Jacov Levy

Clinical spectrum of X-linked hyper-IgM syndrome

We report the clinical and immunologic features and outcome in 56 patients with X-linked hyper-IgM syndrome, a disorder caused by mutations in the CD40 ligand gene. Upper and lower respiratory tract infections (the latter frequently caused by Pneumocystis carinii), chronic diarrhea, and liver involvement (both often associated with Cryptosporidium infection) were common. Many patients had chronic neutropenia associated with oral and rectal ulcers. The marked prevalence of infections caused by intracellular pathogens suggests some degree of impairment of cell-mediated immunity. Although lymphocyte counts and in vitro proliferation to mitogens were normal, a defective in vitro proliferative response to antigens was observed in some patients, and additional defects of cell-mediated immunity may be presumed on the basis of current knowledge of CD40-ligand function. All patients received regular infusions of immunoglobulins. Four patients underwent liver transplantation because of sclerosing cholangitis, which relapsed in there. Three patients underwent bone marrow transplantation. Thirteen patients (23%) died of infection and/or liver disease. X-linked hyper-IgM syndrome, once considered a clinical variant of hypogammaglobulinemia, is a severe immunodeficiency with significant cellular involvement and a high mortality rate.

Nerve Growth Factor-Tyrosine Kinase A Pathway Is Involved in Thermoregulation and Adaptation to Stress: Studies on Patients with Hereditary Sensory and Autonomic Neuropathy Type IV

Hereditary sensory and autonomic neuropathy type IV (HSAN IV) is caused by mutations in the tyrosin kinase A (TrkA) gene, encoding for the high-affinity receptor of nerve growth factor (NGF). The NGF-TrkA system is expressed in many endocrine glands. We hypothesized that HSAN IV represents a natural model for impaired NGF effect on the neuroendocrine system in humans. We have documented the clinical outcome of 31 HSAN IV patients in a single medical center, and investigated their basal endocrine system status. The endocrine system response to thirst was compared between six patients and six healthy children. High rates of mortality (22%) and severe morbidity (30%) have been found in HSAN IV patients. Hypothermia was noted in 40% of the patients and unexplained fever was observed in 56%. Subnormal adrenal function was demonstrated in six (30%) of the patients studied. Furthermore, we found lower plasma norepinephrine (NE) levels in six HSAN IV patients compared with a control group after the thirst test. Our findings emphasize the importance of NGF-TrkA pathway in the physiology of the neuroendocrine system and its response to stress. Inadequate response to stress might contribute to the observed significant mortality, morbidity, and temperature instability in HSAN IV patients.

Decreased first phase insulin response in children with congenital insensitivity to pain with anhidrosis.

Nerve growth factor (NGF) and its receptor tyrosine kinase A (TrkA) participate in endocrine pancreas morphogenesis and insulin secretion in vitro. Mutations in the TrkA gene cause the syndrome of congenital insensitivity to pain with anhydrosis (CIPA). We hypothesized that CIPA may represent a natural model for impaired NGF effect on insulin secretion in humans. Glucose challenge tests were performed in seven children with CIPA. We calculated the first phase insulin response (FPIR), the second phase insulin response (SPIR) and glucose disposal rate. FPIR was impaired in four and borderline in two patients. SPIR and glucose disposal rate were within the normal range. Oral glucose tolerance test was normal in all patients. Low FPIR in. CIPA suggests for the first time that the NGF-TrkA pathway may play a role in insulin secretion in response to glucose challenge in humans. Additional studies on the clinical significance of NGF-TrkA effects on insulin secretion are required.

Morbidity characteristics of patients with congenital insensitivity to pain with anhidrosis (CIPA)

Abstract Background: Congenital insensitivity to pain with anhidrosis (CIPA) is a congenital autonomic sensory neuropathy. In southern Israel, there are many patients with this disease. We here tried to characterize the different infections acquired by children with CIPA. Methods: We collected all the available data about CIPA patients in southern Israel in the year 1991–2005, including the lesion types, area in the body where the infection occurs, and the treatment given. Results: The current study included 30 children with CIPA, out of 44 known CIPA patients in southern Israel (68.2%). A total of 382 different episodes of infections, fever, orthopedic lesions, and jaw and mouth lesions led our patients to our outpatient clinic or resulted in hospitalization. Conclusion: We found that children with CIPA mainly have infections of the skin and skeleton, and that the most frequent pathogen is Staphylococcus aureus. We also found that a fair amount of these pathogens are resistant to conventional treatment regimens.

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

Abstract 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 β1 deficiency that presented with autoimmune manifestations and photosensitivity dermatitis and describe possible pathogenetic mechanisms leading to development of clinically significant autoimmune phenomena.

CLINICAL AND MOLECULAR FEATURES OF X-LINKED IMMUNODEFICIENCY WITH HYPER-IgM: A EUROPEAN SURVAY 5

X-linked immunodeficiency with hyper-IgM (XHIM) is a rare primary disorder of immunity that is caused by mutations affecting the expression of CD40 ligand (CD40L) on T lymphocytes. With the purpose of improving our knowledge on the biology of this disease, a European Registry of CD40L mutations(CD40Lbase) has been recently established that collects information on molecular, immunological and clinical aspects of XHIM. Fifty-six XHIM patients from 47 European families have been entered in the database. Analysis of collected data shows that mutations are widely scattered along the CD40L gene although not evenly distributed, most mutations being located in the TNF homology, extracellular domain. Missense mutations are more common than nonsense or frameshift aberrations. Clinically, most XHIM patients with defined mutation have a clinical history of multiple and often severe infections from bacterial opportunistic pathogens; upper and lower respiratory tract infections are particularly common, and 43% of patients with an early onset of the disease present with interstitial pneumonia by Pneumocystis carinii. One third of the patients experience chronic, watery diarrhoea that results in failure to thrive and may require total parenteral nutrition. Chronic inflammation and/or carcinomas of the liver, pancreas and biliary tree are observed in about 20% of the patients. The most commonly reported hematological abnormality in XHIM patients is chronic neutropenia that is typically associated to oral ulcers. Immunological findings include normal B and T cell counts, but markedly decreased serum levels of IgG, IgA, and IgE. IgM levels are normal in 50% of XHIM patients at the time of diagnosis; about 70% of patients, however, develop high levels of IgM later in life. In vitro proliferative responses to mitogens are usually normal, whereas impairment of responses to T-cell dependent stimuli (i.e. tetanus toxoid) is often observed. The inadequacy of XHIM patients immunity accounts for the overall poor prognosis of this disease. Death usually occurs because of severe infections early in life, whereas, after the first decade, XHIM patients more often succumb to severe liver disease or cancer. Current survival rate for XHIM patients at 25 years is only 20%. For this reason allogeneic bone marrow (BMT) from HLA-identical siblings is now indicated and has proven successful applied. BMT from HLA-matched unrelated donors has also recently achieved positive results. For patients who lack HLA-identical bone marrow donors the recommended treatment is based on antibiotic prophylaxis with trimethoprimsulfamethoxazole, regular infusions of intravenous immunoglobulins and careful monitoring of liver complications and cancer.

CHOLANGIOPATHY AND HEPATOBILIARY CANCER IN X-LINKED IMMUNODEFICIENCY WITH HYPER-IGM (XHIM). • 55

CHOLANGIOPATHY AND HEPATOBILIARY CANCER IN X-LINKED IMMUNODEFICIENCY WITH HYPER-IGM (XHIM). • 55