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 60 of 30,432 patients who presented with musculoskeletal complaints were referred to the pediatric genetics department and that almost one-third of the 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 findings; multiple anomalies, genetic disorders based on the results of the radiological examination; and the lack of clinical and laboratory signs of inflammation. They had some common features of skeletal dysplasias, such as short stature, ligamentous laxity, spinal deformity, progressive finger contractures, and extremity deformities (12, 13). Systemic physical examination, systemic findings, 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 definitive clinical diagnosis had direct radiography findings specific 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, noninflammatory arthropathy, progressive coxa vara deformity, and noninflammatory 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 fluid and contributes to the elastic absorption and energy dissipation of synovial fluid at physiologic shear frequencies (18). Joint findings of CACP syndrome may be confused with the joint findings of juvenile idiopathic arthritis (7). Many mutations have been identified in the PRG4 gene, and new mutations continue to be identified (19). Diagnosis of CACP is based on clinical, radiologic, and echocardiography findings. Genetic testing can confirm 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, inflammatory 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 inflammatory 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 fibroblasts. 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 fibroblasts. 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 findings 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 findings since the phenotype is often evident (25). We reported the case of a patient with clinical and radiological features (especially cone-shaped epiphyses) that were highly suspicious for TRPS. However, a confirmatory 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 calcifications on radiological examination. In three of these patients who were previously published, radiographic findings 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-deficient patients have been reported to have immunodeficiency, 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 findings 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/flexion contractures (30). In addition to these findings, patients may have cardiac anomalies, various hematologic abnormalities, pancreatic exocrine deficiency, 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, nonspecific 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 findings of each system to occur, such as ectopia lentis, aortic root dilation, and mitral valve prolapse in children. Thus, a definite diagnosis may be delayed. Our patients who were followed up as possibly having HCTD, may have a definitive 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. Larger-scale and multi-center studies are required. Despite this limitation, to the best of our knowledge, this study represents the first of its kind in the literature evaluating the diagnostic profile of referred patients.