Structural abnormalities and osteopathic considerations in primary immunodeficiencies

Case report

We present a 28-year-old White female with a PID associated with B cell abnormalities and PIK3R1 heterozygous gene mutation (c.1425 + 1G>A). She presented to the clinic in June 2019. Her anterior craniofacial structural anomalies had been previously described [4] and became more pronounced with age: triangular facies, ocular depression, lipodystrophy, and hypoplastic nasal alae (Figure 1). Informed consent was obtained on paper by author Marija Rowane, and an osteopathic structural clinical examinations (OSCEs) was independently performed by an attending, fellow, and osteopathic medical student, without disclosing findings until concluding each regional evaluation [5]. The use of three evaluators was utilized in order to mitigate any errors in the evaluation of the patient’s osteopathic examination. Severity, tissue texture changes, asymmetry, altered range of motion (ROM), and tenderness were organized under anatomical regions in the DO-Touch.NET Physical Examination and Treatment Form (Table 1) [5, 6]. Discrepancies were re-evaluated to confirm the diagnoses, and the table displays the consensus of the evaluators.

Figure 1:

Craniofacial presentations of a 28-year-old female patient with phosphatidylinositol 3-kinase regulatory subunit 1 (PIK3R1) mutation. (A) Anterior view. (B) Lateral view.

An extensive literature search was performed by author MC and reviewed by mentor RH utilizing the standard immunological text from Stiehm’s Immune Deficiencies textbook published in 2022 (Editors: Kathleen E. Sullivan and E. Richard Stiehm) by reviewing for musculoskeletal issues. An additional literature review was conducted utilizing PubMed, Google Scholar, OSTMED.DR, AOA Osteopathic Research Database, American Academy of Osteopathy Journal – Index, Osteopathic Research Web, CORE, iSEEK, BASE, and MEDLINE. The search terms that were utilized included “osteopathy”, “musculoskeletal”, “immune”, “skeletal dysplasia”, “skeletal”, and “PID”, and by searching the specific PIDs found within the previously mentioned Stiehm’s Immune Deficiencies textbook.

The most significant findings of the osteopathic examination included a right sidebending rotation cranial strain pattern with decreased left temporal bone motion, temporomandibular joint crepitus, and right deviation upon mandibular opening. The thoracolumbar region revealed tissue tenderness and restricted psoas ROM. Bilateral sacroiliac joint tenderness, right superior sheering, anterior innominate rotation, and left-on-left sacral flexion were associated with valgus knees.

Discussion

The skeletal frame to which the muscles, nerves, vessels, and connective tissue suspend serves as the fulcrum for the movement of the structure and bodily fluids. Movement allows for the fluids of the lymph system containing predetermined immunoglobulins and T cells to flow to an inflammatory or homeostatic site of the body for repair, infection fighting, or maintenance [7]. Although this may suggest that the bone is only an observer in the process, it also provides a microenvironment within which the immune precursors may develop and prepare for departure into the nonosseus structure. This science has been characterized as osteoimmunology [2].

Although the understanding of osteoimmunology may reflect the immune system’s effect on bone disorders, it also focuses on the effects of the bone structure on immune development. Aberrations of the structure of the bone may impact the output of effector cells of both innate and adaptive immune systems such as what are found in many primary immunodeficiencies such as DiGeorge syndrome [8], ADA deficiency [9, 10], signal transducer and activator of transcription 3 (STAT3) and 5b mutations [11, 12], cartilage-hair hypoplasia [13], and PIK3R1 mutations (described previously). Although the aberrancies of the skeletal structure do not play a role in the isolated molecular mutations found in such immune issues, these aberrancies may contribute to the overall immunological responses. A review of the structural abnormalities have not been performed in the literature, possibly due to the rarity of these disorders.

A mutation in PIK3R1 causes broad immune deficiencies, such as low serum immunoglobulin G (IgG) and A (IgA) levels with elevated IgM that progressed to an absence of IgM over the course of intravenous immunoglobulin replacement therapy [4]. The characteristic skeletal abnormalities associated with this syndrome include short stature, triangular facies, hypoplastic nasal alae, and other anterior facial bone abnormalities [9].

Combined immune deficiencies have been associated with structural abnormalities. Adenosine deaminase severe combined immunodeficiency (ADA-SCID) is a genetic defect causing immune deficiency due to the accumulation of purines within the lymphocytes [14]. The aggregation of these molecules can manifest as lymphopenia and recurrent infections. This multiorgan disorder commonly presents with skeletal abnormalities and defects. These are due to improper osteoblast activity leading to reduced bone volume and formation [14]. This has manifested previously as flared ribs, leading to a rachitic rosary [15], large low-set ears, and small bones [8].

Isolated T cell defects have been associated with structural abnormalities. DiGeorge syndrome is a genetic disorder caused by a 22q11.2 microdeletion [16]. One of the hallmarks of this disease is a hypoplastic or absent thymus, which leads to immune deficiencies caused by abnormal T cell development [16, 17]. The characteristic skeletal defects of these patients involve the cranium, jaw, palate, and other facial defects [18]. These structural irregularities can be the root of somatic dysfunctions, and osteopathic consideration should be given to these patients to enhance their bodily function.

B cell defects caused by STAT3 mutations in Hyper-IgE have also been associated with skeletal issues. Hyper-IgE syndrome can be caused by numerous mutations, but the autosomal dominant STAT3 mutation is the most prevalent [19]. The normal triad of symptoms is eczema rashes, cold skin abscesses, and recurrent sinopulmonary infections [19]. There are many nonimmunologic clinical features of this disease including characteristic facies, hyperextensibility, and scoliosis [19].

Generalized bone growth defects has been associated with immunological aberrancies. Cartilage-hair hypoplasia (CHH) is a rare disorder caused by a mutation in the RNA component of the mitochondrial RNA processing endonuclease (RMRP) RNA gene causing immune deficiencies in both cellular and humoral immunity [20]. In addition to immune dysregulation, CHH presents with growth defects, scoliosis, lumbar lordosis, thin hair, and cranial growth abnormalities [21].

Other immunodeficiencies associated with skeletal abnormalities are described elsewhere, but individual discussion is beyond the scope of this article [3]. Skeletal features found in immunodeficient patients, such as the one describe with PIK3R1 mutation, suggest that there may be additive effects on PID immunological responses.

Conclusions

Although manipulation of the skeleton has been shown not to influence the immune system, its ability to act as a fulcrum or motion, to allow flow of effector cells through lymph and its internal microenvironment, for immune development points to the importance of a full osteopathic structural examination in patients with PIDs [22]. We have described the first concise osteopathic examination of an immunodeficient patient with a PIK3R1 mutation and a review of musculoskeletal abnormalities found in more common PIDs. Our study and review of the literature does not completely identify all of the PIDs that have an associated skeletal disease due to the lack of attention to the skeletal system in these disorders.