Kozlowski Type Research Articles

Kazimierz S. Kozlowski, 1928.

This history page in the series "Leaders in MSK Radiology" is dedicated to the achievements of the Polish radiologist Kazimierz Kozlowski, whose name is associated with the Kozlowski type of spondylometaphyseal dysplasia.

Compressive Myelopathy Secondary to TRPV4 Skeletal Dysplasia: Spondylometaphyseal Dysplasia, Kozlowski Type.

Transient receptor potential vanilloid 4 channel ( TRPV4 ) gene mutations have been described in skeletal system and peripheral nervous system pathology. The case described here is a 9-year-old male child patient, born to a nonconsanguineous marriage with normal birth history who had difficulty in walking and stiffness of joints for the last 7 years, and progressive weakness of all four limbs and urine incontinence for 1 year following falls. Physical examination showed below-average weight and height and short trunk. Musculoskeletal examination revealed bony prominence bilaterally in the knee joints and contractures in knee and elbow joints with brachydactyly; muscle tone was increased, with brisk deep tendon reflexes. Skeletal survey showed platyspondyly with anterior beaking with metaphyseal dysplasia. Magnetic resonance imaging of the spine revealed atlantoaxial instability with hyperintense signal changes at a cervicomedullary junction and upper cervical cord with thinning and spinal canal stenosis suggestive of compressive myelopathy with platyspondyly and anterior beaking of the spine at cervical, thoracic and lumbar vertebrae. Exome sequencing revealed a heterozygous de novo variant c.2389G > A in exon 15 of TRPV4 , which results in the amino acid substitution p.Glu797Lys in the encoded protein. The characteristics observed indicated spondylometaphyseal dysplasia, Kozlowski type (SMD-K). The child underwent surgical intervention for compressive myelopathy by reduction of atlantoaxial dislocation with C1 lateral mass and C2 pars fusion using rib graft and fixation using screws and rods. To conclude, for any child presenting with progressive kyphoscoliosis, short stature, platyspondyly, and metaphyseal changes, a diagnosis of SMD-K should be considered and the patient and family should be advised to avoid spinal injuries.

SMD Kozlowski type caused by p.Arg594His substitution in TRPV4 reveals abnormal ossification and notochordal remnants in discs and vertebrae

Spondylometaphyseal dysplasia Kozlowski type (SMDK) is a monogenic disorder within the TRPV4 dysplasia spectrum and has characteristic spinal and metaphyseal changes. We report skeletal MR imaging in a two-year-old patient who manifested typical clinical and radiographic features of SMDK. The diagnosis was confirmed by molecular analysis which revealed a mutation NM_021625.4:c.1781G > A - p.(Arg594His) in exon 11 of the TRPV4 gene. We have documented abnormalities in endochondral formation of the long and short tubular bones as well as round bones of the wrists and feet. The vertebral bodies had increased thickness of hyaline cartilage which enveloped ossification centers. The vertebrae and discs also had abnormalities in size, shape and structure. These anomalies were most likely the consequence of notochordal remnants presence within the intervertebral discs and in the vertebral bodies. The advantages of MR imaging in bone dysplasias caused by TRPV4 mutations are emphasized in this article.

Pyle type spondylometaphyseal dysplasia in a neonate: An interesting case

Spondylo-metaphyseal dysplasia (SMD) is a bone dysplasia with characteristic vertebral and metaphyseal changes and has different grades of severity depending on the subtype. The exact diagnosis of this infrequently seen skeletal disorder is difficult because of spectrum of severity of bone involvement seen at different ages of life. The most common reported SMD in literature is Kozlowski type (OMIM 184252) and the second most common is SMD corner fracture type (OMIM 184255). We report a case of neonatal SMD on the basis of radiological characteristics.

William Menzies Clow

<h3>Background</h3> Mutations in <i>TRPV4</i>, a gene that encodes a Ca²⁺ permeable non-selective cation channel, have recently been found in a spectrum of skeletal dysplasias that includes brachyolmia, spondylometaphyseal dysplasia, Kozlowski...

The L596-W733 Bond between S4-S5 Linker and TRP Domain Maintains Basal Activity and Enables Inactivation of TRPV4

Unlike other cation channels, all TRP (Transient Receptor Potential) channel subunits have a TRP-domain helix immediately trailing S6 that bears the gate. The role(s) of TRP-domain helix is unclear. Recent cryo-EM TRPV1 structures revealed that this helix forms a bond with the beginning of the S4-S5 linker. By homology modeling, we identified the corresponding L596-W733 bond in TRPV4 (Vanilloid type 4). L596P, likely a gain-of-function (GOF) mutation, causes bone-developmental blockage of the spondylometaphyseal dysplasia Kozlowski type (SMDK) in human. Our previous screen also isolated W733R as a GOF that suppresses grows of yeast expressing TRPV4. Here we show, when expressed in Xenopus oocytes, TRPV4 with L596P or W733R mutation displays normal depolarization-induced activation and outward rectification. However, as expected from their biological GOF phenotypes, these mutant channels indeed have higher basal open probabilities and limited responses to the strong agonist GSK1016790A. In addition, W733R current also fails to inactivate after activation during depolarization. Systematic substitutions of W733 with amino acids of different properties produce similar electrophysiological defects. The results can be consistently interpreted in the context of the homology model of TRPV4 that we have developed. Our results indicate that the TRP domain stabilizes various functional conformations by bonding to other structures, especially to the S4-S5 linker.

Mutations in PCYT1A, Encoding a Key Regulator of Phosphatidylcholine Metabolism, Cause Spondylometaphyseal Dysplasia with Cone-Rod Dystrophy

The spondylometaphyseal dysplasias (SMDs) are a group of about a dozen rare disorders characterized by short stature, irregular, flat vertebrae, and metaphyseal abnormalities. Aside from spondylometaphyseal dysplasia Kozlowski type (MIM 184252) caused by mutations in TRPV4 (MIM 605427) and spondyloenchondrodysplasia (MIM 607944) resulting from mutations in ACP5 (MIM 171640), the genetic etiologies of SMDs are unknown. 1 Two of these unexplained SMDs have ophthalmologic manifestations: SMD with cone-rod dystrophy (SMD-CRD [MIM 608940]) and axial SMD with retinal degeneration (MIM 602271). Delineated clinically a decade ago, SMD-CRD is a presumed autosomal-recessive disorder with postnatal growth deficiency leading to profound short stature; rhizomelia with bowing of the lower extremities; platyspondyly with anterior vertebral protrusions; progressive metaphyseal irregularity and cupping with shortened tubular bones; and early-onset, progressive visual impairment associated with a pigmentary maculopathy and electroretinographic evidence of cone-rod dysfunction. 2‐5 In contrast to retinitis pigmentosa, the CRDs have early involvement of cone photoreceptors. 6

TRPV4‐associated skeletal dysplasias

Dominant mutations in the TRPV4 gene result in a bone dysplasia family and form a continuous phenotypic spectrum that includes, in decreasing severity, lethal, and nonlethal metatropic dysplasia (MD), spondylometaphyseal dysplasia Kozlowski type (SMDK), and autosomal dominant brachyolmia. Several rare variant phenotypes that have some overlap but deviate in some ways from the general pattern have also been described. The known variant phenotypes are spondyloepiphyseal dysplasia Maroteaux type (Pseudo-Morquio type 2), parastremmatic dysplasia, and familial digital arthropathy with brachydactyly. Interestingly, different TRPV4 mutations have been associated with dominantly inherited neurologic disorders such as congenital spinal muscular atrophy and hereditary motor and sensory neuropathy. Finally, a small number of patients have been identified in whom a TRPV4 mutation results in a phenotype combining skeletal dysplasia with peripheral neuropathy. The TRPV4 gene encodes a regulated calcium channel implicated in multiple and diverse cellular processes. Over 50 different TRPV4 mutations have been reported, with two codons appearing to be mutational hot spots: P799 in exon 15, mostly associated with MD, and R594 in exon 11, associated with SMDK. While most pathogenic mutations tested so far result in activation of the calcium channel in vitro, the mechanisms through which TRPV4 activation results in skeletal dysplasia and/or peripheral neuropathy remain unclear and the genotype-phenotype correlations in this group of disorders remains somewhat mysterious. Since the phenotypic expression of most mutations seems to be relatively constant, careful clinical and radiographic assessment is useful in directing molecular analysis.

TRPV4‐pathy manifesting both skeletal dysplasia and peripheral neuropathy: A report of three patients

Heterozygous missense mutations of transient receptor potential vanilloid 4 channel (TRPV4) cause a spectrum of skeletal disorders, including brachyolmia, spondylometaphyseal dysplasia Kozlowski type, metatropic dysplasia, parastremmatic dysplasia, and spondyloepimetaphyseal dysplasia Maroteaux type. Similarly, heterozygous missense mutations of TRPV4 cause a spectrum of peripheral neuropathy, including hereditary motor and sensory neuropathy type IIC, congenital spinal muscular atrophy, and scapuloperoneal spinal muscular atrophy. There are no apparent differences in the amino acid positions affected or type of change predicted by the TRPV4 mutations responsible for the two disease spectrums; nevertheless, no fundamental phenotypic overlap has been shown between the two spectrums. Here, we report on three patients who had both skeletal dysplasia and peripheral neuropathy caused by heterozygous TRPV4 missense mutations. The skeletal and neurologic phenotypes of these patients covered the wide spectrum of reported TRPV4-pathies (disease caused by TRPV4 mutations). The molecular data are complementary, proving that "neuropathic" mutations can cause skeletal dysplasia but also the "skeletopathic" mutations can lead to neuropathies. Our findings suggest that pathogenic mechanisms of TRPV4-pathies in skeletal and nervous systems are not always mutually exclusive and provide further evidence that there is no clear genotype-phenotype correlation for either spectrum. Co-occurrence of skeletal dysplasia and degenerative neuropathy should be kept in mind in clinical practice including diagnostic testing, surgical evaluation, and genetic counseling.

Human skeletal dysplasia caused by a constitutive activated transient receptor potential vanilloid 4 (TRPV4) cation channel mutation.

The transient receptor potential vanilloid 4 (TRPV4) cation channel, a member of the TRP vanilloid subfamily, is expressed in a broad range of tissues where it participates in the generation of Ca2+ signals and/or depolarization of the membrane potential. Regulation of TRPV4 abundance at the cell surface is critical for osmo- and mechanotransduction. Defects in TRPV4 are the cause of several human diseases, including brachyolmia type 3 (MIM:113500) (also known as brachyrachia or spondylometaphyseal dysplasia Kozlowski type [MIM:118452]), and metatropic dysplasia (MIM:156530) (also called metatropic dwarfism or parastremmatic dwarfism [MIM:168400]). These bone dysplasia mutants are characterized by severe dwarfism, kyphoscoliosis, distortion and bowing of the extremities, and contractures of the large joints. These diseases are characterized by a combination of decreased bone density, bowing of the long bones, platyspondyly, and striking irregularities of endochondral ossification with areas of calcific stippling and streaking in radiolucent epiphyses, metaphyses, and apophyses. In this review, we discuss the potential effect of the mutation on the regulation of TRPV4 functions, which are related to human diseases through deviated function. In particular, we emphasize how the constitutive active TRPV4 mutant affects endochondral ossification with a reduced number of hypertrophic chondrocytes and the presence of cartilage islands within the zone of primary mineralization. In addition, we summarize current knowledge about the role of TRPV4 in the pathogenesis of several diseases.

Fetal akinesia in metatropic dysplasia: The combined phenotype of chondrodysplasia and neuropathy?

Dominant mutations in the receptor calcium channel gene TRPV4 have been associated with a family of skeletal dysplasias (metatropic dysplasia, pseudo-Morquio type 2, spondylometaphyseal dysplasia, Kozlowski type, brachyolmia, and familial digital arthropathy) as well as with dominantly inherited neuropathies (hereditary motor and sensory neuropathy 2C, scapuloperoneal spinal muscular atrophy, and congenital distal spinal muscular atrophy). While there is phenotypic overlap between the various members of each group, the two groups were considered to be totally separate with the former being strictly a structural skeletal condition and the latter group being confined to the peripheral nervous system. We report here on fetal akinesia as the presenting feature of severe metatropic dysplasia, suggesting that certain TRPV4 mutations can cause both a skeletal and a neuropathic phenotype. Three cases were detected on prenatal ultrasound because of absent movements in the second trimester. Case 4 presented with multiple joint contractures and absent limb movements at birth and was diagnosed with "fetal akinesia syndrome". Post-interruption and post-natal X-rays showed typical features of metatropic dysplasia in all four. Sequencing of the TRPV4 gene confirmed the presence of de novo heterozygous mutations predicting G78W (Case 1), T740I (Cases 2 and 3), and K276E (Case 4). Although some degree of restriction of movements is not uncommon in fetuses with skeletal dysplasia, akinesia as leading sign is unusual and suggests that certain TRPV4 mutations produce both chondrodysplasia and a peripheral neuropathy resulting in a severe "overlap" phenotype.

TRPV4 related skeletal dysplasias: a phenotypic spectrum highlighted byclinical, radiographic, and molecular studies in 21 new families

BackgroundThe TRPV4 gene encodes a calcium-permeable ion-channel that is widely expressed, responds to many different stimuli and participates in an extraordinarily wide range of physiologic processes. Autosomal dominant brachyolmia, spondylometaphyseal dysplasia Kozlowski type (SMDK) and metatropic dysplasia (MD) are currently considered three distinct skeletal dysplasias with some shared clinical features, including short stature, platyspondyly, and progressive scoliosis. Recently, TRPV4 mutations have been found in patients diagnosed with these skeletal phenotypes.Methods and ResultsWe critically analysed the clinical and radiographic data on 26 subjects from 21 families, all of whom had a clinical diagnosis of one of the conditions described above: 15 with MD; 9 with SMDK; and 2 with brachyolmia. We sequenced TRPV4 and identified 9 different mutations in 22 patients, 4 previously described, and 5 novel. There were 4 mutation-negative cases: one with MD and one with SMDK, both displaying atypical clinical and radiographic features for these diagnoses; and two with brachyolmia, who had isolated spine changes and no metaphyseal involvement.ConclusionsOur data suggest the TRPV4 skeletal dysplasias represent a continuum of severity with areas of phenotypic overlap, even within the same family. We propose that AD brachyolmia lies at the mildest end of this spectrum and, since all cases described with this diagnosis and TRPV4 mutations display metaphyseal changes, we suggest that it is not a distinct entity but represents the mildest phenotypic expression of SMDK.

TRPV4-pathy, a novel channelopathy affecting diverse systems

Transient receptor potential cation channel, subfamily V, member 4 (TRPV4) is a calcium-permeable nonselective cation channel of unknown biological function. TRPV4 mutation was first identified in brachyolmia, and then in a spectrum of autosomal-dominant skeletal dysplasias, which includes Kozlowski type of spondylometaphyseal dysplasia, metatropic dysplasia, Maroteaux type of spondyloepiphyseal dysplasia and parastremmatic dysplasia. Recently, TRPV4 mutation has also been identified in a spectrum of neuromuscular diseases that includes congenital distal spinal muscular atrophy (SMA), scapuloperoneal SMA, and hereditary motor and sensory neuropathy type IIC. These diverse spectrums of diseases compose a novel channelopathy, TRPV4-pathy, which could further include polygenic traits such as serum sodium concentration and a chronic obstructive pulmonary disease. In this review, we clarified the TRPV4 mutation spectrum, and discussed the phenotypic complexity of TRPV4-pathy and its pathogenic mechanisms. TRPV4-pathy may extend further to other monogenic and polygenic diseases.

Spondylo‐epiphyseal dysplasia, Maroteaux type (pseudo‐Morquio syndrome type 2), and parastremmatic dysplasia are caused by TRPV4 mutations

Recent discoveries have established the existence of a family of skeletal dysplasias caused by dominant mutations in TRPV4. This family comprises, in order of increasing severity, dominant brachyolmia, spondylo-metaphyseal dysplasia Kozlowski type, and metatropic dysplasia. We tested the hypothesis that a further condition, Spondylo-epiphyseal dysplasia (SED), Maroteaux type (MIM 184095; also known as pseudo-Morquio syndrome type 2), could be caused by TRPV4 mutations. We analyzed six individuals with Maroteaux type SED, including three who had previously been reported. All six patients were found to have heterozygous TRPV4 mutations; three patients had unreported mutations, while three patients had mutations previously described in association with metatropic dysplasia. In addition, we tested one individual with a distinct rare disorder, parastremmatic dysplasia (MIM 168400). This patient had a common, recurrent mutation seen in several patients with Kozlowski type spondylo-metaphyseal dysplasia. We conclude that SED Maroteaux type and parastremmatic dysplasia are part of the TRPV4 dysplasia family and that TRPV4 mutations show considerable variability in phenotypic expression resulting in distinct clinical-radiographic phenotypes.

Mutations in the Gene Encoding the Calcium-Permeable Ion Channel TRPV4 Produce Spondylometaphyseal Dysplasia, Kozlowski Type and Metatropic Dysplasia

The spondylometaphyseal dysplasias (SMDs) are a group of short-stature disorders distinguished by abnormalities in the vertebrae and the metaphyses of the tubular bones. SMD Kozlowski type (SMDK) is a well-defined autosomal-dominant SMD characterized by significant scoliosis and mild metaphyseal abnormalities in the pelvis. The vertebrae exhibit platyspondyly and overfaced pedicles similar to autosomal-dominant brachyolmia, which can result from heterozygosity for activating mutations in the gene encoding TRPV4, a calcium-permeable ion channel. Mutation analysis in six out of six patients with SMDK demonstrated heterozygosity for missense mutations in TRPV4, and one mutation, predicting a R594H substitution, was recurrent in four patients. Similar to autosomal-dominant brachyolmia, the mutations altered basal calcium channel activity in vitro. Metatropic dysplasia is another SMD that has been proposed to have both clinical and genetic heterogeneity. Patients with the nonlethal form of metatropic dysplasia present with a progressive scoliosis, widespread metaphyseal involvement of the appendicular skeleton, and carpal ossification delay. Because of some similar radiographic features between SMDK and metatropic dysplasia, TRPV4 was tested as a disease gene for nonlethal metatropic dysplasia. In two sporadic cases, heterozygosity for de novo missense mutations in TRPV4 was found. The findings demonstrate that mutations in TRPV4 produce a phenotypic spectrum of skeletal dysplasias from the mild autosomal-dominant brachyolmia to SMDK to autosomal-dominant metatropic dysplasia, suggesting that these disorders should be grouped into a new bone dysplasia family.

Non-collagenous protein screening in the human chondrodysplasias: link proteins, cartilage oligomeric matrix protein (COMP), and fibromodulin.

A gel-electrophoretic screening for link proteins, cartilage oligomeric matrix protein (COMP), and fibromodulin abnormalities was performed in fetuses, newborn infants, and children with various types of chondrodysplasia. Microdissected freeze-dried sections of upper tibial growth cartilage were extracted with 4M guanidinium chloride in the presence of proteolysis inhibitors. After dialysis against 8M urea, the extracts were submitted to stepwise ion-exchange chromatography to separate the large proteoglycans (aggrecans) from the other components. The latter were analyzed by gel electrophoresis, electrotransferred onto nitrocellulose membranes, and reacted with specific antibodies. Control samples from individuals with apparently normal growth were analyzed in the same runs. Two link protein bands with abnormal electrophoretic migration were found in a sporadic case of spondylometaphyseal dysplasia, Kozlowski type. Three link protein bands with the same migration as in the control samples were found in thanatophoric dysplasia, homozygous achondroplasia, achondrogenesis type II, hypochondrogenesis, Goldblatt syndrome, Desbuquois dysplasia, pseudoachondroplasia, and diastrophic dysplasia. In several pathologic cases with normal electrophoretic pattern of the link proteins, small link protein fragments appeared after reduction. The gel electrophoretic pattern of COMP was studied in thanatophoric dysplasia, diastrophic dysplasia, homozygous achondroplasia, fibrochondrogenesis, hypochondrogenesis, Goldblatt syndrome, and Kniest dysplasia. In all these cases the pattern was the same as in the control samples. The main band of fibromodulin had a normal migration rate in fibrochondrogenesis, Desbuquois dysplasia, Kniest dysplasia, and pseudoachondroplasia. It was delayed in diastrophic dysplasia.

The spondylometaphyseal dysplasias. A tentative classification

The spondylometaphyseal dysplasias constitute a very complex group of disorders. In addition to the Kozlowski type, three subgroups can be distinguished by the appearance of the femoral neck. In the first group (A) the changes are severe with absent ossification of the femoral neck and coxa vara. In the second group (B) the changes of the femoral neck are moderate and in the third (C) mild metaphyseal irregularities are only visible. This classification is not definitive but tries to put order in this confusing section of constitutional bone diseases.

Intermittent radiographic changes of rickets without defective trabecular bone mineralization in a case of spondylometaphyseal dysplasia

Although a variety of metaphyseal and spondylometaphyseal dysplasias have been identified, the natural course of the skeletal defects in these disorders has not been well characterized. We describe an 8-year-old girl with spondylometaphyseal dysplasia, most closely resembling the Kozlowski type, in whom rachitic metaphyseal involvement underwent dramatic radiographic healing when she wore leg braces; discontinuation of the braces was followed by recurrence of the growth plate abnormalities. A generalized disturbance in mineral metabolism or skeletal remodeling to explain these radiographic changes was excluded by extensive biocheḿical studies and histologic examination of an undecalcified iliac crest specimen. Our observations suggest that the defect in endochondral bone formation in the Spondylometaphyseal dysplasias may be responsive to mechanical factors and that interventions that alter stress and strain on the skeleton, such as immobilization or use of orthopedic braces, may considerably modify the radiographic appearance of the growth plate disturbance.

Pathogenic mechanisms in osteochondrodysplasias.

We performed histochemical, immunohistochemical, electron-microscopic, and microchemical studies on cartilage growth plates from sixty-eight patients with nineteen different forms of human osteochondrodysplasia. Cartilage biopsies were obtained during orthopaedic procedures. Postmortem specimens were obtained within a short time after death. The combined morphological and biochemical studies revealed specific abnormalities suggestive of a particular biochemical defect in several chondrodysplasias. In pseudoachondroplasia, non-collagenous protein accumulated in the rough endoplasmic reticulum of chondrocytes and a proteoglycan species that normally is present in the extracellular matrix was not detected by gel electrophoresis. The accumulated material was stained with antibodies against the core protein of proteoglycan. This strongly suggested that in this syndrome an abnormal core protein of a proteoglycan species is not properly transferred to the Golgi system. In Kniest syndrome, intracytoplasmic accumulation of metachromatic material, dilatation of rough endoplasmic reticulum, and an abnormal gel-electrophoretic pattern of cartilage proteoglycans suggested an abnormality of cartilage proteoglycan metabolism. Abnormalities that probably are related to degradative lysosomal processes of proteoglycans in chondrocytes were found in spondylometaphyseal dysplasia of the Kozlowski type. An abnormal organization of type-II collagen was found in fibrochondrogenesis. In diastrophic dysplasia, an abnormal organization of collagen was found in areas of interterritorial matrix and around many degenerated cells, but also in the lacunae of cells without ultrastructural signs of degeneration. The segment-long-spacing form of collagen prepared from cartilage of three patients with diastrophic dysplasia showed an abnormal cross-striation pattern in a portion between bands 42 and 45, corresponding to the position of the alpha 1(II) cyanogen-bromide-derived 10,5 peptide. This suggested that in this syndrome there is a structural alteration of the type-II collagen molecule. There was an accumulation of intracellular lipid in pyknodysostosis and in hypochondrogenesis, and of glycoproteins in several atypical cases of spondyloepiphyseal dysplasia. In a pair of twins with an atypical form of spondyloepiphyseal dysplasia, the presence of many multinucleated chondrocytes suggested a primary impairment of cell division. A knowledge of the pathogenic mechanisms in osteochondrodysplasias might improve the classification; aid in diagnosis, prognosis, and genetic counseling; and contribute to the understanding of normal endochondral growth.(ABSTRACT TRUNCATED AT 400 WORDS)

Growth cartilage abnormalities in osteochondrodysplasias

Histological histochemical, electron microscopical and microchemical studies were performed on growth cartilage in 68 cases of 19 different forms of osteochondrodysplasia. 14 “atypical” cases were also studied.Abnormalities of proteoglycans were found in Kniest disease, pseudo-achondroplasia, spondilo-epiphyseal dysplasia (Kozlowski type) and strongly suggested in thanatophoric dwarfism. Abnormalities of collagen were found in fibrochondrogenesis and in diastrophic dwarfism. There was an accumulation of intracellular lipid in pycnodysostosis and hypochondrogenesis and of glycoproteins in several atypical cases. In a pair of twins with atypical spondilo-epiphyseal dysplasia the presence of many multinucleate chondrocytes suggested an impairment of cell division. The cytochemical and ultrastructural abnormalities found in cases of polyepiphyseal dysplasia with a probably recessive transmission were different from those observed in typical polyepiphyseal dysplasia (dominant, Fairbank type). A heterogeneous group of cartilage abnormalities was found in chondrodysplasia punctata. In several cases of chondrodysplasia prococious hip arthrosis developed; abnormalities of articular chondrocytes were histochemically identical to those found in growth cartilage of patients with the disease.