Rhizomelic chondrodysplasia punctata (RCDP) is a peroxisomal disorder characterized by disproportionately short stature primarily affecting the proximal parts of the extremities, typical facial appearance including a broad nasal bridge, epicanthus, high-arched palate, dysplastic external ears, and micrognathia, congenital ... Rhizomelic chondrodysplasia punctata (RCDP) is a peroxisomal disorder characterized by disproportionately short stature primarily affecting the proximal parts of the extremities, 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, 2004). 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. While RCDP1 is a peroxisomal biogenesis disorder (PBD), RCDP2 and RCDP3 are classified as single peroxisome enzyme deficiencies (Waterham and Ebberink, 2012).
RCDP 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 ... RCDP 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, 2004). 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), Philips (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.
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 ... 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.
Classic rhizomelic chondrodysplasia punctata type 1 (RCDP1) is recognized in the neonatal period by the presence of: ...
DiagnosisClinical DiagnosisClassic rhizomelic chondrodysplasia punctata type 1 (RCDP1) is recognized in the neonatal period by the presence of: Cataracts Skeletal features. Classic findings include the following: Rhizomelia (proximal shortening of the long bones) Chondrodysplasia punctata (CDP): punctate calcifications observed in radiographs in the epiphyseal cartilage at the knee, hip, elbow, and shoulder that can be more extensive, involving the hyoid bone, larynx, costochondral junctions, and vertebrae. Metaphyseal abnormalities may be present. Radiolucent coronal clefts of the vertebral bodies on lateral spine radiographs that represent unossified cartilage Classic RCDP1 is recognized in childhood by the presence of: Congenital cataracts Severe intellectual disability Profound growth retardation Resolution of the punctate calcifications leaving abnormal epiphyses and flared and irregular metaphyses after age one to three years Possible calcification of the intervertebral discs Milder RCDP1 phenotype is recognized by: Congenital cataracts Chondrodysplasia (manifesting as mild epiphyseal changes)Variable rhizomelia Milder intellectual disability and growth deficiency TestingBiochemical tests. Three biochemical tests of peroxisome function are routinely used to confirm the diagnosis of RCDP1: Red blood cell concentration of plasmalogens (Table 1) Plasma concentration of phytanic acid (Table 2) Plasma concentration of very long chain fatty acids (VLCFA)The finding of a deficiency of plasmalogens in red blood cells, increased plasma concentration of phytanic acid, and normal plasma concentration of very long chain fatty acids has consistently predicted the PEX7 receptor defect in RCDP1.These assays are extremely specialized and are reliably performed in only a few laboratories worldwide.Table 1. Values for Red Blood Cell Plasmalogens (Dimethylacetals) in RCDP1View in own windowC16 Saturated Dimethylacetals (DMA) to C16 Saturated Fatty AcidMeanRange Normal 0.077±0.0090.051-0.090Abnormal (RCDP1) 0.001-0.025 1 Values are expressed as a ratio of C16 or C18 dimethylacetyls to fatty acid molecules.1. Values are for the classic RCDP1 phenotype; individuals with a mild RCDP1 phenotype may fall outside this range.Table 2. Plasma Concentration of Phytanic Acid in RCDP1View in own windowMeanRangeNormal 0.80 µg/mL ± 0.400-2.5 µg/mL 1 Abnormal (RCDP1) ≤300 µg/mL 1. Plasma concentration of phytanic acid varies with dietary intake of animal fat. It can be normal in infants with RCDP1 because breast milk is low in phytanic acid and most formulas use vegetable fat.Assays in cultured skin fibroblasts Defective plasmalogen biosynthesis, defective phytanic acid (PA) oxidation, and normal VLCFA oxidation are confirmed in cultured fibroblasts. The absence of processed thiolase is determined in some laboratories. The fibroblast assays allow more complete characterization of peroxisomal functions and are critical in establishing the diagnosis in individuals with milder forms of RCDP1, whose plasmalogen levels may not be markedly abnormal. Molecular Genetic Testing Gene. PEX7, which encodes the receptor for a subset of peroxisomal matrix enzymes, is the only gene in which mutations are known to cause RCDP1. Clinical testingTable 3. Summary of Molecular Genetic Testing Used in Rhizomelic Chondrodysplasia Punctata Type 1View in own windowGene Symbol Test MethodMutations DetectedMutation Detection Rate 1Test Availability Two mutationsOne mutationPEX7Sequence analysisSequence variants 2, 394% 46% 4Clinical Targeted mutation analysis 5p.Leu292X, p.Gly217Arg, p.Ala218Val 651%-68% of mutant alleles1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.3. Some laboratories may offer sequence analysis of select exons; exons tested may vary by laboratory.4. Sequence analysis of PEX7 coding and flanking intronic regions in 133 individuals with RCDP1 from the United States and the Netherlands identified 97% of mutant alleles [Braverman et al 2002, Motley et al 2002]. Note: In all individuals with biochemically confirmed RCDP1, at least one mutant PEX7 allele was identified. 5. Targeted mutation analysis refers to testing for specific common mutation(s). Mutations detected may vary among laboratories.6. p.Leu292X was the most common, accounting for 51% of alleles. c.903+1G>C, p.Gly217Arg, and p.Ala218Val together account for 17% of alleles. Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a proband1.When the diagnosis of RCDP is considered, blood should be sent first for measurement of red blood cell plasmalogen, plasma phytanic acid, and plasma very long chain fatty acid concentrations. 2.When abnormalities are identified (see 1), the diagnosis is confirmed by enzymatic assays in cultured fibroblasts.3.Molecular genetic testing is used to identify the two disease-causing alleles in the proband, establish genotype-phenotype correlations, and enable prenatal diagnosis and carrier testing of at-risk relatives. Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family. Prenatal diagnosis by biochemical testing is also possible; however, ideally the biochemical defects in cultured fibroblasts from an affected family member should be confirmed first. Genetically Related (Allelic) DisordersDefects in PEX7 can result in at least two phenotypes distinct from RCDP1:Isolated congenital cataracts A disorder similar to adult Refsum disease In both disorders, plasmalogen biosynthesis is nearly normal, although phytanic acid oxidation in skin fibroblast assays is severely reduced [Braverman et al 2002, van den Brink et al 2003].
The characteristic clinical features observed in RCDP1 are skeletal abnormalities, cataracts, growth retardation, and intellectual disability. The majority of children do not survive beyond the first decade of life and a proportion die in the neonatal period. In a review of 69 children with RCDP diagnosed by the Peroxisomal Diseases Laboratory at the Kennedy Krieger Institute, 60% of children survived the first year and 39% the second; a few survived beyond age ten years. In a review of 35 affected children older than age one month, White et al [2003] reported 90% survival at age one year, 50% survival to age six years, and approximately 20% survival at age 12 years. Most deaths were secondary to respiratory complications. Clinical experience suggests that neonatal deaths have been associated with congenital heart disease or pulmonary hypoplasia [Oswald et al 2011]. ...
Natural HistoryClassic RCDP1The characteristic clinical features observed in RCDP1 are skeletal abnormalities, cataracts, growth retardation, and intellectual disability. The majority of children do not survive beyond the first decade of life and a proportion die in the neonatal period. In a review of 69 children with RCDP diagnosed by the Peroxisomal Diseases Laboratory at the Kennedy Krieger Institute, 60% of children survived the first year and 39% the second; a few survived beyond age ten years. In a review of 35 affected children older than age one month, White et al [2003] reported 90% survival at age one year, 50% survival to age six years, and approximately 20% survival at age 12 years. Most deaths were secondary to respiratory complications. Clinical experience suggests that neonatal deaths have been associated with congenital heart disease or pulmonary hypoplasia [Oswald et al 2011]. Skeletal findings. Infants with RCDP1 have bilateral shortening of the humerus and to a lesser degree the femur. They typically have contractures and stiff, painful joints, causing irritability in infancy. Cartilaginous structures of the face are affected, resulting in frontal bossing and a short, concave nasal ridge. Cataracts. Bilateral cortical cataracts develop in virtually all affected individuals. They are usually present at birth or appear in the first few months of life and are progressive. Growth retardation. Whereas birth weight, length, and head circumference are often at the lower range of normal, postnatal growth deficiency is profound.Intellectual disability. Developmental quotients are below 30. Early developmental skills such as smiling and recognizing voices are achieved by most children with RCDP, but at delayed ages. Skills usually achieved in normal children beyond age six months are never seen [White et al 2003]. The majority of children develop seizures.Routine brain imaging is normal or has shown cerebral and cerebellar atrophy with enlargement of the ventricles and CSF spaces [Powers et al 1999]. MR imaging and MR spectroscopy have shown delayed myelinization, signal abnormalities in supratentorial white matter, decreased choline-to-creatine ratios, and increased levels of mobile lipids, thought to reflect the deficiency of plasmalogens, which are substantial components of myelin [Alkan et al 2003, Bams-Mengerink et al 2006]. Other. Most children with RCDP1 have recurrent respiratory tract infections caused by neurologic compromise, aspiration, immobility, and a small chest with restricted expansion. Radiologic and MRI evidence of multilevel cervical stenosis with or without compression of the spinal cord has been observed. Spinal cord compression may complicate the neurologic picture, which often includes spastic quadriplegia [Khanna et al 2001]. Ichthyotic skin changes are noted in fewer than one third of individuals. Approximately 5%-10% of individuals have a cleft of the soft palate.Other malformations observed in individuals with RCDP1 include congenital heart disease and ureteropelvic junction (UPJ) obstruction. Mild RCDP1Only a few individuals with milder forms of RCDP1 have been described. All have had chondrodysplasia and cataracts but variable expression of punctate calcifications, rhizomelia, growth retardation, and intellectual disability [Braverman et al 2002, Bams-Mengerink et al 2006]. One child, presenting with developmental delay and poor growth, subsequently developed retinitis pigmentosa and peripheral neuropathy, features overlapping those of adult Refsum disease [Braverman et al 2002]. Thus, it is likely that a continuum of phenotypes will emerge within the RCDP group. Molecular analysis of PEX7 may identify individuals with unusual phenotypes.
The degree of plasmalogen deficiency correlates directly with phenotypic severity:...
Genotype-Phenotype CorrelationsThe degree of plasmalogen deficiency correlates directly with phenotypic severity:Individuals in the milder RCDP group exhibit intermediate defects in fibroblast plasmalogen synthesis and RBC plasmalogen concentrations that are approximately 30% of the mean in controls and more than two standard deviations above the mean in children with classic RCDP. Individuals with more variant phenotypes have near-normal plasmalogen biochemistry. Defects in phytanic acid oxidation in fibroblast assays are severe in all PEX7 defects. Some correlations between the predicted severity of PEX7 mutations and phenotype have emerged: All individuals homozygous for the p.Leu292X mutation studied thus far have had classic RCDP1. In individuals who are compound heterozygotes for p.Leu292X and another mutation, the effect of the other allele is important in determining the phenotype. Several PEX7 alleles that are associated with a milder RCDP phenotype, adult Refsum disease, or isolated congenital cataracts have been identified. It is predicted that these encode either residual amounts of a normal Pex7 protein or a defective protein with residual function [Braverman et al 2002, Motley et al 2002, van den Brink et al 2003].
The classic RCDP1 phenotype can be mimicked by isolated deficiencies of either of two peroxisomal enzymes involved in plasmalogen biosynthesis, as well as by severe Conradi-Hünermann syndrome. In addition, several different disorders, described below, have similar punctate cartilaginous changes and various combinations of limb asymmetry, short stature, intellectual disability, cataracts, and skin changes. The radiologic finding of chondrodysplasia punctata (CDP) has been observed in various metabolic disorders, skeletal dysplasias, chromosome abnormalities, and teratogen exposures. Exhaustive classifications of CDP have been published [Irving et al 2008]. ...
Differential DiagnosisThe classic RCDP1 phenotype can be mimicked by isolated deficiencies of either of two peroxisomal enzymes involved in plasmalogen biosynthesis, as well as by severe Conradi-Hünermann syndrome. In addition, several different disorders, described below, have similar punctate cartilaginous changes and various combinations of limb asymmetry, short stature, intellectual disability, cataracts, and skin changes. The radiologic finding of chondrodysplasia punctata (CDP) has been observed in various metabolic disorders, skeletal dysplasias, chromosome abnormalities, and teratogen exposures. Exhaustive classifications of CDP have been published [Irving et al 2008]. Rhizomelic chondrodysplasia punctata, type 2 (RCDP2) and type 3 (RCDP3). RCDP2 is caused by deficiency of the peroxisomal enzyme dihydroxyacetone phosphate acyltransferase, encoded by GNPAT (OMIM 602744). RCDP3 is caused by deficiency of the peroxisomal enzyme alkyl-dihydroxyacetone phosphate synthase, encoded by AGPS (OMIM 600121). The clinical phenotypes resemble that seen in RCDP1, emphasizing the role of plasmalogen deficiency in determining the RCDP phenotype. RCDP2 and RCDP3 are inherited in an autosomal recessive manner and are rarer than RCDP1. The specific enzyme defect is confirmed by measurement of the enzyme activity in cultured skin fibroblasts and/or identification of two disease causing mutations by sequence analysis of AGPS or GNPAT. X-linked recessive chondrodysplasia punctata, or brachytelephalangic type (CDPX1) is caused by defects in arylsulfatase E (ARSE), a vitamin K-dependent enzyme. Affected males have hypoplasia of the distal phalanges without limb shortening or cataracts. The diagnosis is confirmed by molecular genetic testing. Contiguous gene deletions involving ARSE result in more complex phenotypes, including ichthyosis and corneal opacities resulting from steroid sulfatase deficiency. Warfarin embryopathy and other fetal vitamin K deficiencies (including vitamin K epoxide reductase deficiency (OMIM 277450]) are phenotypically similar to CDPX1. Maternal systemic lupus erythematosis (SLE) (OMIM 152700) and other maternal autoimmune diseases can cause CDP in the offspring that is phenotypically similar to CDPX1.X-linked dominant chondrodysplasia punctata, or Conradi-Hünermann syndrome (CDPX2) is usually lethal in males. It is caused by defects in sterol- Δ8-isomerase which catalyzes an intermediate step in the conversion of lanosterol to cholesterol. Lyonization in females results in phenotypic variability and asymmetric findings. Cataracts are sectorial and limb shortening is rhizomesomelic and usually asymmetric. Severely affected infants have bilateral findings resembling those of RCDP1. The diagnosis is confirmed by measuring the plasma concentration of sterols, which show accumulation of the precursors 8(9)-cholestenol and 8-dehydrocholesterol and/or identification of two disease-causing mutations by molecular genetic testing of EBP. Chondrodysplasia punctata, tibia-metacarpal type (OMIM 118651) and humero-metacarpal type [Fryburg & Kelly 1996] are inherited in an autosomal dominant manner. The gene(s) in which mutation is causative are unknown. Affected individuals have short metacarpals with shortening of various long bones. No cataracts or skin changes are present. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with rhizomelic chondrodysplasia punctata type I (RCDP1), the following evaluations are recommended:...
ManagementEvaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with rhizomelic chondrodysplasia punctata type I (RCDP1), the following evaluations are recommended:Full skeletal survey (with flexion and extension views of the neck)Ophthalmologic examination Growth parameters Developmental assessment MR imaging of brain (with MR spectroscopy) Cardiac ultrasound examinationRenal ultrasound examinationMedical genetics consultationTreatment of ManifestationsManagement is supportive and limited because of the multiple handicaps present at birth and the poor outcome.Cataract extraction may preserve some vision. Physical therapy is recommended to assist in the improvement of contractures; orthopedic procedures have improved function in some individuals.Prevention of Primary ManifestationsDietary restriction of phytanic acid to avoid the consequences of phytanic acid accumulation over time may benefit individuals with milder forms of RCDP. Prevention of Secondary ComplicationsPoor feeding and recurrent aspiration necessitate the placement of a gastrostomy tube. Note: Improved nutrition does not enhance linear growth. Individuals with RCDP1 require good pulmonary toilet and careful attention to respiratory function. Influenza vaccine and RSV monoclonal antibody should be provided. Low plasmalogen levels can be associated with low levels of docosohexanoic acid (DHA). DHA can be measured in plasma; oral supplementation should be provided if levels are low. SurveillanceBased on a retrospective review of the natural history of 35 individuals with RCDP, White et al [2003] provide health supervision guidelines for primary caretakers of children with RCDP, including the following:Growth curves that allow weight comparisons to help determine the need for gastrostomy The ages at which developmental milestones are achieved to provide realistic expectations Recommendations for medical assessments including seizure control, vision, hearing, orthopedic care, and prevention of respiratory infections and contractures Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder. OtherData suggest that oral plasmalogen supplementation using alkylglycerol sources can increase tissue plasmalogen concentrations in rodents and red blood cell (RBC) plasmalogen concentrations in individuals with Zellweger syndrome spectrum disorders. Anecdotal reports of alkylglycerol supplementation in a few individuals with classic RCDP1 have not indicated dramatic clinical benefit; however, alkylglycerol supplementation has not yet been studied in a systematic fashion. Studies in Pex7-deficient mouse models have shown that plasmalogen precursors can partially recover plasmalogen levels in body tissues, but not in brain [Brites et al 2004, Wood et al 2011]Nonsense suppressor drugs were unable to recover protein production in individuals with the common p.Leu292X allele [Dranchak et al 2011].
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Rhizomelic Chondrodysplasia Punctata Type 1: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDPEX76q23.3Peroxisomal targeting signal 2 receptordbPEX, PEX7 Gene Database PEX7 homepage - Mendelian genesPEX7Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Rhizomelic Chondrodysplasia Punctata Type 1 (View All in OMIM) View in own window 215100RHIZOMELIC CHONDRODYSPLASIA PUNCTATA, TYPE 1; RCDP1 601757PEROXISOME BIOGENESIS FACTOR 7; PEX7Molecular Genetic PathogenesisRole of the peroxisome targeting signal 2 receptor, PEX7, in peroxisome assembly. Peroxisomal matrix enzymes are synthesized on free polyribosomes and directed to the peroxisome by cytosolic receptors. The peroxisome targeting signal 1 receptor (encoded by PEX5) binds a C-terminal peroxisome targeting signal, PTS1, present on most matrix proteins. PEX7 binds an N-terminal PTS2, present on three. The two receptors themselves interact and carry their protein cargo to the peroxisome membrane; the matrix proteins are then translocated inside, the import complex is disassembled, and the receptors are recycled for another round of import. This import process, along with the formation of new peroxisomes and division of existing ones, is termed peroxisome biogenesis. Fourteen human proteins are required for peroxisome biogenesis; collectively they are called peroxins and they are encoded by PEX genes. Metabolic pathways dependent on PEX7. The three PTS2 proteins transported to the peroxisome by PEX7 are alkyl-dihydroxyacetone phosphate synthase (AGPS), phytanoyl-CoA hydroxylase (PhyH), and peroxisomal 3-ketoacyl-CoA thiolase (ACAA1). AGPS catalyzes the initial steps of plasmalogen biosynthesis in a complex with the PTS1 protein, dihydroxyacetone phosphate acyltransferase (GNPAT). Plasmalogens are a class of membrane phospholipids, in which the fatty acid at the C1 position of the glycerophospholipid is replaced by a fatty alcohol. Plasmalogens are present in significant proportions in plasma membranes and myelin, and their specific functions are now being investigated [Braverman & Moser 2012]. These compounds may protect against oxidative damage, be required for membrane fusion and fission processes, and function as lipid messengers. Since isolated defects in GNPAT or AGPS also result in RCDP (RCDP types 2 and 3), plasmalogen deficiency must play a major role in the pathogenesis of this disorder. PhYH catalyzes the initial step in the catabolism of phytanic acid, a 16-carbon methyl-branched fatty acid of dietary origin. Isolated defects in PhYH cause adult Refsum disease. Peroxisomal thiolase (ACAA1) catalyzes the last step in beta oxidation of very long straight-chain fatty acids. Beta oxidation is normal in RCDP1, presumably because the thiolase activity of sterol carrier protein-X, a PTS1 protein, compensates for this deficiency. Other proteins with PTS2 targeting signals have been recently identified by bioinformatics and proteomics experiments [Wiese et al 2007, Kunze et al 2011] Their role in human disease caused by PEX7 mutation is not known. Normal allelic variants. PEX7 contains ten exons that span 91 kb of genomic DNA. No normal allelic variants have been identified yet in the coding sequence. Pathologic allelic variants. Approximately 39 unique PEX7 mutations have been identified thus far (see www.dbpex.org). The majority are nonsense, missense, or splice site mutations, small insertions, or deletions. The mutant allele p.Leu292X accounts for 51% of alleles; less common alleles are c.903+1G>C, p.Gly217Arg, p.Ala218Val, and p.Tyr40X. Alleles associated with milder RCDP phenotypes, variant phenotypes, or adult Refsum disease are either missense alleles located on the surfaces of the PEX7 protein and thus unlikely to disrupt its structural integrity (p.Ser25Phe, p.His285Arg, p.Thr14Pro), or 'leaky' alleles, potentially able to generate residual amounts of normal PEX7 protein (c.-45C>T,c.442-10A>G) and re-initiate translation in-frame (p.His18Argfs*35) or at a downstream methionine residue (p.Gly7Valfs*51) [Braverman et al 2002, Motley et al 2002, van den Brink et al 2003]. Table 4. Selected PEX7 Pathologic Allelic VariantsView in own windowDNA Nucleotide Change (Alias 1)Protein Amino Acid ChangeReference Sequencesc.-45C>T--NM_000288.3 NP_000279.1c.340-10A>G (IVS3-10A>G)--c.45_52dupGGGACGCC (52insGGGACGCC)p.His18Argfs*35c.12_18dupGTGCGGTp.Gly7Valfs*51c.74C>Tp.Ser25Phec.854A>Gp.His285Argc.40A>Cp.Thr14Proc.903+1G>C (IVS9+1G>C)--c.649G>Ap.Gly217Argc.653C>Tp.Ala218Valc.875T>Ap.Leu292XSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).1. Variant designation that does not conform to current naming conventionsNormal gene product. PEX7, the peroxisome-targeting signal 2 receptor, is a 323-amino acid protein with serial WD40 repeats (short structural motif of approximately 40 amino acids, often terminating in a tryptophan-aspartic acid (W-D) dipeptide). These repeat domains fold into blades of a propeller-like structure, which resembles a torus on its side and provides several surfaces for protein interactions [Braverman et al 2002]. PEX7 is a receptor for a subclass of peroxisomal matrix enzymes and binds the PTS2 signal at the N-terminus of these proteins. PEX7 carries its cargo to the peroxisome membrane by virtue of its interaction with PEX5. Abnormal gene product. Defects in PEX7 result in deficient activity of PTS2 enzymes, but other peroxisomal functions remain intact. Fibroblast assays show that PTS2 proteins remain cytosolic in individuals with RCDP1 and are degraded, but PTS1 proteins are imported into peroxisomes normally. Peroxisome morphology is normal in fibroblasts but abnormal in liver, according to several case reports.