Oral Tongue Malignancies in Autoimmune Polyendocrine Syndrome Type 1.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) or Autoimmune polyendocrine syndrome type-1 (APS-1) (APECED, OMIM 240300) is a rare, childhood onset, monogenic disease caused by mutations in the Autoimmune Regulator (AIRE) gene. The overall mortality is increased compared to the general population and a major cause of death includes malignant diseases, especially oral and esophageal cancers. We here present a case series of four APS-1 patients with oral tongue cancers, an entity not described in detail previously. Scrutiny of history and clinical phenotypes indicate that chronic mucocutaneous candidiasis and smoking are significant risk factors. Preventive measures and early diagnosis are important to successfully manage this potentially fatal disease.

Disruption of Thrombocyte and T Lymphocyte Development by a Mutation in ARPC1B.

Regulation of the actin cytoskeleton is crucial for normal development and function of the immune system, as evidenced by the severe immune abnormalities exhibited by patients bearing inactivating mutations in the Wiskott-Aldrich syndrome protein (WASP), a key regulator of actin dynamics. WASP exerts its effects on actin dynamics through a multisubunit complex termed Arp2/3. Despite the critical role played by Arp2/3 as an effector of WASP-mediated control over actin polymerization, mutations in protein components of the Arp2/3 complex had not previously been identified as a cause of immunodeficiency. Here, we describe two brothers with hematopoietic and immunologic symptoms reminiscent of Wiskott-Aldrich syndrome (WAS). However, these patients lacked mutations in any of the genes previously associated with WAS. Whole-exome sequencing revealed a homozygous 2 bp deletion, n.c.G623DEL-TC (p.V208VfsX20), in Arp2/3 complex component ARPC1B that causes a frame shift resulting in premature termination. Modeling of the disease in zebrafish revealed that ARPC1B plays a critical role in supporting T cell and thrombocyte development. Moreover, the defects in development caused by ARPC1B loss could be rescued by the intact human ARPC1B ortholog, but not by the p.V208VfsX20 variant identified in the patients. Moreover, we found that the expression of ARPC1B is restricted to hematopoietic cells, potentially explaining why a mutation in ARPC1B has now been observed as a cause of WAS, whereas mutations in other, more widely expressed, components of the Arp2/3 complex have not been observed.

Serum Tumor Necrosis Factor-Alpha Levels in Children with Nephrotic Syndrome: A Pilot Study.

BACKGROUND: Several studies link the pathogenesis of nephrotic syndrome to tumor necrosis factor-alpha (TNFα). However, data on the serum TNFα level in children with nephrotic syndrome are sparse. OBJECTIVES: To investigate serum TNFα levels and the effect of steroid therapy in children with nephrotic syndrome. METHODS: A prospective cohort pilot study of children with nephrotic syndrome and controls was conducted during a 1 year period. Serum TNFα levels were measured at presentation and at remission, or after a minimum of 80 days if remission was not achieved. RESULTS: Thirteen patients aged 2-16 years with nephrotic syndrome were compared with 12 control subjects. Seven patients had steroid-sensitive and six had steroid-resistant nephrotic syndrome. Mean baseline serum TNFα level was significantly higher in the steroid-resistant nephrotic syndrome patients than the controls (6.13 pg/ml vs. 4.36 pg/ml, P = 0.0483). Mean post-treatment TNFα level was significantly higher in the steroid-resistant than in the steroid-sensitive nephrotic syndrome patients (5.67 pg/ml vs. 2.14 pg/ml, P = 0.001). In the steroid-resistant nephrotic syndrome patients, mean serum TNFα levels were similar before and after treatment. CONCLUSIONS: Elevated serum TNFα levels are associated with a lack of response to corticosteroids. Further studies are needed to investigate the role of TNFα in the pathogenesis of nephrotic syndrome.

IL-12 receptor 1ß deficiency with features of autoimmunity and photosensitivity.

Primary immunodeficiences are often accompanied by autoimmune phenomena. IL-12 receptor deficiency is a well characterized primary immunodeficiency that leads to propensity to intracellular infections mainly with mycobacteria and Salmonella. We report on two patients with IL-12 receptor ß1 deficiency that presented with autoimmune manifestations and photosensitivity dermatitis and describe possible pathogenetic mechanisms leading to development of clinically significant autoimmune phenomena.

Primary varicella infection presenting with headache and elevated intracranial pressure.

Primary varicella infection may be associated with neurologic complications, such as cerebritis and meningoencephalitis. Several cases of varicella infection with elevated intracranial pressure have been reported. We describe a 13-year-old immunocompetent girl who presented with a clinical picture of headaches and elevated intracranial pressure as the only manifestation of primary varicella zoster infection. The working diagnosis at first was pseudotumor cerebri based on complaints of headache of 2 weeks' duration, in addition to vomiting and papilledema, without fever or skin eruption. On lumbar puncture, opening pressure was 420 mmH2O, but mild pleocytosis and mildly elevated protein level ruled out the diagnosis of pseudotumor cerebri. Our patient had no history of previous varicella infection, and she did not receive the varicella zoster vaccine. Serology tests, done on admission and repeated 2 months later, suggested primary varicella infection. The literature on varicella infection associated with pseudotumor cerebri or elevated intracranial pressure is reviewed.

Medical And Surgical Management Of Orbital Cellulitis In Children.

OBJECTIVE: The purpose of this study was to identify features of orbital cellulitis that predict response to conservative treatment without surgical intervention and factors associated with a decision for surgery. PATIENTS AND METHODS: The medical files of patients diagnosed with orbital cellulitis at a tertiary medical center in central Israel between 1995 and 2010 were reviewed for clinical data, diagnosis, complications, and type of treatment. Comparison was made between patients treated with antibiotics and patients treated with antibiotics and surgery. RESULTS: Fifty-one patients (35 male) with a mean age of 6.1 years were identified. Main clinical signs included fever (mean 38.5°C), proptosis (82.3%), extraocular motility restriction (74.5%), and ocular pain (41.1%). Forty-one patients were successfully treated with antibiotics and 10 required endoscopic sinus surgery. On between-group comparison, the surgery group had severe eye pain (p = 0.009), severe proptosis (P = 0.02), longer intravenous antibiotic treatment (13.2 vs. 9.2 days, p = 0.04), and several imaging findings. Additional factors associated with surgical intervention included older children, subperiorbital abscess, larger dimension of the abscess (mean 15 mm), involvement of frontal sinuses and findings of intraorbital air bubbles. There was no visual deterioration in either group and no late sequelae. CONCLUSION: Factors associated with surgery included age older than 9 years, severe ocular pain, severe proptosis, and subperiorbital large abscess. These may be used for early identification of patients at risk of failure of only medical management.

Reduced bone density in patients with autosomal dominant hyper-IgE syndrome.

BACKGROUND AND PURPOSE: Autosomal dominant hyper-IgE syndrome (AD-HIES) is a rare primary immunodeficiency disorder . It has been recognized as a multisystem disorder and is characterized by both immunologic and non-immunologic manifestations. Possible bone involvement in autosomal dominant HIES include fractures, scoliosis, cystic bone changes, and osteopenia. We sought to evaluate the changes in bone density in adolescents and young adults with AD-HIES, mostly with proven STAT3 mutation, followed in our institute. METHODS: We studied eight patients with AD-HIES who attended our immunology clinic. All patients underwent at least one bone mass dual-energy x-ray absorptiometry assessment (dual-energy x-ray absorptiometry scan).These findings were evaluated. RESULTS: The age of the patients at the time of their first bone density scan ranged between 10 and 24 years (mean 16.1 ± 4.0 years); the duration of follow-up was 4-11 years (mean 5.8 ± 3.5 years). Four patients had a history of fractures. Mean Z score in these patients was -1.8 ± 0.7. For three patients, Z score was below -1. The other four patients had no history of fractures. Mean Z score in these patients was -0.9 ± 0.5. Only one patient in this group had a Z score below -1. Bone density was below average in all patients; mean spinal Z score was -1.6 ± 0.4. Four patients were followed through the second decade, and all showed progressive deterioration in bone density. Three were treated with alendronate sodium, with improvement in the bone scan results. CONCLUSIONS: Bone density decreases considerably over time in adolescents and young adults suffering from AD- HIES. Treatment with alendronate sodium may be effective in alleviating osteopenia.

Autoimmunity and cystatin SA1 deficiency behind chronic mucocutaneous candidiasis in autoimmune polyendocrine syndrome type 1.

Patients with the monogenic disease autoimmune polyendocrine syndrome type I (APSI) develop autoimmunity against multiple endocrine organs and suffer from chronic mucocutaneous candidiasis (CMC), a paradoxical complication with an unknown mechanism. We report here that saliva from APSI patients with CMC is defective in inhibiting growth of Candida albicans in vitro and show reduced levels of a salivary protein identified as cystatin SA1. In contrast, APSI patients without CMC express salivary cystatin SA1 and can inhibit C. albicans to the same extent as healthy controls. We evaluated the anti-fungal activity of cystatin SA1 and found that synthesized full length cystatin SA1 efficiently inhibits growth of C. albicans in vitro. Moreover, APSI patients exhibit salivary IgA autoantibodies recognizing myosin-9, a protein expressed in the salivary glands, thus linking autoimmunity to cystatin SA1 deficiency and CMC. This data suggests an autoimmune mechanism behind CMC in APSI and provides rationale for evaluating cystatin SA1 in antifungal therapy.

IgM+IgD+CD27+ B cells are markedly reduced in IRAK-4-, MyD88-, and TIRAP- but not UNC-93B-deficient patients.

We studied the distribution of peripheral B-cell subsets in patients deficient for key factors of the TLR-signaling pathways (MyD88, TIRAP/MAL, IL-1 receptor-associated kinase 4 [IRAK-4], TLR3, UNC-93B, TRIF). All TLRs, except TLR3, which signals through the TRIF adaptor, require MyD88 and IRAK-4 to mediate their function. TLR4 and the TLR2 heterodimers (with TLR1, TLR6, and possibly TLR10) require in addition the adaptor TIRAP, whereas UNC-93B is needed for the proper localization of intracellular TLR3, TLR7, TLR8, and TLR9. We found that IgM(+)IgD(+)CD27(+) but not switched B cells were strongly reduced in MyD88-, IRAK-4-, and TIRAP-deficient patients. This defect did not appear to be compensated with age. However, somatic hypermutation of Ig genes and heavy-chain CDR3 size distribution of IgM(+)IgD(+)CD27(+) B cells were not affected in these patients. In contrast, the numbers of IgM(+)IgD(+)CD27(+) B cells were normal in the absence of TLR3, TRIF, and UNC-93B, suggesting that UNC-93B-dependent TLRs, and notably TLR9, are dispensable for the presence of this subset in peripheral blood. Interestingly, TLR10 was found to be expressed at greater levels in IgM(+)IgD(+)CD27(+) compared with switched B cells in healthy patients. Hence, we propose a role for TIRAP-dependent TLRs, possibly TLR10 in particular, in the development and/or maintenance of IgM(+)IgD(+)CD27(+) B cells in humans.

Selective IgA deficiency in children in Israel.

IgA deficiency is the most common human primary immune-deficiency. We evaluated the clinical and immunological characteristics of selective IgA deficiency in children in Israel. The study group included 63 children diagnosed with IgA deficiency from 1987 to 2005. Mean follow-up time per child was 10.6 years. Average age at diagnosis was 10.5 years. In one child, the IgA deficiency was transient. Infectious diseases, mainly recurrent pneumonia and ear infection, were common and occurred in 25 patients (39.7%). Allergic diseases were documented in 20 (31.7%) of our patients. Thirteen children (20.6%) had autoimmune diseases. Malignancies were diagnosed in three children (4.8%), an association that has not been reported in previous series. IgA deficiency appears to be a risk factor for infections, allergic diseases, autoimmune conditions, and malignancy.

Invasive Kingella kingae infections in children: clinical and laboratory characteristics.

OBJECTIVE: Kingella kingae, a Gram-negative coccobacillus, is being increasingly recognized as an invasive pathogen in children, causing mainly bacteremia and arthritis; however, there have been only a few studies on K kingae infections to date, mostly small-scale series. The aim of this study was to report our experience with invasive K kingae infections in children who were hospitalized at a major tertiary medical center in Israel. METHODS: The medical charts of 62 children with proven invasive K kingae infections were reviewed: 42 with positive blood culture results and 20 with positive synovial fluid culture results. RESULTS: Most infections occurred among previously healthy children aged 5 to 22 months. Eighty percent had a mild concurrent illness of the respiratory or gastrointestinal tract. A chronic underlying disease was documented in 19% of the 1- to 15-year-old children with bacteremia. Three patients had persistent bacteremia, identified by 2 positive blood cultures drawn 1 to 4 days apart. Four (10%) patients from the bacteremia group had endocarditis, and 2 required emergency cardiac surgery. Only a mild-to-moderate elevation of serum inflammatory markers was noted except for patients with endocarditis or a prolonged course of arthritis. Patients with bacteremia received a diagnosis significantly later than those with arthritis, with no other between-group differences in age, month of disease onset, and inflammatory marker levels. All K kingae isolates were resistant to vancomycin and clindamycin. CONCLUSIONS: Our large series indicates that invasive K kingae infections occur in previously healthy children, mostly during the first 2 years of life; affected older children usually have an underlying medical condition. The infection generally elicits only a mild inflammatory response unless accompanied by endocarditis. Despite its low virulence, K kingae might cause a life-threatening heart disease that requires emergent, aggressive treatment.

Pulmonary hypertension in an infant with achondroplasia.

An 18-month-old achondroplastic child presented with respiratory distress and severe pulmonary hypertension which was considered to be due to an atrial septal defect. The septal defect was closed via catheterization with Amplatzer occluder device, but the patient showed only mild to moderate clinical improvement. In addition, sleep monitoring study revealed apneas, oxygen desaturation and CO(2) retention; therefore, magnetic resonance imaging of the brain was performed, showing medullary compression by a stenotic foramen magnum. Surgical craniocervical decompression led to an improvement in sleep disturbances and pulmonary hypertension. In conclusion, several factors, among which medullary compression, may be a cause of pulmonary hypertension in achondroplasia patients.

Trends in the prevalence of asthma symptoms and allergic diseases in Israeli adolescents: results from a national survey 2003 and comparison with 1997.

PURPOSE: To investigate the temporal trends in the prevalence of asthma symptoms and allergies in Israeli adolescents. METHODS: A modified version of the International Study of Asthma and Allergies in Childhood questionnaire was administered to a national sample of Jewish and Arab schoolchildren in Israel. The results were compared to a similar survey conducted in 1997. RESULTS: Asthma prevalence was 7.0% in 1997 and 6.4% 2003 respectively (p = 0.1). Wheezing in the past 12 months decreased significantly from 17.9% in 1997 to 13.8% in 2003 (p < 0.001). Allergic rhinitis and atopic dermatitis increased from 9.4% to 10.5%, and from 5.9% to 8.7% respectively. The prevalence of allergic disease remained higher in Jewish compared with Arabs. CONCLUSIONS: The prevalence of asthma symptoms decreased in Israel from 1997 to 2003 while there was an increase in allergic rhinitis and atopic dermatitis.

Universal versus selective iron supplementation for infants and the risk of unintentional poisoning in young children: a comparative study of two populations.

BACKGROUND: Iron continues to be a common cause of poisoning in young children, in part due to its widespread use and easy accessibility. OBJECTIVE: To determine differences in the epidemiology and outcome of unintentional iron ingestion by young children in populations practicing selective (eg, US) versus universal (eg, Israel) iron supplementation to infants. METHODS: All cases of unintentional iron ingestion in children younger than 7 years in a one year period were identified through the poison control center databases of 2 sites (Illinois and Israel). Parameters compared include patient sex and age; type, form, and dose of iron preparation; circumstances and clinical manifestations; management; and outcome. RESULTS: A total of 602 children were identified: 459 in Illinois and 143 in Israel. The majority of Illinois children ingested multivitamin preparations (94%), whereas Israeli children ingested single-ingredient iron preparations (78%) (p < 0.001). Iron doses ingested were higher in Israel (median 14.5 vs 6.6 mg/kg; p < 0.001) but remained within the nontoxic range for most children. No deaths or severe poisonings were reported, and 93% of children in both groups were asymptomatic. The majority of ingestions in both locations were due to unintentional self-ingestion. However, parental miscalculation occurred more frequently in Israel (16%) than in Illinois (1%). CONCLUSIONS: Universal iron supplementation to infants was not associated with a negative impact on the outcome of pediatric unintentional ingestions. Low-dose exposures were safely managed by on-site observation.

Successful treatment of Wolman disease by unrelated umbilical cord blood transplantation.

Wolman disease is a rapidly fatal lysosomal storage disease caused by the complete absence of lysosomal acid lipase activity. We report the cure of an infant with Wolman disease following transplantation of unrelated HLA-mismatched umbilical cord blood-derived stem cells. Umbilical cord blood was chosen as the stem-cell source because of its immediate availability and reduced tendency to cause graft-versus-host disease. The transplantation resulted in restoration of normal acid lipase levels before the onset of permanent end-organ damage. Four years after transplantation, the patient is thriving and has normal levels of acid lipase in peripheral blood cells. To our knowledge, this is the first report of a successful unrelated cord blood transplant in a patient with Wolman disease. Umbilical cord stem cells transplantation can restore acid lipase levels in Wolman disease, and if performed early, can cure the disease.

Acute hemorrhagic edema of infancy associated with herpes simplex type 1 stomatitis.

Acute hemorrhagic edema of infancy is a benign leukocytoclastic vasculitis occurring in children younger than 2 years. The etiology is unknown. Viral or bacterial infections, immunizations, and the use of several medications, mainly antibiotics, may be involved in the pathogenesis. We report the first instance of this disease associated with herpesvirus type 1 stomatitis.

Facial paralysis as a presenting symptom of leukemia.

Facial paralysis may occur as a complication of central nervous system leukemias in children, but it is rarely a presenting symptom. This report describes an 8-month-old child who presented with peripheral facial palsy, failure to thrive, anemia, and otitis media. Antibiotic and steroid treatment led to an improvement in the clinical condition, but not the paralysis. At readmission 3 weeks later, physical examination revealed bluish, firm, palpable masses on the scalp and facial areas, and laboratory and imaging studies confirmed the diagnosis of acute myeloid leukemia. This case should alert physicians to consider hematologic malignancies in children with facial paralysis.

Endocarditis after closure of ventricular septal defect by transcatheter device.

Advances in interventional cardiology have enabled the treatment of severe congenital heart defects without the need for surgery. The percutaneous closure of atrial septal defects and, more recently, ventricular septal defects is considered a safe procedure with fewer complications and less morbidity compared with surgery. We report on a 2-year-old child who developed endocarditis after ventricular septal defect closure with an Amplatzer device. The patient recovered after intravenous antibiotics and anticoagulation. To the best of our knowledge, this is the first report of endocarditis associated with ventricular septal defect closure device insertion.