The Morphology of the Long Bone Physis in Hypochondroplasia and Comparison with Other Growth Disorders
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THE MORPHOLOGY OF THE LONG BONE PHYSIS IN HYPOCHONDROPLASIA AND COMPARISON WITH OTHER GROWTH DISORDERS Frederick R. Dietz* Blayne L. Fritzt Laura J. Trombinott Jerry Maynard* ABSTRACT The morphology of fibular physes from three growth disorders (achondroplasia, hypochondroplasia, and pseudoachondroplasia) were compared with normal phy- ses. Al growth disorders' physes were abnormal with the e. most consistent abnormalty occurring in the hypertrophic zone (HZ). Marked shortening of the HZ was seen in the hypochondroplast and the achondroplast. The shortening of the HZ was more severe in the achondroplast compared to the hypochondroplast. Good column formation was present in most of the physis in both of these disorders. Disorganlzation of the entire physis was present in pseudoachondroplasia. These observations are consistent with the hypothesis that physeal elongation is driven by HZ cell enlargement directed longitudinally by the extra cellular matrix. These observations suggest that abnormal HZ function may be the final common pathway of growth disorders. Hypochondroplastic dwarfism was clearly delineated from achondroplasia in the late 1960's,1'43 although de- scriptions of the condition were published in 1913 by Ravenna31 and in 1924 by Leri and Linoussier.Y Hypo- chondroplasia results in disproportionate short limbed dwarfing without rhizomelia. 1,35,38,43,45 Trunk height is normal or near normal and "stocky" build is typical. The head and facies are normal without the frontal bossing or Figure 1 the depressed nasal bridge seen in achondroplasia. A The patient at 14 years of age-typical features of hypochondropla- moderately increased lumbar lordosis is usually present. sia are present including disproportionate short limbed dwarfing and normal head and facies. Mild residual varus of legs persists 3 The hands and feet are short and broad without the trident years after fibular epiphysiodesis. hand seen in achondroplasia. Bowing of the legs is com- mon (Fig. 1). have a mild "V" shaped physis although this is less Radiographic features of hypochondroplasia include pronounced than in achondroplasts. The pelvis is small but short, relatively broad long bones with metaphyseal of flaring." 35'38'43'45 The ulnar styloid process is frequently fairly normal shape with normal flaring of the iliac crests. long as are the fibulae. Young hypochondroplasts may Narrowing of lumbar interpedicular distance is present in only 15% of hypochondroplasts and is milder than that seen in achondroplasts.45 A key radiographic feature of Department of Orthopaedics, University of Iowa Hospitals and Clinics. hypochondroplasia is the relatively normal skull. The markedly shortened base of the skull, small foramen t Medical Student, University of Iowa Hospitals and Clinics. magnum, enlarged neurocranium and frontal prominence tt Department of Orthopaedics, Northwestern University Medical seen in achondroplasia are absent (Fig. 2). School Volume 12 35 F. R. Dietz, B. L. Fritz, L. J. Trombino, J. Maynard Figure 2 A) Short, broad long bones with metaphyseal flaring are apparent at 2 years of age. B) The normal pelvis with normal flaring of iliac wings is shown at 1 year of age. Narrowing of the lumbar interpedicular distance is absent. C) Short, broad tubular bones of the hand are seen at 1 year of age. D) The relatively normal skull as compared with achondropla- sia is shown, also at 1 year of age. Hypochondroplasia is estimated to be 1/12 as common morphology. Second, iliac crest apophyses are morpho- as achondroplasia and is inherited as an autosomal domi- logically quite variable in normals and the radiographic nant trait with most cases being new mutations.38 appearance of the ilium in hypochondroplasia is normal. The distinction of hypochondroplasia as separate from Finally, normal or near normal morphology of the iliac achondroplasia is clearly illustrated by matings between apophysis has been reported in achondroplasts, who have achondroplasts and hypochondroplasts.20'43 Their progeny distinctly abnormal long bone physes.232832 are phenotypically either typical achondroplasts or hypo- We are reporting the microscopic and ultrastructural chondroplasts rather than an intermediate appearance. morphology of the fibular physis in an 11 1/2 year old boy The pathophysiology of hypochondroplasia is unknown. with hypochondroplasia and comparing this specimen with The only report of physeal morphology was by David fibular physeal specimens from a normal child, an achon- Rimoin in 1976.34 Rimoin studied iliac crest biopsies from droplastic dwarf and a pseudoachondroplastic dwarf. seven patients and felt the morphology was entirely normal. Normal physeal morphology in this disorder is CASE REPORT suspect for three reasons. First, no other described An 11 1/2 year old boy presented at the Orthopaedic dwarfing condition has entirely normal long bone physeal Clinic for evaluation of progressive bow leggedness. He 36 The Iowa Orthopaedic Journal The Morphology of the Long Bone Physis was diagnosed with hypochondroplasia based on typical clinical and roentgenographic findings (Figs. 1 & 2). His standing height was 115 cm. His weight was 26.5 kg. According to the growth chart for boys his standing height was well below the 5th percentile. His upper to lower segment ratio was 1.75. He had full range of motion of all joints and no complaints of pain. He had a 130 varus deformity of the right tibia and a 160 varus deformity of the left tibia. Radiographs revealed short broad long bones with apparent metaphyseal flaring. Lumbar interpedicular nar- rowing was not present. The pelvis and skull were Ak radiographically normal. .4&wJ Proximal and distal fibular epiphysiodeses were indi- cated for correction of the varus deformities of the tibiae. Figure 3 This photomicrograph is a 1OOX magnification of the fibular physis. Note the moderate disruption of PZ columns and the narrowed HZ MATERIAL AND METHODS consisting of only a few cells. Proximal and distal fibular physes were obtained with adjacent epiphyseal and metaphyseal bone and prepared Comparative Physeal Morphology of for light and electron microscopy. Light specimens were Hypochondroplasia, Achondroplasia and fixed in 10% neutral buffered formalin, decalcified in 5% Pseudoachondroplasia formic acid, dehydrated in alcohol, embedded in paraffin, The physeal morphology of the proximal fibula from this sectioned and stained with 1) hematoxylin and eosin, 2) 11 1/2 year old boy with hypochondroplasia was compared alcian blue and 3) safranin-0. Montages of the entire width with proximal fibular physes from a 10 year 5 month old of the excised portion of the growth plate were compared girl with achondroplasia, a 14 year old boy with using magnified photographs. The montages were exam- pseudoachondroplasia, and children with normal physes ined qualitatively to assess typical areas and variability. aged 12 year-11 months, 12 years and 14 years (Fig. 4). Specimens for electron microscopy were fixed in 2.5% 40 One of the normal specimens was obtained at autopsy glutaraldehyde in 0.05 M cacodylate buffer (ph 7.4) at C after trauma, one at for contralateral hemi- in 1% osmium tetroxide in 0.05 M sodium epiphysiodesis and post fixed and the at for leg length cacodylate with 1.5% potassium ferrocyanide. They were atrophy other epiphysiodesis then dehydrated in ethanol and acetone, and infiltrated discrepancy due to a mild contralateral congenital spastic with and embedded in Spurr embedding medium. Thin hemiparesis. sections were then cut, stained with uranyl acetate and Resting zone abnormalities were present only in lead citrate and examined on an Hitachi H-7000 electron pseudoachondroplasia. The abnormalities were fewer microscope at 75 kv. cells, cell enlargement due to the rough endoplasmic reticulum (RER) inclusions, and some cell degeneration. RESULTS Proliferative zone abnormalities were present in all dwarfing disorders. Pseudoachondroplasia had complete Morphologic Observations of the Physis in disorganization of the normal column arrangement. The Hypochondroplasia majority of the achondroplasia physis had a normal appear- The physis was abnormal in both the proliferative zone ing PZ with mild columnar disorganization. Areas of (PZ) and the HZ (Fig. 3). The morphology of the resting complete disorganization previously referred to as "cluster zone (RZ) and the zone of provisional calcification ap- areas" were uncommon.23 The hypochondroplasia PZ had peared normal. The PZ showed mild to moderate disrup- more disorganization than did the achondroplasia PZ but tion of the normal columnar arrangement in the majority of columns were still well maintained in comparison with the physis. However, the height of the PZ appeared pseudoachondroplasia. normal. The most striking finding was narrowing of the Hypertrophic zone abnormalities were striking in all HZ. Although some variability existed, the majority of the conditions. Narrowing of the HZ was present in hypochon- HZ was only 2-3 cells thick. The size of individual HZ cells droplasia and achondroplasia. The hypochondroplasia HZ appeared normal. Electron microscopic assessment of the showed 2-3 cell thickness with normal enlargement of chondrocytes appeared normal in each zone. Cell degen- cells. The achondroplasia HZ had only 1-2 cells that were eration, abnormal matrix, and intracellular inclusions were clearly in the HZ and these cells showed less enlargement not found as in some other dwarfing conditions. than in hypochondroplasia or the normal specimens. The Volume