Different Diagnoses, Common Ancestry: 22q11.2 Deletion Syndrome and Wiskott-Aldrich Syndrome in the Same Family

Abstract

Introduction

Newborn screening program enable pre-symptomatic detection patients with severe forms of T and B cell immunodeficiency. Despite the high prevalence of 22q11.2 deletion syndrome, only 1 in 10 patients develop lymphopenia that can be detected by newborn screening program. This report presents a unique familial case of 22q11.2 deletion syndrome and Wiskott-Aldrich syndrome, highlighting the importance genetic counseling and a detailed analysis of the family history.

Case Presentation

The article presents a case of the two rare genetic diseases in patients from the same family: 22q11.2 deletion syndrome in one and Wiskott-Aldrich syndrome in the other. Both diseases belong to the group of combined immunodeficiencies with syndromic features and are potentially life-threatening conditions requiring follow-up by a wide range of specialists: immunologists, geneticists, cardiologists, endocrinologists, and medical psychologists.

Conclusion

Our work aimed to describe the clinical manifestations, genetic characteristics, and diagnosis of these disorders. It is worth emphasizing that the timely diagnosis of not only 22q11.2 deletion syndrome but also other primary immunodeficiencies in the Russian Federation became possible due to the introduction of extended neonatal screening into widespread practice. For such patients, comprehensive early interventional treatment and follow-up by a wide range of specialists is important to improve prognosis and quality of life.

Established Facts

• 22q11.2 deletion syndrome is a rare genetic disorder characterized by broad clinical heterogeneity. In the majority of cases (approximately 90–95%), 22q11.2 deletion syndrome arises de novo; however, inherited cases from an affected parent have also been reported.

• Wiskott-Aldrich syndrome is another rare disorder that cannot be reliably detected by newborn screening as T-lymphocyte differentiation is not significantly impaired during the first months of life.

• Co-occurrence of two different syndromes in one family is a rare event.

Novel Insights

• Apparently healthy parents of patients with 22q11.2 deletion syndrome should be also examined.

• The со-occurrence of two rare syndromes in one family is unlikely, but never ruled out, so it is extremely important to obtain a complete family history.

Introduction

According to the existing classification, the inborn errors of immunity (IEI) are divided into several groups, among which combined immunodeficiencies (CID) with associated or syndromic features are singled out [1]. Most of them exhibit marked clinical polymorphism, which makes their diagnosis difficult in some cases. With the introduction of the newborn screening (NBS) program, it has become possible to diagnose a number of IEIs at the pre-symptomatic stage [2]. NBS program in Russia aimed to detect patients with severe forms of T and B cell immunodeficiency. It is based on the measurement of T-cell receptor excision circles (TREC) and kappa-deleting recombination excision circles (KREC) levels in dried blood spot for each child, regardless of clinical manifestations [2]. If second-tier PCR revealed deviations from normal values, subsequent confirmation suggests performing multi-color flow cytometry and FISH analysis for 22q11.2 deletion syndrome and trisomy 21 by FISH analysis [2].

22q11.2 deletion syndrome (22q11.2DS) (OMIM #188400) is a rare genetic disorder with a birth prevalence of approximately 1/4,000 newborns [3]. Despite the high prevalence, only one in ten 22q11.2DS patients develop lymphopenia that can be detected by NBS using FISH analysis on the confirmation step [2]. 22q11.2DS is characterized by a characteristic cranio-facial dysmorphism, congenital heart defects, delayed psychomotor development of varying degrees, disorders of the thymus and parathyroid, resulting in T-cell immunodeficiency and hypocalcemia, respectively [3]. The 22q11.2 locus is considered one of the most unstable loci in the human genome due to the presence of a cluster of eight low-copy repeats (LCR22). They are commonly denoted as LCR22A-to-H and act as ideal substrates for nonallelic homologous recombination, resulting in heterozygous deletions of different sizes and the reciprocal duplication syndrome 22q11.2. 22q11.2DS is characterized by an autosomal dominant type of inheritance and exhibits incomplete penetrance. Most cases of 22q11.2DS occur de novo, but familial cases are also described, accounting for about 5–10% of all patients [3].

Wiskott-Aldrich syndrome (WAS, OMIM #301000) is another rare genetic disease also belonging to the group of syndromal CID, its incidence in Russia is approximately 1/250,000 newborns [4]. WAS clinically manifests with thrombocytopenia and various degrees of immune dysregulation symptoms such as infections, autoimmunity, dermatitis, and malignancies. WAS exhibits an X-linked type of inheritance and is caused by hemizygous variants in the WAS gene [5]. Though some lymphopenia is common in WAS, it is not usually enough for affected newborns to be detected by NBS [5]. This article presents a case of two rare genetic diseases within the same family and highlights the importance of genetic counseling and a detailed analysis of the family history.

Case Report

Proband S., born in the 38th week of gestation, from non-consanguineous parents, demonstrated low TREC (10 copies/10⁵ cells; N: >100 copies/10⁵ cells) and normal KREC values upon NBS. Immunophenotyping of peripheral blood lymphocytes revealed decrease in CD3+ (596 cells/μL, N: 1,900–3,900), CD3+CD4+ (458 cells/μL, N: 1,300–3,100), CD3+CD4+CD45RA+ (74%, N: 78–92%), CD3+CD8+ (113 cells/μL, N: 400–1,300), CD3+CD8+CD45RA+ (73.8%, N: 79–94%) subpopulations of T-lymphocytes with normal levels of B-cells (1,394 cells/μL, N: 200–800). According to the NBS algorithm [6], FISH analysis was performed, which revealed the microdeletion of 22q11.2, which confirmed the diagnosis of 22q11.2DS (shown in Fig. 1a). Further MLPA analysis (using SALSA^® MLPA^® Probemix P250 DiGeorge ver. B2 by MRC Holland BV, Amsterdam, the Netherlands, according to the manufacturer’s protocol) revealed a classical 3 Mb deletion of the region LCR22A-LCR22D (shown in Fig. 1b). Due to the presence of phenotypic characteristics, the mother of the proband was also examined, and the deletion was found in her as well (shown in Fig. 1c). Notably, she experienced no significant complaints in somatic status and infections history.

Fig. 1.

Genetic analysis of the family. a Interphase FISH-analysis result with TBX1 (22q11.2)/SHANK3 (22q13) probes on uncultured blood cells of proband S: deletion of the DiGeorge locus shows hybridization only to the control (SHANK3) green probe. b results of MLPA analysis of proband S.’s DNA. The upper blue line indicates a peak ratio of 1.3, and any probes above this line represent a duplication; the lower red line indicates a peak ratio of 0.75, and any probes below this line indicate a deletion. The probes between the two lines are considered normal. The black vertical line indicates the position of LCR regions in 22q11.2. The patient has LCR22A-LCR22D deletion, spanning 3 Mb (red spots). c Metaphase FISH-analysis result on a cultured peripheral blood lymphocytes of the proband’s mother: the normal chromosome 22 with both red (TBX1, 22q11.2) and green (SHANK3, 22q13) probes hybridization, while the chromosome 22 with deletion of the DiGeorge locus shows hybridization only to the control (SHANK3) green probe (indicated by arrows). d Pedigree of the described family. The proband is indicated by an arrow. The cousin of the proband with WAS is indicated in yellow. Examined individuals are marked with a star. Analysis of variant NM_000377.2:c.1421T>C in the WAS gene in WAS patient S. (e) and his mother (f).

Analysis of the family history revealed that the maternal cousin of Proband S. has been found to have a diagnosis of WAS (shown in Fig. 1d, e). He was born from the first pregnancy at 38–39 weeks of gestation. The initial symptoms included atopic dermatitis, the presence of blood in the stool, and bronchitis. Thrombocytopenia with a count as low as 40,000 cells/μL was observed at the age of 2 months. The molecular-genetic diagnosis identified a novel missense variant in the WAS gene NM_000377.2:c.1421T>C, p.(Met474Thr), in the hemizygous state, affecting the VCA-domain of the protein. The variant is not found in the gnomAD database (v3.1.2) and is evaluated as potentially affecting protein function according to the predictive tools. According to the ACMG recommendations, the variant should be classified as a likely pathogenic based on criteria PM1, PM2, PP4, and PP3. The variant was shown to be inherited from his healthy mother (shown in Fig. 1f). Additionally, MLPA analysis was performed to evaluate the presence of 22q11.2 deletion syndrome in the buccal swab sample of the proband S; the results showed no evidence of a 22q11.2 deletion. The father of the WAS patient is unavailable for 22q11.2 deletion testing.

Discussion

The co-occurrence of two different genetic syndromes within a single family is a rare event, particularly when both conditions are IEIs. In the present family, two distinct IEIs – 22q11.2 deletion syndrome and WAS – were identified in different family members.

22q11.2DS is a rare disease characterized by broad clinical polymorphism. In most cases (90–95%), the 22q11.2DS occurs de novo, but it is possible to be inherited from parents [3]. In our case, the proband’s mother has a mild phenotype, which is why she was not diagnosed earlier. NBS can detect only 5–10% of all patients with 22q11.2DS because not all of them develop lymphopenia due to wide clinical polymorphism [7]. The clinical manifestation in a patient with WAS fits into the classical clinical picture of the disease: thrombocytopenia, atopic manifestations, and immunological impairment [5]. In the cytoplasm, the WAS protein (WASP) is predominantly autoinhibited due to the interaction between the C-terminal VCA-domain and the GBD-domain of the same molecule [8]. Activation of WASP occurs when the GBD-domain and the GTPase interact and release the C-terminal site to bind to the complex of other proteins [8]. The proband’s variant affecting the VCA-domain could potentially change the stability of the interaction between the WASP domains or prevent binding of the C-terminal domain with other molecules. Though functional analysis is lacking, the variant likely results in loss of function due to the correlation between variant type and immunological changes [9]. WAS cannot be detected by NBS because T-lymphocyte differentiation is not significantly impaired in the first months of life [10].

The case of the occurrence of two hereditary diseases in one family is very rare, but it is possible and requires a thorough analysis of family history and a step-by-step diagnostic approach. To date, no cases of a co-occurrence of WAS and 22q11.2DS within the same family have been reported. Although this specific combination appears to be novel, the coexistence of multiple genetic disorders within a single family results in a complex and potentially misleading diagnostic picture. It is a rare but well-recognized phenomenon. For example, a case of the co-occurrence of 22q11.2DS and Noonan syndrome, which required additional testing, such as whole-exome sequencing, has been described in the literature [11]. Another case of a combination of 22q11.2DS with hypoparathyroidism, deafness, and renal dysplasia syndrome due to GATA3 haploinsufficiency has been reported [12]. WAS is considerably rarer; consequently, reports describing its combination with other genetic conditions are limited, although one such case has been documented in the literature: a familial case of detection of WAS syndrome and Fanconi anemia with overlapped clinical features of both syndromes, such as thrombocytopenia, increased susceptibility to both malignancy and autoimmune disease [13]. In certain situations, establishing an accurate diagnosis may be further complicated by the overlap and clinical heterogeneity of the involved disorders [11, 13]. In this context, genetic testing of apparently unaffected parents represents an important component of medical genetic counseling as it informs recurrence risk assessment, long-term follow-up, and individualized treatment planning for affected individuals.

These diagnostic challenges highlight the critical importance of advanced screening approaches, which can be effectively addressed through NBS. Early diagnosis of IEIs has been significantly improved by the NBS program, and it is now possible to diagnose CID at the pre-symptomatic stage and improve prognosis.

Statement of Ethics

The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Ethics Committee of the Research Centre for Medical Genetics (Protocol No. 7, dated December 12, 2022). Written informed consent was obtained from each participant and/or their legal representative, as appropriate. Written informed consent was obtained from the parent/legal guardian of the patient for publication of the details of their medical case and any accompanying images. The CARE Checklist has been completed by the authors for this case report and is attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000550498).

Conflict of Interest Statement

The authors declare that they have no conflict of interest.

Funding Sources

This study was supported by the state assignment of the Ministry of Science and Higher Education of the Russian Federation.

Author Contributions

A.B.: conceptualization; investigation; visualization; and writing – original draft preparation, review, and editing. A.M.: writing – original draft preparation and conceptualization. Z.M., D.P., N.B., and E.R.: investigation, validation, and writing – review and editing. D.Z., I.E., D.B., A.O., D.Y., Y.R., G.S., D.O., G.D., and I.S.: resources, data curation, and writing – review and editing. R.Z.: project administration, supervision, and writing – review and editing. N.S., A.P., S.V., and A.S.: supervision, project administration, and writing – review and editing. S.K.: resources and writing – review and editing. A.M.: conceptualization, investigation, writing – review and editing, project administration, resources, and data curation.

Funding Statement

This study was supported by the state assignment of the Ministry of Science and Higher Education of the Russian Federation.

Data Availability Statement

The data presented in this study are available on reasonable request from the corresponding author.