linked to autosomal recessive variants of the syndrome.

Autosomal recessive inheritance means an affected individual receives one copy of a mutated gene from each of their parents, giving them two copies of a mutated gene. Parents, who carry only one copy of the gene mutation will not generally show any symptoms, but have a 25% chance of passing the copies of the gene mutations onto each of their children.

What are the main symptoms of Hyper-IgE Recurrent Infection syndrome?

The main symptoms are frequent infections, including pneumonia and inflammation. Recurrent pneumonia can also cause air-filled cysts to develop in the lungs. While constant and repeating inflammation can cause damage to body tissue. Recurrent skin infections are also triggered by the syndrome, and specifically eczema.

Skeletal abnormalities are also a common feature of this syndrome, including scoliosis, a reduction in bone density also features, and individuals may be more susceptible to bone fractures. Individuals may also experience symptoms that affect their teeth, particularly the failure of baby or first teeth to fall out when they should.

Other possible symptoms include heart abnormalities, brain abnormalities (that do not impact on intellectual and cognitive ability and or functioning) and unique facial features.

Possible clinical traits/features:
Lymphoma, Joint hypermobility, Abnormal eosinophil morphology, Osteopenia, Hypertelorism, High palate, Increased circulating IgE level, Gingivitis, Wide nose, Cellulitis, Atelectasis, Abnormality of the nose, Abnormal fingernail morphology, Abnormality of temperature regulation, Dilatation, Abnormal blistering of the skin, Coarse facial features, Cleft palate, Delayed eruption of teeth, Eczematoid dermatitis, Eosinophilia, Deeply set eye, Craniosynostosis, Otitis media, Persistence of primary teeth, Paronychia, Osteomyelitis, Autosomal dominant inheritance, Skin rash, Pruritus, Frontal bossing, Prominent forehead, Recurrent fungal infections, Scoliosis, Recurrent Staphylococcus aureus infections, Recurrent fractures, Recurrent sinopulmonary infections, Reduced bone mineral density, Skin ulcer

How does someone get tested for Hyper-IgE Recurrent Infection syndrome?

The initial testing for Hyper-IgE Recurrent Infection syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.

Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing

Medical information on Hyper-IgE Recurrent Infection syndrome

This syndrome has as its main features recurrent, severe, cutaneous and pulmonary staphylococcal infections, chronic eczema, eosinophilia and high levels of IgE. A newborn rash, often mistakenly called atopic dermatitis is frequent (Eberting et al., 2004). Many, but not all of these patients have dysmorphic facial features which include coarse facial features, a prominent jaw (prognathism) and poorly formed external ears. Grimbacher et al., (1999) provide a good review of the condition, and examples of the 'characteristic face' which are not convincing. Autosomal dominant and recessive inheritance have been postulated, although Grimbacher et al., (1999) favour the former. Marked osteoporosis involving the vertebral bodies is a common finding. A defect in granulocyte chemotaxis is one of the variable immunological findings, but it should be noted that hyper-IgE is probably very heterogeneous. The syndrome named after Job is similar, but in general it is said to affect girls with red hair (is this really true ?) who have persistent eczema and cold staphylococcal abscesses. Grimbacher et al., (1999) mapped the gene to 4q in dominant pedigrees. Retinal detachment and keratoconus have been reported (Arora et al., (2009).
The condition is well reviewed by DeWitt et al., (2006). Note the case reported by Walsh and Reardon (2008) with fractures and mistaken for non-accidental injury. The oral manifestations (deep fissures of the tongue and buccal mucosa, diffuse palatal fibrotic bands and nodules, retention of primary teeth) are reviewed by Freeman et al., 2009). An association with Coeliac disease has been reported (Zeyrek et al., 2009).
Two sibs with the hyper IgE syndrome were reported by Sagiv-Friedgut et al., (2007). Father had the same condition. Both sibs had patent ductus venosus ( a shunt from the fetal umbilical vein to the inferior vena cava). Spontaneous closure of the ductus is the rule in normal infancy. Sibs with this latter anomaly have been reported before (see Sagiv-Friedgut et al., 2007). The parents were non-consanguineous. A patient reported by Fuller et al., (2007) had in addition deficiencies of IgA and IgG. There was bilateral webbing between the thumb and index finger. Note the association with a cervical rib and natal teeth (Roshan et al., 2009).
Mutations have now been found in STAT3 and this includes the original Job patient (Renner et al., 2007, Holland et al., 2007). Another STAT3 mutation was found in a patient (Beitzke et al., 2011), The patient was said to have features compatible with Dubowitz syndrome (growth retardation, microcephaly and eczema).
Velayos et al. (2017) described a female patient with heterozygous mutations in the STAT3 gene. Clinical characteristics included neonatal diabetes mellitus with detectable islet autoantibodies, neonatal hypothyroidism with positive thyroid autoantibodies, gastritis and colitis.
Arora et al. (2017) described gastrointestinal characteristics of 70 patients with heterozygous STAT3 mutations. Clinical characteristics included gastroesophageal reflux (41%), dysphagia (31%), abdominal pain (24%), food impaction (13%) and colonic perforation (6%). Most frequent radiological findings were diffuse esophageal wall thickening (74%), solid stool in the right colon (50%), and hiatal hernia (26%). Esophagogastroduodenoscopy performed in 23 patients showed tortuosity (35%), esophageal ulceration (17%), esophageal strictures requiring dilation (9%), and gastric ulceration (17%). Biopsy pathology was done in 49 patients and showed esophageal eosinophilic infiltration in 65%.

* This information is courtesy of the L M D.
If you find a mistake or would like to contribute additional information, please email us at: [email protected]

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