Kniest Dysplasia
Kniest dysplasia is a type II collagenopathy with character- istic clinical, radiographic, and histological findings.
GENETICS/BASIC DEFECTS
1. Inheritance
a. Autosomal dominant
b. New dominant mutations in most cases 2. Molecular basis
a. Caused by mutations in the gene (COL2A1) that encodes type II collagen, the predominant protein of cartilage
b. A specific type of mutation and/or position of muta- tion within the collagen chain may explain the unique features of Kniest dysplasia among the type II col- lagenopathies
3. Kniest dysplasia in the middle of the following phenotyp- ic spectrum of disease
a. Achondrogenesis type II/hypochondrogenesis at the severe end
b. Spondyloepiphyseal dysplasias/spondyloepimetaphy- seal dysplasias in the middle
c. Genetically heterogeneous Stickler syndrome and familial osteoarthritis at the milder end
CLINICAL FEATURES
1. Skeletal anomalies
a. Disproportionate dwarfism b. A short trunk
c. Short, slightly bowed limbs
d. More severe rhizomelic shortness in the lower limbs e. Prominent joints
f. Delayed motor milestones secondary to joint defor- mities
g. Progressive and painful joint enlargement accompa- nied by joint contractures
h. Muscle atrophy resulting from disuse
i. Short and broad thorax with sternal protrusion j. Kyphoscoliosis
i. Dorsal kyphosis
ii. Accentuated lumbar lordosis iii. Thoracic scoliosis
k. Odontoid hypoplasia resulting in atlanto-axial insta- bility
l. Clubfoot m. Small pelvis
n. Premature osteoarthritis that restrict movement o. Waddling gait
2. Craniofacial characteristics a. Relatively large head b. Flat face
c. Shallow supraorbital ridges
d. Prominent eyes e. Flat nasal bridge
f. Short nose g. Micrognathia h. Cleft palate 3. Ocular manifestations
a. Abnormal long axial length causing high early onset myopia
b. Vitreoretinal degeneration c. Retinal detachment
d. Cortical and posterior subcapsular opacity of the lens e. Veil-like vitreous opacity in the periphery
f. Congenital glaucoma g. Blindness
4. Hearing loss
5. Prognosis: phenotype varying significantly
a. Frequently potentially life threatening complications i. Early postnatal tracheomalacia resulting in respi-
ratory insufficiency and feeding difficulties ii. Secondary failure to thrive
b. Can lead a relatively normal life with mild dispropor- tionate short stature, kyphoscoliosis, and/or craniofa- cial manifestations
DIAGNOSTIC INVESTIGATIONS
1. Radiography
a. Distinguishing radiographic features from other type II collagenopathies identifiable at birth
i. Coronal clefts of the vertebrae ii. Dumbbell-shaped femora b. Other radiographic features
i. Narrowed joint spaces ii. Platyspondyly iii. Kyphoscoliosis
iv. Short tubular bones
v. Dysplastic epiphyses and metaphyses a) Broad metaphyses
b) Enlarged and deformed epiphyses 2. Histopathology:
a. Pathologic changes of cartilage
i. “Swiss-cheese” appearance of the cartilage matrix
ii. Soft crumbly cartilage b. Microscopic changes
i. Disorganization of the growth plate ii. Deficiency of collagen matrix
iii. Poorly staining cartilage with myxoid degeneration iv. PAS positive cytoplasmic inclusions in many chondrocytes. Ultrastructurally the inclusions correspond to pools of proteinaceous material within dilated rough endoplasmic reticulum 3. Hearing test
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4. Visual evaluation
5. Molecular genetic analysis of COL2A1 mutation a. Targeted mutation
b. Mutation scanning and sequencing of entire coding region
GENETIC COUNSELING
1. Recurrence risk
a. Patient’s sib: low recurrence risk unless a parent is affected or has gonadal mosaicism
b. Patient’s offspring: 50%
2. Prenatal diagnosis
a. Difficult to diagnose Kniest dysplasia by early sonog- raphy since the biometry does not become notably abnormal until the third trimester
b. Molecular genetic analysis of COL2A1 mutation on fetal DNA obtained from amniocentesis or CVS for previously characterized disease-causing gene muta- tion in the proband
3. Management
a. Cleft palate repair
b. Hearing aid for hearing loss
c. Vitrectomy and silicon oil injection for reattaching the retina from retinal detachment
d. Orthopedic care for clubfoot and kyphoscoliosis
REFERENCES
Bromley B, Miller W, Foster SC, et al.: The prenatal sonographic features of Kniest syndrome. J Ultrasound Med 10:705–707, 1991.
Chen H, Yang SS, Gonzalez E: Kniest dysplasia: neonatal death with necropsy.
Am J Med Genet 6:171–178, 1980.
Cole WG: Abnormal skeletal growth in Kniest dysplasia caused by type II col- lagen mutations. Clin Orthop 162–169, 1997.
Douglas GR: The ocular findings in Kniest dysplasia. Am J Ophthalmol 100:860–861, 1985.
Gilbert-Barnes E, Langer LO, Jr., Opitz JM, et al.: Kniest dysplasia: radiologic, histopathological, and scanning electronmicroscopic findings. Am J Med Genet 63:34–45, 1996.
Hicks J, De Jong A, Barrish J, et al.: Tracheomalacia in a neonate with Kniest dysplasia: histopathologic and ultrastructural features. Ultrastruct Pathol 25:79–83, 2001.
Horton WA, Rimoin DL: Kniest dysplasia. A histochemical study of the growth plate. Pediatr Res 13:1266–1270, 1979.
Kniest W: Zur Abgrenzung der Dysostosis enchondralis von der Chondrodystophie. Ztschr Kinderh 70:633–640, 1952.
Kozlowski K, Barylak A, Kobielowa Z: Kniest syndrome (report of two cases).
Australas Radiol 21:60–67, 1977.
Lachman RS, Rimoin DL, Hollister DW, et al.: The Kniest syndrome. Am J Roentgenol Radium Ther Nucl Med 123:805–814, 1975.
Maumenee IH, Traboulsi EI: The ocular findings in Kniest dysplasia. Am J Ophthalmol 100:155–160, 1985.
Rimoin DL, Siggers DC, Lachman RS, et al.: Metatropic dwarfism, the Kniest syndrome and the pseudoachondroplastic dysplasias. Clin Orthop 70–82, 1976.
Siggers CD, Rimoin DL, Dorst JP, et al.: The Kniest syndrome. Birth Defects Orig Artic Ser 10:193–208, 1974.
Springer JW, Maroteaux P: Kniest disease. Birth Defects Original Article Series X(12):50–56, 1974.
Spranger J, Menger H, Mundlos S, et al.: Kniest dysplasia is caused by domi- nant collagen II (COL2A1) mutations: parental somatic mosaicism man- ifesting as Stickler phenotype and mild spondyloepiphyseal dysplasia.
Pediatr Radiol 24:431–435, 1994.
Spranger J, Winterpacht A, Zabel B: The type II collagenopathies: A spectrum of chondrodysplasias. Eur J Pediatr 153:56–65, 1994.
Spranger J, Winterpacht A, Zabel B: Kniest dysplasia: Dr. W. Kniest, his 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.
Wilkin DJ, Bogaert R, Lachman RS, et al.: A single amino acid substitution (G103D) in the type II collagen triple helix produces Kniest dysplasia.
Hum Mol Genet 3:1999–2003, 1994.
Winterpacht A, Hilbert M, Schwarze U, et al.: Kniest and Stickler dysplasia phenotypes caused by collagen type II gene (COL2A1) defect. Nat Genet 3:323–326, 1993.
Yokoyama T, Nakatani S, Murakami A: A case of Kniest dysplasia with retinal detachment and the mutation analysis. Am J Ophthalmol 136:1186–1188, 2003.
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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.
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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.
