Allogeneic Hematopoietic Stem Cell Transplantation in Immunodeficiency-Centromeric Instability-Facial Dysmorphism (ICF) Syndrome: an EBMT/ESID Inborn Errors Working Party Study.

Immunodeficiency-Centromeric instability-Facial dysmorphism (ICF) syndrome is an inborn error of immunity characterized by progressive immune dysfunction and multi-organ disease usually treated with antimicrobial prophylaxis and immunoglobulin substitution. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment, but data on outcome are scarce. We provide a detailed description of disease characteristics and HSCT outcome in an international cohort of ICF syndrome patients. Eighteen patients (including all four genotypes) were enrolled. Main HSCT indications were infections (83%), enteropathy/failure to thrive (56%), immune dysregulation (22%) and myelodysplasia/haematological malignancy (17%). Two patients underwent pre-emptive HSCT after early diagnosis. Patients were transplanted between 2003-2021, at median age 4.3 years (range 0.5-19), after myeloablative or reduced-intensity conditioning, from matched sibling or matched family donors, matched unrelated or mismatched donors in 39%, 50% and 12% of cases respectively. Overall survival was 83% (all deaths occurred within the first 5 months post-HSCT; mean follow-up 54 months (range 1-185)). Acute GvHD occurred in 35% of patients, severe (grade III) in two (12%), while none developed chronic GvHD. At latest follow-up (median 2.2 years (range 0.1-14)), complete donor chimerism was achieved in 15/17 surviving patients. All survivors demonstrated normalized T and B cell numbers. Immunoglobulin substitution independence was achieved in all but two patients. All survivors recovered from pre-transplant infections, enteropathy/failure to thrive and immune dysregulation. All three patients transplanted at young age (≤ 3 years), after early diagnosis, survived. The favourable clinical and immunological HSCT outcome in this cohort of patients supports the timely use of this curative treatment in ICF syndrome.

Screening Newborns for Low T Cell Receptor Excision Circles (TRECs) Fails to Detect Immunodeficiency, Centromeric Instability, and Facial Anomalies Syndrome.

BACKGROUND: Assessment of T-cell receptor excision circles (TRECs) in dried blood spots of newborns allows the detection of severe combined immunodeficiency (SCID) (T cells <300/µL at birth) with a presumed sensitivity of 100%. TREC screening also identifies patients with selected combined immunodeficiency (CID) (T cells >300/µL, yet <1500/µL at birth). Nevertheless, relevant CIDs that would benefit from early recognition and curative treatment pass undetected. OBJECTIVE: We hypothesized that TREC screening at birth cannot identify CIDs that develop with age. METHODS: We analyzed the number of TRECs in dried blood spots in archived Guthrie cards of 22 children who had been born in the Berlin-Brandenburg area between January 2006 and November 2018 and who had undergone hematopoietic stem-cell transplantation (HSCT) for inborn errors of immunity. RESULTS: All patients with SCID would have been identified by TREC screening, but only 4 of 6 with CID. One of these patients had immunodeficiency, centromeric instability, and facial anomalies syndrome type 2 (ICF2). Two of 3 patients with ICF whom we have been following up at our institution had TREC numbers above the cutoff value suggestive of SCID at birth. Yet all patients with ICF had a severe clinical course that would have justified earlier HSCT. CONCLUSIONS: In ICF, naïve T cells may be present at birth, yet they decline with age. Therefore, TREC screening cannot identify these patients. Early recognition is nevertheless crucial, as patients with ICF benefit from HSCT early in life.

Clinical, Immunologic and Molecular Spectrum of Patients with Immunodeficiency, Centromeric Instability, and Facial Anomalies (ICF) Syndrome: A Systematic Review.

BACKGROUND: Immunodeficiency, centromeric instability and facial dysmorphism (ICF) syndrome is a rare autosomal recessive immune disorder presenting with hypogammaglobulinemia, developmental delay, and facial anomalies. The ICF type 1, type 2, type 3 and type 4 are characterized by mutations in DNMT3B, ZBTB24, CDCA7 or HELLS gene, respectively. This study aimed to present a comprehensive description of the clinical, immunologic and genetic features of patients with ICF syndrome. METHODS: PubMed, Web of Science, and Scopus were searched systemically to find eligible studies. RESULTS: Forty-eight studies with 118 ICF patients who met the inclusion criteria were included in our study. Among these patients, 60% reported with ICF-1, 30% with ICF-2, 4% with ICF-3, and 6% with ICF-4. The four most common symptoms reported in patients with ICF syndrome were: delay in motor development, low birth weight, chronic infections, and diarrhea. Intellectual disability and preterm birth among patients with ICF-2 and failure to thrive, sepsis and fungal infections among patients with ICF-1 were also more frequent. Moreover, the median levels of all three immunoglobulins (IgA, IgG, IgM) were markedly reduced within four types of ICF syndrome. CONCLUSION: The frequency of diagnosed patients with ICF syndrome has increased. Early diagnosis of ICF is important since immunoglobulin supplementation or allogeneic stem cell transplantation can improve the disease-free survival rate.

The spectrum of primary immunodeficiencies at a tertiary care hospital in Pakistan.

BACKGROUND: Primary Immunodeficiency Disorders (PIDs) are well-known disorders in the West. but the recognition and diagnosis of these disorders is challenging in developing countries. We present the spectrum of PIDs seen at a tertiary care center in Pakistan, identified using clinical case definitions and molecular methods. METHODS: A retrospective chart review of children suspected to have PID was conducted at the Aga Khan University Hospital (AKUH) Karachi, Pakistan from 2010 to 2016. Data on demographics, clinical features, family history of consanguinity, sibling death, details of laboratory workup done for PID and molecular tests targeted panel next generation sequencing (NGS) or whole exome sequencing (WES) performed at the Geha laboratory at Boston Children's Hospital, USA was collected. The study was exempted from the Ethical Review Committee of AKUH. RESULTS: A total of 43 children visited the hospital with suspected PID during the study period. Genetic testing was performed in 31/43 (72.1%) children. A confirmed diagnosis of PID was established in 20/43 (46.5%) children. A pathogenic gene variant was identified in 17(85%) of the 20 confirmed cases (Table 1). Twelve (60%) of the confirmed cases of PID were male. The most common presenting symptom was recurrent diarrhea 11/20 (55%). The mean (±S.D) age of the cases at the time of diagnosis was 4.2 (±4.1) years. Chronic granulomatous disease (CGD) was the most common 6/20 (30%) disorder, followed by severe combined immunodeficiency (SCID) 3/20 (15%), leukocyte adhesion deficiency (LAD) 3/20 (15%), agammaglobulinemia/hypogammaglobulinemia 3/20 (15%), and Hermansky-Pudlak Syndrome (HPS) 2/20 (10%). Wiskott-Aldrich Syndrome, Immunodeficiency Centromeric Instability and Facial Anomalies Syndrome (ICF 2), Trichohepatoenteric syndrome (TRES), and C3 deficiency were each diagnosed once {1/20 (4.3%) each} (Table 1). Of these 20 confirmed cases, almost all 19/20 (95%) had a family history of consanguinity. Sibling death was reported in 5/20 (25%) of these cases. Five out of the 20 (25%) children died over the 7-year period for various reasons. CONCLUSION: PIDs are not uncommon in Pakistan; their diagnosis may be missed or delayed due to the overlapping of clinical features of PID with other diseases and a lack of diagnostic facilities. There is a need to build capacity for early recognition and diagnosis of PIDs to decrease morbidity and mortality.

Hematopoietic Stem Cell Transplantation in an Infant with Immunodeficiency, Centromeric Instability, and Facial Anomaly Syndrome.

Immunodeficiency, centromeric instability, and facial anomaly (ICF) syndrome is a rare autosomal recessive genetic condition with severe immunodeficiency, which leads to lethal infections if not recognized and treated in early childhood. Up-to-date treatment regimens consist of prophylactic and supportive treatment of the recurrent infections. Here, we report the case of a 1-year-old boy of Moroccan consanguineous parents, who was diagnosed at 4 months of age with ICF syndrome with a homozygous missense mutation in the DNMT3B gene. He was initially admitted to the hospital with recurrent pulmonary infections from the opportunistic pathogen Pneumocystis jirovecii (PJ). Further immunological workup revealed agammaglobulinemia in the presence of B cells. After successful recovery from the PJ pneumonia, he underwent hematopoietic stem cell transplantation (HSCT) from the HLA-matched healthy sister using a chemotherapeutic conditioning regimen consisting of treosulfan, fludarabine, and thiotepa. Other than acute chemotherapy-associated side effects, no serious adverse events occurred. Six months after HSCT immune-reconstitution, he had a stable chimerism with 2.9% autologous portion in the peripheral blood and a normal differential blood cell count, including all immunoglobulin subtypes. This is one of the first cases of successful HSCT in ICF syndrome. Early diagnosis and subsequent HSCT can prevent severe opportunistic infections and cure the immunodeficiency. Centromeric instability and facial anomaly remain unaffected. Although the long-term patient outcome and the neurological development remain to be seen, this curative therapy for immunodeficiency improves life expectancy and quality of life. This case is meant to raise physicians awareness for ICF syndrome and highlight the consideration for HSCT in ICF syndrome early on.

Genetic, Cellular and Clinical Features of ICF Syndrome: a French National Survey.

PURPOSE: Autosomal recessive deficiencies of DNMT3B or ZBTB24 account for two-thirds of cases of immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome). This primary immunodeficiency (PID) is characterized mainly by an antibody deficiency, facial abnormalities and centromeric instability. We analyzed the national cohort of patients with ICF syndrome with the aim of providing a more detailed description of the phenotype and management of patients with ICF syndrome. METHODS: Demographic, genetic, immunological, and clinical features were recorded for each patient. RESULTS: In the French cohort, seven of the nine patients carried DNMT3B mutations, six of which had never been described before. One patient had compound heterozygous ZBTB24 mutations. All patients were found to lack CD19(+)CD27(+) memory B cells. This feature is a major diagnostic criterion for both ICF1 and ICF2. Patients suffered both bacterial and viral infections, and three patients developed bronchiectasis. Autoimmune manifestations (hepatitis, nephritis and thyroiditis) not previously reported in ICF1 patients were also detected in two of our ICF1 patients. The mode of treatment and outcome of the French patients are reported, by genetic defect, and compared with those for 68 previously reported ICF patients. Immunoglobulin (Ig) replacement treatment was administered to all nine French patients. One ICF1 patient presented severe autoimmune manifestations and pancytopenia and underwent allogeneic hematopoietic stem cell transplantation (HSCT), but she died from unknown causes 6 years post-transplant. CONCLUSION: Autoimmune signs are uncommon in ICF syndrome, but, when present, they affect patient outcome and require immunosuppressive treatment. The long-term outcome of ICF patients has been improved by the combination of IgG replacement and antibiotic prophylaxis.