the hyperimmunoglobulin e ( hyper - ige ) syndromes were initially described as a single entity 
job syndrome  in 1966 in two girls who presented with recurrent cold staphylococcal abscesses , severe eczema , recurrent bronchopulmonary infections , and elevated serum ige .
generally , the hyper - ige syndromes were thought of as primary immunodeficiency diseases and could be grouped into three general categories : autosomal dominant ( ad ) , autosomal recessive ( ar ) , and sporadically occurring .
autosomal dominant hyperimmunologlobulin e syndrome is characterized by a mutation in the stat3 gene and is associated with the classical picture of immunodeficiency as well as non - immunological features including characteristic facial features , retained primary teeth , hyperextensibility , recurrent pathological fractures , and scoliosis .
autosomal recessive hyperimmunoglobulin e syndrome is a distinct disease entity characterized by more severe viral infections and neurological manifestations and without the skeletal or dental abnormalities seen in their autosomal dominant counterparts .   in general , non - immunological manifestations of hyperimmunoglobulin e syndrome
do not appear until well into childhood , but are almost always present after the age of 8 .
a three and a half year old boy was referred to pediatric infectious disease clinic with a history of asthma , environmental allergies , multiple lung infections , long bone fractures , and hand - foot - mouth disease , for evaluation of recurrent skin abscesses and bullae . by the time of evaluation in pediatric infectious disease clinic
a , referral to genetics had already been initiated to evaluate the child for osteogenesis imperfecta because of the history of recurrent long bone fractures . according to the patient s mother
, the abscesses and bullae usually occurred on the face and were generally of rapid onset .
most often , they began as a pimple on the cheek in the morning and progress forming large mildly erythematous bullae by the afternoon .
the mother first noticed very bad lesions on the patient s face as a small infant , initially attributing these lesions to bad baby acne ; however , the complexion was much worse than her other children , as well as other children who she knew . additionally ,
the patient also experienced multiple , severe blisters over the leg when a cast was removed due to a distal tibia fracture . additionally , approximately one and a half months prior to evaluation the patient was admitted to an outside hospital for recurring bullae on the medial aspect of the left foot .
these bullae were surgically debrided and the fluid expressed was cultured , revealing budding yeast .
the patient had a similar infection when he was three years old . at that time
the patient was the product of a 37 week 2 day uncomplicated pregnancy , but was hospitalized in the nicu for ten days , requiring mechanical ventilation secondary to pulmonary edema .
a review of the patients past medical history revealed a combination left tibia and fibula fractures at age 21 months , a combination left radius and ulna fracture at 29 months , and a fracture of the left tibia at 41 months .
laboratory studies obtained from the outside hospitalization revealed a white blood cell count of 11.4 cell / cm , hemoglobin of 12.0 g / dl , and platelets of 385,000 cell / cm .
the differential demonstrated 52% lymphocytes , 5% monocytes , 11% eosinophils , 31% neutrophils , and 1% basophils .
the erythrocyte sedimentation rate ( esr ) and c - reactive protein ( crp ) were both normal .
a biopsy of the debrided tissue on his left foot revealed dermal changes consistent with a hypersensitivity reaction to a fungal infection .
the subtyping of igg were within normal limits , igg1 of 894 mg / dl , igg2 of 164 mg / dl , igg3 of 17 mg / dl , and igg4 of 133 mg / dl , with a normal antibody response to the diptheria toxoid and tetanus toxoid and t and b cell subtypes were normal .
partial immunizations had been given to date and the patient history revealed allergies to sulfa drugs , eggs , and some wheat products by skin test .
his family history was significant for a paternal grandmother with cvid and asthma , asthma and allergies on the paternal side , and the patient s mother and maternal grandmother had systemic lupus . on physical exam , in pediatric infectious disease clinic at the university of michigan ,
the height was in the 89 percentile , the weight is in the 96 percentile , and he appeared as a playful young boy in no apparent distress . there were multiple small , non - erythematous , hard papules over the cheeks and bridge of his nose .
no blue tint of hue was noted in the sclera and the pupils were equal round and reactive to light .
the abdomen was soft , non - tender , non - distended with no hepatosplenomegaly .
the medial aspect of the left foot had new granulation tissue with a lesion approximately 3 cm by 4 cm from a previous bulla .
muscle mass , strength and tone were within normal limits and the joints were not hyper - extensible .
laboratory studies obtained from pediatric infectious disease clinic revealed an immunoglobulin panel with an iga level of 214 mg / dl ( normal 15 - 160 mg / dl ) , igg level of 1260 mg / dl ( normal 405 - 1160 mg / dl ) , igm level of 117 mg / dl ( normal 40 - 190 mg / dl ) , and an ige level of > 10,000 ku / l ( normal 0 - 150
the subtyping of igg were within normal limits , igg1 of 947 mg / dl , igg2 of 92 mg / dl , igg3 of 18.3 mg / dl , and igg4 of 42 mg / dl , with a normal antibody response to the rubella .
a ch50 level was normal at 101 units ( normal 52 - 128 units ) .
the esr and crp were normal and a gram stain and culture from the left foot were negative .
this patient was referred to the pediatric infectious diseases and immunology service at the university of michigan , with suspected osteogenesis imperfecta ( oi ) , for evaluation of the immune system due to a history of frequent infections .
oi is a rare genetic disorder ( 85 - 90% autosomal dominant ) caused by a mutation in one of the type i collagen genes .
type i collagen is an important component of the bone matrix and collagen homeostasis is important for both bone and connective tissue integrity .
clinical findings in conjunction with the multiple fractures include loose joints and muscle weakness blue sclera , triangular face , brittle teeth , hearing loss , short stature , barrel - shaped rib cage , respiratory problems , underdeveloped lungs , spinal curvature , coxa vera , and extremely poor skeletal mineralization , none of which were present in this patient . de novo mutations in col1a1 or col1a2 account for a majority of the cases of oi which can be confirmed by molecular genetic testing or collagen biopsy analysis .
while frequent fractures and a variety of collagen related problems are characteristic of oi , recurrent infections and susceptibility to staphylococcus aureus and candida species are not .
however , infections with both organisms as well as frequent fractures can be found in patients with hyperimmunoglobulin e syndrome .
attempts have been made to establish diagnostic criteria for hyper - ige , many of which utilize non - immunologic factors as guides .
an nih scoring system consists of 20 different characteristics and assigning a varying number of points to each fulfilled criteria has been proposed . using this system ,
scores of greater than 40 out of a theoretical maximum of 109 made the diagnosis more likely and scores less than 20 made the diagnosis less likely .
relying on non - immunologic factors to aid in diagnosing hyperimmunoglobulin e syndrome presents a unique challenge to early detection in childhood , because many skeletal features such as scoliosis and characteristic facial features occur with disease progression rather than with initial symptoms .
there have been many reports of this disorder being undiagnosed or misdiagnosed as osteogenesis imperfecta , ehlers - danlos syndrome , medication non - compliance , and non - accidental trauma , particularly in the young patient .
the nih scoring system that has been utilized in many studies has an age correction factor to address this very issue , early diagnosis is difficult .
the patient , presented in the case report , would have a score of 37 on presentation to the pediatric infectious diseases clinic ( table 1 ) .
because of the unusual cutaneous manifestations of yeast serum ige levels were obtained [ > 10,000 ku / l ( normal 0 - 150 ku / l ) ] increasing the nih score to 47 increasing the likelihood of a diagnosis of hyper - ige syndrome .
genetic testing was performed by confirming a mutation in stat 3 and a diagnosis of autosomal dominant hyper - ige syndrome .
these patients have less skeletal and dental involvement but are more susceptible to viral infections such as severe molluscum contagiosum . in a recent review of 100 patients ,
the most frequent manifestations , characteristic face ( 82.8% ) , failure to shed deciduous teeth ( 69% ) , and lung cyst formation ( 68% ) were not present in our patient , likely because he was too young to do so . however , frequent pathologic fractures was present in our patient , but was seen in only 34% of the cohort studied ( table 2 ) .
the nih scoring system still represents a means of prioritizing the diagnostic evaluation of a patient with frequent fractures .
 we present a case of hyperimmunoglobulin e ( hyper - ige ) syndrome in a three year old boy . 
 there are many pitfalls in diagnosing this disease in the very young population , mainly due to the ambiguity of some diagnostic criteria in this population . recognizing this syndrome early in life 
 can potentially be very beneficial to the patients involved and the medical system as a whole . 
 early diagnosis can lead to fewer diagnostic tests , fewer referrals , and more focused exams , thus potentially reducing medical cost while also reducing the number of serious infections later in life , including those which are potentially fatal . 
 additionally , a wellknown association between lymphoma and hyper - ige syndrome has been established ; while no recommendations are currently in place for screening , early diagnosis could help medical providers have a higher threshold for diagnosis of this disease . 
Introduction
Case Report
Discussion