Genetic Disorders With Symptoms Mimicking Rheumatologic Diseases: A Single-Center Retrospective Study

Ummusen Kaya Akca Hacettepe Universitesi Tip Fakultesi Pelin Ozlem Simsek Kiper Hacettepe Universitesi Tip Fakultesi Gizem Urel Demir Hacettepe Universitesi Tip Fakultesi Erdal Sag Hacettepe Universitesi Tip Fakultesi Erdal Atalay Hacettepe Universitesi Tip Fakultesi Gulen Eda Utine Hacettepe Universitesi Tip Fakultesi Mehmet Alikasifoglu Hacettepe Universitesi Tip Fakultesi Koray Boduroglu Hacettepe Universitesi Tip Fakultesi Yelda Bilginer Hacettepe Universitesi Tip Fakultesi Seza Özen (  sezaozen@gmail.com ) Hacettepe University https://orcid.org/0000-0003-2883-7868

The most commonly affected joints in all patients, in general, were those in the hands, knees, and spine, whereas in 19 patients with genetic disorders, the most commonly affected joints were those in the hands, knees, and hips.
In the laboratory evaluation of eleven patients presenting with arthralgia, joint swelling, or effusion, acute phase reactants, including erythrocyte sedimentation rate and C-reactive protein concentrations, were all within normal laboratory reference values.
Among these 60 patients, 19 (n= 19/60, 31.6%) had a nal diagnosis of a genetic disorder. The diagnoses (in decreasing frequency) were as follows: nonspeci c connective tissue disorders (n: 8), CACP syndrome (n: 3), spondyloenchondrodysplasia (SPENCD) (n: 3), PPRD (n: 2), trichorhinophalangeal syndrome (TRPS) (n: 1), LIG4 syndrome (n: 1), and H syndrome (n: 1). Parental consanguinity was detected in 25% of the patients, and this rate was similar among patients with genetic disorders. Two of the three patients who were diagnosed with SPENCD were siblings. The siblings or rst-degree relatives of the patients with other diagnoses did not have a de nitive genetic diagnosis.
Among patients with genetic diagnosis (n=19), six (31.5%) had de nite clinical and molecular diagnosis, while ve (26.3%) had de nite clinical diagnosis. Clinical features of patients with de nite clinical and molecular diagnosis and those with de nite clinical diagnosis are shown in Table 1.
Eight patients are still being followed up in the pediatric genetics department with a strongly probable diagnosis of "nonspeci c connective tissue disorder." These patients were examined for hereditary connective tissue disorders (HCTD) because joint hypermobility was detected on physical examination. Accompanying clinical ndings included easy bruising (n: 3), pes planus (n: 2), a history of spontaneous pneumothorax (n: 1), cardiac defect (n: 1), and striae (n: 1).
The remaining 41 patients without a de nite diagnosis of genetic disease were divided into ve groups: patients diagnosed with rheumatic disease at followup (n: 7), patients who were continually followed up by both the pediatric rheumatology and genetics departments (n: 18), patients followed up by the pediatric rheumatology department only (n: 8), patients followed up by the pediatric genetics department only (n: 6), and patients excluded from follow-up (n: 2) (Fig. 1).
Direct radiography ndings contributed to the diagnosis, especially in six patients. Epiphyseal enlargement of the metacarpophalangeal and interphalangeal joints (patient 5), and enlarged epiphyses of the femoral heads, platyspondyly of vertebral bodies, anterior wedging of vertebrae, and erosion in the endplates (patient 6), were observed in patients with PPRD ( Fig. 2). Radiologic examination of patient 4 revealed cone-shaped epiphyses that were highly suspicious for TRPS ( Fig. 3). Moreover, radiological examination of the 9th, 10th, and 11th patients showed platyspondyly with irregular vertebral endplates, attening of the posterior vertebral bodies, metaphyseal changes in the long bones, and enchondromatous lesions in the distal radius and ulna were consistent with the radiographic ndings of SPENCD (Fig. 4).
A total 27 patients were referred to the pediatric genetics department in the same period. The reasons for the consultation were suspicion of autoin ammatory disease in 12 (44.4%), followed by a search for juvenile idiopathic arthritis in 6 (22.2%), rheumatological diseases accompanying genetic disorders in 5 (18.5%), pre-diagnosis of chronic recurrent multifocal osteomyelitis in 2 (7.4%), and Raynaud's disease in 2 (7.4%) patients.

Discussion
In this study, 60 patients who were initially admitted to the Department of Pediatric Rheumatology but were thought to have genetic disorders were evaluated retrospectively. One-third of patients (n=19/60, 31.6%) who were subsequently evaluated at the pediatric genetics department were diagnosed with genetic disorders. Considering the high diagnosis rate, the threshold value should be kept low with regards to genetic disorders.
Non-rheumatic diseases are a substantial part of the pediatric rheumatology department referrals. As a result of a 3-year study conducted by the Pediatric Rheumatology Database Research Group in the United States, 12,939 patients were recorded in the registry and over 50% of them had non-rheumatic diagnosis (10). Similarly, among 3269 patients who presented to the pediatric rheumatology department between 1981 and 2004, 2026 of them were diagnosed (61.9%): rheumatic disease in 1032 (50.9%) and non-rheumatic disease in 994 (49.1%) of the patients (11). The distribution of non-rheumatic disease was orthopedic, mechanical or traumatic conditions (n: 345), infection (n: 231), hematologic or neoplastic disease (n: 45), and a variety of other conditions (n: 336). Genetic disorders were present in 14 of 336 patients in the other conditions category, with the most frequent (n: 4) being HCTD. In our study, a total of 30,432 patients presented to the pediatric rheumatology department over a period of 5 years. Among them, 60 were referred to the pediatric genetics department, and 19 (31.6%) were diagnosed with genetic disorders, with HCTD being the most common diagnosis (n=8/19, 42.1%) The fact that only referred patients were diagnosed, may be regarded as a "low yield." Joint swelling, deformity in the extremity, arthralgia, and skin rash were the most common symptoms presented to the rheumatology department by the referred patients. We referred the patients to the pediatric genetic department due to the presence of skeletal anomalies, short stature, joint deformity, joint hyperlaxity, and dysmorphic ndings; multiple anomalies, genetic disorders based on the results of the radiological examination; and the lack of clinical and laboratory signs of in ammation. They had some common features of skeletal dysplasias, such as short stature, ligamentous laxity, spinal deformity, progressive nger contractures, and extremity deformities (12,13). Systemic physical examination, systemic ndings, evaluation of growth and development, family history, and concomitant diseases provide an idea regarding possible genetic disorders (14).
Radiological examination has a crucial role in the diagnosis of rheumatologic diseases. Radiological imaging methods provide noninvasive information about the pathological processes that develop in the musculoskeletal system and help the diagnosis. Six patients with a de nitive clinical diagnosis had direct radiography ndings speci c to the diagnosis in our study. Direct radiography, which is the basic method of imaging, provides a differential diagnosis as well as a diagnosis of rheumatological diseases (15). According to the European League against Rheumatism (EULAR)-Pediatric Rheumatology European Society (PReS) recommendations, direct radiography is recommended, especially to detect structural abnormalities (16).
Genetic skeletal disorders can mimic juvenile idiopathic arthritis. CACP syndrome (OMIM 208250) is a rare autosomal recessive disease characterized by early onset camptodactyly, nonin ammatory arthropathy, progressive coxa vara deformity, and nonin ammatory pericardial effusion. CACP is caused by a homozygous mutation in the PRG4 gene (OMIM 604283) on chromosome 1q31 (17). The gene encodes the protein lubricin, which is involved in the diffusive behavior of synovial uid and contributes to the elastic absorption and energy dissipation of synovial uid at physiologic shear frequencies (18). Joint ndings of CACP syndrome may be confused with the joint ndings of juvenile idiopathic arthritis (7). Many mutations have been identi ed in the PRG4 gene, and new mutations continue to be identi ed (19). Diagnosis of CACP is based on clinical, radiologic, and echocardiography ndings. Genetic testing can con rm the diagnosis. However, the absence of a mutation does not rule out the diagnosis.
Another genetic skeletal disorder that may be confused with juvenile idiopathic arthritis is PPRD (OMIM 208230), which is an autosomal recessive disease caused by mutations in the WISP3 (Wnt1-inducible signaling pathway protein 3, OMIM 603400) gene. Patients usually present with polyarticular involvement and gait abnormalities. Subsequently, the involvement of the large joints and spine can cause severe joint contractures, hip disease, and spinal deformities (20,21). Swelling in the interphalangeal joints may be confused with polyarticular juvenile idiopathic arthritis; however, in ammatory markers are normal and do not respond to antirheumatic therapy (22). Ekbote et al. reported 14 patients with PPRD and stated that all of them were misdiagnosed with in ammatory arthropathy at some point in their lives (23). Numerous WISP3 mutations have been reported. However, intronic mutations leading to splicing aberrations can only be extracted from cultured skin broblasts. As in our two patients diagnosed with PPRD, the absence of mutation in the WISP-3 gene does not rule out the diagnosis without making cultured skin broblasts. Al-Mayouf stated that genetic disorders, such as mucopolysaccharidosis and idiopathic multicentric osteolysis can also mimic juvenile idiopathic arthritis as PPRD and CACP (6).
TRPS tip 1 (OMIM 190350) is characterized by craniofacial and skeletal abnormalities. The main ndings are sparse, thin hair, bulbous nasal tip, short stature, and cone-shaped epiphyses of the hands and feet, which were present in our patient (24). The diagnosis of TRPS is frequently based on clinical and radiological ndings since the phenotype is often evident (25). We reported the case of a patient with clinical and radiological features (especially coneshaped epiphyses) that were highly suspicious for TRPS. However, a con rmatory genetic diagnosis was not available because we could not perform DNA sequence analysis.
SPENCD (OMIM 607944) is a rare autosomal recessive skeletal dysplasia, characterized by neurological involvement and immune dysfunction (26). SPENCD is a member of the interferonopathy group. Immune dysregulation in SPENCD may cause autoimmune diseases such as SLE, as in our 3 patients. Our patients had short stature, arthralgia/arthritis, lupus nephritis, hypocomplementemia, and positive autoantibodies. All of them showed dense intracranial calci cations on radiological examination. In three of these patients who were previously published, radiographic ndings included metaphyseal changes in long tubular bones and platyspondyly in the vertebral bodies (27). Patients with SPENCD should be monitored for SLE and other comorbidities, while the possibility of SPENCD should be considered in SLE patients with proportionate short stature and skeletal abnormalities.
LIG4 syndrome (OMIM 606593), also known as DNA ligase IV syndrome, is a rare autosomal recessive disorder. LIG4-de cient patients have been reported to have immunode ciency, abnormal facial features, growth retardation, and predisposition to malignancy (28). Most patients may have hypothyroidism and history of lung infection. Our patient had Behçet-like ndings which have not been reported before, along with hypothyroidism, lung infection, and growth retardation (29).
H syndrome is an autosomal recessive condition, and common clinical features are hyperpigmentation, hypertrichosis, hepatosplenomegaly, hearing loss, heart anomalies, hypogonadism, low height, hyperglycemia, and hallux valgus/ exion contractures (30). In addition to these ndings, patients may have cardiac anomalies, various hematologic abnormalities, pancreatic exocrine de ciency, recurrent febrile episodes, and lymphadenopathy (31). Our patient had no conditions other than hyperpigmented lesions, type 1 diabetes mellitus, hypogonadism, short stature, and joint contractures. Mutations in the SLC29A3 gene associated with H syndrome were detected.
HCTD are caused by genetic defects of proteins that constitute the connective tissue. The most common syndromes are benign joint hypermobility syndrome, Ehlers-Danlos syndrome, and Marfan syndrome (32). Skeletal, cardiovascular and respiratory, skin, and eye features may also be present. In the genetics discipline, nonspeci c connective tissue disorder is considered according to the following scores: for systemic features <7 and/or borderline aortic root measurements (Z <3), in the absence of FBN1 mutation (33). It may take years for clinical ndings of each system to occur, such as ectopia lentis, aortic root dilation, and mitral valve prolapse in children. Thus, a de nite diagnosis may be delayed. Our patients who were followed up as possibly having HCTD, may have a de nitive diagnosis on long-term follow-up.
This study has some limitations. We included a selected group of patients who were initially referred to the Department of Pediatric Rheumatology. Largerscale and multi-center studies are required. Despite this limitation, to the best of our knowledge, this study represents the rst of its kind in the literature evaluating the diagnostic pro le of referred patients.

Conclusion
In conclusion, concomitant diseases should be considered in patients who presented to the rheumatology outpatient clinics with musculoskeletal ndings without in ammation,. Summarizing the genetic diagnostic spectrum detected in these patients will hopefully increase the awareness of the physicians involved in patients' care.

Declarations
Financial Disclosure: The authors have indicated they have no nancial relationships relevant to this article to disclose.  Radiological images of patients with SPENCD (a: metaphyseal changes in the long bones, b: platyspondyly with irregular vertebral endplates, attening of the posterior vertebral bodies)