Importance of neonatal screening: A case study of sickle cell disease and cystic fibrosis coexistence

Abstract

BACKGROUND

Neonatal screening (NS) is a public health policy to identify genetic pathologies such as cystic fibrosis (CF), sickle cell disease, and other diseases. Sickle cell disease is the comprehensive term for a group of hemoglobinopathies characterized by the presence of hemoglobin S. CF is an autosomal recessive multisystemic disease with pathophysiology involving deleterious mutations in the transmembrane regulatory gene that encodes a protein that regulates the activity of chloride and sodium channels in the cell surface epithelium. NS is crucial for early diagnosis and management, which ensures a better quality of life.

AIM

To report a case of the coexistence of sickle cell anemia (SCA) and CF and perform an integrative literature review.

METHODS

This is an observational study and a review of the literature focusing on two rare genetic pathologies identified simultaneously in NS from the perspective of a clinical case. The authors identified only 5 cases of SCA associated with CF. No clinical trials or review articles were identified considering the rarity of the coexistence of these two pathologies.

RESULTS

Herein, the authors reported the case of a girl who after undergoing NS on day 8 of life was diagnosed with SCA with an alteration in the dosage of immunoreactive trypsin. The diagnosis of CF was confirmed by the Coulometry Sweat Test. The rarity of the co-occurrence of these two severe genetic pathologies (CF and SCA) is a challenge for medical science.

CONCLUSION

This study adds to the few case reports present in the literature that highlight the identification of two severe diseases via NS.

Key Words: Sickle cell disease; Sickle cell anemia; Children; Cystic fibrosis; Neonatal Screening; Case reports

Core Tip: The key finding of this study was that the early identification and diagnosis of two severe genetic diseases determined by neonatal screening can improve life expectancy and quality of life. The co-occurrence of sickle cell anemia and cystic fibrosis is rare. To the best of our knowledge, only 5 cases are currently reported in the literature. This manuscript contributes to the scientific community by adding another case of the co-occurrence of serious genetic diseases to the body of knowledge. When recognizing the existence of both pathologies in an association, there is a broader view of patients with these disorders, improving their quality of life and reducing morbidity and mortality.

INTRODUCTION

Neonatal screening (NS) is a public health policy instituted in many countries to identify genetic pathologies and introduce early management and therapy, which reduces morbimortality and improves the prognosis of newborns diagnosed with rare diseases[1]. In Brazil, the National Program of Neonatal Screening (NPNS) recommends collecting blood samples for the Heel Prick Test by day 5 of life in Basic Health Units[2,3]. NS includes diagnostic research for phenylketonuria, congenital hypothyroidism, cystic fibrosis (CF), sickle cell disease, glucose-6-phosphate deficiency, congenital adrenal hyperplasia, biotinidase deficiency, congenital toxoplasmosis, and five other diseases associated with defects in fatty acid beta-oxidation. Since May 2021, the NPNS has guaranteed the detection of other rare diseases according to the five stages of expansion of the NPNS, which may be extended due to the need for technological equipment and trained teams[4].

Data regarding the concomitant incidence of both CF and sickle cell anemia (SCA) are rarely reported in the literature. In Brazil, there are approximately 30000 people with SCA, and it is estimated that 3000 more are born each year. In the state of Minas Gerais, a pioneer in NS in the southeast of Brazil, 7000000 newborns have undergone NS since 1998, and approximately 4340 people have been followed up and treated for SCA, resulting in an incidence of 1 out of every 1400 live births. In Minas Gerais, 355 people are living with CF, an incidence of 1 out of every 10000 live births[5,6]. Data available from the December 2023 Nucleus of Actions and Research in Diagnostic Support (NUPAD) of the Federal University of Minas Gerais (UFMG) identified only 1 patient under outpatient follow-up for the concurrence of SCA and CF (Núcleo de Ações e Pesquisa em Apoio Diagnóstico, 2023, Belo Horizonte: Centro de Comunicação Social da Faculdade de Medicina da UFMG. Available from: URL https://www.nupad.medicina.ufmg.br; accessed on April 27, 2024).

Sickle cell disease is the comprehensive term for a group of hemoglobinopathies characterized by the presence of hemoglobin S (HbS) including SCA, HbSC, and HbSβ-thalassemia, among others[7]. The pathophysiology of sickle cell disease is characterized by the polymerization of HbS, which when deoxygenated interacts with leukocytes and platelets inside the capillary beds through adhesion molecules. Red blood cells that contain HbS have a shortened survival, determining compensatory hematopoiesis with an increase in reticulocyte production and endothelial dysfunction since hemolysis releases hemoglobin and heme groups into the circulation, leading to nitric oxide depletion and the ensuing vasoconstriction. As a result of this hemolytic phenomenon, there is the activation of an inflammatory cascade with interactions between the endothelium, white blood cells, and platelets. The increase in cytokine levels, the release of reactive oxidative substances, and endothelial dysfunction perpetuate the vaso-occlusion stimulus. Recurrent erythrocyte sickling and hemolysis, combined with endovascular inflammation, result in severe acute and chronic systemic damage[8].

CF is a multisystem autosomal recessive disease whose physiopathology involves deleterious mutations in the transmembrane regulator gene (CFTR) that encodes a protein that regulates the activity of chloride and sodium channels in the cell surface epithelium. The defective CFTR protein generates missing or defective chloride channels in the apical membrane of the glandular epithelium and lung surface, resulting in thick, sticky mucus that obstructs the airways, leading to severe lung infections, especially ones caused by Pseudomonas. There is a massive infiltration of neutrophils releasing elastase, which overwhelms pulmonary antiproteases, contributing to tissue destruction. In addition, degranulating neutrophils release large amounts of nucleic acids and cytosol matrix proteins, contributing to mucus hyperviscosity[9,10]. We aimed to perform a literature review on this subject and reported a rare clinical case in which SCA and CF (both rare diseases with high infection and mortality rates) were simultaneously diagnosed in a patient through NS.

MATERIALS AND METHODS

This was a single-arm observational study and a review of the literature that focused on two rare genetic pathologies diagnosed simultaneously via NS from the perspective of a clinical case. The literature search was performed in the PubMed databases via Medline, SciELO, and Lilacs using the following keywords: “Sickle Cell Disease,” “Sickle Cell Anemia,” “Children,” “Cystic Fibrosis,” and “Neonatal Screening” through March 2024. All studies that presented the PICO strategy with the two pathologies associated were included. A search was also carried out in the NS database of UFMG and the Brazilian Ministry of Health to identify concomitant pathologies. Next, the authors reported the case of a child with positive NS for SCA and CF.

RESULTS

In the literature review, the authors identified only 5 case reports in which the co-occurrence of SCA and CF was present. This shows the importance of another case report to broaden scientific knowledge in the academic world. No clinical trials and review articles were identified due to the rarity of this association.

Case report description

A female neonate was born at 36 weeks of gestation through vaginal delivery in October 2021 with a birth weight of 1850 kg, height of 41 cm, head circumference of 31 cm, and an Apgar score of 8 in the first minute and 9 in the fifth minute. The patient evolved with mild respiratory distress requiring oxygen support by hood for 72 hours and jaundice without needing phototherapy. NS performed on the 8^th day of life detected SCA and CF. The second sample for CF reassessment, collected in November 2021, revealed an increase in immunoreactive trypsinogen. The diagnosis of CF was confirmed by the sweat test (Table 1). The child was referred by the Nucleus of Actions and Research in Diagnostic Support of the UFMG to Fundação Hemominas for the first reference service in hemoglobinopathies on October 27, 2021. The patient was prescribed folic acid, vitamin D, and penicillin-V.

Table 1 Results of neonatal screening and confirmatory sweat test.

Exam	Method	Collection date	Result date	Result	Reference value
Hemoglobin analysis	Isoelectric focusing	10/13/2021	10/20/2021	FS	FA
Immunoreactive trypsinogen measurement	Immunoassay based on time-resolved fluorometry	10/13/2021	10/20/2021	92.81 ng/mL	< 70 ng/mL
Immunoreactive trypsinogen measurement	Immunoassay based on time-resolved fluorometry	11/08/2021	11/08/2021	216.70 ng/mL	< 70 ng/mL
Sweat test	Coulometria	11/18/2021	11/18/2021	98 mmol/L	< 60 mmol/L

FA: Fetal and adult hemoglobin; FS: Fetal and sickle hemoglobin.

In November 2021, she attended the first outpatient consultation for CF follow-up at the UFMG specialized pulmonology service. It was recommended to maintain hemoglobin levels above 9 g/dL. In November 2021, the patient presented alterations in laboratory tests, which resulted in hospitalization for the evaluation of pediatric hematology data due to anemia (Table 2). Transfusion was necessary with two units of concentrate of deleukotized and phenotyped red blood cells. Moreover, therapy with pancreatic enzymes was initiated. Erythrocyte phenotyping was performed prior to the first blood transfusion.

Table 2 Laboratory tests upon admission in November 2021.

Test	Result	Test	Result
Hb	8.9 g/dL	Creatinine	0.0189 µmol/L
HTC	27.5%	pH	7.54
MCV	98.7 fL	pO2	11.19 kPa
RDW	16%	pCO2	2.67 kPa
WBC	7990/L	HCO3	16.8 mEq/L
Platelets	330000/L	BE	-4.5
TBil	6.46 mg/dL	Glucose	5.27 mmol/L
DB	0.21mg/dL	Na	132 mEq/L
AST	86 U/L	K	4.7 mEq/L
ALT	30 U/L	Cl	109 mEq/L
AP	377 U/L	Albumin	1.8 g/dL
GGT	228 U/L	PTT	38.5 (35 seconds)
Urea	0.333 mmol/L	PA	51%

ALT: Alanine aminotransferase; AP: Alkaline phosphatase; AST: Aspartate aminotransferase; BE: Base excess; Cl: Chlorine; DB: Direct bilirubin; GGT: Gamma-glutamyl transferase; Hb: Hemoglobin; HTC: Hematocrit; K: Potassium; MCV: Mean corpuscular volume; Na: Sodium; PA: Prothrombin activity; PTT: Partial thromboplastin time; RDW: Red cell distribution width; TBil: Total bilirubin; WBC: White blood count.

In January 2022, a new follow-up consultation was performed at the hemoglobinopathies service. The child presented with adequate weight-structural development (weight 4200 g, height 52 cm, head circumference 39 cm). The hemoglobin level was 7.9 g/dL, requiring hemotherapy support with concentrate of deleukotized and phenotyped red blood cells. The patient’s personal and family history was otherwise unremarkable for genetic diseases. Physical examination revealed stable vital signs with manual blood pressure 11/7 kPa (< 95^th percentile for age, height, and sex), pulse of 127 beats per minute, temperature 96.2° F, weight of 2450 kg, height of 43 cm, head circumference of 34 cm, and 100% oxygen saturation in ambient air.

Cardiovascular examination was normal as the heart rate and rhythm were regular with no murmurs, rubs, or gallops. No surgical scars were detected. Abdominal examination was normal, except for the presence of an umbilical hernia. There were normal bowel sounds with no rebound tenderness or guarding. The neurological examination revealed no abnormalities. The coexistence of mutations for alpha thalassemia (α-tal^3,7) was not identified.

The final diagnosis was SCA and CF. The patient was still on prophylactic antibiotic therapy and pancreatic enzymes. Special immunization through the Reference Center for Special Immunobiologicals was being taken. No new transfusions have been necessary since January 2022. Currently, the patient undergoes periodic control consultations at Fundação Hemominas and at the Pneumology service. Follow-up with serologies for diseases transmissible by blood, tests of liver and kidney function, and iron metabolism are performed according to the care protocol for patients with SCD as well as the performance of transcranial Doppler and other necessary radiological exams[8]. The patient’s last control consultation was in March 2024 when she was 29-months-old, and there was satisfactory evolution despite two severe pathologies. She was adhered to the prescribed medications. She had received all recommended vaccines.

DISCUSSION

The importance of this study was to report a rare case concerning the concomitance of SCA and CF, considering the scarcity of the scientific literature published to date. The relevance of NS in identifying rare diseases is evident, allowing for better management, surveillance, follow-up, and the mitigation of the impact of a poor prognosis through early diagnosis[11].

To the best of our knowledge, there are only 5 case reports describing the concurrence of CF and SCA in the literature between 1979 and 2024[12-16] with 5 patients included in these studies. In one study, two cases are reported[15], and two separate studies[12,16] report the case of the same patient.

SCA and CF are both autosomal recessive genetic diseases. Given that the β-globin genetic cluster is located on chromosome 11 and the CFTR gene is located on chromosome 7, the possibility of linked inheritance under normal circumstances is small[17]. The probability of the coexistence of these pathologies is 0.0001%[18].

Both genetic disorders increase the patient’s susceptibility to infections despite having entirely distinct mechanisms. Patients with CF present with recurrent cases of lung infection due to chronic colonization caused by inflammation and decreased ciliary mucus clearance[13]. In SCA, the greatest risk of infection is due to functional asplenia secondary to splenic infarction and reduced cell-mediated and humoral immune response capacity[19,20].

Asthmatic bronchitis is one of the most common underlying diseases in children with CF and SCA. Hypoxemia may be considered a problem, especially in patients with bronchiectasis and chronic pulmonary infections[12]. Patients with both comorbidities are more likely to develop hypoxia at an earlier age, and they may have a more severe pulmonary outcome. Considering this, it is reasonable to study chronic transfusion and chelation regimens for these patients[21]. It is significant to enhance the importance of phenotyping patients with SCA to avoid the risk of alloimmunization[22].

Undernutrition and underweight are common conditions in both diseases due to energy imbalance secondary to increased metabolic demand and reduced calorie intake[23]. In SCA, there is malabsorption secondary to pancreatic exocrine insufficiency as well, with the likelihood of micronutrient deficiency including folic acid, 25-OH-vitamin D, zinc, and iron[24]. Since the present study reports the case of a child who is still being monitored by the specialized hemoglobinopathies service, the follow-up period was 3 years. Given the rarity of the concomitance of SCA and CF, this manuscript involves a single case. Therefore, by describing an extremely rare association, this study adds to the few already reported cases, contributing to the existing literature. With the expansion of NS, the identification of the co-occurrence of two congenital diseases may become more common.

CONCLUSION

Managing the co-occurrence of SCA and CF is complex. Thus, the authors emphasized that rare cases (like the one presented herein) are important to enlighten the medical community about two pathologies that if not correctly treated and viewed from the perspective of their integral association can lead to high morbidity and mortality. Broadening genetic disease identification through NS enables the early diagnosis and management of these two concomitant pathologies, improving the patient’s quality of life[25,26].

ACKNOWLEDGEMENTS

We would like to thank the Minas Gerais NS team for the data provided and the patient’s family for allowing us to document the case.