Is a definite genetic diagnosis all we need to manage patients with Inborn Error of Immunity prenatally and during childbearing? Running title: Prenatal and Childbearing Considerations

doi:10.21203/rs.3.rs-3752248/v1

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Is a definite genetic diagnosis all we need to manage patients with Inborn Error of Immunity prenatally and during childbearing? Running title: Prenatal and Childbearing Considerations

https://doi.org/10.21203/rs.3.rs-3752248/v1

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Background: Patients with inborn errors of immunity (IEI) who want to have children face concerns about the impact of their condition on fertility, pregnancy, and disease inheritance. In tribal cultures with consanguineous marriages, prenatal genetic counseling is critical. Case presentation: 10 families with genetically confirmed IEI were reported: An architect with an autosomal dominant STAT-1 gain of function who had planned preimplantation genetic diagnosis (PGD) to prevent disease transmission. However, she unexpectedly became pregnant and underwent prenatal diagnosis (PND) at 12 weeks. Despite the diagnosis, her husband refused to allow her to abort the affected child.

Another case involved a consanguineous family who lost their first child to leukocyte adhesion deficiency type 1 (LAD1). The second child was also affected. Despite the availability of PND during the second pregnancy, the father refused the procedure.

In another instance, a first cousin couple had two children with Bruton disease. Despite being informed about the disease, the mother refused to abort her second child. Likewise, a consanguineous couple with two children affected by Ataxia Telangiectasia opted for a donated oocyte for their third child, resulting in a healthy child.

Recurrent pregnancy loss (RPL) was observed in a mother who was later diagnosed with ZAP70 deficiency. In another case, a mother with a child affected by Wiskott Aldrich Syndrome (WAS) underwent in vitro fertilization (IVF) without sex selection, resulting in a healthy boy after PND was performed during pregnancy.

In a family with multiple cases of WAS, another child was mistakenly diagnosed with anaplastic anemia. A case of LAD1 resulted in the parents' divorce, with the father denying the child's condition and impeding necessary bone marrow transplantation. In a non-consanguineous couple, the father was diagnosed with TACHI deficiency and Hypogammaglobulinemia. PND revealed that the mother and child had the same heterozygote gene, leading the mother to decide against continuing the pregnancy.

Conclusion: Genetic diagnosis alone is not enough for optimal prenatal care in immune dysregulation disorders. Factors like patient awareness, social beliefs, ethics, and economic considerations impact pregnancy decisions. Clinical immunologists must consider these factors and provide guidance for better outcomes.

Immunodeficiency Diseases

Prenatal Care

Genetic Counseling

Consanguinity

Inborn error of immunity (IEI) constitutes more than 485 (1)inherited heterogeneous disorders secondary to mutations of immune-related genes, which inclines patients to a higher risk of infectious diseases and autoimmune and lymphoproliferative manifestations (2). The current classification of IEI covers a range of disorders(3). The actual prevalence and incidence rates of IEI are debatable. The estimated prevalence of IEI is approximately 1:10,000 to 1:50,000 individuals (4–6); however, worldwide databases have demonstrated racial and geographical variation in the epidemiology of IEI (7). This variation can be explained by inheritance patterns and geographical customs such as consanguineous marriage. Inheritance patterns of IEI can vary in patients but the three main patterns are autosomal recessive (AR) pattern as the most frequent form in the offspring of consanguineous marriage, X-linked recessive (XR) and autosomal dominant (AD) (8). The global consanguinity rate ranges from approximately 1–9%, whereas it is approximately 20–56% in the Middle East/Northern Africa (MENA) region (9). Approximately 20% of the global population resides in countries with a tendency toward consanguineous marriages (10). A consanguineous marriage is defined in clinical genetics as a marriage between two couples who are second cousins or closer (7). This can be a foundation of where autosomal recessive (AR) diseases are plentiful. Among the 10 warning signs of IEI, family history is the most significant predictor, and parental consanguinity in addition to previous sibling death is associated (11). This study aims to explore the challenges faced by families with a history of IEI and to provide guidance and education to these families, particularly in high-risk regions where consanguineous marriages are prevalent. Additionally, it intends to raise public awareness regarding the significance of genetic testing in reducing the risk of inherited diseases and to highlight the need for increased access to healthcare services, medications, and social support for patients with IEI(12).

Case 1

A 31-year-old female architect has been followed up by a clinical immunologist since adolescence due to chronic mucocutaneous candidiasis and hypothyroidism. Genetic evaluation revealed autosomal dominant STAT-1 gain of function (c.812A > C, Q27lP). She has been suggested to undergo a preimplantation genetic diagnosis (PGD) or prenatal diagnosis (PND) if she decides to have a child after she gets married. However, she became unexpectedly pregnant after three recurrent abortions and therefore underwent prenatal diagnosis, which showed that the fetus was affected. The doctor recommended therapeutic abortion to prevent the potential health problems associated with the condition, but unfortunately, her husband and father refused to allow the procedure to take place. At six months old, the baby was taken to the immunology clinic with oral candidiasis, and her father still did not want to accept that the child was affected.

Case 2

A consanguine couple lost their first child due to leukocyte adhesion deficiency type 1 (LAD1) (c.1413 − 149_2080 + 839del2518insAAAA) and complications of her surgical site adhesion and severe infections. Unfortunately, for the first child, no HLA match could be found for bone marrow (B. M) transplantation (T. X) before death. The father did not accept her wife go through PND during the second pregnancy, and the second child was also affected with LAD1 and presented with several complications, such as omphalitis, recurrent anal abscesses, esophageal candidiasis, phlegmon as a complication of appendicitis, recurrent pneumonia and fungal esophagitis. She is now 8 years old, and again, no donor has been found to transplant the second child.

Case3

A first cousin couple had two boys affected with Bruton's disease. The first boy presented at the age of four with recurrent Sino-Pulmonary infections since early infancy, which caused hospitalizations several times, and had a history of meningitis and pericarditis and was referred to a clinical immunologist who started on intravenous immunoglobulins. His laboratory workup showed very low B cells (CD19 = 0.2%, CD20 = 0.5%) and hypogammaglobulinemia. Due to these clinical findings, the child was suspected to have Bruton disease and was sent for genetic diagnosis (c.163 del T mutation (Deletion)). Unfortunately, the mother becomes pregnant before genetic results are available for the first child. Amniocentesis was performed for the mother as soon as genetic results were obtained and revealed that the fetus was also affected by the disease. Although the parents were aware of Bruton's disease complications, they decided not to abort the child and gave birth to another baby boy with Bruton disease.

Case4

A consanguine couple had two children affected by ataxia telangiectasia (autosomal recessive). The first child had recurrent respiratory infections and ataxia and died when he was eight years old due to gastric cancer. The second child also began walking at a delayed age and walked on an unusually narrow base and was diagnosed with A.T. (c.6658C > T, pGln2220Ter). Now, at the age of nineteen, she could not walk with her own and relies on a wheelchair. Her speech was also impaired, and she had an abnormal liver function test and gastric discomfort.

Seven years ago, the parents decided to have a third child and were fortunate to conceive through egg donation. The third child is now healthy.

Case5

A 30-year-old female presented with recurrent abortion and was treated for auto alloimmune recurrent pregnancy loss. During her pregnancy, she received treatment to prevent abortion and gave birth to a son who was apparently healthy with a birth weight of 2700 grams. He received vaccinations regularly, but after his third dose of DTP at 6 weeks old, he developed high-grade refractory fever and lethargy. He was hospitalized, and unfortunately, the boy died a few weeks later, and genetic test results revealed ZAP70 deficiency and severe combined immunodeficiency (1). The affected boy's parents were consanguine, and his cousin from another consanguine family presented with recurrent respiratory infections at the age of 10 months. Laboratory tests showed hypogammaglobulinemia in this case as well as Zap70 deficiency (c.T250C p.C84R variant in exon 3 of the ZAP70 gene (NM-001079)).

Case6

A 13-year-old was born into a consanguineous family and presented at the age of 5 years with recurrent pneumonia, bronchiectasis, eczema, thrombocytopenia, and recurrent molluscum contagion. He was diagnosed with Wiskott-Aldrich syndrome (WAS) (c.738_739insTG) and is still waiting for a matched donor for bone marrow transplantation.

The parents decided to have another child and were referred to gynecology for sex selection, but the gynecologist performed IVF without sex selection for the mother and did not notice the referral notes at the time of operation. Fortunately, the mother gave birth to a healthy son.

Case7

An 18-year-old male presented with a history of allergic manifestations (including atopic dermatitis), purpuric lesions and low platelets, recurrent infection, and dysentery since childhood. Laboratory tests showed an increase in the level of IgE (IgE = 678 mg/dl), a low level of IgM (IgM = 0.1 mg/dl), thrombocytopenia (platelets = 20,000), and microcytic anemia. Although there were five deceased females in his mother's side family due to Wiskott-Aldrich syndrome (C.777 + lG > A), he had never been tested for sequence analysis of his genomic DNA and was treated for aplastic anemia for several years with cyclosporine, prednisone, and cyclophosphamide, but unfortunately, the hematologist did not notice the family history. Later, genetic analysis revealed that mutations of the WAS gene on the X chromosome were responsible for his clinical manifestations, yet no suitable donor could be found among the family members or unrelated donors.

Case8

A 6-year-old girl presented with a history of omphalitis, delayed detachment of the umbilical cord, gingivitis, and recurrent diarrhea. She also experienced abdominal pain, colitis, and arthritis. During early infancy, she had leukocytosis and neutrophilia in several blood tests. DNA sequencing led to the diagnosis of leukocyte adhesion deficiency type 1 (LAD I) (INTEGRIN, BETA-2; cytogenetic location: 21q22.3), and she was referred for bone marrow transplantation. However, while waiting for an appropriate donor, she underwent treatment for active osteomyelitis in her right knee. Unfortunately, her parents divorced because her father did not accept his child's condition as a case of immunodeficiency, and he did not allow his wife to follow up on the bone marrow transplantation.

Case9

A 30-year-old nonconsanguineous male in marriage presented with recurrent upper and lower respiratory tract infections and was diagnosed with hypogammaglobulinemia, specifically TACI deficiency. Prenatal screening was performed during his wife's pregnancy, which showed the same heterozygous gene in both the fetus and mother. This led to a decision on whether to end the pregnancy by abortion, but ultimately, they decided to continue the pregnancy. A baby boy was delivered, but unfortunately, her mother refused to bring her child for the follow-up visit after the immunologist informed her mother that her immunoglobulin level was lower than normal on the first visit at six months old. The father informs his physician that her wife wants a divorce because of his recent illness.

Case10

A 25-year-old female presented with autoimmune hepatitis and recurrent upper and lower respiratory tract infections and urticaria since childhood. Immunophenotyping showed a decrease in CD4 and CD8 T cells, normal numbers of NK cells, and hypogammaglobulinemia. Whole exome sequencing revealed a mutation in the Nuclear Factor Kappa-B subunit 2 (NFKB2) gene (c.1009C > T (p. Arg337Ter)). Despite her clinical condition, she decided to become pregnant. Her pregnancy was complicated with preeclampsia and terminated at 35 weeks. Her healthy daughter was born via cesarean section. However, weeks after cesarean delivery, the mother was diagnosed with acute myeloid leukemia (AML) and passed away due to severe fungal pneumonia. The child was subsequently adopted by her maternal grandparents, and her father refused to take care of her.

Inborn Errors of Immunity (IEI) constitute more than 485 inherited heterogeneous disorders and are rare diseases affecting the body's ability to fight infections (13). As autosomal recessive (AR) is the most frequent form in the offspring of consanguineous marriage, this can be a foundation of where autosomal recessive (AR) diseases are profuse. Among the 10 warning signs of IEI, family history is the most significant predictor (11).

The prevalence of IEIs varies depending on the region, but consanguineous marriages increase the risk of these disorders. Families with a positive history of IEIs face significant challenges, including the need for genetic counseling and carrier screening. The ethical and cultural considerations surrounding reproductive choices for families with IEIs are complex. Prenatal diagnosis, preimplantation genetic diagnosis, and abortion, which in Iran require the husband's consent due to cultural and legal norms, could lead to family conflicts and disruption and is heavily influenced by national laws as well as traditional and religious beliefs, are options that families may consider. However, these options may conflict with cultural and religious beliefs. Therefore, it is critical to provide social support and education to families to help them make informed decisions. Another choice involves utilizing egg donation to conceive healthy children, as was done in the fourth case, to prevent a third child from being affected by ataxia telangiectasia. The alternate option is to undergo prenatal diagnosis (PND). We recommended PND for both the first case (STAT-1 gain of function) and the second case (LAD1), but the first family declined to undergo the procedure, while the second expressed doubt in the reliability of the test results and subsequently chose not to proceed with an abortion. As a result, children born in both cases were affected. The other option for healthy children is preimplantation genetic diagnosis (PGD), which suggests STAT-1 gain of function, as in the first case, but she had already conceived before following the PGD process. The second and third cases chose to give birth to affected babies with LAD1 and Bruton disease, but in case number 9, the affected fetus with query immunodeficiency was not brought for follow-up. Recent research on the DHX15 and TACI genes may lead to new diagnostic and treatment options for IEIs. However, further research is necessary to fully understand the implications of these findings. DHX15, a newly identified DEAH-box RNA helicase, is commonly overexpressed in AML patients and associated with poor overall survival, and overexpression of DHX15 activates NF-kB transcription, as was observed in case 10 (13, 14) TACI stimulates T-cell-independent antibody responses and plasma cell differentiation and stabilizes BAFF-driven B-cell activation. Mutations in encoding the TACI gene are associated with common variable immunodeficiency (CVID), and these mutations predispose CVID patients to autoimmunity and lymphoproliferation (15)

Islamic law permits sex selection for X-linked disorders(16, 17), as demonstrated in the sixth case. Additionally, in the third case, sex selection could be beneficial to prevent the birth of a son with Bruton disease. The rising incidence of X-linked disorders is a significant concern, particularly since they can account for up to 22% of cases in first-degree cousin marriages. This figure stands in stark contrast to the incidence of marriages between unrelated individuals(18). Regrettably, in case seven, consanguineous marriage persisted as a habit despite more than five fatalities among those affected by WAS. In Iran, for instance, where cousin marriage is a common practice due to its acceptance in Islamic culture, terminating a pregnancy may be deemed culturally or religiously sensitive and therefore unacceptable; abortion is only permitted for affected fetal cases before the 19th week of gestation or when the pregnancy poses a risk to maternal health. Nonfetal/nonmaternal cases are not legally allowed (19). There are additional concerns similar to those encountered in case 6, such as the use of in vitro fertilization for sex selection. However, it is important to consider several factors, including the expertise of the gynecologist, to know the exact aim of choosing sex selection for families who had an affected child by an X-linked genetic disorder. Additionally, there is potential discomfort or embarrassment felt by the father during sperm separation (20). It may be helpful to include information about these topics in educational plans for families considering this option (21).

In addition to some other Middle Eastern countries, there is a husband who exercised marital control in Iran, as some women are emotionally and financially completely marital dependent or under partner violence, as they cannot look for medical treatment without the permission of their husbands, their father, mothers-in-law or other family members, sometimes even if they are experiencing severe illness, as case 10 had the same issue (22, 23). Because of political boycotts, these patients have low access to immunotherapy medications, making it even more difficult to keep them in a stable level of immunity. These women need social support to be educated about the burden of giving birth to an affected child and the need for health services in case of need for any medical or psychological care. In addition, there are new authorized rules in the Islamic Republic of Iran, outlined in Article 53 of the Youth of the Crowd Law, regarding screenings during pregnancy. The article specifies that these tests are no longer covered by insurance services, and primary care physicians are no longer permitted to request screening tests(24).

Another crucial topic to consider in the next step is when we encounter a child who is affected, it is important to also take into account their psychosocial needs when preparing for a bone marrow transplantation. According to a study conducted by Divdar et al, bone marrow transplant candidates have a significantly higher mean score for psychosocial needs compared to candidates for kidney and liver transplants, which are among the most common types of transplant surgeries (25). Despite being a candidate for bone marrow transplant, Case 8 refers to an individual who is suffering from LAD1 is currently living in a family on the verge of divorce. This situation may exacerbate their psychosocial needs and make it even more challenging for them to cope with the demands of the transplant process.

In conclusion, families with a history of IEIs face significant challenges, including ethical and cultural considerations surrounding reproductive choices and the need for emotional and psychological support throughout the treatment process. Clinical immunologists play an essential role in providing guidance and education to patients and their families, and new research may lead to improved diagnostic and treatment options for these disorders. Therefore, definite genetic diagnosis would not explain all we need to manage patients with Inborn Error of Immunity prenatally.

IEI - Inborn errors of immunity

PGD - Preimplantation genetic diagnosis

PND - Prenatal diagnosis

LAD1 - Leukocyte adhesion deficiency type 1

WAS - Wiskott Aldrich Syndrome

IVF - In vitro fertilization

RPL - Recurrent pregnancy loss

ZAP70 - Zeta-chain-associated protein kinase 70

TACHI - T-cell receptor alpha chain deficiency

AR - Autosomal recessive

XR - X-linked recessive

AD - Autosomal dominant

MENA - Middle East/Northern Africa

B.M. - Bone marrow

T.X. - Transplantation

CD - Cluster of Differentiation

AT - Ataxia telangiectasia

DTP - Diphtheria, Tetanus, Pertussis vaccination

IgE - Immunoglobulin E

IgM - Immunoglobulin M

DNA - Deoxyribonucleic acid

TACI - Transmembrane activator and calcium-modulating cyclophilin ligand interactor

NK cells - Natural killer cells

NFKB2 - Nuclear Factor Kappa-B subunit 2

AML - Acute myeloid leukemia

Ethics Approval and Consent to Participate:

In this study, all methods and procedures were conducted in accordance with relevant guidelines and regulations. Prior to the commencement of the study, ethics approval (approval ID: IR.MUI.MED.REC.1399.1190) was obtained from the Institutional Research Ethics Committee at the Isfahan University of Medical Sciences in Isfahan, Iran. For study participation, oral informed consent was obtained from all participants and their parents or legal guardians (for participants under 16 years old), as approved by the Institutional Research Ethics Committee. Participants were provided with a clear explanation of the study's purpose, potential risks and benefits, and their rights as participants. Confidentiality and anonymity were strictly maintained throughout the research process to ensure privacy.

Consent for Publication:

Not applicable

Availability of Data and Materials:

The data and materials used in this study are available upon request. Interested parties can contact the corresponding author to discuss access to the data. Access to the data is subject to meeting ethical and legal requirements concerning participant confidentiality and privacy.

Competing Interests:

The authors declare no competing interests. There are no financial or non-financial conflicts of interest that could influence the interpretation or presentation of the findings.

Funding:

This research was not supported by any funding sources. The authors declare no financial or non-financial conflicts of interest that could influence the interpretation or presentation of the findings.

Authors' Contributions

The authors of this article made equal contributions to the research, writing, and editing of the manuscript. Each author brought their unique expertise and perspectives to the project. Negin Salemi and Shima Bakhshesh conducted the primary data analysis and provided statistical expertise. Aryana Zamanifar conducted the literature review and contributed theoretical expertise. Roya Sherkat, Amir Bahreini, and Rasoul Salehi supervised the project, offering guidance on study design and interpretation of results. All authors thoroughly reviewed and edited the manuscript, and they all approved the final version.

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No competing interests reported.

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Is a definite genetic diagnosis all we need to manage patients with Inborn Error of Immunity prenatally and during childbearing? Running title: Prenatal and Childbearing Considerations

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Abstract

Background

Case presentation

Discussion

Abbreviations

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References

Additional Declarations

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