Clinical Diagnosis

Classic 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 mental deficiency

• 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

• Variable rhizomelia

• Milder mental and growth deficiency

Testing

Biochemical 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. For laboratories offering biochemical testing, see .

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 mutation is known to cause RCDP1.

Clinical testing

• Sequence analysis of all ten exons of PEX7 and flanking intronic regions from genomic DNA 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]. Both alleles were identified in 94% of affected individuals and a single allele in 6%.
  
  Note: In all individuals with biochemically confirmed RCDP1, at least one mutant PEX7 allele was identified.

  • 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.

Table 3. Summary Molecular Genetic Testing Used in Rhizomelic Chondrodysplasia Punctata Type 1 (RCDP1)

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Rate 1, 2		Test Availability
			Two mutations	One mutation
PEX7	Sequence analysis	Sequence variants 2	94%	6%	Clinical
	Targeted mutation analysis 3, 4	p.Leu292X, p.Gly217Arg, p.Ala218Val	51%-68% of mutant alleles

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Braverman et al [2002], Motley et al [2002]

3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

4. Targeted mutation analysis refers to testing for specific common mutation(s). Mutations detected may vary among laboratories.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband

1.

When the diagnosis of RCDP is considered, blood should be sent first for measurement of plasmalogen, phytanic acid, and 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.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

Defects 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 is severely reduced [Braverman et al 2002, van den Brink et al 2003].

Natural History

Genotype-Phenotype Correlations

The 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 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].

Nomenclature

RCDP1 is one of two groups of peroxisome biogenesis disorders (PBD). The other PBD group is the Zellweger syndrome spectrum.

Although individuals with RCDP1 have a perturbation in matrix protein import consistent with a peroxisomal assembly defect, they have a biochemical, cellular, and clinical phenotype distinct from PBD of the Zellweger syndrome spectrum.

Prevalence

The prevalence of RCDP1 is estimated to be lower than 1:100,000. The disorder is pan ethnic. The high frequency of the p.Leu292X allele is secondary to a founder effect in individuals of Northern European descent [Braverman et al 2000].

Evaluations 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

• Ophthalmologic examination

• Growth parameters

• Developmental assessment

• MR imaging of brain with MR spectroscopy

• Cardiac ultrasound examination

• Renal ultrasound examination

Treatment of Manifestations

Management 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 Manifestations

Dietary 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 Complications

Poor feeding and recurrent aspiration necessitate the placement of a gastrostomy tube; despite improved nutrition, linear growth is not enhanced.

Individuals with RCDP1 require good pulmonary toilet and careful attention to respiratory function. Influenza and RSV vaccines should be provided.

Low plasmalogen levels can be associated with low levels of docohexanoic acid (DHA). DHA can be measured in plasma; oral supplementation can be provided if levels are low.

Surveillance

Based 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:

• 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

Testing of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search 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.

Other

Data 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.

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

RCDP1 is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of a proband are obligate heterozygotes (carriers) and therefore carry one mutant allele.

• Heterozygotes are asymptomatic.

Sibs of a proband

• At conception, each sib of a proband has a 25% chance of inheriting both mutant alleles and being affected, a 50% chance of inheriting one mutant allele and being an unaffected carrier, and a 25% chance of inheriting both normal alleles.

• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.

• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. Affected individuals do not reproduce.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

• Carriers cannot be identified by biochemical methods.

• Carrier testing of at-risk relatives using molecular genetic techniques is possible if the mutations have been identified in an affected family member.

Related Genetic Counseling Issues

Family planning. The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.

Biochemical testing. Prenatal diagnosis for pregnancies at 25% risk for RCDP1 is also available by assay of plasmalogen biosynthesis in cultured chorionic villi obtained by CVS at approximately ten to 12 weeks' gestation or in cultured amniocytes obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation.

The determination of enzyme activity of alkyl-dihydroxyacetone phosphate synthase (ADAPS) and the subcellular localization of peroxisomal thiolase have also been performed successfully on uncultured chorionic villi.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Ultrasound examination. Rhizomelia and punctate calcifications have been noted on ultrasound examination as early as 18 to 19 weeks [Krakow et al 2003]. Others have reported these findings along with bilateral cataracts at 32 weeks, and epiphyseal stippling shown four weeks later [Basbug et al 2005]; however, the diagnosis of RCDP was not verified after delivery in all cases.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified in an affected family member. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

Role 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. More than 20 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 (ADHAPS or AGPS), phytanoyl-CoA hydroxylase (PhyH), and peroxisomal 3-ketoacyl-CoA thiolase.

• ADHAPS catalyzes the initial steps of plasmalogen biosynthesis in a complex with the PTS1 protein, dihydroxyacetone phosphate acyltransferase (DHAPAT or 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. These compounds may protect against oxidative damage, be required for membrane fusion and fission processes, and function as lipid messengers [Brites et al 2004]. Since isolated defects in DHAPAT or ADHAPS 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 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.

Normal allelic variants. PEX7 contains ten exons that span 91 kb of genomic DNA. No normal allelic variants have been identified in the coding sequence.

Pathologic allelic variants. Approximately 74 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.His18ArgfsX35) or at a downstream methionine residue (p.Gly7ValfsX51) [Braverman et al 2002, Motley et al 2002, van den Brink et al 2003].

Normal gene product. PEX7, the peroxisome-targeting signal 2 receptor, is a 323-amino acid protein with serial WD40 repeats. 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 all 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.

Literature Cited

1. Alkan A, Kutlu R, Yakinci C, Sigirci A, Aslan M, Sarac K. Delayed myelination in a rhizomelic chondrodysplasia punctata case: MR spectroscopy findings. Magn Reson Imaging. 2003;21:77–80. [PubMed: 12620550]
2. Bams-Mengerink AM, Majoie CBLM, Duran M, Wanders RJA, Van Hove J, Scheurer CD, Barth PG, Poll-The BT. MRI of the brain and certical spinal cord in rhizomelic chondrodysplasia punctata. Neurology. 2006;66:798–803. [PubMed: 16567694]
3. Basbug M, Serin IS, Ozcelik B, Gunes T, Akcakus M, Tayyar M. Prenatal ultrasonographic diagnosis of rhizomelic chondrodysplasia punctata by detection of rhizomelic shortening and bilateral cataracts. Fetal Diagn Ther. 2005;20:171–4. [PubMed: 15824492]
4. Braverman N, Chen L, Lin P, Obie C, Steel G, Douglas P, Chakraborty PK, Clarke JT, Boneh A, Moser A, Moser H, Valle D. Mutation analysis of PEX7 in 60 probands with rhizomelic chondrodysplasia punctata and functional correlations of genotype with phenotype. Hum Mutat. 2002;20:284–97. [PubMed: 12325024]
5. Braverman N, Steel G, Lin P, Moser A, Moser H, Valle D. PEX7 gene structure, alternative transcripts, and evidence for a founder haplotype for the frequent RCDP allele, L292ter. Genomics. 2000;63:181–92. [PubMed: 10673331]
6. Brites P, Waterham HR, Wanders RJ. Functions and biosynthesis of plasmalogens in health and disease. Biochim Biophys Acta. 2004;1636:219–31. [PubMed: 15164770]
7. Fryburg JS, Kelly TE. Chondrodysplasia punctata, humero-metacarpal type: a second case. Am J Med Genet. 1996;64:493–6. [PubMed: 8862628]
8. Irving MD, Chitty LS, Mansour S, Hall CM. Chondrodysplasia punctata: a clinical diagnostic and radiological review. Clin Dysmorphol. 2008;17:229–41. [PubMed: 18978650]
9. Khanna AJ, Braverman NE, Valle D, Sponseller PD. Cervical stenosis secondary to rhizomelic chondrodysplasia punctata. Am J Med Genet. 2001;99:63–6. [PubMed: 11170096]
10. Krakow D, Williams J, Poehl M, Rimoin DL, Platt LD. Use of three-dimensional ultrasound imaging in the diagnosis of prenatal-onset skeletal dysplasias. Ultrasound Obstet Gynecol. 2003;21:467–72. [PubMed: 12768559]
11. Motley AM, Brites P, Gerez L, Hogenhout E, Haasjes J, Benne R, Tabak HF, Wanders RJ, Waterham HR. Mutational spectrum in the PEX7 gene and functional analysis of mutant alleles in 78 patients with rhizomelic chondrodysplasia punctata type 1. Am J Hum Genet. 2002;70:612–24. [PMC free article: PMC384941] [PubMed: 11781871]
12. Powers JM, Kenjarski TP, Moser AB, Moser HW. Cerebellar atrophy in chronic rhizomelic chondrodysplasia punctata: a potential role for phytanic acid and calcium in the death of its Purkinje cells. Acta Neuropathol (Berl). 1999;98:129–34. [PubMed: 10442551]
13. van den Brink DM, Brites P, Haasjes J, Wierzbicki AS, Mitchell J, Lambert-Hamill M, de Belleroche J, Jansen GA, Waterham HR, Wanders RJ. Identification of PEX7 as the second gene involved in Refsum disease. Am J Hum Genet. 2003;72:471–7. [PMC free article: PMC379239] [PubMed: 12522768]
14. White AL, Modaff P, Holland-Morris F, Pauli RM. Natural history of rhizomelic chondrodysplasia punctata. Am J Med Genet. 2003;118A:332–42. [PubMed: 12687664]

Suggested Reading

1. Gould SJ, Raymond GV, Valle D. The peroxisome biogenesis disorders. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York: McGraw-Hill. Chap 129. Available at www.ommbid.com. Accessed 2-26-10.
2. Steinberg SJ, Dodt G, Raymond GV, Braverman NE, Moser AB, Moser HW. Peroxisome biogenesis disorders. Biochim Biophys Acta. 2006;1763:1733–48. [PubMed: 17055079]
3. Wanders RJ, Waterham HR. Peroxisomal disorders: the single peroxisomal enzyme deficiencies. Biochim Biophys Acta. 2006;1763:1707–20. [PubMed: 17055078]

Revision History

• 2 March 2010 (me) Comprehensive update posted live

• 18 July 2006 (me) Comprehensive update posted to live Web site

• 7 February 2005 (cd) Revision: test availability

• 26 February 2004 (cd) Revision: test availability

• 13 February 2004 (me) Comprehensive update posted to live Web site

• 16 November 2001 (me) Review posted to live Web site

• 10 June 2001 (nb) Original submission