Rhizomelic Chondrodysplasia Punctata, Type 1

A number sign (#) is used with this entry because of evidence that rhizomelic chondrodysplasia punctata type 1 (RCDP1) is caused by homozygous or compound heterozygous mutation in the PEX7 gene (601757), which encodes the peroxisomal type 2 targeting signal (PTS2) receptor, on chromosome 6q23.

Mutations in the PEX7 gene can also cause an atypical phenotype with longer survival and less neurologic involvement than rhizomelic chondrodysplasia punctata, normal or near-normal growth, and absence of rhizomelia (see PBD9B, 614879).

Description

Rhizomelic chondrodysplasia punctata (RCDP) is a peroxisomal disorder characterized by disproportionately short stature primarily affecting the proximal parts of the extremities, a typical facial appearance including a broad nasal bridge, epicanthus, high-arched palate, dysplastic external ears, and micrognathia, congenital contractures, characteristic ocular involvement, dwarfism, and severe mental retardation with spasticity. Biochemically, plasmalogen synthesis and phytanic acid alpha-oxidation are defective. Most patients die in the first decade of life. RCDP1 is the most frequent form of RCDP (summary by Wanders and Waterham, 2005).

Individuals with RCDP1, carrying mutations in the PEX7 gene, have cells of peroxisome biogenesis disorder (PBD) complementation group 11 (CG11, equivalent to CGR). For information on the history of PBD complementation groups, see 214100.

Genetic Heterogeneity of Rhizomelic Chondrodysplasia Punctata

RCDP2 (222765) is caused by mutation in the gene encoding acyl-CoA:dihydroxyacetonephosphate acyltransferase (GNPAT; 602744) on chromosome 1q42. RCDP3 (600121) is caused by mutation in the gene encoding alkyldihydroxyacetonephosphate synthase (alkyl-DHAP synthase) (AGPS; 603051) on chromosome 2q31. RCDP5 (616716) is caused by mutation in the gene encoding peroxisomal biogenesis factor-5 (PEX5; 600414) on chromosome 12p13.

Whereas RCDP1 is a peroxisomal biogenesis disorder (PBD), RCDP2 and RCDP3 are classified as single peroxisome enzyme deficiencies (Waterham and Ebberink, 2012).

Nomenclature

Baroy et al. (2015) called the peroxisomal fatty acyl-CoA reductase 1 disorder (PFCRD; 616154) RCDP4 despite the fact that patients with PFCRD do not have the characteristic skeletal abnormalities observed in RCDP.

Clinical Features

Rhizomelic chondrodysplasia punctata is a rare, multisystem, developmental disorder, characterized by severe bilateral shortening and metaphyseal changes of femora and/or humeri, microcephaly, characteristic facial features, and severe psychomotor retardation and spasticity. Cataracts are present in about 72% of cases, and skin changes in about 28% (Spranger et al., 1971). The coronal cleft of the vertebral bodies is demonstrable radiologically and appears to represent embryonic arrest with cartilage occupying the cleft between the anterior and posterior parts of the vertebral bodies (Wells et al., 1992).

There are several different disorders with similar punctate cartilaginous changes, e.g., X-linked chondrodysplasia punctata (see 302960); the multiple forms of the Zellweger syndrome (see 214100); maternal ingestion of certain anticoagulants (dicoumarol or warfarin; 118650) in early pregnancy; and even occasionally trisomy 18 (Rosenfield et al., 1962). Thus, care must be taken in diagnosing an infant or child presenting with punctate calcifications (Spranger et al., 1971). The combination of punctate calcifications, rhizomelia, and the biochemical abnormalities (deficient red cell plasmalogens and accumulation of phytanic acid) is pathognomic for RCDP (Wanders and Waterham, 2005).

Melnick (1965) observed a child with punctate calcifications in the offspring of a father-daughter mating.

Early literature on CDP is confusing because the heterogeneous etiology of punctate calcifications was not recognized. For example, the evolution of punctate calcifications in early life into multiple epiphyseal dysplasia was observed by Silverman (1961) and the inheritance seemed to be dominant; thus it is likely that an entity (or entities) other than RCDP was represented (see 118650). Fifteen-year follow-up of a heterogeneous group of patients with punctate calcifications was provided by Comings et al. (1968). Saddle nose secondary to involvement of the facial bones was noted in about 40% of cases in a series of cases of punctate calcifications according to Fritsch and Manzke (1963) and is more typical of warfarin embryopathy. In Australia this feature led to the designation koala bear syndrome (Danks, 1970). It was the suggestion of a group convened in Paris by the European Society of Pediatric Radiology that this phenotype be called chondrodysplasia punctata (Maroteaux, 1970). They suggested that cases labeled as chondrodystrophia calcificans by De Lange and Janssen (1949), Gekle (1963), Phillips (1957) (case 2), and Putschar (1951) actually included patients with Zellweger syndrome.

Happle (1981) suggested that cataracts are consistently absent in the autosomal dominant form of chondrodysplasia punctata (118650) and present in about two-thirds of the rhizomelic and X-linked dominant (302950) forms. In the rhizomelic form, the opacities tend to be bilateral and symmetric; in the X-linked form, they are usually asymmetric and often unilateral.

Gray et al. (1992) reported an affected female, the offspring of first-cousin parents, who had no punctate calcification evident at birth, although there was coronal clefting of the vertebrae. Early cataract formation was evident by 18 weeks, and at 8 months of age a further skeletal survey revealed traces of punctate calcification of the epiphyses and spine. The patient had pulmonary stenosis and atrial septal defect. The electroretinogram was grossly abnormal.

Heymans et al. (1985) first suggested that rhizomelic CDP is a peroxisomal disorder. Because of clinical similarities to Zellweger syndrome, they did studies that showed evidence for their proposal. In 5 patients with rhizomelic chondrodysplasia punctata, they found a severe deficiency of plasmalogens in phospholipids from red cells and deficient activity of the enzyme acyl-CoA:dihydroxyacetone-phosphate acyltransferase in platelets and cultured skin fibroblasts. Moreover, as in Zellweger syndrome, the plasma phytanic acid concentrations were found to be elevated.

Wanders et al. (1986) did cell-fusion studies of complementation between RCDP and either Zellweger syndrome or the infantile form of Refsum disease (266500). In either case the activity of acyl-CoA:dihydroxyacetonephosphate acyltransferase was restored, thus indicating the distinctness of RCDP from these other 2 conditions. The other 2 did not complement; this may indicate that they are caused by allelic mutations, or contrariwise they may be nonallelic but perhaps 'complementation cannot occur after fusion because of the absence of preexisting peroxisomes' (Wanders et al., 1986).

Poulos et al. (1988) studied 2 patients, 1 of whom survived only 13 days and the other of whom was still alive at age 8 years. Both showed markedly reduced fibroblast alkyldihydroxyacetone phosphate synthase activity (approximately 10% of control mean); in contrast, dihydroxyacetone phosphate acyltransferase activity was only moderately reduced (50% of control mean). Plasmalogen levels were very low in brain and liver. The accumulation of phytanic acid observed in plasma and liver was paralleled by a reduced ability of the patients' fibroblasts to oxidize phytanic acid. There appear to be abnormalities in 2 seemingly unrelated pathways, phytanic acid oxidation and ether lipid biosynthesis.

Heikoop et al. (1990) demonstrated a deficiency of 3-oxoacyl-CoA thiolase in peroxisomes and impaired processing of the enzyme. Peroxisomal thiolase is present in its unprocessed precursor form (44 kD).

By complementation analysis after somatic cell fusion, Heikoop et al. (1992) investigated the genetic relationship among 10 patients with clinical manifestations of rhizomelic chondrodysplasia punctata. Biochemically, 9 of 10 patients had a partial deficiency of acyl-CoA:dihydroxyacetone phosphate acyltransferase (DHAP-AT) and impairment of plasmalogen biosynthesis, phytanate catabolism, and the maturation of peroxisomal 3-oxoacyl-CoA thiolase. A fusion of fibroblasts from these 9 patients with Zellweger fibroblasts resulted in complementation as indicated by restoration of DHAP-AT activity, plasmalogen biosynthesis, and punctate fluorescence after staining with a monoclonal antibody to peroxisomal thiolase. No complementation was observed after fusion of different combinations of the 9 RCDP cell lines, suggesting that they belong to a single complementation group. The tenth patient was characterized biochemically by a deficiency of DHAP-AT and an impairment of plasmalogen biosynthesis. Maturation and localization of peroxisomal thiolase were normal, however. Furthermore, fusion of fibroblasts from this patient with fibroblasts from the other 9 patients resulted in complementation as indicated by the restoration of plasmalogen biosynthesis. Heikoop et al. (1992) concluded that at least 2 different genes can lead to the clinical phenotype of RCDP.

Sheffield et al. (1989) reviewed 103 cases of chondrodysplasia punctata seen in Melbourne over a 20-year period. In 8 cases RCDP was diagnosed; only in this type were abnormalities of peroxisomal function found. In 21 cases Conradi-Hunermann CDP was diagnosed but difficulties in defining this subcategory were evident. Two cases appeared to represent an X-linked dominant form. No definite X-linked recessive cases were seen. In 57 cases the CDP was of the mild type, including 9 cases due to phenytoin exposure during pregnancy and 3 cases due to Warfarin embryopathy. A newly characterized mesomelic form was present in 2 cases. Classification was impossible in 13 cases. Sheffield et al. (1989) concluded that Binder syndrome (155050) should be classified as a mild form of chondrodysplasia punctata.

Wardinsky et al. (1990) reported 5 patients with this disorder, 3 of whom survived beyond 1 year of age. Three of the 5 patients had no radiographic evidence of vertebral body clefts. Three biochemical abnormalities appear to be distinctive of the peroxisome abnormality of RCDP: reduced phytanic acid oxidation activity; a defect in plasmalogen synthesis; and presence of the unprocessed form of peroxisomal thiolase. Poll-The et al. (1991) described the case of a female infant, offspring of consanguineous parents, with RCDP and characteristic biochemical findings but distinctive clinical features. At 12 days of age, the girl showed absence of movement of the upper limbs with pain on passive movement of both shoulders. There were no other clinical abnormalities except for a flattened nasal bridge. Stippled epiphyses were found at many sites. At 7.5 months of age, bilateral cataracts were present. Length was at the 10th percentile.

Borochowitz (1991) described a girl with unusual features that included short and broad humeri, symmetrical brachymetacarpy, especially of the fourth metacarpals, and hypoplastic distal phalanges as well as sagittal clefting of vertebral bodies and punctate calcifications at various areas including the entire spine, sacrum, hands, feet, trachea, and thyroid cartilage. He suggested that this represents a distinct form of chondrodysplasia punctata which might be called the humerometacarpal (HM) type.

Dimmick et al. (1991) found de novo deletion del(4)(p14p16) in a newborn male with what they called rhizomelic CDP, but with normal peroxisomes as indicated by electron microscopy and normal plasmalogen synthesis in cultured fibroblasts. Fetal ultrasound demonstrated rhizomelia with epiphyseal stippling and diaphragmatic hernia. Facial anomalies with left cleft lip and bilateral cleft palate were present. The infant died soon after birth. Autopsy findings included polymicrogyria, pulmonary hypoplasia, and polysplenia.

Agamanolis and Novak (1995) examined the brain of a girl with CDP who died at the age of 3 years. The brain weighed 525 g (half of normal size) but myelination was normal. The thalamus and basal ganglia were diminished in size and the cerebellum showed severe loss of Purkinje cells.

Khanna et al. (2001) described a 2-year-old female with RCDP leading to advanced cervical stenosis as detected by MRI studies of the cervical spine. MRI studies were done when the patient was 13 months old because of radiographic findings and the presence of lower extremity spasticity greater than upper extremity spasticity.

White et al. (2003) delineated the natural history of RCDP through analysis of 35 previously unreported cases and a review of 62 published cases with respect to length of survival and cause of death. Survival was greater than previously reported, with 90% surviving up to 1 year and 50% surviving up to 6 years. The cause of death was usually respiratory in nature. All infants were found to have joint contractures, bilateral cataracts, and severe growth and psychomotor delays.

Clinical Management

To aid in the clinical management of children with RCDP, Duker et al. (2017) presented detailed growth curves for length, weight, and head circumference for individuals from infancy to 12 years of age, derived from retrospective data from 23 individuals with RCDP types 1 and 2 confirmed by molecular and/or biochemical studies. The growth curves were stratified by age as well as by plasmalogen level, with those with higher plasmalogen levels grouped as 'non-classic.'

Molecular Genetics

Braverman et al. (1997), Motley et al. (1997), and Purdue et al. (1997) demonstrated that homozygous or compound heterozygous mutations in the PEX7 gene (601757) are responsible for RCDP1, otherwise known as peroxisomal biogenesis disorder complementation group 11 (CG11). PEX7, identified in yeast, encodes the receptor for peroxisomal matrix proteins with the type 2 peroxisome targeting signal (PTS2). PTS2 is an N-terminal sequence with the consensus arg/lys-leu-X5-gln/his-leu. By homology probing, Braverman et al. (1997) identified human and murine PEX7 genes and found that expression of either corrects the PTS2-import defect characteristic of RCDP cells. They also expressed an N-terminal epitope-tagged version of the PEX7 protein in mammalian cells and found that it was localized mainly in the cytosol. With the caveat that this was an overexpressed, epitope-tagged form of the protein, this result suggested that the PTS2 receptor (PEX7), like the PTS1 receptor (PEX5; 600414), binds its protein ligands in the cytosol. In a collection of 36 RCDP probands, Braverman et al. (1997) found 2 inactivating PEX7 mutations: the first, L292X (601757.0001), was present in 26 of the probands, all with a severe phenotype; the second, A218V (601757.0002), was present in 3 probands, including 2 with a milder phenotype. A third mutation, G217R (601757.0003), the functional significance of which was yet to be determined, was present in 5 probands, all compound heterozygotes with L292X. They suspected the founder effect as the explanation for the high frequency of L292X in northern Europeans; none of the 26 patients either heterozygous or homozygous for L292X was of African or Asian descent.

Motley et al. (1997) stated that 86% of RCDP patients belong to CG11 (also known as complementation group I in the Amsterdam nomenclature). Cells from CG11 show a tetrad of biochemical abnormalities: a deficiency of (i) dihydroxyacetonephosphate acyltransferase, (ii) alkyldihydroxyacetonephosphate synthase, (iii) phytanic acid alpha-oxidation, and (iv) inability to import peroxisomal thiolase. These deficiencies indicated involvement of a component required for correct targeting of these peroxisomal proteins. Deficiencies in peroxisomal targeting are also found in Saccharomyces cerevisiae pex5 and pex7 mutants, which show differential protein input deficiencies corresponding to 2 peroxisomal targeting sequences (PTS1 and PTS2). These mutants lack PTS1 and PTS2 receptors, respectively. Like S. cerevisiae pex7 cells, RCDP cells from CG11 cannot import a PTS2 reporter protein. Motley et al. (1997) cloned PEX7 based on its similarity to 2 yeast orthologs. All RCDP patients in CG11 with detectable PEX7 mRNA were found to contain mutations in PEX7. A mutation resulting in a C-terminal truncation of PEX7 (601757.0001) cosegregated with the disease, and expression of PEX7 and RCDP fibroblasts from CG11 corrected the PTS2 protein import deficiency. Purdue et al. (1997) likewise cloned the human ortholog of yeast PEX7 and demonstrated that the gene is defective in RCDP.

Animal Model

Brites et al. (2003) generated Pex7-knockout mice (Pex7 -/-), which were severely hypotonic at birth and exhibited growth impairment. Mortality was highest in the perinatal period, although some mice survived beyond 18 months. Biochemically, Pex7 -/- mice displayed a severe depletion of plasmalogens, impaired alpha-oxidation of phytanic acid, and impaired beta-oxidation of very long chain fatty acids. Pex7 -/- mice displayed increased neuronal density in parts of the cerebral cortex and had a delay in neuronal migration. Analysis of bone ossification in newborn Pex7 -/- mice revealed a defect in ossification of distal bone elements of the limbs as well as parts of the skull and vertebrae.