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How to recognize something is wrong? Common skeletal dysplasia

• Introduction with general terminology and classification o Skeletal dysplasias (SD) are generalized disorders of bone and cartilage. o Characterized by the disturbance of normal process of its development and growth. o SD are genetically heterogeneous group of orthopaedic conditions with extremely broad spectrum of skeletal abnormalities that have effect on development and growth of extremities and the spine. Many patients with SD are with short stature. o SD are rare when considered individually, but as whole could consist up to 15 per cent of children in the office of paediatric orthopaedic surgeon. o Prevalence of SD is 2, 3 to 7, 8 per 10000 births and 1, 5 per 10000 births are lethal SD. o There are over 380 different genetic diseases in the group of SD. One gene could manufacture more than one protein. o Terminology. Skeletal anomalies could have four modes of pathogenesis:  Deformations caused by mechanical forces (prenatal or postnatal onset)  Disruptions occur in previously normal structures in which come agent has cause cell death (amniotic band sequence, thalidomide, rubeola embriopathy).  Dysplasia are abnormal development of particular tissue (e.g. ectoderm = chondro- ectodermal dysplasia i, e, Ellis-van Creveld syndrome).  Malformations are an inherently abnormal developmental process of particular structure.  Proportionate short stature is when trunk and limbs are equally affected.  Disproportionate short stature could be short-limb type (normal or nearly normal spine) and short-limb type with considerable spine involvement.  In SD limbs are often intrinsically disproportionate:  Rhizomelia when proximal segments are short (both femur or humerus)  Mesomelia when middle segments are short (forearms or tibias)  Acromelia when hands and feet are short. o Classification.  Traditionally SD are classified based on radiographic findings and anatomic region of the bone involved (descriptive and clinically based).  Radiographic classification is based on the different parts of the long bones that are abnormal (epiphyses, metaphyses, diaphyses). The epiphyseal, metaphyseal, and diaphyseal disorders can be further differentiated depending on whether the spine is involved (spondyloepiphyseal, spondylometaphyseal dysplasias [SMDs], or spondyloepimetaphyseal dysplasias [SEMDs]).  Multiple attempts to classify these disorders, (International Nomenclature of Constitutional Diseases of Bone, 1970, 1977, 1983, 1992, 2001, 2005, and 2009) aiming to their diagnosis and pathogenicity by clinicians and scientists.1  The SD are grouped by causative gene type, based on the underlying molecular genetic cause, most recently. This is classification that recognizes families of disorders that share a common molecular basis or pathway. In combination of the older clinical and radiographic description could be helpful to understand how growth plate might be affected in a particular disorder2, 3.  The most recent updated classification2 can be found at www.isds.ch • Ostegenesis imperfecta (OI) o OI is a heritable disorder of bone characterized by hypomineralization of the skeleton due to a defect in collagen. OI is a common (approx. freq. 1/20, 000) generalized disorder of connective tissue that predominantly affects bone4. o OI is multi-systemic and life-long disorder with a broad spectrum of phenotypic variability. o Most cases of autosomal dominant OI are caused by mutations in the genes encoding α1 or α2 chains of type I collagen (COL1A1 and COL1A2). o Four types of OI were described by Sillence in 1979. Mild (Type I) Lethal (Type II) Severe (Type III) and Moderate to Severe (Type IV). However, a number of other types of OI have recently been recognized according to genetic mutations not connected with collagen – up to XI types were described. o In childhood. many OI patients experience numerous fractures. It is not uncommon for them to have as many as 20 fractures by the age of five. Sclerae are blue that becomes gray to pale blue in adulthood. Ocular defects include scleromalalcia, keratoconus, and retinal detachment are reported. In some families, the teeth may manifest dentinogenesis imperfecta (DI) due to abnormal dentin. o Head may be tri-angular in shape. Basilar invagination, short stature, scoliosis and acetabular protrusion are frequent in Type III OI. o Treatment. There is no causative treatment for OI4. o Current pharmacologic approach is cyclic intravenous pamidronate medical therapy for moderate to severe OI (Type III and IV). o Physiotherapy is aimed to improve muscle strength, mobility, physical fitness, and pulmonary function. o Conservative treatment could be applied for mild acute fracture with short period of immobilisation to avoid vicious cycle of fracture-immobilisation-osteopenia-fracture. o Surgical solutions include telescoping intra-medullary nails of Fassier-Duval type. Non-telescoping nails could be utilized but have higher rate of re-operation. o Ultimate aim of treatment is to reduce long bone deformity and pain, preserve mobility and improve function of OI patients with combination of well balanced available treatment4. • Achondroplasia o The most common of the non-lethal SD (approx. freq. 1/20, 000) has a mutation in the gene coding for Fibroblast Growth Factor Receptor 3 (FGFR3) – a major mitogenic stimulus for proliferation of chondrocytes. o Phenotype is with dysmorphology of the head and with short stature of short-limb type (rhizomelic). o The majority of patients have normal intelligence, and lifespan, and lead independent and productive lives. The mean final height is 130 cm (M), 125 cm (F), o In early infancy, there is the potential for serious compression of the cervicomedullary spinal cord secondary to a narrow foramen magnum, cervical canal, or both. o MR imaging with studies in flexion and extension are necessary to document the cerebrospinal fluid obstruction, which can require decompression surgery. Craniofacial abnormalities can lead to dental malocclusion and tongue thrusting. o Clinically, infants can have central or obstructive sleep apnea, profound hypotonia, motor delay or excessive sweating, and can awake from sleep with emesis. Other complications include nasal obstruction, and occasionally hydrocephaly. o From early childhood, individuals with achondroplasia can develop several orthopedic manifestations that include thoraco-lumbar kyphosis, progressive bowing of the legs (genu varum), hip flexion contractures and lumbar lordosis. o Thoraco-lumbar kyphosis is accentuated with sitting approx. 90% improve without treatment. If kyphosis is >400 in child older than 6 y. surgery with concept similar to congenital kypohosis is recommended. o Growth hormone has not been effective in increasing height5. o Surgical limb lengthening has been used successfully to increase limb length by up to 12 inches, but patients need to recognize that this technique should be done during the teen years and is performed over a 2-year period. It is associated with numerous complications including stiff joints, increased fracture rate, and nerve damage6. It is controversial as to whether young children should be subjected to this procedure. o As adults, the main potential medical complication is spinal stenosis caused by narrowing of inter-pediculate distance of vertebra, worst in lumbar spine. Spinal stenosis can manifest by lower limb paresthesias, claudication, clonus, and bladder or bowel dysfunction. It is critical that these complaints are addressed promptly since without appropriate decompression surgery, paraplegia can result. • Multiple epiphyseal dysplasia is group of bone and joint disorder with variable clinical and radiographic features. Usually autosomal dominant trait but can be transmitted as an autosomal recessive trait. More detailed differentiation of MED as COMP-MED ; MATN3-MED ; rMED ; or COL9-MED with different phenotypes and prognosis. Causative gene for MED are COMP ; MATN3 ; Col9A1 ; Col9A2 ; Col9A3 ; SLC26A2. o Disease defined by radiographic findings o A skeletal dysplasia characterized by symmetrical abnormalities in long bone epiphyses, mainly at the hips, knees, ankles, and rarely wrists and hands, with relatively normal spine. o Remain unrecognized until 5 to 10 years of age. A child is shorter than peers. o Trunk is normal but shortening of limbs is variable. Symptoms are morning stiffness, difficulty in running and/or climbing stairs, joint discomfort and pain in the lower limbs, especially. o Radiographic features are bilateral symmetrical epiphyseal abnormalities in the hip similar to Legg-Calve-Perthes disease. o In the knee joint there is common sign - double-layered patella bipartite. o Ankle joints could be affected, as well as ossification of the epiphyses in hand and wrist which is delayed. o In young adult age hip or/and knee total joint replacement could be necessary. Literature 1. Superti-Furga A, Unger S. Nosology and classification of genetic skeletal disorders: 2006 revision. Am J Med Genet A 2007 ; 143:1–18. 2. Krakow D, Rimoin DL. The skeletal dysplasias. Genetics in Medicine 2010 ; 12, 327– 41 ; doi:10.1097/GIM.0b013e3181daae9b. 3. Camacho-Hübner C, Nilsson O, Sävendahl L. (Editors) Cartilage Bone Development and Its Disorders. Krager, Basel, 2011. 4. Shapiro JR, Byers PH, Glorieux FH, Sponseller PD. (Editors) Osteogenesis Imperfecta. A Translational Approach to Brittle Bone Disease. Elsevier - Academic Press, Amsterdam, Boston, Heidelberg, 2014. 5. Baron J, Sävendahl L, De Luca F, Dauber A, Philip M, Wit JM, Nilsson O. Short and tall stature: a new paradigm emerges. Nature Reviews Endocrinology 2015 ; 11:735–46. doi:10.1038/nrendo.2015.165 6. Schiedel F, Rödl R. Lower limb lengthening in patients with disproportionate short stature with achondroplasia: a systematic review of the last 20 years. Disabl Rehabil 2012 ; 34(12):982- 7. 7. National Centre for Biotechnology Information (NIH and NLM) http ; //www.ncbi.nlm.nih.gov

skeletal dysplasia ; Osteogenesis imperfecta ; Achondroplasia ; Multiple epiphyseal dysplasia

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