(a) Two sibs with MONA – note mild coarsening of the face. (b) Painful, claw hand of a child. (c) Radiograph showing osteoporosis, modeling deformities of metacarpals, and decreased number of carpal bones. (d) Adolescent boy with MONA showing significant coarsening of the face. (e) The loss of carpal bones and osteoporosis. (f) Fibrofatty masses on the soles
MONA is caused by mutations in MMP2 gene. There is gradual loss of carpal bones (osteolysis) and coarsening of features that increases with age (Fig. 47.1d, e), and there may be nodules on the soles of the feet (Fig. 47.1f). Due to marked osteoporosis, bisphosphonates have been tried but not found to be effective . Though there are very few published cases in the literature ; Indian experience shows that the disorder is seen often in India . Risk of recurrence is 25 % in the sibs of an affected child. Mutation detection is not only confirmatory but is essential for prevention of recurrences by prenatal diagnosis.
A 13-year-old boy presented with agonizing pain in the toes every evening for the last 3–4 years. There were no other signs or symptoms other than the mild coarsening of his facial features (Fig. 47.2a). His 16-year-old brother had similar symptoms and facial features. Due to agonizing pain, both brothers had left schooling. On careful examination, his back showed a few raised red non-blanching spots consistent with angiokeratomas (Fig. 47.2b). Slit-lamp examination showed corneal opacities. These findings are sufficient to make clinical diagnosis of Fabry’s disease.
(a) Note mild coarsening of the faces and agony due to pain on the face of a boy with Fabry’s disease. (b) Characteristic angiokeratomas on the back
Fabry’s disease is a lysosomal storage disease. Due to the lack of signs, most of the patients with Fabry’s disease are labeled as patients with psychiatric diseases, and the average time from symptoms to diagnosis is about 10 years or more. Fabry’s disease is a cause of chronic renal failure, stroke in young adults, and cardiomyopathy. Awareness of this disease helps in early diagnosis and prevention of complications by early institution of enzyme replacement therapy (ERT). ERT not only reduces pain but also decreases the risk of stroke and heart and kidney involvement . Hence, early diagnosis is important. Relatives of the proband including females should be investigated to identify asymptomatic affected individuals .
Genetic Disorders Presenting as Limb and Joint Pains
The two cases discussed above had some pointers toward the possibility of non-autoimmune etiology. In the presence of consanguinity, similarly affected family member, associated features such as coarse facies, angiokeratomas, corneal clouding, characteristic radiological abnormalities including involvement of other bones like spine usually point towards genetic etiology of the arthropathy. However, the first suspicion should come when the rheumatologist concludes that a case presenting with joint pains does not fit a recognizable immunoinflammatory pattern; the blood reports show normal acute-phase reactants, and the autoantibodies are negative. The most important reason to consider a genetic arthropathy is the awareness about various monogenic diseases that can present with joint and limb pains.
Progressive Pseudo-rheumatoid Arthropathy of Childhood (PPAC) (OMIM No. 208230)
This is an autosomal recessive disease caused by mutations in the WISP3 gene  which codes for a protein with roles in cell growth and differentiation. As the name suggests, the joint involvement and age of presentation are clinically very similar to rheumatoid arthritis. There is involvement of finger joints with pain, limitation of movements, and widening of interphalangeal joints mimicking rheumatoid arthritis (Fig. 47.3a, b). The patient’s height may be on the lower centile, but the stature is usually proportionate. When clinically suspected lateral radiograph of thoraco-lumbar spine should be done and presence of platyspondyly clinches the diagnosis (Fig. 47.3c), there is generalized bone dysplasia and osteoporosis. Destructive bone changes are characteristically absent. This disorder is progressive and can lead to a significant handicap (Fig. 47.3d). The disease is caused by mutation in the WISP3 gene. Two large series of 79 families with mutation proved PPAC have been reported from India [7, 8]. Identification of the disease-causing mutations in the affected member of the family or carrier parents is essential for providing prenatal diagnosis as different mutations can cause the same disease and the phenotype cannot accurately predict the genotype.
(a) The hands of a girl with PPAC showing widening of interphalangeal joints and early contractures. (b) Radiograph showing widening of interphalangeal joints and flattening of epiphyses. There are no destructive changes. (c) Platyspondyly. (d) Significant handicap due to joint involvement
Spondyloepiphyseal Dysplasia (SED) Group
Spondyloepiphyseal dysplasias are a group of disorders of varying severity. The commonest type that can present as joint pains is SED tarda. This disorder presents as difficulty in squatting and pain in the hip joints and spine in the second decade. There may be involvement of the knee joints as well. Detailed anthropometric measurements including height, arm span, and the upper segment–lower segment ratio are important to document disproportion. Shortening of the spine can be clinically suspected when the patient’s hands reach below mid-thighs (Fig. 47.4a). Radiograph of the spine shows platyspondyly, irregularity of ends with or without posterior hump on the vertebral bodies or anterior wedging (Fig. 47.4b). The hips show small and flattened femoral epiphyses during childhood and varying degree of changes of arthritis such as decreased joint space and mushrooming of head of the femur at later stages (Fig. 47.4c). In adults, mushrooming of femoral head (Fig. 47.4d), decreased joint space, and other findings of osteoarthritis are seen.
(a) A child with spondyloepiphyseal dysplasia – note the short trunk and hands reaching almost up to the knees. (b) Radiograph of hip joint showing small and fragmented epiphysis. (c) Hip radiograph of an adult with SED showing mushrooming of the head and decreased joint space. (d) Spine showing flattening of vertebral bodies
There are many varieties of SED including SED with joint laxity, Kniest dysplasia, and Stickler syndrome. The causative genes are different and many. Stickler syndrome (hereditary arthro-ophthalmopathy) needs special mention as there is associated high myopia and increased risk of retinal detachment . Etiological diagnosis of type of SED is important to look for treatable complications such as retinal dysplasia, atlantoaxial dislocation, joint contractures or dislocations, etc. A type of SED first described from Handigodu village of Karnataka (OMIM no. 6113343) is similar to Mseleni joint disease described from South Africa [10, 11].
Multiple Epiphyseal Dysplasia (MED)
The genetic bone disorders predominantly involving epiphyses are difficult to diagnose clinically. There is no disproportion and the height is usually normal. The presentation is as an early onset of osteoarthritis involving multiple joints or predominantly the hip joints, and this disease is commonly inherited in an autosomal dominant fashion. The presence of multiple affected members over generations is an important clue to diagnosis and can be obtained by drawing a pedigree. Brachydactyly and genu valgum are important clinical clues for suspecting MED (Fig. 47.5a). Radiological changes of small, irregular, or fragmented epiphyses are present only during childhood and disappear with age (Fig. 47.5b, c). The diagnosis in the adult is aided by the changes in the distal tibia. A deficiency in the lateral part of the distal tibial ossification center seen in children results in a sloping end of the tibia in adulthood. Some cases may show mild flattening of vertebral bodies. More than ten causative genes have been identified, and making a DNA-based genetic diagnosis is thus difficult. Long-term management includes judicious use of physiotherapy, analgesics, and modification of lifestyle. Some cases may need joint replacement.
Multiple epiphyseal dysplasia. (a) Genu valgum is the only obvious abnormality. (b, c) Small and flattened epiphyses of femora with irregular margins
Mucopolysaccharidosis (MPS) and Other Lysosomal Storage Disorders
Mucopolysaccharidoses are a group of genetic disorders presenting with coarse facial features, joint contractures, and hepatosplenomegaly. Some types of MPS have mental retardation. Classical cases are easy to diagnose. Milder varieties sometimes present only with joint contractures making the diagnosis difficult. Mild facial coarsening, corneal clouding on slit-lamp examination, and hepatosplenomegaly, if present, suggest the diagnosis (Fig. 47.6a–c). Radiological changes of dysostosis multiplex are diagnostic (Fig. 47.6c, d). Diagnosis of milder types like MPS ISH and MPS II without intellectual disability is important as enzyme replacement therapy (ERT) has now become available for the last few years and shows good results especially for joint contractures, hepatosplenomegaly, and skin changes. Characteristic changes of dysostosis multiplex especially in the metacarpals and spine suggest the diagnosis (Fig. 47.6c–e). Confirmation of diagnosis of type of MPS by enzyme assay is necessary before starting ERT and providing genetic counseling. Enzyme replacement therapy is available for MPS types I, II, and VI and is found to be effective in improving the outcome especially in cases without involvement of the brain . Bone marrow transplantation is another option for treatment especially in cases with early diagnosis and without significant brain involvement.
MPS ISH with normal cognitive function. (a–c) Finger contractures, umbilical hernia, mild coarsening of features, and corneal clouding. (d) Characteristic metacarpals showing pointing of proximal ends and the loss of modeling giving bullet shape. (e) Vertebrae showing anterior beaking
There are many other lysosomal storage disorders such as mucolipidosis, mannosidosis, fucosidosis, etc. which have clinical phenotypes similar to MPS (Fig. 47.7a–c). These disorders need to be considered in the differential diagnosis of a case with an MPS-like presentation but with a negative urine test for MPS. Accurate diagnosis is essential for prognosis, genetic counseling, and prenatal diagnosis to prevent recurrence in the family. Mutation testing for all lysosomal storage disorders is available in India . Importantly, prenatal diagnosis by DNA-based techniques is more accurate than the enzyme levels in fetal samples.
(a) Mucolipidosis II – note coarse faces and joint contractures. (b) Radiograph of the same child showing bullet-shaped metacarpals suggestive of lysosomal storage disorder. (c) Mucolipidosis III – predominant finger joint contractures. Eye findings like astigmatism and retinal and optic nerve abnormalities may be present
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This condition usually appears around puberty, progresses for about 10 years, and then becomes relatively static . The main features are coarsening of the facial features, clubbing of the digits, thickening of legs near ankles, and periosteal new bone formation, particularly of the distal ends of the long bones (Fig. 47.8). Clinical problems are hyperhidrosis and pain in joints. The severity of pain varies greatly. It is important to rule out systemic diseases causing clubbing. Milder forms are difficult to diagnose . Autosomal recessive and dominant inheritance has been observed. Two causative genes have been identified for the autosomal recessive and one for the autosomal dominant variety till date. The skin of the eyelids and scalp may get massively thickened giving the coarse appearance.