Early Clinical Warning Signs of Inborn Errors of Immunity in the Neonatal Intensive Care Unit: A Retrospective Observational Study

Abstract

Objectives

Inborn errors of immunity (IEI) may manifest in neonates as severe or unusual infections and syndromic features, yet early recognition remains challenging, especially in settings without routine newborn screening. Early clinical warning signs—including recurrent or atypical infections, absent thymic shadow, unexplained hydrops fetalis, or treatment-resistant metabolic disturbances—can facilitate timely diagnosis. This study aimed to determine the prevalence and subtypes of IEI in a tertiary neonatal intensive care unit (NICU) and to characterize early diagnostic indicators that guide life-saving interventions.

Methods

We conducted a retrospective observational study of neonates diagnosed with IEI between August 2023 and August 2025 in a 61-bed, level 4 NICU. Seventeen infants meeting IUIS and ESID criteria were identified through the immunology–neonatology council registry. Demographic, clinical, laboratory, and outcome data were analyzed descriptively, with an emphasis on early warning signs.

Results

Among 11,276 live births and 2,942 NICU admissions, 17 neonates were diagnosed with IEI (1.51 per 1,000 live births). Combined immunodeficiencies were the most frequent subtype (58.8%). Diagnostic evaluation was primarily prompted by syndromic features or severe/unusual infections. Four infants (23.5%) died, while survivors remained clinically stable with immunoglobulin replacement therapy and antimicrobial prophylaxis. One infant underwent hematopoietic stem cell transplantation (HSCT). Early recognition facilitated the timely initiation of appropriate management strategies.

Conclusion

IEI should be suspected in neonates presenting with syndromic features or atypical infections. Awareness of subtle neonatal warning signs and prompt evaluation for appropriate interventions can improve outcomes, particularly in settings without routine newborn screening.

Inborn errors of immunity (IEI) are a heterogeneous group of monogenic disorders caused by defects in immune cells, receptors, or signaling pathways, resulting in increased susceptibility to infections. IEI include combined immunodeficiencies (CID), predominantly antibody deficiencies (PAD), phagocytic defects, and immune dysregulation disorders.^[1]

Although severe forms such as CID may present in the neonatal period, diagnosis is particularly challenging due to physiological immune immaturity, transplacentally acquired maternal antibodies, and variable penetrance of monogenic defects.^[2] Nevertheless, early recognition in the neonatal intensive care unit (NICU) is critical, as it allows the timely implementation of protective isolation, antimicrobial prophylaxis, appropriate transfusion practices, avoidance of live vaccines, and, when indicated, early hematopoietic stem cell transplantation (HSCT), which significantly improves survival in severe combined immunodeficiency.^[3-5]

While many immunodeficiencies manifest after 6 months of age, early warning signs in neonates may be overlooked. Data on the incidence and clinical spectrum of IEI among neonates admitted to the NICU remain limited, particularly in countries without routine newborn screening. Therefore, this study aimed to determine the prevalence and subtypes of IEI in a tertiary NICU, describe their clinical and laboratory features, and identify findings that may facilitate early diagnosis and management.

Methods

Study Design and Setting

This retrospective observational study was conducted in the NICU of a tertiary referral center with a pediatric immunology clinic, an HSCT unit, and a perinatology referral service.

Newborns admitted to the NICU between August 2023 and August 2025 who were diagnosed with IEI according to the International Union of Immunological Societies (IUIS) and European Society for Immunodeficiencies (ESID) criteria were included.^[6] This study was designed to reflect real-life diagnostic pathways in a tertiary NICU, where early recognition of IEI relies primarily on clinical suspicion rather than population-based screening.

After high-risk cases were identified, eligible patients were selected through the joint immunology–neonatology council registry and hospital electronic medical records.

During the study period, all neonates admitted to the NICU who were clinically suspected of having an IEI were evaluated by the immunology–neonatology council. Those who met the diagnostic criteria for IEI were included in the study.

Patients who did not meet the diagnostic criteria or had evidence of secondary immunodeficiency, such as HIV positivity, malnutrition, congenital infection, or drug exposure, were excluded.

This study presents only descriptive data on the clinical and laboratory characteristics of the included neonates; no control group was used.

Diagnostic Definitions

The diagnosis and classification of IEI were based on the IUIS and ESID guidelines.^[1]

According to the ESID diagnostic framework, the criteria were categorized as follows:

Clinical criteria: recurrent or severe infections, infections with unusual pathogens, poor response to antibiotics, autoimmune manifestations, or lymphoproliferation.

Laboratory criteria: lymphopenia, neutropenia, low serum immunoglobulin (Ig) levels, abnormal B/T/NK cell counts or function, and impaired antibody responses. Lymphocyte subset abnormalities, including T-, B-, and NK-cell deficiencies, were interpreted according to age-adjusted neonatal reference ranges. B-cell deficiency was defined as CD19+ B-cell counts below age-adjusted neonatal reference ranges.

Genetic criteria: identification of a pathogenic variant in a disease-associated gene (e.g., BTK, RAG1, IL2RG).

Diagnostic certainty was defined as follows:

Definite diagnosis: compatible clinical and laboratory findings with a confirmed genetic defect.

Probable diagnosis: consistent clinical and laboratory findings without genetic confirmation.

Possible diagnosis: suggestive clinical features alone.

Classification of IEI Subtypes

The classification of IEI subgroups was performed according to the IUIS 2024 update on IEI.^[1]

Based on this classification, patients were grouped into the following categories:

Severe Combined Immunodeficiency: profound T- and B-cell functional defects, often presenting in the neonatal period.

Combined Immunodeficiencies: disorders involving both cellular and humoral immune dysfunction of variable severity.

Predominantly Antibody Deficiencies: defects primarily affecting antibody production (e.g., X-linked agammaglobulinemia, CVID).

Immune Dysregulation Disorders: conditions characterized by defective immune tolerance and cytotoxic regulation (e.g., Griscelli syndrome).

Participants and Data Collection

Data were retrospectively extracted from the immunology–neonatology council registry and hospital electronic database.

For each infant, demographic and clinical characteristics were recorded, including gestational age, sex, birth weight, length, head circumference, percentiles, reason for NICU admission, timing of immune-related symptoms, infection history, family history of immunodeficiency, parental consanguinity, and sibling deaths before 1 year of age.

Laboratory Procedures

All laboratory analyses were performed in the hospital’s clinical laboratory following internal quality control procedures. Certified laboratory technicians performed all assays according to the manufacturers’ protocols.

Primary Screening Tests: Screening for inborn errors of immunity was performed when infants presented with the following warning signs: infections caused by unexpected pathogens, severe or treatment-resistant infections, a family history of immunodeficiency, absence of thymic shadow on chest radiography, or syndromic features on physical examination.

Initial screening included a complete blood count performed using an automated hematology analyzer manufactured by Mindray (Mindray Bio-Medical Electronics, China), serum immunoglobulin concentrations (IgG, IgA, IgM, and IgE), isohemagglutinins, and postvaccination antibody responses when applicable. Serum immunoglobulin concentrations were measured by nephelometry (Dade Behring Marburg GmbH, Germany), and values were compared with age-matched reference ranges for Turkish neonates.^[7]

Flow Cytometry: Peripheral blood lymphocyte subsets—including T (CD3, CD4, CD8), B (CD19, CD21/38), and natural killer (CD16/56) cells; recent thymic emigrants (RTEs); double-negative T cells; and CD45RA/RO subsets—were analyzed using four-color flow cytometry (BD FACSCalibur, BD Biosciences, San Jose, CA, USA) on the same day that the blood sample was collected.

Additional and Confirmatory Tests: To exclude secondary immunodeficiencies, all patients were tested for anti-HIV IgG antibodies.

When clinically indicated, additional investigations such as dihydrorhodamine (DHR) testing, chromosomal analysis, and fluorescence in situ hybridization (FISH) for chromosome 22q11.2 deletion were performed.

Genetic analyses were performed in selected cases in collaboration with a clinical geneticist.

Interpretation of immunological parameters was performed using age-adjusted neonatal reference ranges when available. Immunoglobulin levels and lymphocyte subset analyses were evaluated together with the clinical presentation, infectious history, and accompanying immunological findings. In patients with suspected IEI, abnormal immunological results were reassessed during follow-up when clinically feasible. Transient neonatal immune alterations related to prematurity, physiological immune immaturity, or maternal antibody transfer were considered during the diagnostic evaluation.

Statistical Analysis

Data analysis was performed using IBM SPSS Statistics for macOS version 29.0 (IBM Corp., Armonk, NY, USA).

Categorical variables were summarized as frequencies and percentages, and continuous variables as medians with minimum and maximum values. Normality of distribution was assessed using the Kolmogorov–Smirnov test.

A priori power analysis was not performed because of the descriptive design of the study. The rate of missing data was below 5% for all variables. The datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request.

Ethical Approval

The study was approved by the Ümraniye Training and Research Hospital ethics committee (Approval No: B.10.1.TKH.4.34.H.GP.0.01/301, Date: October 3, 2024). The requirement for written informed consent was waived due to the retrospective design of the study. The study was conducted in accordance with the Declaration of Helsinki.

Results

Demographic and Clinical Characteristics

During the study period, a total of 11,276 live births and 2,942 NICU admissions were recorded at our hospital. Thirty-five neonates were evaluated by the immunology council due to clinical suspicion of an IEI. A definitive diagnosis of IEI was established in 17 infants. This corresponded to a hospital-based observed frequency of 1.51 per 1,000 live births (0.15%; 95% CI: 0.08–0.22%) and 5.78 per 1,000 NICU admissions (0.58%; 95% CI: 0.30–0.85%).

The median birth weight of the cohort was 2,680 g (range: 1,128–3,650 g), and the mean gestational age was 37+1 weeks (range: 27–39 weeks). Eleven infants were male (64.7%), 11 were born at term (64.7%), and 12 were delivered by cesarean section (70.6%). Parental consanguinity was present in six cases (35.3%), five of which involved first cousins. A family history of IEI was observed in two cases (11.8%), and early (<1 year) sibling death was reported in two families (11.8%). Demographic characteristics and family histories are summarized in Table 1.

Table 1.

Demographic characteristics and family history of patients diagnosed with immunodeficiency

Cases	Gestational Age (weeks+days)	Birth Weight (grams)	Gender	Method of Birth	Consanguinity	Family History of Immunodeficiency	Story of a Family Member Who Died Before the Age of One
1	38+5	2865	Female	CS	No	No	No
2	38	3050	Female	CS	No	No	No
3	36	2620	Male	CS	No	No	No
4	38	2680	Female	NSD	Yes, cousin	No	No
5	37+3	2400	Male	CS	No	No	No
6	27	1128	Female	NSD	No	No	Yes
7	35+1	1990	Male	CS	No	No	No
8	35+1	1495	Male	CS	Yes, cousin	No	Yes
9	38+2	3650	Male	CS	Yes, cousin	Yes	No
10	35	1935	Female	NSD	No	No	No
11	36	3240	Male	CS	No	Yes	No
12	38	2380	Male	NSD	Yes, cousin	No	No
13	37+6	2820	Male	CS	Yes, cousin	No	No
14	39	2920	Male	CS	No	No	No
15	39	3340	Male	CS	No	No	No
16	38+3	2650	Female	NSD	No	No	No
17	38+2	3430	Male	CS	Yes, cousin	No	No

CS:cesarean section; NSD: Normal spontaneous delivery

Classification of IEI

Clinical classification of IEI was performed according to the 2024 IUIS phenotypic classification. Ten cases (58.8%) were classified as combined immunodeficiencies, five cases (29.4%) as predominantly antibody deficiencies, one case (5.9%) as severe combined immunodeficiency (SCID), and one case (5.9%) as an immune dysregulation disorder. According to the predefined diagnostic certainty criteria, eight patients were classified as having definite diagnoses and nine as having probable diagnoses. The primary diagnoses, associated syndromic features, diagnostic certainty, and reasons for NICU admission are presented in Table 2.

Table 2.

Reason for hospitalization, type of ID, accompanying syndromes and diagnostic certainity

Cases	Diagnosis Leading to Admission	Type of ID	Presence and Type of Syndrome	Diagnostic Certainity
1	Diaphragmatic hernia	CID	Genetic analysis ongoing	Probable
2	Spina bifida	CID	Di George Syndrome	Definite
3	Pneumonia	PAD	Genetic analysis ongoing	Probable
4	Vomiting	PAD	Down Syndrome, RAC2 mutation	Definite
5	Congenital heart disease	CID	Genetic analysis ongoing	Probable
6	Respiratory distress	PAD	TACI deficiency	Definite
7	Intestinal obstruction	PAD	Down Syndrome and SPI mutation	Probable
8	Respiratory distress	CID	Genetic analysis ongoing	Probable
9	NIHF	Immune dysregulation	Griscelli Syndrome RAB27A gene mutation	Definite
10	Congenital heart disease	CID	Di George Syndrome	Definite
11	Family history	PAD	Bruton’s agammaglobulinemia	Definite
12	HIE	CID	SPTBN4 gene mutation	Probable
13	NIHF	SCID	Genetic analysis ongoing	Probable
14	Congenital heart disease	CID	Ivemark Syndrome	Probable
15	Antenatal diagnosis	CID	Di George Syndrome	Definite
16	Hyperbilirubinemia	CID	Di George Syndrome	Definite
17	Intestinal obstruction	CID	Down Syndrome and unclassified hypogammaglobulinemia	Probable

CID: Combined immunodeficiencies; PAD: Predominantly antibody deficiencies; HIE: Hypoxic ischemic encephalopathy; NIHF: Non-immun hydrops fetalis; SCID: Severe combined immunodeficiency

All patients in our cohort were diagnosed with immunodeficiency based on compatible clinical and immunological findings. Genetic testing was performed in all cases. Eight patients had genetically confirmed diagnoses that explained their clinical and immunological findings, while genetic analyses were still ongoing in five patients. In the remaining four patients, genetic studies did not identify variants that fully explained the clinical phenotype.

Clinical Presentation and Management

When reviewing the findings that prompted suspicion of IEI, most cases were investigated because of physical features suggestive of an underlying syndrome (n=9), followed by recurrent, severe, or unusual infections caused by unexpected pathogens (n=8). Additional findings included absence of a thymic shadow on posteroanterior chest radiographs (n=4), unexplained nonimmune hydrops fetalis (n=2), and treatment-resistant hypocalcemia (n=1). Antenatal detection of thymic aplasia in one neonate enabled early FISH analysis and subsequent diagnosis of DiGeorge syndrome.

Based on these clinical triggers, a pragmatic diagnostic roadmap was developed and applied by the immunology–neonatology council to prioritize high-risk neonates for targeted immunological evaluation (Fig. 1).

Figure 1.

Diagnostic roadmap for suspected IEI in the NICU.

A history of sepsis was documented in nine infants (52.9%), including one early-onset and eight late-onset cases.

The interval between the onset of clinical manifestations and definitive diagnosis ranged from 3 to 98 days, with a mean of 27.6 days.

Following diagnosis, supportive therapy was administered to all patients, consisting of intravenous immunoglobulin replacement therapy (IgRT) and antibiotic prophylaxis. One infant (5.9%) diagnosed with an immune dysregulation disorder underwent HSCT. The oldest surviving patient was 2 years and 4 months old, and all surviving infants continued to receive supportive therapy at the time of data collection.

Outcomes

Among the 17 cases, four deaths (23.5%) were recorded. Causes of death included fungal sepsis (n=2), myocarditis (n=1), and heart failure secondary to congenital heart disease (n=1). Eight patients (47.0%) had lymphopenia, and two patients (11.8%) had agammaglobulinemia (IgG<100 mg/dL). Table 3 summarizes immunoglobulin levels at diagnosis. Five patients (29.4%) had CD3 lymphopenia, and six patients (35.2%) had B-cell deficiency. Lymphocyte subset analyses are presented in Table 4.

Table 3.

Immunoglobulin levels, white blood cell and absolute lymphocyte count

Cases	Ig G (g/dL)	Ig A (g/dL)	Ig M (g/dL)	WBC /mm3	ALC % /mm3	Timing of Test weeks+days (PMA)
1	105	19	52	15900	16.8 / 2670	47+5
2	438	64	34	13070	51 / 6670	42+2
3	601	8	40	16580	63.7 / 10570	43+5
4	757	32	41	5620	36.1 / 2030	39+5
5	NA	NA	NA	21810	30.9 / 6740	47+6
6	209	3	9	9800	34.1 / 3340	39+1
7	62	7	36	7220	34.9 / 2520	43+5
8	87	14	32	6250	32.4 / 2030	50+6
9	911	31	40	2160	84.9 / 1830	41+5
10	404	42	29	5250	54.8 / 2880	41+6
11	326	0	31	18080	28.5 / 5140	47+4
12	313	28	50	9160	30 / 2750	46+5
13	NA	NA	NA	14780	55.8 / 8250	41+5
14	1154	165	98	22520	24 / 5410	41+6
15	935	7	16	9260	28.5 / 3070	40+4
16	523	8	11	6060	56.2 / 3400	44+1
17	1148	8.9	62	4040	31.8 / 1280	50

Ig: Immunoglobulin; WBC: White blood cell count; ALC: Absolute lymphocyte count, PMA: Postmenstrual age, NA: Not available; immunoglobulin measurements were not performed in these

Table 4.

Lymphocyte subgroup analysis results

Cases	CD3+ % / mm3	CD4+ % / mm3	CD8+ % /mm3	CD19+ % /mm3	CD3-CD56+ %	RTE %	double - %	CD4+CD45 RO %	CD4+ CD45 RA %	CD8+CD45 RO %	CD8+CD45 RA %	Timing of Test PMA (weeks + days)
1	51.4 1372	32.3 864	13.3 356	22.2 592	21.2	64.7	10.3	14.9	83.6	28.8	71.2	47+5
2	55 3668	42.1 2813	11.2 748	26.5 1767	15.5	69.2	2.4	15.8	85.9	21.8	78.4	42+2
3	67.2 7103	26 2748	39.8 4204	7.4 782	20.4	46.1	1.1	21.9	77.4	78.4	21	43+5
4	90.2 1831	76.3 1549	12.2 249	7.7 156	2	51.3	1.6	14.2	85.1	3.2	96.1	39+5
5	82.3 5547	42.3 2851	33.8 2279	0.8 53.7	16.8	NA	6.3	NA	NA	NA	NA	47+6
6	77.3 2581	64.8 2166	9.4 315	21.6 721	1	55.4	0.7	5.2	94.6	3.1	96.9	39+1
7	90.1 2270	56.6 1428	30.0 756	3.6 90.7	6.2	58.3	3.3	6.2	93.7	4.5	94.6	43+5
8	47.9 972	33.2 673	13.6 276	35.7 724	16.3	44.4	4.3	25.3	74.7	5.8	94.2	50+6
9	59.8 1094	28.7 526	22.7 415	2 36.7	38.2	8.2	7.9	89.1	11.8	93.7	6.4	41+5
10	73.4 2113	60 1729	11.4 330	16.5 475	9.9	51	1.9	14.1	85.9	9.7	90.3	41+6
11	95.7 4918	70.4 3620	23.3 1195	0 0	4.3	NA	2.0	NA	NA	NA	NA	47+4
12	52.5 1443	41.1 1131	9.9 273	29 797	18.5	42	4.2	25.6	74.4	14.6	85.4	46+5
13	0 0	0 0	0 0	0 0	0	0	0	0	0	0	0	41+5
14	78.2 4230	48.1 2606	27.4 1484	16.4 887	6	24.1	3.1	54.1	45.9	29.4	67.8	41+6
15	38.2 1180	26.6 820	9.9 304	20.5 630	19.9	57.9	3.2	17.5	82.5	15.5	84.5	40+4
16	44.3 1506	33.7 1147	9.7 330	34.5 1173	0.1	2	NA	NA	NA	NA	NA	44+1
17	74.6 3483	37.3 1742	37.2 1737	14.3 183	12.3	52.4	3.2	22.4	78.1	46.5	53.0	50

CD: Cluster of Differentiation; PMA: Postmentrual age; NA: Not available

Discussion

In this study, we evaluated the incidence and distribution of IEI among neonates admitted to a tertiary NICU and found markedly higher rates than those reported for the general neonatal population. The observed incidence of 1.51 per 1,000 live births and 5.78 per 1,000 NICU admissions exceeds previously reported population-based estimates of 1–10 per 10,000 live births.^[8] This difference likely reflects the characteristics of our level 4 tertiary referral NICU, which manages a high proportion of syndromic and medically complex neonates and benefits from close collaboration with pediatric immunology services, facilitating heightened diagnostic awareness and early case identification. Nevertheless, as a single-center, hospital-based study, our findings should be interpreted with caution and may not be generalizable to population-level incidence.^[9]

Classically, IEI are categorized according to the primarily affected immune component, with predominantly antibody deficiencies reported as the most common subtype in the general population.^[1] However, the burden of IEI in the neonatal period may be underestimated, as maternally transferred antibodies can mask humoral defects and delay recognition. In contrast to population-based data, combined immunodeficiencies predominated in our cohort, accounting for 58.8% of cases, followed by predominantly antibody deficiencies. Isolated cases of SCID and immune dysregulation disorders were also identified. The predominance of CID likely reflects the referral profile of our tertiary unit, while the observed SCID frequency aligns with data from nationwide neonatal screening studies in Türkiye.^[9,10]

Although first-line immunological evaluations can be performed and interpreted within the first week of life in term neonates, considering immunodeficiency during this period remains challenging. This difficulty largely stems from the physiological immaturity of the neonatal immune system, which manifests as transient antibody deficiencies, reduced complement levels, and lower absolute neutrophil counts with impaired neutrophil function. Careful clinical assessment is essential, and laboratory investigations should be repeated at least twice to confirm abnormal findings while excluding secondary causes of immunodeficiency.^[11] In addition, calculating the required serum volumes for testing and systematically applying a stepwise differential diagnosis are crucial to avoid compromising the hemodynamic stability of the neonate. In preterm infants, prematurity itself constitutes a potential cause of secondary immunodeficiency; therefore, when IEI is suspected, repeat testing at 40 weeks of postmenstrual age is recommended to minimize confounding effects.^[12] In this context, structured NICU protocols and close collaboration with immunology specialists are essential to balance timely diagnosis against the risks of overinvestigation in fragile neonates.

In our case series, the mean gestational age was 37 1/7 weeks (range: 27–39), with detailed gestational ages at diagnosis provided in Tables 3, 4 and 5. All patients diagnosed before 40 weeks of postmenstrual age had genetically confirmed IEI, including one case with a RAC2 mutation and trisomy 21 and one case with TACI deficiency. These findings highlight the complexity of diagnosing immunodeficiency in the neonatal period, which is not only challenging but also time-consuming. Consistent with this, the mean interval between the first clinical suspicion and definitive diagnosis in our series was 27.6 days (range: 3–98 days).

Table 5.

Sites of infection and identified pathogens

Cases	IEI Classification	Site of Infection	Identified Pathogen
1	CID	Bloodstream infection	Stenotrophomonas maltophilia
4	PAD	Bloodstream infection and meningitis	Escherichia coli
5	CID	Bloodstream infection and peritonitis	Candida parapsilosis
6	PAD	Bloodstream infection	Klebsiella pneumoniae
8	CID	Bloodstream infection	Stenotrophomonas maltophilia
12	CID	Bloodstream infection	Serratia marcescens
13	SCID	Bloodstream infection	Saprochaete clavata
17	CID	Bloodstream infection	Candida parapsilosis

IEI: Inborn errors of immunity

Beyond these diagnostic difficulties, some neonates are admitted to the NICU for nonspecific conditions such as jaundice, vomiting, or respiratory distress. In our cohort, four infants presented with such conditions, yet careful clinical evaluation facilitated recognition of their underlying immunodeficiency, underscoring the importance of maintaining a high index of suspicion even in apparently routine neonatal presentations.

Infections were a significant cause of morbidity and mortality in our cohort, with both common and uncommon pathogens contributing to clinical manifestations. Infections among patients with CID varied considerably: some patients developed serious bacterial and fungal infections, including pneumonia, sepsis, urinary tract infections, and intraperitoneal infections, while a few were diagnosed before experiencing any infection. Notably, a patient with SCID succumbed to Saprochaete clavata sepsis while receiving treatment for Stenotrophomonas maltophilia pneumonia and undergoing HSCT.

A positive family history provided another important diagnostic clue in our cohort. A history of miscarriage, stillbirth, or early childhood death within the family may provide valuable diagnostic information for IEI.^[3] In our series, two infants had a known family history of IEI, two families reported sibling deaths due to sepsis or recurrent infections before 1 year of age, and one mother had a history of unexplained miscarriage. One infant with a sibling diagnosed with Bruton’s agammaglobulinemia was identified before developing any infection, allowing the timely initiation of isolation and prophylactic measures. In contrast, in another case, the family initially concealed the sibling’s immunodeficiency history, and the diagnosis was unfortunately made only after the infant developed severe sepsis. These examples underscore the critical role of a thorough family history in the early identification of neonatal IEI. Similar patterns have been noted in other series, emphasizing that unexplained early sibling deaths should raise suspicion for hereditary immunodeficiency.^[13]

Recognition of these familial patterns is particularly valuable in populations with higher consanguinity rates, as in our study (35.3%), which increase the likelihood of autosomal recessive forms of IEI manifesting with severe neonatal phenotypes.^[14]

Awareness of IEI not only allows timely intervention to save the life of the affected neonate but also helps inform families about potential genetic susceptibilities that may be important for planning future pregnancies.^[12] All neonates diagnosed with IEI in our cohort were evaluated by a pediatric geneticist, who recommended further genetic testing as needed and provided genetic counseling.

Routine newborn screening for SCID has not yet been implemented in our country; nevertheless, it is crucial that all neonatologists are familiar with the purpose, methodology, and potential early warning signs of such screening programs.^[10-15]

Despite all diagnostic challenges and delays, the management of IEI cases requires rapid decision-making, early initiation of life-saving interventions, and timely implementation of preventive measures. Consultation with an immunology specialist is critical whenever IEI is suspected.^[16]

Until a definitive diagnosis is established, the implementation of isolation and prophylactic measures as if the patient had IEI has become standard practice in our unit to ensure patient safety.

Hematopoietic stem cell transplantation is a recommended treatment option for many IEI categories associated with high morbidity and mortality, particularly SCID.^[17] Another potential approach is gene therapy; however, these options can only be considered after the patient has received a confirmed diagnosis.^[4] Our patient, who was admitted with nonimmune hydrops fetalis and diagnosed with Griscelli syndrome, developed hemophagocytic lymphohistiocytosis and received appropriate chemotherapy. Subsequently, a suitable unrelated donor was identified, allowing HSCT to be performed. The patient continues to be followed and currently exhibits no signs of immunodeficiency.

Of the 17 patients followed in our unit, four (23.5%) died. The patient with SCID succumbed to fungal sepsis while preparing for HSCT. Among three patients with CID receiving appropriate antimicrobial prophylaxis and regular IgRT, one died during surgical preparation due to coexisting aortic hypoplasia, another died from sepsis, and the third died from myocarditis of presumed viral origin, although no causative agent was identified.

The remaining 13 patients continue to be followed in the pediatric immunology clinic, receiving appropriate antimicrobial prophylaxis and regular IgRT. None of these patients have experienced recurrent hospitalizations or severe infections. These outcomes highlight the beneficial impact of early diagnosis and appropriate prophylactic management.

This study has several limitations. First, it was conducted at a single tertiary referral NICU, which may introduce referral bias and limit the generalizability of our findings to the broader neonatal population. Second, the retrospective design and relatively small sample size may restrict our ability to fully characterize the clinical spectrum of neonatal IEI. Finally, the absence of routine newborn screening for IEI in our setting may have influenced case detection, and the true population incidence may therefore differ from our estimates.

Conclusion

In countries where national newborn screening programs do not include IEI, neonatologists’ awareness of IEI and the use of structured NICU-based diagnostic approaches are crucial for preventing morbidity and mortality in these immunologically vulnerable infants. A multidisciplinary approach, with timely diagnosis and appropriate follow-up programs, can help reduce adverse outcomes. Inborn errors of immunity should be considered in neonates presenting with atypical or severe infections, particularly when syndromic features are present.

Disclosures

Ethics Approval

Ethics committee approval for this study was obtained from the Ümraniye Training and Research Hospital (Approval no: : B.10.1.TKH.4.34.H.GP.0.01/301; date: October 3, 2024)

Informed consent

The requirement for written informed consent was waived due to the retrospective design of the study.

Conflict of Interest

The authors declare that there is no conflict of interest.

Financial Disclosure

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Use of AI for Writing Assistance

The authors declare that no artificial intelligence (AI)–assisted technologies (including large language models, chatbots, or image generation tools) were used in the preparation of this manuscript.

Authorship Contributions

Concept – F.I., D.C., H.B.B., I.M.A.; Design – F.I., D.C., H.B.B., I.M.A.; Supervision – F.I., O.S., O.G., F.Y.A., H.B.B., I.M.A.; Materials − F.I., F.Y.A., O.G., O.S.; Data collection &/or processing – F.I., D.C.; Analysis and/or interpretation – F.I., D.C., I.M.A., O.S., O.G.; Literature search – F.I., D.C., H.B.B.; Writing – F.I., D.C., H.B.B.; Critical review – F.I., D.C., O.S., O.G., F..Y.A., H.B.B., I.M.A.

Peer-review

Externally peer-reviewed.