Skeletal and Joint Manifestations of Primary Immunodeficiency Diseases

Patients with certain types of primary immunodeficiencies display a number of musculoskeletal changes. In patients with primary immunodeficiencies, septic arthritis due to pyogenic bacteria or mycoplasmal arthritis is the most common osteoarticular manifestation. In certain PIDs, chronic, noninfectious arthritis resembling rheumatoid arthritis may occur. In this paper we have extensively reviewed musculoskeletal and osteoarticular changes in PIDs and presented them under most recent IUIS primary immunodeficiency classification.


Discussion
Patients with certain types of primary immunodeficiencies display a number of musculoskeletal changes.In patients with primary immunodeficiencies, septic arthritis due to pyogenic bacteria or mycoplasmal arthritis is the most common osteoarticular manifestation.In certain PIDs, chronic, noninfectious arthritis resembling rheumatoid arthritis may occur.In this paper we have extensively reviewed musculoskeletal and osteoarticular changes in PIDs and presented them under most recent IUIS primary immunodeficiency classification.
In SCID, a number of patients developing osteomyelitis following BCG vaccination have been reported [11].A T-B+NK+ SCID patient developed Mycobacteria marinum arthritis and osteomyelitis [12].Reticular dysgenesis is associated with bone anomalies of square shaped scapular tips and cupped costochondral junctions [13].Characteristic skeletal changes of anterior rib junction, metaphyseal changes, and scapular squaring have been reported in SCID due to adenosine deaminase deficiency [14,15].Chronic adenoviral arthritis and microcephaly have been reported in Cernunnos deficiency [16].
In Wiskott-Aldrich syndrome, 29% of patients have aseptic arthritis [17][18][19][20].Ataxia Telangiectasia has been associated with rickets where all three members of a family had rickets [21].Ataxia Telangiectasia-like syndrome has been associated with microcephaly in 40% of patients [22].Nijmegen-Breakage syndrome (a rare DNA repair disorder characterized by microcephaly, immunodeficiency, and predisposition to

Introduction
Primary Immune deficiencies (PIDs) are inherited disorders that qualitatively or quantitatively affect components of the innate and adaptive immune systems.The pulmonary [1], dermatological [2], gastrointestinal [3], rheumatological [4], autoimmune [5], and hematological/oncological [6,7] manifestations of PIDs have been reviewed.However, skeletal manifestations of PIDs have not been reviewed.There are 200 different PIDs and more than 270 genes have been described that are associated with or cause PIDs.Registry data has been used in epidemiological studies to gauge PID prevalence: 5.38/100,000 in France, 5.6/100,000 in Australia, USA 86.3/100,000 inhabitants [8].Bousfiha and colleagues [9] calculated the number of PID cases based on the prevalence estimates which ranges from 390,546 using the Australian model, 6 million using the USA model while PID registries and Jeffrey Modell Centers list 27,243-60,000 cases.These PIDs have recently been reclassified into nine different categories.PID treatment ranges from immunoglobulin replacement therapy to hematopoietic stem cell transplant [10].We present a comprehensive review of skeletal and joint manifestations in PIDs according to the most recent classifications.
In familial hemophagocytic lymphohistiocytosis type 3 due to mutations in UNC13D deficiency; one patient had juvenile idiopathic arthritis [85].In Immune Dysregulation, Polyendocrinopathy, Enteropathy X linked (IPEX), 33% of patients had aseptic arthritis [86].In STAT5b deficiency, patients present with dwarfism, eczema, lymphocytic pneumonitis with 10% of patients having juvenile idiopathic arthritis [87].In Autoimmune Polyendocrinopathy with Candidiasis and Ectodermal Dystrophy (APCED), there exists a case report of a patient that had juvenile idiopathic arthritis [88].In ITCH deficiency, mutations in an E3 ubiquitin ligase called ITCH, patients may have chronic lung disease, autoimmune disease as well as dysmorphic facial features; 90% of patients had macrocephaly while all patients in the case report of 10 had dolichocephaly [89].In Autoimmune Lymphoproliferative Syndrome (ALPS) due to FAS mutation, 33% of patients developed aseptic arthritis, whereas in ALPS due to FASL mutation rarely osteopenia has been reported [90,91].IL-10Rα and IL-10Rβ deficiency are associated with aseptic arthritis [92].In Aicardi-Goutieres Syndrome Type 5 due to SAMHD1 mutations, patients present with encephalopathy, cerebral atrophy, vasculitis as well as aseptic arthritis, microcephaly, osteopenia, and sporadic reports of aseptic arthritis and scoliosis [93,94].In case reports of Spondyloenchondrodysplasia with Immune Dysregulation (SPENCD), two patients had vertebral changes and platyspondyly [95].The bone and joint findings above have also been listed for each disease in Table 4 or Table 9.
In summary, osteomyelitis and septic and aseptic (rheumatoid arthritis and lupus arthritis, respectively) are the most common osseous and joint manifestations in PID; however frequency of certain other osseous abnormalities may be observed with specific PID syndrome.

Table 2 :
Well Defined Syndrome with Immunodeficiencies.

Table 5 :
Congenital Defects of Phagocytes number, Function or Both.

Table 9 :
Phenocopies of PID Associated with Somatic Mutations.