Hematopoietic stem cell transplantation for progressive combined immunodeficiency and lymphoproliferation in patients with activated phosphatidylinositol-3-OH kinase δ syndrome type 1.

BACKGROUND: Activated phosphatidylinositol-3-OH kinase δ syndrome type 1 (APDS1) is a recently described primary immunodeficiency syndrome characterized by recurrent respiratory tract infections, lymphoid hyperplasia, and Herpesviridae infections caused by germline gain-of-function mutations of PIK3CD. Hematopoietic stem cell transplantation (HSCT) can be considered to ameliorate progressive immunodeficiency and associated malignancy, but appropriate indications, methods, and outcomes of HSCT for APDS1 remain undefined. OBJECTIVE: Our objective was to analyze the clinical manifestations, laboratory findings, prognosis, and treatment of APDS1 and explore appropriate indications and methods of HSCT. METHODS: We reviewed retrospectively the medical records of cohorts undergoing HSCT at collaborating facilities. RESULTS: Thirty-year overall survival was 86.1%, but event-free survival was 39.6%. Life-threatening events, such as severe infections or lymphoproliferation, were frequent in childhood and adolescence and were common indications for HSCT. Nine patients underwent HSCT with fludarabine-based reduced-intensity conditioning. Seven patients survived after frequent adverse complications and engraftment failure. Most symptoms improved after HSCT. CONCLUSION: Patients with APDS1 showed variable clinical manifestations. Life-threatening progressive combined immunodeficiency and massive lymphoproliferation were common indications for HSCT. Fludarabine-based reduced-intensity conditioning-HSCT ameliorated clinical symptoms, but transplantation-related complications were frequent, including graft failure.

Airway obstruction caused by rapid enlargement of cervical lymphangioma in a five-month-old boy.

Cervical lymphangioma can cause airway obstruction secondary to enlargement following infection. Physicians should be aware that the airway obstruction can progress rapidly when patients with cervical lymphangioma have respiratory symptoms. Sclerotherapy for lymphangioma can cause both transient swelling and airway obstruction; thus, prophylactic and elective tracheostomy should be considered.

Phosphatase and tensin homolog (PTEN) mutation can cause activated phosphatidylinositol 3-kinase δ syndrome-like immunodeficiency.

BACKGROUND: Activated phosphatidylinositol 3-kinase δ syndrome (APDS) is a recently discovered primary immunodeficiency disease (PID). Excess phosphatidylinositol 3-kinase (PI3K) activity linked to mutations in 2 PI3K genes, PIK3CD and PIK3R1, causes APDS through hyperphosphorylation of AKT, mammalian target of rapamycin (mTOR), and S6. OBJECTIVE: This study aimed to identify novel genes responsible for APDS. METHODS: Whole-exome sequencing was performed in Japanese patients with PIDs. Immunophenotype was assessed through flow cytometry. Hyperphosphorylation of AKT, mTOR, and S6 in lymphocytes was examined through immunoblotting, flow cytometry, and multiplex assays. RESULTS: We identified heterozygous mutations of phosphatase and tensin homolog (PTEN) in patients with PIDs. Immunoblotting and quantitative PCR analyses indicated that PTEN expression was decreased in these patients. Patients with PTEN mutations and those with PIK3CD mutations, including a novel E525A mutation, were further analyzed. The clinical symptoms and immunologic defects of patients with PTEN mutations, including lymphocytic AKT, mTOR, and S6 hyperphosphorylation, resemble those of patients with APDS. Because PTEN is known to suppress the PI3K pathway, it is likely that defective PTEN results in activation of the PI3K pathway. CONCLUSION: PTEN loss-of-function mutations can cause APDS-like immunodeficiency because of aberrant PI3K pathway activation in lymphocytes.

Neonatal Meckel diverticulum: Obstruction due to a short mesodiverticular band.

This is the first report of symptomatic Meckel diverticulum in a newborn, in which direct compression by a short mesodiverticular band (MDB) caused intestinal obstruction. A short MDB can cause intestinal obstruction due to direct compression. There are two mechanisms by which Meckel diverticulum with MDB can cause intestinal obstruction: internal hernia and direct compression. Onset of intestinal obstruction due to direct compression by a short MDB might be earlier than that for internal hernia with long MDB.

A female patient with incomplete hemophagocytic lymphohistiocytosis caused by a heterozygous XIAP mutation associated with non-random X-chromosome inactivation skewed towards the wild-type XIAP allele.

X-linked lymphoproliferative disease (XLP) is a rare inherited immunodeficiency that often leads to hemophagocytic lymphohistiocytosis (HLH). XLP can be classified as XLP1 or XLP2, caused by mutations in SH2D1A and XIAP, respectively. In women, X-chromosome inactivation (XCI) of most X-linked genes occurs on one of the X chromosomes in each cell. The choice of which X chromosome remains activated is generally random, although genetic differences and selective advantage may cause one of the X chromosomes to be preferentially inactivated. Here we describe three patients with pancytopenia, including one female patient, in a Japanese family with a novel XIAP mutation. All three patients exhibited deficient XIAP protein expression, impaired NOD2/XIAP signaling, and augmented activation-induced cell death. In the female patient, the paternally derived X chromosome was non-randomly and exclusively inactivated in her peripheral blood and hair root cells. In contrast to asymptomatic females, this patient exhibied non-random XCI skewed towards the wild-type XIAP allele. This is the first report of a female patient with incomplete HLH resulting from a heterozygous XIAP mutation in association with non-random XCI.