Keywords

Introduction

There are a variety of genetic syndromes that are associated with defects in the immune system. They are sometimes collectively referred to as “syndromic primary immunodeficiencies” (PIDs) or “syndromic immunodeficiencies” [1, 2]. Syndromic PIDs are usually considered to encompass diseases which feature prominent non-immune system problems that form a recognizable syndrome. The immunodeficiencies associated with these syndromes can be highly variable, and not all patients may have immunodeficiency.

The International Union of Immunological Societies (IUIS) primary immunodeficiency expert committee regularly publishes a classification of inborn errors of immunity. The 2019 update on the classification included over 400 inborn errors of immunity [3]. More than 60 genetic diseases with associated immunodeficiencies are classified as “combined immunodeficiencies with associated or syndromic features,” and additional inborn errors of immunity with syndromic features can be found elsewhere in the IUIS Classification. For instance, DNA ligase IV deficiency due to mutations in LIG4, which is characterized by microcephaly, is classified with the severe combined immune deficiencies, and several pigmentary syndromes are classified with the diseases of immune dysregulation because they also cause hemophagocytic lymphohistiocytosis (HLH).

Genetic syndromes with associated immunodeficiencies can be caused by known single-gene defects or complex chromosomal abnormalities, or the cause of disease may be unknown. The spectrum of immunologic defects varies from severe and life-threatening to relatively mild. Even within the same disorder the clinical spectrum of immunologic disease may be wide. A good example of this clinical heterogeneity is DiGeorge syndrome. A patient with DiGeorge syndrome may have a complete athymia and absence of T cells (complete DiGeorge syndrome) which will result in life-threatening infections and a high likelihood of death without correction, or may manifest with only very mild/subtle immune abnormalities which can be asymptomatic [4]. While a complete review of all genetic syndromes associated with syndromic immunodeficiency is outside the scope of this chapter, we present two representative cases to illustrate their complexity and discuss additional generalities.

Case Presentation 1

A 10-year-old female was referred to immunology clinic for a history of recurrent upper respiratory infections, otitis media, and two episodes of pneumonia. She had a history of developmental delay and dysmorphism. The patient did not walk until 2.5 years of age, and speech development was also delayed. She is below grade level at school and has been in special reading and math classes. She wears hearing aids. She has not been fully vaccinated due to parental concern for association with developmental delay.

Physical examination revealed a well-nourished but short pre-pubertal female whose height and weight were <3rd percentile and 40th percentile, respectively. Facial abnormalities were noted and included long palpebral fissures, eversion of the lower lateral eyelids, long eyelashes, arched eyebrows, flattened tip of nose, and large ears (Fig. 11.1). A close inspection of the hands revealed that the fifth fingers bilaterally appeared abnormally shorter than the other digits.

Fig. 11.1
figure 1

Typical facial features of a patient with Kabuki syndrome

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Given the characteristic facial features and developmental delay, Kabuki syndrome, an autosomal dominant congenital epigenetic disease, was suspected. Laboratory evaluations were notable for low levels of IgG (240 mg/dL), IgA (13 mg/dL), and IgM (24 mg/dL). Lymphocyte subset analysis was normal. Mitogen-stimulated proliferation studies were normal. Complete blood count revealed a mildly low platelet count of 97 × 103/mcL. Genetic testing revealed a de novo heterozygous pathologic variant in the KMT2D gene, which is the most common cause of Kabuki syndrome (also known as type 1 Kabuki syndrome). KMT2D encodes lysine-specific methyltransferase 2D, part of a family of proteins that function as histone methyltransferases [5]. In contrast, type 2 Kabuki syndrome is caused by pathologic variants in KDM6A which encodes lysine-specific demethylase 6A, a histone demethylase located in the pseudoautosomal region of the X chromosome [5]. Defects in either enzyme lead to abnormal histone methylation and are thought to disrupt normal regulation of genes important in developmental and other processes [5].

Following the diagnosis, the patient was started on immunoglobulin replacement for treatment of humoral deficiency [6]. Additional screening evaluations were undertaken to look for clinical abnormalities associated with Kabuki syndrome (Table 11.1) such as renal/urinary tract and cardiac malformations which can be observed in approximately 30–40% and 40–50% of patients, respectively [7]. An abdominal ultrasound was normal. A cardiac echo revealed an atrial septal defect, and the patient was referred to cardiology. Skeletal X-rays were normal. An endocrinology referral was made for evaluation of short stature, and the patient was found to be growth hormone deficient, another complication of Kabuki syndrome [7]. A hematology referral was made and a diagnosis of immune thrombocytopenia was made after testing for platelet autoantibodies. The patient was also referred to genetics and developmental clinics.

Table 11.1 Selected non-immune features that may be present in a number of genetic syndromes with associated immunodeficiencies
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Case Presentation 2

A 15-month-old female was referred to immunology clinic for a history of recurrent severe infections. At 3 months of age, she required hospitalization for diarrhea and respiratory distress requiring oxygen. She was found to have enterovirus and rhinovirus infections. At 4 months of age, she was hospitalized with enterovirus meningitis. At that time, she was noted to have a low IgG and was started on intravenous immunoglobulin replacement. At 6 months of age, she developed Pneumocystis jirovecii pneumonia. She also had a history of failure to thrive.

On examination, the patient was noted to be thin with a protuberant abdomen. Facial features were notable for mild hypertelorism and low-set ears. Immunologic evaluations were notable for undetectable IgA and IgM, normal lymphocyte subset analysis, lack of class-switched memory B cells, normal distribution of naïve and memory T cells, and normal mitogen-stimulated proliferation studies.

A syndromic immune deficiency was suspected based on the facial features. A large commercially available genetic panel for primary immunodeficiencies was ordered and resulted with one likely pathologic and one variant of uncertain clinical significance in the DNMT3B gene which is associated with immunodeficiency, centromeric instability, and facial dysmorphism (ICF) syndrome [1] . ICF syndrome is caused by defective chromosomal methylation. Metaphase chromosomes from phytohemagglutinin-stimulated blood cultures that are performed during routine clinical chromosome analysis can exhibit several anomalies such as whole-arm deletions and pericentromeric breaks of chromosomes 1, 9 and 16, and multiradial configurations containing three or more arms of these chromosomes are striking [8,9,10,11,12]. A routine chromosome analysis was performed and revealed the typical multi-radial configurations involving chromosome 1, which confirmed the clinical diagnosis (Fig. 11.2) [13]. Due to the severity of the primary immunodeficiency, the patient ultimately underwent successful allogeneic hematopoietic cell transplantation.

Fig. 11.2
figure 2

Radial figures identified for chromosome 1 after phytohemagglutinin stimulation of a blood sample collected from a patient with ICF syndrome. (Image courtesy of Teresa Smolarek, PhD)

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General Considerations in Genetic Syndromes with Associated Immunodeficiencies

The immune evaluation for patients suspected to have a primary immunodeficiency component of their syndromic disease is essentially the same as for other patients suspected to have primary immunodeficiencies. Evaluations can be tailored or emphasized depending on the underlying disorder if it is known. For example, a patient with Barth syndrome should have a complete blood count to screen for neutropenia, and a patient with GINS1 deficiency should be screened for neutropenia as well as NK-cell deficiency. A known Kabuki syndrome patient should have careful humoral deficiency evaluations [14, 15]. A patient with DiGeorge syndrome should have careful T-cell deficiency evaluations since the syndrome is associated with athymia and partial athymia but should also have humoral deficiency evaluations since a small percentage of patients have evidence of humoral deficiency [16]. Beyond disease-specific evaluations, most patients should have broad immunologic screening tests performed as suggested in Table 11.2.

Table 11.2 Suggested initial screening immunologic evaluations to consider in patients suspected of having a genetic syndrome with associated immunodeficiency
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In patients who lack a known genetic syndrome diagnosis, immunologic testing and genetic testing should be performed in tandem when appropriate. Routine chromosome analysis and microarray should be considered in patients who lack a known underlying genetic diagnosis. Additionally, targeted sequencing of any genes linked to suspected genetic disorders should be performed. Alternatively, a primary immunodeficiency panel or whole-exome sequencing should be pursued in appropriate patients with a clear immune phenotype, syndromic features, but no obvious unifying genetic diagnosis. Collaboration with a clinical geneticist should be considered during the evaluation of complex patients so that newly described, emerging, or very rare genetic syndromes that are not common to the immunologist are not overlooked.

After a thorough immune evaluation, any needed interventions can be instigated as appropriate. Treatment is highly variable depending on the underlying disorder and the extent of immune deficiency, as observed in the two example cases above. Patients with humoral deficiency should be started on immunoglobulin replacement. Patients with significant T-cell deficiencies may require prophylaxis against Pneumocystis jirovecii and other pathogens. Patients with severe neutropenia may need antifungal and other appropriate antimicrobial prophylaxis or treatment with granulocyte-colony stimulating factor. These interventions can significantly improve the quality of life for patients and prevent life-threatening infections. Some patients with severe disorders are optimally treated with allogeneic hematopoietic cell transplantation.

Importantly, many patients will require multi-specialty evaluations and care. Obvious problems such as a cleft lip or palate will be easy to recognize and more straightforward to treat. Some syndromic complications are not obvious, and thoughtful consideration should be given to screening evaluations when appropriate if they have not been performed prior to referral to immunology clinic. For example, patients with CHARGE syndrome should be examined/evaluated for many associated problems such as colobomas, heart malformations, kidney malformations, choanal atresia, cleft lip, cleft palate, tracheoesophageal fistula, growth problems, ear malformations, hearing problems, genital abnormalities, problems with the digits or limbs, cognitive abnormalities or learning disabilities, and other problems. Selected associated complications of other syndromic PID disorders are listed in Table 11.2. Patients may need consultation and/or care with specialists in clinical genetics, neurology, cardiology, developmental pediatrics, gastroenterology, nutrition, nephrology, urology, pulmonology, otolaryngology, orthopedics, general and specialty surgery, and psychiatry and other specialists along with a variety of physical, occupational, and speech therapy services. Appropriate placements in schools and individualized education program (IEP) development may be needed as children progress through school. Multi-subspecialty care clinics can be helpful when available.

Conclusion

The evaluation and treatment of patients with genetic syndromes with associated immunodeficiencies can be complex. There are a large number of phenotypically heterogeneous disorders, many with overlapping non-immune features and a wide spectrum of immunologic defects. Some disorders are common in the primary immunodeficiency clinic and are simple to manage. For syndromes that are ill-defined or complex, evaluations and treatments can be undertaken in collaboration with clinical geneticists and multi-disciplinary specialists as appropriate. Immunologists are often able to have a significant positive impact on the quality of life of patients with syndromic PIDs through the recognition and treatment of the associated immunodeficiencies in these patients.

Clinical Pearls and Pitfalls

  • Genetic syndromes with associated immunodeficiencies are diverse.

  • Most patients suspected to have a syndromic immunodeficiency should have broad immunologic and genetic testing performed to quantify the degree of immunodeficiency and determine the underlying genetic disorder.

  • Patients may need multi-subspecialty evaluations and care.

  • Treatment interventions for immunodeficiency depend on the underlying disorder and extent of immunodeficiency.