Kniest Dysplasia

Kniest dysplasia is a type II collagenopathy with character- d. Prominent eyes istic clinical, radiographic, and histological findings. e. Flat nasal bridge f. Short nose GENETICS/BASIC DEFECTS g. Micrognathia h. Cleft palate 1. Inheritance 3. Ocular manifestations a. Autosomal dominant a. Abnormal long axial length causing high early onset b. New dominant mutations in most cases myopia 2. Molecular basis b. Vitreoretinal degeneration a. Caused by mutations in the gene (COL2A1) that c. encodes type II , the predominant protein of d. Cortical and posterior subcapsular opacity of the lens cartilage e. Veil-like vitreous opacity in the periphery b. A specific type of mutation and/or position of muta- f. Congenital glaucoma tion within the collagen chain may explain the unique g. Blindness features of Kniest dysplasia among the type II col- 4. Hearing loss lagenopathies 5. Prognosis: phenotype varying significantly 3. Kniest dysplasia in the middle of the following phenotyp- a. Frequently potentially life threatening complications ic spectrum of disease i. Early postnatal tracheomalacia resulting in respi- a. Achondrogenesis type II/ at the ratory insufficiency and feeding difficulties severe end ii. Secondary failure to thrive b. Spondyloepiphyseal dysplasias/spondyloepimetaphy- b. Can lead a relatively normal life with mild dispropor- seal dysplasias in the middle tionate short stature, kyphoscoliosis, and/or craniofa- c. Genetically heterogeneous and cial manifestations familial osteoarthritis at the milder end DIAGNOSTIC INVESTIGATIONS CLINICAL FEATURES 1. Radiography 1. Skeletal anomalies a. Distinguishing radiographic features from other type II a. Disproportionate collagenopathies identifiable at birth b. A short trunk i. Coronal clefts of the vertebrae c. Short, slightly bowed limbs ii. Dumbbell-shaped femora d. More severe rhizomelic shortness in the lower limbs b. Other radiographic features e. Prominent joints i. Narrowed joint spaces f. Delayed motor milestones secondary to joint defor- ii. Platyspondyly mities iii. Kyphoscoliosis g. Progressive and painful joint enlargement accompa- iv. Short tubular bones nied by joint contractures v. Dysplastic epiphyses and metaphyses h. Muscle atrophy resulting from disuse a) Broad metaphyses i. Short and broad thorax with sternal protrusion b) Enlarged and deformed epiphyses j. Kyphoscoliosis 2. Histopathology: i. Dorsal kyphosis a. Pathologic changes of cartilage ii. Accentuated lumbar lordosis i. “Swiss-cheese” appearance of the cartilage iii. Thoracic matrix k. Odontoid hypoplasia resulting in atlanto-axial insta- ii. Soft crumbly cartilage bility b. Microscopic changes l. Clubfoot i. Disorganization of the growth plate m. Small pelvis ii. Deficiency of collagen matrix n. Premature osteoarthritis that restrict movement iii. Poorly staining cartilage with myxoid degeneration o. Waddling gait iv. PAS positive cytoplasmic inclusions in many 2. Craniofacial characteristics chondrocytes. Ultrastructurally the inclusions a. Relatively large head correspond to pools of proteinaceous material b. Flat face within dilated rough endoplasmic reticulum c. Shallow supraorbital ridges 3. Hearing test

585 586 KNIEST DYSPLASIA

4. Visual evaluation Gilbert-Barnes E, Langer LO, Jr., Opitz JM, et al.: Kniest dysplasia: radiologic, 5. Molecular genetic analysis of COL2A1 mutation histopathological, and scanning electronmicroscopic findings. Am J Med Genet 63:34–45, 1996. a. Targeted mutation Hicks J, De Jong A, Barrish J, et al.: Tracheomalacia in a neonate with Kniest b. Mutation scanning and sequencing of entire coding dysplasia: histopathologic and ultrastructural features. Ultrastruct Pathol region 25:79–83, 2001. Horton WA, Rimoin DL: Kniest dysplasia. A histochemical study of the growth plate. Pediatr Res 13:1266–1270, 1979. GENETIC COUNSELING Kniest W: Zur Abgrenzung der Dysostosis enchondralis von der 1. Recurrence risk Chondrodystophie. Ztschr Kinderh 70:633–640, 1952. Kozlowski K, Barylak A, Kobielowa Z: Kniest syndrome (report of two cases). a. Patient’s sib: low recurrence risk unless a parent is Australas Radiol 21:60–67, 1977. affected or has gonadal mosaicism Lachman RS, Rimoin DL, Hollister DW, et al.: The Kniest syndrome. Am J b. Patient’s offspring: 50% Roentgenol Radium Ther Nucl Med 123:805–814, 1975. 2. Prenatal diagnosis Maumenee IH, Traboulsi EI: The ocular findings in Kniest dysplasia. Am J a. Difficult to diagnose Kniest dysplasia by early sonog- Ophthalmol 100:155–160, 1985. Rimoin DL, Siggers DC, Lachman RS, et al.: Metatropic dwarfism, the Kniest raphy since the biometry does not become notably syndrome and the pseudoachondroplastic dysplasias. Clin Orthop 70–82, abnormal until the third trimester 1976. b. Molecular genetic analysis of COL2A1 mutation on Siggers CD, Rimoin DL, Dorst JP, et al.: The Kniest syndrome. Birth Defects fetal DNA obtained from amniocentesis or CVS for Orig Artic Ser 10:193–208, 1974. previously characterized disease-causing gene muta- Springer JW, Maroteaux P: Kniest disease. Birth Defects Original Article Series X(12):50–56, 1974. tion in the proband Spranger J, Menger H, Mundlos S, et al.: Kniest dysplasia is caused by domi- 3. Management nant collagen II (COL2A1) mutations: parental somatic mosaicism man- a. Cleft palate repair ifesting as Stickler phenotype and mild spondyloepiphyseal dysplasia. b. Hearing aid for hearing loss Pediatr Radiol 24:431–435, 1994. c. Vitrectomy and silicon oil injection for reattaching Spranger J, Winterpacht A, Zabel B: The type II collagenopathies: A spectrum of chondrodysplasias. Eur J Pediatr 153:56–65, 1994. the retina from retinal detachment Spranger J, Winterpacht A, Zabel B: Kniest dysplasia: Dr. W. Kniest, his d. Orthopedic care for clubfoot and kyphoscoliosis patient, the molecular defect. Am J Med Genet 69:79–84, 1997. Wilkin DJ, Artz AS, South S, et al.: Small deletions in the type II collagen triple helix produce Kniest dysplasia. Am J Med Genet 85:105–112, 1999. REFERENCES Wilkin DJ, Bogaert R, Lachman RS, et al.: A single amino acid substitution Bromley B, Miller W, Foster SC, et al.: The prenatal sonographic features of (G103D) in the type II collagen triple helix produces Kniest dysplasia. Kniest syndrome. J Ultrasound Med 10:705–707, 1991. Hum Mol Genet 3:1999–2003, 1994. Chen H, Yang SS, Gonzalez E: Kniest dysplasia: neonatal death with necropsy. Winterpacht A, Hilbert M, Schwarze U, et al.: Kniest and Stickler dysplasia Am J Med Genet 6:171–178, 1980. phenotypes caused by collagen type II gene (COL2A1) defect. Nat Genet Cole WG: Abnormal skeletal growth in Kniest dysplasia caused by type II col- 3:323–326, 1993. lagen mutations. Clin Orthop 162–169, 1997. Yokoyama T, Nakatani S, Murakami A: A case of Kniest dysplasia with retinal Douglas GR: The ocular findings in Kniest dysplasia. Am J Ophthalmol detachment and the mutation analysis. Am J Ophthalmol 136:1186–1188, 100:860–861, 1985. 2003. KNIEST DYSPLASIA 587

Fig. 1. A neonate with Kniest dysplasia showing short trunk and large head, similar to SED congenita. However, the moderately shortened limbs show prominent joints. Radiographs show enlarged metaphyses of limb bones (dumbbell-shaped femora) and coronal clefts of the ver- tebrae. The remaining findings are similar to those of SED congenita. The physeal growth zone of femur is hypercellular and disorganized. The transverse cleft beneath the physis is an artifact. Many chondro- cytes contain cytoplasmic inclusions (arrows); they are seen in the resting cartilage and the zone of proliferation, similar to those of SED congenita. 588 KNIEST DYSPLASIA

Fig. 2. Three children with Kniest dysplasia showing varying features of the dysplasia: short trunk dwarfism, flat facies, myopia, deafness requiring hearing aids, dorsal kyphosis, accentuated lumbar lordosis, short and broad thorax with sternal protrusion, and prominent joints with restricted joint mobility.