Defining the Clinical, Emotional, Social, and Financial Burden of Congenital Athymia.

INTRODUCTION: Characterize the burden of illness in pediatric patients with congen̄ital athymia who were receiving supportive care. METHODS: This cross-sectional study of adult caregivers of patients with congenital athymia used both a quantitative survey and qualitative interviews. Caregivers of patients currently receiving supportive care responded to questions about the past 12 months and completed the parent proxy version of the Pediatric Quality of Life Inventory Generic instrument (PedsQL) for patients aged 2-4 years. For caregivers of patients who had received supportive care in the past, questions were asked about the period when they were receiving supportive care only. RESULTS: The sample included caregivers of 18 patients, 5 who were currently receiving supportive care and 13 who received investigational cultured human thymus tissue implantation before study enrollment and had received supportive care in the past. The impact of congenital athymia was substantial. Reports included the need to live in isolation (100% of respondents); caregiver emotional burden such as fear of death, infection, and worries about the future (100%); financial hardship (78%); and the inability to meet family/friends (72%). Patients had frequent and prolonged hospitalizations (78%) and had high utilization of procedures, medications, and home medical supplies. Caregiver-reported PedsQL scores for patients currently receiving supportive care (n = 4) indicated low health-related quality of life. CONCLUSIONS: Caregivers of patients with congenital athymia reported high clinical, emotional, social, and financial burden on patients and their families.

Economic burden of congenital athymia in the United States for patients receiving supportive care during the first 3 years of life.

AIMS: Congenital athymia is an ultra-rare pediatric condition characterized by the lack of thymus in utero and the naïve T cells critical for infection defense and immune regulation. Patients with congenital athymia receive supportive care to minimize and treat infections, autoimmune phenomena, and autologous graft-versus-host disease (aGVHD) manifestations, but historically, die within the first 3 years of life with supportive care only. We estimated the healthcare resource utilization and economic burden of supportive care over patients' first 3 years of life in the United States. METHODS: A medical chart audit by the treating physician was used to collect patient data from birth to age 3 on clinical manifestations associated with congenital athymia (clinical manifestations due to underlying syndromic conditions excluded). Using costs and charges from publicly available sources, the total economic burden of direct medical costs and charges for the first 3 years of life (considered "lifetime" for patients receiving supportive care) and differences in economic burden between patients with higher and lower inpatient hospitalization durations were estimated. RESULTS: All patients (n = 10) experienced frequent infections and aGVHD manifestations; 40% experienced ≥1 episode of sepsis, and 20% had recurrent sepsis episodes annually. The estimated mean 3-year economic burden per patient was US$5,534,121 (2020 US dollars). The annual mean inpatient hospitalization duration was 150.6 days. Inpatient room charges accounted for 79% of the economic burden, reflecting the high costs of specialized care settings required to prevent infection, including isolation. Patients with high inpatient utilization (n = 5; annual mean inpatient hospitalization duration, 289.6 days) had an estimated 3-year economic burden of US$9,926,229. LIMITATIONS: The total economic burden may not be adequately represented due to underestimation of some direct costs or overestimation of others. CONCLUSIONS: Current treatment of patients with congenital athymia (supportive care) presents a high economic burden to the healthcare system.

Clinical Phenotype, Immunological Abnormalities, and Genomic Findings in Patients with DiGeorge Spectrum Phenotype without 22q11.2 Deletion.

BACKGROUND: The phenotype of early embryonic fourth branchial arch defects encompasses a wide spectrum of clinical conditions including DiGeorge syndrome (DGS), velocardiofacial syndrome, and conotruncal anomaly face syndrome. The majority of the patients have a 22q11.2 deletion. However, in 6% to 17% of patients, the identification of a genetic cause remains unknown through fluorescence in situ hybridization. In these patients, the clinical features and the immunological abnormalities are not well defined. OBJECTIVE: To describe the main genomic abnormalities, clinical features, and immunological abnormalities of a cohort of patients resembling the 22q11.2 deletion phenotype in the absence of 22q11.2 locus alterations. METHODS: Eleven patients from unrelated nonconsanguineous families with suspected 22q11.2 deletion syndrome (22q11.2DS) according to Tobias criteria were enrolled. Array-comparative genomic hybridization was performed in 10 patients. A phenotypic and immunological assessment was performed in all patients. RESULTS: The majority of patients had a phenotype overlapping with 22q11.2DS and immunological abnormalities suggestive of abnormalities in T-cell development, being severe in 2 of them. Most subjects suffered from recurrent infections. Clinically overt autoimmune manifestations were identified in 2 (18%) subjects. New pathogenic or likely pathogenic genomic regions associated with 22q11.2DS features were identified. CONCLUSION: Patients with a DGS-like phenotype share the same features of the classical 22q11.2DS associated with other rare genomic alterations. Severe forms of immunodeficiency may also be observed in this group.

Abordaje inmunológico del síndrome por deleción 22q11 / Immunological approaches to 22q11 deletion syndrome

El síndrome por deleción 22q11 (SD22q11) es el síndrome por deleción cromosómica más frecuente en humanos y se caracteriza por la tríada clínica que incluye cardiopatía congénita, hipocalcemia e inmunodeficiencia primaria. El 85-90% de los pacientes tienen microdeleciones en el cromosoma 22q11.2. Tomando como punto cardinal la cardiopatía congénita, se diseñó una estrategia para tamización y diagnóstico de SD22q11 con énfasis en la evaluación inmune. Es imprescindible realizar una historia clínica detallada y, posteriormente, un análisis cuantitativo y funcional de las subpoblaciones de linfocitos en sangre periférica para clasificarlo en SD22q11 completo (<1%) o parcial (95-99%) e instaurar las pautas de tratamiento en aspectos como: aislamiento del paciente, vacunación, profilaxis contra microorganismos oportunistas, uso de productos sanguíneos irradiados y reconstitución inmunológica. Sin embargo, el abordaje del paciente debe ser multidisciplinario para detectar y prevenir complicaciones a largo plazo que pueden ser graves, especialmente en los pacientes con SD22q11 completo.

In humans, 22q11 deletion syndrome (22q11DS) is considered the most common chromosome deletion syndrome. It is characterised by a clinical triad that includes congenital heart disease, hypocalcaemia and primary immunodeficiency. Approximately 85-90% of patients with this syndrome exhibit microdeletions in chromosome 22q11.2. Using congenital heart disease as a starting point, we designed a strategy for the screening and diagnosis of 22q11DS with an emphasis on immunological evaluation. A detailed clinical history and the subsequent quantitative and functional analyses of the lymphocyte subpopulations in the peripheral blood is crucial to classify as complete (<1%) or partial (95-99%) the disease and to guide clinicians in terms of patient isolation, vaccination, prophylaxis for opportunistic infections, use of irradiated blood products and immunological reconstitution. However, multidisciplinary care is necessary to detect and prevent long-term complications that could be severe, particularly in cases of complete 22q11DS.