Hyper IgM syndrome is a heterogeneous group of immune defects characterized by normal or increased production of IgM contrasting with a marked decrease or an absence of other isotypes (i.e., IgG, IgA, and IgE). The humoral immunodeficiency results in susceptibility to bacterial infections particularly affecting the respiratory tract. Patients with HIGM often present infections by opportunistic intracellular pathogens, such as Pneumocystis carinii[10, 15], Cryptosporidium species
, Toxoplasma gondii, and Mycobacteria species
. A common complication of both clinical and subclinical infections is represented by cholangiopathy, which may lead to the development of liver function tests alterations, sclerosing cholangitis, and cirrhosis that may eventually result in cholangiocarcinoma
. Chronic intestinal cryptosporidiosis may lead to weight loss, persistent diarrhea, and failure to thrive. Significant neurologic complications, such as cerebral toxoplasmosis
[19, 20] and cryptococcosis
, are seen in 10-to-15% of affected males. Disseminated cytomegalovirus infection may be observed as presenting sign
. Moreover, neutropenia may often complicate CD40-ligand deficiency, while autoimmune complications are relatively common in patients with defects of CD40 signalling. Malignancies may also occur in patients with HIGM and usually affect the biliary tree
[9, 16] and the gastrointestinal tract in the form of neuroendocrine tumours
. As in other immunodeficiencies, patients also have an increased risk for lymphomas, particularly Hodgkin's disease associated with Epstein-Barr virus infection
[24, 25]. Indeed, AID deficiency causes the most frequent autosomal recessive alteration of CSR. Marked lymphoid hypertrophy represent a clinical feature of AID deficiency, even though malignant lymphoproliferation has not been ever described. Nevertheless, knock out mice for the UNG gene are prone to B cell lymphomas
. Furthermore, lymphomas are common in forms of HIGM due to DNA repair defects such as Ataxia-telangiectasia and Nijmegen Breakage syndrome. Allogeneic hematopoietic cell transplantation can be curative and feasible for the X-linked forms of HIGM without severe cryptosporidial infection and its related complications. If available, transplantation from either an HLA-matched sibling or an HLA-matched unrelated donor can be performed safely
Mutations in five different genes involved in CSR have so far been associated with HIGM. X-linked forms are due to alterations of CD40-ligand and NEMO genes, while autosomal recessive forms are associated with mutations in CD40, AID, and UNG genes. The first recognized and most frequent form of HIGM, accounting for at least 70% of patients with CSR, is CD40-ligand deficiency
[28, 29]. Up to now, alterations of NEMO have been excluded in our patient, while mutations in AID and UNG genes have not. However, we are planning to search for these genetic alterations in the near future.
Specialist referral to diagnose CSLD/bronchiectasis is recommended for children who have either two or more episodes of chronic wet cough per year, or chest radiographic abnormalities persisting for at least 6 weeks after appropriate therapy
. In previous large series, the majority of cases of CSLD appeared associated to extrinsic factors, especially childhood respiratory infections (severe pneumonia, pertussis, complicated measles and tuberculosis) that caused chronic endobronchial suppuration with or without bronchiectasis. Singleton et al. reviewed the case histories of 46 Alaskan native children with bronchiectasis born in the 1970s, and concluded that recurrent pneumonia was the major preceding medical condition leading to bronchial damage
. In a study by Eastham et al., previous pneumonia was the most common cause found in 93 cases of non-CF bronchiectasis
. Likewise, nearly 50% of children were found to have developed bronchiectasis after tuberculosis or severe pneumonia in a review study by Karakoc et al.
. Nowadays, with early immunization and the widespread use of antibiotics in childhood, post-infectious damage is likely to be less relevant than in non-vaccinated children
. Nonetheless, detailed investigations must be carried out to determine the underlying cause of the condition
. In CSLD, type, extent and severity of lung changes is evaluated by chest imaging techniques, including HRCT or magnetic resonance imaging
Our case report highlights the importance to search for noninfectious extrinsic insults or intrinsic defects that predispose to bronchial inflammation or infection resulting in CSLD. These must include aspiration of irritants and congenital disorders, as immunodeficiencies and ciliary defects
[37–39]. The identification of the underlying disorder is mandatory in that a delayed diagnosis is associated with more severe disease
Written informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.