Rhizomelic Chondrodysplasia Punctata Type 1

Mendelian MONDO:0008972 Pathograph 20 Show in embeddings browser peroxisome biogenesis disorder inborn errors of metabolism

Rhizomelic chondrodysplasia punctata type 1 (RCDP1) is an autosomal recessive peroxisome biogenesis disorder caused by biallelic loss-of-function variants in PEX7, which encodes the cytosolic receptor for peroxisomal matrix proteins carrying the type-2 peroxisome targeting signal (PTS2). Unlike the Zellweger spectrum disorders — in which generalized failure of peroxisomal matrix import blocks both PTS1- and PTS2-dependent enzymes — RCDP1 produces a selective PTS2-import defect: PTS1-dependent very-long-chain fatty acid beta-oxidation (imported via PEX5) is largely preserved, while the PTS2 enzymes dihydroxyacetonephosphate acyltransferase and alkyldihydroxyacetonephosphate synthase (plasmalogen biosynthesis), phytanoyl-CoA hydroxylase (phytanic acid alpha-oxidation), and peroxisomal thiolase are mislocalized to the cytosol and rendered non-functional. The resulting ether-phospholipid (plasmalogen) deficiency and phytanic acid accumulation cause a distinctive developmental phenotype of rhizomelic limb shortening, chondrodysplasia punctata (stippled epiphyses), coronal vertebral clefts, congenital cataracts, severe growth and intellectual impairment, and seizures. A classic (severe) and a nonclassic (mild) form exist, with severity correlating with residual PEX7 allele activity. RCDP types 2-5 phenocopy RCDP1 through direct defects in individual plasmalogen-synthesis enzymes rather than through the PTS2 import receptor.

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1
Inheritance
6
Pathophys.
8
Phenotypes
20
Pathograph
1
Genes
3
Medical Actions
2
Subtypes
2
Differentials
🏷

Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE ENDOCRINOLOGY METABOLISM
ICIMD (Inherited Metabolic Disorders)
peroxisomal biogenesis
ISDS Skeletal Nosology
chondrodysplasia punctata
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
RCDP1 requires biallelic pathogenic variants in PEX7 and is inherited as an autosomal recessive trait.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:20301447 SUPPORT Human Clinical
"PEX7-RCDP is inherited in an autosomal recessive manner."
GeneReviews directly states autosomal recessive inheritance for PEX7-RCDP.
◆

Subtypes

2
Classic (severe) PEX7-RCDP
The severe form, with proximal (rhizomelic) limb shortening, chondrodysplasia punctata, coronal vertebral clefts, congenital cataracts, profound postnatal growth deficiency, severe intellectual disability, and seizures. Most affected children do not survive the first decade of life. Associated with PEX7 alleles that retain little or no residual receptor activity.
Show evidence (1 reference)
PMID:20301447 SUPPORT Human Clinical
"Most affected children do not survive the first decade of life; a proportion die in the neonatal period."
GeneReviews supports the severe natural history of the classic RCDP1 form.
Nonclassic (mild) PEX7-RCDP
The milder form, characterized by congenital or childhood cataracts, milder or minimal chondrodysplasia, joint contractures, neurobehavioral abnormalities, and less severe intellectual disability and growth restriction. Associated with PEX7 alleles retaining partial receptor activity.
Show evidence (1 reference)
PMID:20301447 SUPPORT Human Clinical
"Nonclassic (mild) PEX7-RCDP is characterized by congenital or childhood cataracts, CDP or, infrequently, chondrodysplasia manifesting only as mild epiphyseal changes, joint contractures, neurobehavioral abnormalities, and milder intellectual disability and growth restriction than classic PEX7-RCDP."
GeneReviews directly defines the nonclassic (mild) RCDP1 phenotype.
⚙

Pathophysiology

6
Selective PTS2 Import Failure
Loss of functional peroxin 7 (PEX7), the cytosolic PTS2 receptor, prevents import of the subset of peroxisomal matrix enzymes that carry the type-2 targeting signal. These enzymes are mislocalized to the cytosol and rendered non-functional, while PTS1-dependent import (mediated by PEX5) — including very-long-chain fatty acid beta-oxidation — remains largely intact. This selective import lesion distinguishes RCDP1 from the generalized matrix-import failure of the Zellweger spectrum.
PEX7 hgnc:8860 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PEX7 (hgnc:8860). hgnc:8860 is a gene from the HUGO Gene Nomenclature Committee.
protein targeting to peroxisome GO:0006625 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein targeting to peroxisome (GO:0006625). GO:0006625 is a biological process from the Gene Ontology. ↓ DECREASED
peroxisome signal sequence receptor activity GO:0000268 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased peroxisome signal sequence receptor activity (GO:0000268). GO:0000268 is a molecular function from the Gene Ontology. ↓ DECREASED
peroxisome GO:0005777 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves peroxisome (GO:0005777). GO:0005777 is a cellular component from the Gene Ontology.
Downstream
Plasmalogen (Ether Lipid) Deficiency Mislocalization of the PTS2 enzymes dihydroxyacetonephosphate acyltransferase and alkyldihydroxyacetonephosphate synthase blocks the peroxisomal steps of ether-phospholipid synthesis, depleting plasmalogens.
Phytanic Acid Accumulation Loss of imported phytanoyl-CoA hydroxylase impairs peroxisomal phytanic acid alpha-oxidation, allowing dietary phytanic acid to accumulate progressively in plasma and tissues.
Show evidence (3 references)
PMID:9090381 SUPPORT In Vitro
"PEX7, a candidate gene for RCDP identified in yeast, encodes the receptor for peroxisomal matrix proteins with the type-2 peroxisome targeting signal (PTS2)."
This study identifies PEX7 as the PTS2 import receptor whose loss causes RCDP, establishing the selective PTS2-import lesion.
PMID:9090382 SUPPORT In Vitro
"Like S. cerevisiae pex cells, RCDP cells from CG11 cannot import a PTS2 reporter protein."
Demonstrates that RCDP (CG11) cells specifically fail to import PTS2-tagged cargo, the defining selective import defect.
PMID:11781871 SUPPORT In Vitro
"the cytosolic PTS2-receptor protein required for targeting a subset of enzymes to peroxisomes. These enzymes are deficient in cells of patients with RCDP, because of their mislocalization to the cytoplasm."
Confirms that only a subset of enzymes (the PTS2 cargo) is lost, by cytosolic mislocalization, in RCDP patient cells.
Plasmalogen (Ether Lipid) Deficiency
Plasmalogens are ether glycerophospholipids whose peroxisomal synthesis depends on the PTS2 enzymes lost in RCDP1. Their deficiency disrupts membrane and myelin composition and developmental signaling in bone, brain, lens, and other tissues, accounting for the skeletal, ocular, and neurologic manifestations.
ether lipid biosynthetic process GO:0008611 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased ether lipid biosynthetic process (GO:0008611). GO:0008611 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Skeletal Dysplasia Plasmalogen deficiency disrupts cartilage and bone development, producing rhizomelic shortening and chondrodysplasia punctata.
Congenital Cataract Plasmalogen deficiency disrupts lens fiber development, producing congenital cataracts.
Neurological Impairment Plasmalogen deficiency disrupts CNS neuronal and myelin development, producing intellectual disability and seizures.
Show evidence (1 reference)
PMID:22627108 SUPPORT Human Clinical
"The RCDP phenotype predicts developmental roles for plasmalogens in bone, brain, lens, lung, kidney and heart."
This review links plasmalogen deficiency to the multisystem developmental phenotype of RCDP.
Phytanic Acid Accumulation
Defective peroxisomal alpha-oxidation allows phytanic acid, derived from dietary sources, to accumulate over time. Accumulation is progressive and diet-dependent, contributing to disease in the milder, longer-surviving nonclassic form and providing the rationale for dietary phytanic acid restriction.
fatty acid alpha-oxidation GO:0001561 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased fatty acid alpha-oxidation (GO:0001561). GO:0001561 is a biological process from the Gene Ontology. ↓ DECREASED
Show evidence (1 reference)
PMID:20301447 SUPPORT Human Clinical
"Dietary restriction of phytanic acid to avoid the consequences of phytanic acid accumulation over time may benefit individuals with mild PEX7-RCDP."
GeneReviews documents progressive phytanic acid accumulation and its diet-modifiable consequences in RCDP1.
Skeletal Dysplasia
Plasmalogen-dependent disruption of cartilage and bone development produces rhizomelic (proximal) limb shortening, chondrodysplasia punctata with stippled epiphyses, and coronal vertebral clefts.
chondrocyte CL:0000138 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves chondrocyte (CL:0000138). CL:0000138 is a cell type from the Cell Ontology.
Downstream
Rhizomelia The skeletal dysplasia produces proximal limb shortening, especially of the humerus.
Chondrodysplasia Punctata Abnormal cartilage and epiphyseal development produces punctate calcifications and epiphyseal stippling.
Coronal Cleft Vertebrae Vertebral-body dysplasia produces characteristic coronal clefts.
Postnatal Growth Deficiency Severe developmental skeletal disease is accompanied by profound postnatal growth deficiency.
Joint Contractures Musculoskeletal involvement includes multiple joint contractures, especially in nonclassic disease.
Show evidence (1 reference)
PMID:20301447 SUPPORT Human Clinical
"Classic (severe) PEX7-RCDP is characterized by proximal shortening of the humerus (rhizomelia) and to a lesser degree the femur, punctate calcifications in cartilage with epiphyseal and metaphyseal abnormalities (chondrodysplasia punctata, or CDP), coronal clefts of the vertebral bodies, and..."
GeneReviews enumerates the rhizomelic shortening, chondrodysplasia punctata, and coronal vertebral clefts of classic RCDP1.
Congenital Cataract
Plasmalogen deficiency disrupts lens fiber development, producing cataracts usually present at birth or in the first months of life.
lens fiber cell CL:0011004 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves lens fiber cell (CL:0011004). CL:0011004 is a cell type from the Cell Ontology.
Downstream
Cataract Lens fiber developmental disruption produces congenital or early-infantile cataracts.
Show evidence (1 reference)
PMID:20301447 SUPPORT Human Clinical
"cataracts that are usually present at birth or appear in the first few months of life"
GeneReviews documents congenital/early-infantile cataracts in RCDP1.
Neurological Impairment
CNS plasmalogen deficiency impairs neuronal and myelin development, producing severe intellectual disability and seizures.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology. oligodendrocyte CL:0000128 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves oligodendrocyte (CL:0000128). CL:0000128 is a cell type from the Cell Ontology.
Downstream
Intellectual Disability CNS developmental impairment produces severe intellectual disability in classic RCDP1.
Seizures CNS involvement in classic RCDP1 commonly includes seizures.
Show evidence (1 reference)
PMID:20301447 SUPPORT Human Clinical
"Intellectual disability is severe, and most children develop seizures."
GeneReviews documents severe intellectual disability and seizures in classic RCDP1.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Rhizomelic Chondrodysplasia Punctata Type 1 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

8
Eye 1
Cataract HP:0000518 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cataract (HP:0000518), qualified as congenital onset. HP:0000518 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Show evidence (1 reference)
PMID:20301447 SUPPORT Human Clinical
"cataracts that are usually present at birth or appear in the first few months of life"
GeneReviews documents congenital/early-infantile cataracts in RCDP1.
Musculoskeletal 3
Chondrodysplasia Punctata Epiphyseal stippling HP:0010655 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epiphyseal stippling (HP:0010655), qualified as congenital onset. HP:0010655 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Show evidence (1 reference)
PMID:20301447 SUPPORT Human Clinical
"punctate calcifications in cartilage with epiphyseal and metaphyseal abnormalities (chondrodysplasia punctata, or CDP)"
GeneReviews documents the punctate cartilage calcification / epiphyseal stippling that defines chondrodysplasia punctata.
Coronal Cleft Vertebrae HP:0003417 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Coronal cleft vertebrae (HP:0003417), qualified as congenital onset. HP:0003417 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Show evidence (1 reference)
PMID:20301447 SUPPORT Human Clinical
"coronal clefts of the vertebral bodies"
GeneReviews lists coronal vertebral clefts among the defining skeletal features.
Joint Contractures HP:0034392 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Joint contracture (HP:0034392). HP:0034392 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301447 SUPPORT Human Clinical
"joint contractures, neurobehavioral abnormalities, and milder intellectual disability"
GeneReviews lists joint contractures among the nonclassic RCDP1 features.
Nervous System 2
Intellectual Disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301447 SUPPORT Human Clinical
"Intellectual disability is severe, and most children develop seizures."
GeneReviews documents severe intellectual disability in classic RCDP1.
Seizures HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301447 SUPPORT Human Clinical
"Intellectual disability is severe, and most children develop seizures."
GeneReviews documents seizures in most children with classic RCDP1.
Growth 2
Rhizomelia HP:0008905 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Rhizomelia (HP:0008905), qualified as congenital onset. HP:0008905 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Show evidence (1 reference)
PMID:20301447 SUPPORT Human Clinical
"proximal shortening of the humerus (rhizomelia) and to a lesser degree the femur"
GeneReviews directly describes rhizomelic proximal limb shortening as a defining clinical feature of RCDP1.
Postnatal Growth Deficiency Postnatal growth retardation HP:0008897 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Postnatal growth retardation (HP:0008897). HP:0008897 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301447 SUPPORT Human Clinical
"postnatal growth deficiency is profound."
GeneReviews documents profound postnatal growth deficiency in classic RCDP1.
🧬

Genetic Associations

1
PEX7 (Biallelic loss-of-function variants in PEX7 cause RCDP1 (PBD complementation group 11). Disease severity correlates with residual PEX7 allele activity; the recurrent L292ter null allele is associated with the severe phenotype.)
Gene: PEX7 hgnc:8860 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PEX7 (hgnc:8860). hgnc:8860 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:11781871 SUPPORT In Vitro
"we show by functional analysis that disease severity correlates with PEX7 allele activity"
Functional analysis of patient alleles ties disease severity to residual PEX7 receptor activity.
PMID:9090381 SUPPORT Human Clinical
"we found two inactivating PEX7 mutations: one, L292ter, was present in 26 of the probands, all with a severe phenotype"
Identifies the recurrent L292ter null allele associated with severe RCDP1.
💊

Medical Actions

3
Dietary Phytanic Acid Restriction
Action: dietary interventionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is dietary intervention (NCIT:C15447). NCIT:C15447 is a clinical intervention from the NCI Thesaurus. Ontology label: Dietary Intervention NCIT:C15447
Platform: Behavioral / lifestyle
Dietary restriction of phytanic acid may benefit individuals with mild (nonclassic) RCDP1 by limiting progressive phytanic acid accumulation.
Target Phenotypes: Intellectual disability HP:0001249 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301447 SUPPORT Human Clinical
"Dietary restriction of phytanic acid to avoid the consequences of phytanic acid accumulation over time may benefit individuals with mild PEX7-RCDP."
GeneReviews supports dietary phytanic acid restriction in mild RCDP1.
Supportive and Rehabilitative Care
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Management is supportive: physical therapy and orthopedic procedures for contractures, and cataract extraction to preserve vision.
Target Phenotypes: Joint contracture HP:0034392 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Joint contracture (HP:0034392). HP:0034392 is a phenotype from the Human Phenotype Ontology. Cataract HP:0000518 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Cataract (HP:0000518). HP:0000518 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301447 SUPPORT Human Clinical
"Physical therapy to improve contractures; orthopedic procedures may improve function in some individuals"
GeneReviews supports physical therapy and orthopedic management of contractures.
Cataract Extraction
Action: surgical procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surgical procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
Surgical removal of cataracts can restore and/or preserve vision.
Target Phenotypes: Cataract HP:0000518 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Cataract (HP:0000518). HP:0000518 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301447 SUPPORT Human Clinical
"cataract extraction may restore and/or preserve vision"
GeneReviews supports cataract extraction to preserve vision in RCDP1.
🔬

Biochemical Markers

2
Plasmalogens (Decreased)
Context: Erythrocyte and tissue plasmalogens are reduced because the PTS2 enzymes of peroxisomal ether-lipid synthesis are mislocalized and non-functional.
Pathograph Readouts
Readout Of Plasmalogen (Ether Lipid) Deficiency Negative Diagnostic
Decreased plasmalogens report failure of peroxisomal ether-lipid synthesis.
Show evidence (1 reference)
PMID:36914043 SUPPORT Human Clinical
"Markedly reduced plasmalogens are a classic feature of peroxisome biogenesis disorders (PBD) because plasmalogen synthesis requires functional peroxisomes."
RCDP1 is a peroxisome biogenesis disorder; markedly reduced plasmalogens are its classic biochemical hallmark.
Phytanic acid (Increased)
Context: Phytanic acid accumulates progressively because peroxisomal alpha-oxidation (phytanoyl-CoA hydroxylase) is deficient. VLCFA levels are characteristically normal, distinguishing RCDP1 from the Zellweger spectrum.
Pathograph Readouts
Readout Of Phytanic Acid Accumulation Positive Diagnostic
Elevated phytanic acid reports impaired peroxisomal alpha-oxidation.
Show evidence (1 reference)
PMID:20301447 SUPPORT Human Clinical
"Dietary restriction of phytanic acid to avoid the consequences of phytanic acid accumulation over time may benefit individuals with mild PEX7-RCDP."
GeneReviews supports phytanic acid accumulation as a biochemical feature of RCDP1.
🔬

Diagnosis

5
Clinical, Radiographic, and Laboratory Case Definition
PEX7-RCDP is established in a proband with the suggestive clinical and radiographic RCDP pattern, compatible laboratory findings, and biallelic pathogenic PEX7 variants.
diagnostic procedure NCIT:C18020 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:20301447 SUPPORT Human Clinical
"The diagnosis of PEX7-RCDP is established in a proband with suggestive clinical, radiographic, and laboratory findings and biallelic pathogenic variants in PEX7 identified on molecular genetic testing."
GeneReviews defines the integrated clinical, radiographic, laboratory, and molecular diagnostic case definition for PEX7-RCDP.
PMID:20301447 SUPPORT Human Clinical
"Classic (severe) PEX7-RCDP is characterized by proximal shortening of the humerus (rhizomelia) and to a lesser degree the femur, punctate calcifications in cartilage with epiphyseal and metaphyseal abnormalities (chondrodysplasia punctata, or CDP), coronal clefts of the vertebral bodies, and..."
Supports the characteristic clinical and radiographic findings that prompt PEX7-RCDP diagnostic evaluation.
Plasmalogen and Phytanic-Acid Biochemical Testing
Laboratory evaluation supports RCDP1 by showing severe plasmalogen deficiency together with the PTS2-import biochemical tetrad, including impaired phytanic-acid alpha-oxidation and loss of peroxisomal thiolase import.
biomarker analysis NCIT:C63333 NCI Thesaurus (NCIT)
Show evidence (3 references)
PMID:36914043 SUPPORT Human Clinical
"Particularly, severe plasmalogen deficiency is the biochemical hallmark of rhizomelic chondrodysplasia punctata (RCDP)."
Supports plasmalogen quantification as a diagnostic biochemical marker for RCDP.
PMID:36914043 SUPPORT Human Clinical
"We developed a liquid-chromatography/tandem mass-spectrometry (LC-MS/MS) method to quantify eighteen phosphoethanolamine plasmalogens in RBCs to diagnose PBD patients, especially RCDP."
Supports RBC plasmalogen LC-MS/MS as a diagnostic assay for RCDP.
PMID:9090382 SUPPORT In Vitro
"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."
Defines the PEX7/CG11 biochemical signature that distinguishes RCDP1 from isolated plasmalogen-enzyme defects and generalized Zellweger-spectrum disease.
PEX7 Molecular Genetic Confirmation
Molecular genetic testing confirms RCDP1 by identifying biallelic pathogenic variants in PEX7, the gene encoding the PTS2 import receptor.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Show evidence (3 references)
PMID:20301447 SUPPORT Human Clinical
"biallelic pathogenic variants in PEX7 identified on molecular genetic testing."
Directly supports PEX7 molecular testing as the confirmatory procedure.
PMID:9090381 SUPPORT Human Clinical
"We conclude that PEX7 is responsible for RCDP (PBD CG11) and suggest a founder effect may explain the high frequency of L292ter."
Supports PEX7 as the causal disease gene for RCDP1 / complementation group 11.
PMID:9090382 SUPPORT In Vitro
"These findings prove that mutations in PEX7 cause RCDP, CG11."
Functional rescue and segregation evidence confirm that PEX7 variants cause RCDP1.
Prenatal Genetic Testing
Prenatal testing can be offered in an affected family after the familial PEX7 pathogenic variants have been identified.
prenatal genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:20301447 SUPPORT Human Clinical
"Once the PEX7 pathogenic variants have been identified in an affected family member, molecular genetic carrier testing of at-risk relatives and prenatal/preimplantation genetic testing are possible."
GeneReviews supports prenatal genetic testing when familial PEX7 variants are known.
Preimplantation Genetic Testing
Preimplantation genetic testing is possible for families once the familial PEX7 pathogenic variants have been identified.
preimplantation genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:20301447 SUPPORT Human Clinical
"Once the PEX7 pathogenic variants have been identified in an affected family member, molecular genetic carrier testing of at-risk relatives and prenatal/preimplantation genetic testing are possible."
GeneReviews supports preimplantation genetic testing when familial PEX7 variants are known.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Rhizomelic Chondrodysplasia Punctata Type 1:

Zellweger Spectrum Disorders MONDO:0019609
Overlapping Features ZSD results from generalized peroxisomal matrix-import failure affecting both PTS1 and PTS2 cargo, producing VLCFA accumulation alongside plasmalogen and bile-acid abnormalities. RCDP1 spares PTS1-dependent VLCFA beta-oxidation, so VLCFA levels are typically normal.
Distinguishing Features
  • RCDP1 has a selective PTS2-import defect with normal VLCFA beta-oxidation; ZSD has generalized import failure with elevated VLCFA.
Rhizomelic Chondrodysplasia Punctata Types 2-5
Overlapping Features RCDP types 2-5 phenocopy RCDP1 through direct deficiency of individual plasmalogen-biosynthesis enzymes (e.g., GNPAT, AGPS, FAR1) rather than through the PEX7 PTS2 import receptor, with preserved phytanic acid alpha-oxidation in the single-enzyme forms.
Distinguishing Features
  • RCDP1 is a PEX7 biogenesis/import-receptor defect causing combined plasmalogen and phytanic-oxidation deficiency; RCDP2-5 are single-enzyme plasmalogen-synthesis defects.
{ }

Source YAML

click to show 
name: Rhizomelic Chondrodysplasia Punctata Type 1
creation_date: "2026-06-11T00:00:00Z"
category: Mendelian
description: >-
  Rhizomelic chondrodysplasia punctata type 1 (RCDP1) is an autosomal recessive
  peroxisome biogenesis disorder caused by biallelic loss-of-function variants
  in PEX7, which encodes the cytosolic receptor for peroxisomal matrix proteins
  carrying the type-2 peroxisome targeting signal (PTS2). Unlike the Zellweger
  spectrum disorders — in which generalized failure of peroxisomal matrix import
  blocks both PTS1- and PTS2-dependent enzymes — RCDP1 produces a selective
  PTS2-import defect: PTS1-dependent very-long-chain fatty acid beta-oxidation
  (imported via PEX5) is largely preserved, while the PTS2 enzymes
  dihydroxyacetonephosphate acyltransferase and alkyldihydroxyacetonephosphate
  synthase (plasmalogen biosynthesis), phytanoyl-CoA hydroxylase (phytanic acid
  alpha-oxidation), and peroxisomal thiolase are mislocalized to the cytosol and
  rendered non-functional. The resulting ether-phospholipid (plasmalogen)
  deficiency and phytanic acid accumulation cause a distinctive developmental
  phenotype of rhizomelic limb shortening, chondrodysplasia punctata (stippled
  epiphyses), coronal vertebral clefts, congenital cataracts, severe growth and
  intellectual impairment, and seizures. A classic (severe) and a nonclassic
  (mild) form exist, with severity correlating with residual PEX7 allele
  activity. RCDP types 2-5 phenocopy RCDP1 through direct defects in individual
  plasmalogen-synthesis enzymes rather than through the PTS2 import receptor.
disease_term:
  preferred_term: rhizomelic chondrodysplasia punctata type 1
  term:
    id: MONDO:0008972
    label: rhizomelic chondrodysplasia punctata type 1
synonyms:
- RCDP1
- PEX7-related rhizomelic chondrodysplasia punctata
- PEX7-RCDP
- Rhizomelic chondrodysplasia punctata, classic
- Peroxisome biogenesis disorder, complementation group 11
parents:
- peroxisome biogenesis disorder
- inborn errors of metabolism
has_subtypes:
- name: Classic RCDP1
  display_name: Classic (severe) PEX7-RCDP
  description: >-
    The severe form, with proximal (rhizomelic) limb shortening, chondrodysplasia
    punctata, coronal vertebral clefts, congenital cataracts, profound postnatal
    growth deficiency, severe intellectual disability, and seizures. Most affected
    children do not survive the first decade of life. Associated with PEX7 alleles
    that retain little or no residual receptor activity.
  evidence:
  - reference: PMID:20301447
    reference_title: PEX7-Related Rhizomelic Chondrodysplasia Punctata.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most affected children do not survive the first decade of life; a
      proportion die in the neonatal period.
    explanation: >-
      GeneReviews supports the severe natural history of the classic RCDP1 form.
- name: Nonclassic RCDP1
  display_name: Nonclassic (mild) PEX7-RCDP
  description: >-
    The milder form, characterized by congenital or childhood cataracts, milder
    or minimal chondrodysplasia, joint contractures, neurobehavioral
    abnormalities, and less severe intellectual disability and growth
    restriction. Associated with PEX7 alleles retaining partial receptor
    activity.
  evidence:
  - reference: PMID:20301447
    reference_title: PEX7-Related Rhizomelic Chondrodysplasia Punctata.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nonclassic (mild) PEX7-RCDP is characterized by congenital or childhood
      cataracts, CDP or, infrequently, chondrodysplasia manifesting only as mild
      epiphyseal changes, joint contractures, neurobehavioral abnormalities, and
      milder intellectual disability and growth restriction than classic
      PEX7-RCDP.
    explanation: >-
      GeneReviews directly defines the nonclassic (mild) RCDP1 phenotype.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    RCDP1 requires biallelic pathogenic variants in PEX7 and is inherited as an
    autosomal recessive trait.
  evidence:
  - reference: PMID:20301447
    reference_title: PEX7-Related Rhizomelic Chondrodysplasia Punctata.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PEX7-RCDP is inherited in an autosomal recessive manner.
    explanation: >-
      GeneReviews directly states autosomal recessive inheritance for PEX7-RCDP.
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      A Mendelian skeletal dysplasia diagnosed and managed as an inherited
      disorder; Harrison's covers it under the genetics/inherited-disease Part
      rather than under a single organ system.
  - classification_value: ENDOCRINOLOGY_METABOLISM
    notes: >-
      Also an inborn error of metabolism: the entity is defined biochemically by
      plasmalogen deficiency with phytanic-acid accumulation, and is diagnosed by
      metabolite assay rather than by radiograph alone.
  icimd_category:
  - classification_value: peroxisomal_biogenesis
    notes: >-
      ICIMD (Ferreira et al. 2021, PMID:33340416): group "Peroxisomal biogenesis
      disorders (peroxin-related)" under category "Disorders of organelle
      biogenesis, dynamics and interactions". PEX7 is a peroxin - the cytosolic
      PTS2 receptor - so the lesion is at the protein-import step, not in any one
      metabolic enzyme. This is the discriminator from the single-enzyme forms
      RCDP2/3/4, which take "Disorders of glycerophospholipid metabolism".
  isds_skeletal_category:
  - classification_value: chondrodysplasia_punctata
    notes: >-
      ISDS Nosology of Genetic Skeletal Disorders, 2023 revision (Unger et al.,
      PMID:36779427), group 23 "Chondrodysplasia punctata (CDP) group", row
      NOS 23-0060 "Rhizomelic CDP, PEX7-related" (MIM 215100). Carried forward
      from the 2019 revision (Mortier et al., PMID:31633310), where the same
      entity sat in group 21, listed as "Rhizomelic CDP, the PEX7 locus" - the
      group was renumbered 21 to 23 but not otherwise changed. The row number is
      quoted because group 23 lists five separate rhizomelic-CDP rows that differ
      only by gene.
pathophysiology:
- name: Selective PTS2 Import Failure
  conforms_to: "peroxisomal_metabolic_failure#Peroxisomal Biogenesis or Enzyme Defect"
  description: >-
    Loss of functional peroxin 7 (PEX7), the cytosolic PTS2 receptor, prevents
    import of the subset of peroxisomal matrix enzymes that carry the type-2
    targeting signal. These enzymes are mislocalized to the cytosol and rendered
    non-functional, while PTS1-dependent import (mediated by PEX5) — including
    very-long-chain fatty acid beta-oxidation — remains largely intact. This
    selective import lesion distinguishes RCDP1 from the generalized matrix-import
    failure of the Zellweger spectrum.
  genes:
  - preferred_term: PEX7
    term:
      id: hgnc:8860
      label: PEX7
  molecular_functions:
  - preferred_term: peroxisome signal sequence receptor activity
    term:
      id: GO:0000268
      label: peroxisome signal sequence receptor activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: protein targeting to peroxisome
    term:
      id: GO:0006625
      label: protein targeting to peroxisome
    modifier: DECREASED
  cellular_components:
  - preferred_term: peroxisome
    term:
      id: GO:0005777
      label: peroxisome
  evidence:
  - reference: PMID:9090381
    reference_title: Human PEX7 encodes the peroxisomal PTS2 receptor and is responsible for rhizomelic chondrodysplasia punctata.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      PEX7, a candidate gene for RCDP identified in yeast, encodes the receptor
      for peroxisomal matrix proteins with the type-2 peroxisome targeting signal
      (PTS2).
    explanation: >-
      This study identifies PEX7 as the PTS2 import receptor whose loss causes
      RCDP, establishing the selective PTS2-import lesion.
  - reference: PMID:9090382
    reference_title: Rhizomelic chondrodysplasia punctata is a peroxisomal protein targeting disease caused by a non-functional PTS2 receptor.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Like S. cerevisiae pex cells, RCDP cells from CG11 cannot import a PTS2
      reporter protein.
    explanation: >-
      Demonstrates that RCDP (CG11) cells specifically fail to import PTS2-tagged
      cargo, the defining selective import defect.
  - reference: PMID:11781871
    reference_title: Mutational spectrum in the PEX7 gene and functional analysis of mutant alleles in 78 patients with rhizomelic chondrodysplasia punctata type 1.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the cytosolic PTS2-receptor protein required for targeting a subset of
      enzymes to peroxisomes. These enzymes are deficient in cells of patients
      with RCDP, because of their mislocalization to the cytoplasm.
    explanation: >-
      Confirms that only a subset of enzymes (the PTS2 cargo) is lost, by
      cytosolic mislocalization, in RCDP patient cells.
  downstream:
  - target: Plasmalogen (Ether Lipid) Deficiency
    description: >-
      Mislocalization of the PTS2 enzymes dihydroxyacetonephosphate
      acyltransferase and alkyldihydroxyacetonephosphate synthase blocks the
      peroxisomal steps of ether-phospholipid synthesis, depleting plasmalogens.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:9090382
      reference_title: Rhizomelic chondrodysplasia punctata is a peroxisomal protein targeting disease caused by a non-functional PTS2 receptor.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        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.
      explanation: >-
        The biochemical tetrad documents loss of the two ether-lipid synthesis
        enzymes upstream of plasmalogen deficiency.
  - target: Phytanic Acid Accumulation
    description: >-
      Loss of imported phytanoyl-CoA hydroxylase impairs peroxisomal phytanic
      acid alpha-oxidation, allowing dietary phytanic acid to accumulate
      progressively in plasma and tissues.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:9090382
      reference_title: Rhizomelic chondrodysplasia punctata is a peroxisomal protein targeting disease caused by a non-functional PTS2 receptor.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        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.
      explanation: >-
        The biochemical tetrad documents the alpha-oxidation deficiency upstream
        of phytanic acid accumulation.
- name: Plasmalogen (Ether Lipid) Deficiency
  conforms_to: "peroxisomal_metabolic_failure#Toxic Fatty-Acid Accumulation with Ether-Lipid Deficiency"
  description: >-
    Plasmalogens are ether glycerophospholipids whose peroxisomal synthesis
    depends on the PTS2 enzymes lost in RCDP1. Their deficiency disrupts membrane
    and myelin composition and developmental signaling in bone, brain, lens, and
    other tissues, accounting for the skeletal, ocular, and neurologic
    manifestations.
  biological_processes:
  - preferred_term: ether lipid biosynthetic process
    term:
      id: GO:0008611
      label: ether lipid biosynthetic process
    modifier: DECREASED
  evidence:
  - reference: PMID:22627108
    reference_title: Functions of plasmalogen lipids in health and disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The RCDP phenotype predicts developmental roles for plasmalogens in bone,
      brain, lens, lung, kidney and heart.
    explanation: >-
      This review links plasmalogen deficiency to the multisystem developmental
      phenotype of RCDP.
  downstream:
  - target: Skeletal Dysplasia
    description: >-
      Plasmalogen deficiency disrupts cartilage and bone development, producing
      rhizomelic shortening and chondrodysplasia punctata.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:22627108
      reference_title: Functions of plasmalogen lipids in health and disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The RCDP phenotype predicts developmental roles for plasmalogens in bone,
        brain, lens, lung, kidney and heart.
      explanation: >-
        Supports a plasmalogen-dependent developmental role in bone underlying
        the skeletal dysplasia.
  - target: Congenital Cataract
    description: >-
      Plasmalogen deficiency disrupts lens fiber development, producing
      congenital cataracts.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:22627108
      reference_title: Functions of plasmalogen lipids in health and disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The RCDP phenotype predicts developmental roles for plasmalogens in bone,
        brain, lens, lung, kidney and heart.
      explanation: >-
        Supports a plasmalogen-dependent developmental role in the lens
        underlying cataract.
  - target: Neurological Impairment
    description: >-
      Plasmalogen deficiency disrupts CNS neuronal and myelin development,
      producing intellectual disability and seizures.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:22627108
      reference_title: Functions of plasmalogen lipids in health and disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The RCDP phenotype predicts developmental roles for plasmalogens in bone,
        brain, lens, lung, kidney and heart.
      explanation: >-
        Supports a plasmalogen-dependent developmental role in brain underlying
        the neurological impairment.
- name: Phytanic Acid Accumulation
  description: >-
    Defective peroxisomal alpha-oxidation allows phytanic acid, derived from
    dietary sources, to accumulate over time. Accumulation is progressive and
    diet-dependent, contributing to disease in the milder, longer-surviving
    nonclassic form and providing the rationale for dietary phytanic acid
    restriction.
  biological_processes:
  - preferred_term: fatty acid alpha-oxidation
    term:
      id: GO:0001561
      label: fatty acid alpha-oxidation
    modifier: DECREASED
  chemical_entities:
  - preferred_term: phytanic acid
    term:
      id: CHEBI:16285
      label: phytanic acid
    modifier: INCREASED
  evidence:
  - reference: PMID:20301447
    reference_title: PEX7-Related Rhizomelic Chondrodysplasia Punctata.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dietary restriction of phytanic acid to avoid the consequences of phytanic
      acid accumulation over time may benefit individuals with mild PEX7-RCDP.
    explanation: >-
      GeneReviews documents progressive phytanic acid accumulation and its
      diet-modifiable consequences in RCDP1.
- name: Skeletal Dysplasia
  description: >-
    Plasmalogen-dependent disruption of cartilage and bone development produces
    rhizomelic (proximal) limb shortening, chondrodysplasia punctata with
    stippled epiphyses, and coronal vertebral clefts.
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  evidence:
  - reference: PMID:20301447
    reference_title: PEX7-Related Rhizomelic Chondrodysplasia Punctata.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Classic (severe) PEX7-RCDP is characterized by proximal shortening of the
      humerus (rhizomelia) and to a lesser degree the femur, punctate
      calcifications in cartilage with epiphyseal and metaphyseal abnormalities
      (chondrodysplasia punctata, or CDP), coronal clefts of the vertebral
      bodies, and cataracts that are usually present at birth or appear in the
      first few months of life.
    explanation: >-
      GeneReviews enumerates the rhizomelic shortening, chondrodysplasia
      punctata, and coronal vertebral clefts of classic RCDP1.
  downstream:
  - target: Rhizomelia
    description: The skeletal dysplasia produces proximal limb shortening, especially of the humerus.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301447
      reference_title: PEX7-Related Rhizomelic Chondrodysplasia Punctata.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        proximal shortening of the humerus (rhizomelia)
      explanation: GeneReviews directly describes the rhizomelic limb-shortening phenotype.
  - target: Chondrodysplasia Punctata
    description: Abnormal cartilage and epiphyseal development produces punctate calcifications and epiphyseal stippling.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301447
      reference_title: PEX7-Related Rhizomelic Chondrodysplasia Punctata.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        punctate calcifications in cartilage with epiphyseal and metaphyseal
      explanation: GeneReviews directly supports chondrodysplasia punctata as a skeletal manifestation.
  - target: Coronal Cleft Vertebrae
    description: Vertebral-body dysplasia produces characteristic coronal clefts.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301447
      reference_title: PEX7-Related Rhizomelic Chondrodysplasia Punctata.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        coronal clefts of the
      explanation: GeneReviews lists coronal vertebral clefts among defining skeletal features.
  - target: Postnatal Growth Deficiency
    description: Severe developmental skeletal disease is accompanied by profound postnatal growth deficiency.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301447
      reference_title: PEX7-Related Rhizomelic Chondrodysplasia Punctata.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        postnatal growth deficiency is profound.
      explanation: GeneReviews documents profound postnatal growth deficiency in classic RCDP1.
  - target: Joint Contractures
    description: Musculoskeletal involvement includes multiple joint contractures, especially in nonclassic disease.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301447
      reference_title: PEX7-Related Rhizomelic Chondrodysplasia Punctata.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        joint contractures, neurobehavioral abnormalities,
      explanation: GeneReviews lists joint contractures in the nonclassic RCDP1 phenotype.
- name: Congenital Cataract
  description: >-
    Plasmalogen deficiency disrupts lens fiber development, producing cataracts
    usually present at birth or in the first months of life.
  cell_types:
  - preferred_term: lens fiber cell
    term:
      id: CL:0011004
      label: lens fiber cell
  evidence:
  - reference: PMID:20301447
    reference_title: PEX7-Related Rhizomelic Chondrodysplasia Punctata.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      cataracts that are usually present at birth or appear in the first few
      months of life
    explanation: >-
      GeneReviews documents congenital/early-infantile cataracts in RCDP1.
  downstream:
  - target: Cataract
    description: Lens fiber developmental disruption produces congenital or early-infantile cataracts.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301447
      reference_title: PEX7-Related Rhizomelic Chondrodysplasia Punctata.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        cataracts that are usually present at birth or appear in
      explanation: GeneReviews documents congenital or early-infantile cataracts in RCDP1.
- name: Neurological Impairment
  description: >-
    CNS plasmalogen deficiency impairs neuronal and myelin development, producing
    severe intellectual disability and seizures.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: oligodendrocyte
    term:
      id: CL:0000128
      label: oligodendrocyte
  evidence:
  - reference: PMID:20301447
    reference_title: PEX7-Related Rhizomelic Chondrodysplasia Punctata.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Intellectual disability is severe, and most children develop seizures.
    explanation: >-
      GeneReviews documents severe intellectual disability and seizures in
      classic RCDP1.
  downstream:
  - target: Intellectual Disability
    description: CNS developmental impairment produces severe intellectual disability in classic RCDP1.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301447
      reference_title: PEX7-Related Rhizomelic Chondrodysplasia Punctata.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Intellectual disability is severe, and most children develop seizures.
      explanation: GeneReviews documents severe intellectual disability in classic RCDP1.
  - target: Seizures
    description: CNS involvement in classic RCDP1 commonly includes seizures.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301447
      reference_title: PEX7-Related Rhizomelic Chondrodysplasia Punctata.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Intellectual disability is severe, and most children develop seizures.
      explanation: GeneReviews states that most children with classic RCDP1 develop seizures.
phenotypes:
- name: Rhizomelia
  category: Musculoskeletal
  diagnostic: true
  description: >-
    Symmetrical proximal shortening of the limbs, most marked in the humerus and
    to a lesser degree the femur, is the defining skeletal feature of RCDP.
  phenotype_term:
    preferred_term: Rhizomelia
    term:
      id: HP:0008905
      label: Rhizomelia
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:20301447
    reference_title: PEX7-Related Rhizomelic Chondrodysplasia Punctata.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      proximal shortening of the humerus (rhizomelia) and to a lesser degree the
      femur
    explanation: >-
      GeneReviews directly describes rhizomelic proximal limb shortening as a
      defining clinical feature of RCDP1.
- name: Chondrodysplasia Punctata
  category: Musculoskeletal
  diagnostic: true
  description: >-
    Punctate calcifications in cartilage with epiphyseal stippling are the
    radiographic hallmark, giving the disorder its name.
  phenotype_term:
    preferred_term: Epiphyseal stippling
    term:
      id: HP:0010655
      label: Epiphyseal stippling
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:20301447
    reference_title: PEX7-Related Rhizomelic Chondrodysplasia Punctata.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      punctate calcifications in cartilage with epiphyseal and metaphyseal
      abnormalities (chondrodysplasia punctata, or CDP)
    explanation: >-
      GeneReviews documents the punctate cartilage calcification / epiphyseal
      stippling that defines chondrodysplasia punctata.
- name: Coronal Cleft Vertebrae
  category: Musculoskeletal
  description: >-
    Coronal clefts of the vertebral bodies are a characteristic spinal
    radiographic finding in classic RCDP1.
  phenotype_term:
    preferred_term: Coronal cleft vertebrae
    term:
      id: HP:0003417
      label: Coronal cleft vertebrae
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:20301447
    reference_title: PEX7-Related Rhizomelic Chondrodysplasia Punctata.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      coronal clefts of the vertebral bodies
    explanation: >-
      GeneReviews lists coronal vertebral clefts among the defining skeletal
      features.
- name: Cataract
  category: Visual
  diagnostic: true
  description: >-
    Cataracts are usually present at birth or appear in the first months of life
    and occur in both classic and nonclassic forms.
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:20301447
    reference_title: PEX7-Related Rhizomelic Chondrodysplasia Punctata.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      cataracts that are usually present at birth or appear in the first few
      months of life
    explanation: >-
      GeneReviews documents congenital/early-infantile cataracts in RCDP1.
- name: Postnatal Growth Deficiency
  category: Growth
  description: >-
    Postnatal growth deficiency is profound in classic RCDP1 and milder in the
    nonclassic form.
  phenotype_term:
    preferred_term: Postnatal growth retardation
    term:
      id: HP:0008897
      label: Postnatal growth retardation
  evidence:
  - reference: PMID:20301447
    reference_title: PEX7-Related Rhizomelic Chondrodysplasia Punctata.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      postnatal growth deficiency is profound.
    explanation: >-
      GeneReviews documents profound postnatal growth deficiency in classic
      RCDP1.
- name: Intellectual Disability
  category: Neurologic
  description: >-
    Intellectual disability is severe in classic RCDP1 and milder in the
    nonclassic form.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:20301447
    reference_title: PEX7-Related Rhizomelic Chondrodysplasia Punctata.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Intellectual disability is severe, and most children develop seizures.
    explanation: >-
      GeneReviews documents severe intellectual disability in classic RCDP1.
- name: Seizures
  category: Neurologic
  description: >-
    Most children with classic RCDP1 develop seizures.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:20301447
    reference_title: PEX7-Related Rhizomelic Chondrodysplasia Punctata.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Intellectual disability is severe, and most children develop seizures.
    explanation: >-
      GeneReviews documents seizures in most children with classic RCDP1.
- name: Joint Contractures
  category: Musculoskeletal
  description: >-
    Multiple joint contractures occur, and are a notable feature of the
    nonclassic (mild) form.
  phenotype_term:
    preferred_term: Joint contracture
    term:
      id: HP:0034392
      label: Joint contracture
  evidence:
  - reference: PMID:20301447
    reference_title: PEX7-Related Rhizomelic Chondrodysplasia Punctata.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      joint contractures, neurobehavioral abnormalities, and milder intellectual
      disability
    explanation: >-
      GeneReviews lists joint contractures among the nonclassic RCDP1 features.
genetic:
- name: PEX7
  gene_term:
    preferred_term: PEX7
    term:
      id: hgnc:8860
      label: PEX7
  association: >-
    Biallelic loss-of-function variants in PEX7 cause RCDP1 (PBD complementation
    group 11). Disease severity correlates with residual PEX7 allele activity;
    the recurrent L292ter null allele is associated with the severe phenotype.
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:11781871
    reference_title: Mutational spectrum in the PEX7 gene and functional analysis of mutant alleles in 78 patients with rhizomelic chondrodysplasia punctata type 1.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we show by functional analysis that disease severity correlates with PEX7
      allele activity
    explanation: >-
      Functional analysis of patient alleles ties disease severity to residual
      PEX7 receptor activity.
  - reference: PMID:9090381
    reference_title: Human PEX7 encodes the peroxisomal PTS2 receptor and is responsible for rhizomelic chondrodysplasia punctata.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we found two inactivating PEX7 mutations: one, L292ter, was present in 26
      of the probands, all with a severe phenotype
    explanation: >-
      Identifies the recurrent L292ter null allele associated with severe RCDP1.
biochemical:
- name: Plasmalogens
  presence: Decreased
  context: >-
    Erythrocyte and tissue plasmalogens are reduced because the PTS2 enzymes of
    peroxisomal ether-lipid synthesis are mislocalized and non-functional.
  readouts:
  - target: Plasmalogen (Ether Lipid) Deficiency
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Decreased plasmalogens report failure of peroxisomal ether-lipid synthesis.
  biomarker_term:
    preferred_term: plasmalogens
    term:
      id: CHEBI:64611
      label: ether lipid
  evidence:
  - reference: PMID:36914043
    reference_title: Quantitative analysis of ethanolamine plasmalogen species in red blood cells using liquid chromatography tandem mass spectrometry for diagnosing peroxisome biogenesis disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Markedly reduced plasmalogens are a classic feature of peroxisome
      biogenesis disorders (PBD) because plasmalogen synthesis requires
      functional peroxisomes.
    explanation: >-
      RCDP1 is a peroxisome biogenesis disorder; markedly reduced plasmalogens
      are its classic biochemical hallmark.
- name: Phytanic acid
  presence: Increased
  context: >-
    Phytanic acid accumulates progressively because peroxisomal alpha-oxidation
    (phytanoyl-CoA hydroxylase) is deficient. VLCFA levels are characteristically
    normal, distinguishing RCDP1 from the Zellweger spectrum.
  readouts:
  - target: Phytanic Acid Accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Elevated phytanic acid reports impaired peroxisomal alpha-oxidation.
  biomarker_term:
    preferred_term: phytanic acid
    term:
      id: CHEBI:16285
      label: phytanic acid
  evidence:
  - reference: PMID:20301447
    reference_title: PEX7-Related Rhizomelic Chondrodysplasia Punctata.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dietary restriction of phytanic acid to avoid the consequences of phytanic
      acid accumulation over time may benefit individuals with mild PEX7-RCDP.
    explanation: >-
      GeneReviews supports phytanic acid accumulation as a biochemical feature
      of RCDP1.
diagnosis:
- name: Clinical, Radiographic, and Laboratory Case Definition
  description: >-
    PEX7-RCDP is established in a proband with the suggestive clinical and
    radiographic RCDP pattern, compatible laboratory findings, and biallelic
    pathogenic PEX7 variants.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  evidence:
  - reference: PMID:20301447
    reference_title: PEX7-Related Rhizomelic Chondrodysplasia Punctata.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of PEX7-RCDP is established in a proband with suggestive
      clinical, radiographic, and laboratory findings and biallelic pathogenic
      variants in PEX7 identified on molecular genetic testing.
    explanation: >-
      GeneReviews defines the integrated clinical, radiographic, laboratory, and
      molecular diagnostic case definition for PEX7-RCDP.
  - reference: PMID:20301447
    reference_title: PEX7-Related Rhizomelic Chondrodysplasia Punctata.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Classic (severe) PEX7-RCDP is characterized by proximal shortening of the
      humerus (rhizomelia) and to a lesser degree the femur, punctate
      calcifications in cartilage with epiphyseal and metaphyseal abnormalities
      (chondrodysplasia punctata, or CDP), coronal clefts of the vertebral
      bodies, and cataracts that are usually present at birth or appear in the
      first few months of life.
    explanation: >-
      Supports the characteristic clinical and radiographic findings that prompt
      PEX7-RCDP diagnostic evaluation.
- name: Plasmalogen and Phytanic-Acid Biochemical Testing
  description: >-
    Laboratory evaluation supports RCDP1 by showing severe plasmalogen deficiency
    together with the PTS2-import biochemical tetrad, including impaired
    phytanic-acid alpha-oxidation and loss of peroxisomal thiolase import.
  diagnosis_term:
    preferred_term: biomarker analysis
    term:
      id: NCIT:C63333
      label: Biomarker Analysis
  evidence:
  - reference: PMID:36914043
    reference_title: Quantitative analysis of ethanolamine plasmalogen species in red blood cells using liquid chromatography tandem mass spectrometry for diagnosing peroxisome biogenesis disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Particularly, severe plasmalogen deficiency is the biochemical hallmark of
      rhizomelic chondrodysplasia punctata (RCDP).
    explanation: >-
      Supports plasmalogen quantification as a diagnostic biochemical marker for
      RCDP.
  - reference: PMID:36914043
    reference_title: Quantitative analysis of ethanolamine plasmalogen species in red blood cells using liquid chromatography tandem mass spectrometry for diagnosing peroxisome biogenesis disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We developed a liquid-chromatography/tandem mass-spectrometry (LC-MS/MS)
      method to quantify eighteen phosphoethanolamine plasmalogens in RBCs to
      diagnose PBD patients, especially RCDP.
    explanation: >-
      Supports RBC plasmalogen LC-MS/MS as a diagnostic assay for RCDP.
  - reference: PMID:9090382
    reference_title: Rhizomelic chondrodysplasia punctata is a peroxisomal protein targeting disease caused by a non-functional PTS2 receptor.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      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.
    explanation: >-
      Defines the PEX7/CG11 biochemical signature that distinguishes RCDP1 from
      isolated plasmalogen-enzyme defects and generalized Zellweger-spectrum
      disease.
- name: PEX7 Molecular Genetic Confirmation
  description: >-
    Molecular genetic testing confirms RCDP1 by identifying biallelic pathogenic
    variants in PEX7, the gene encoding the PTS2 import receptor.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:20301447
    reference_title: PEX7-Related Rhizomelic Chondrodysplasia Punctata.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      biallelic pathogenic variants in PEX7 identified on molecular genetic
      testing.
    explanation: >-
      Directly supports PEX7 molecular testing as the confirmatory procedure.
  - reference: PMID:9090381
    reference_title: Human PEX7 encodes the peroxisomal PTS2 receptor and is responsible for rhizomelic chondrodysplasia punctata.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conclude that PEX7 is responsible for RCDP (PBD CG11) and suggest a
      founder effect may explain the high frequency of L292ter.
    explanation: >-
      Supports PEX7 as the causal disease gene for RCDP1 / complementation group
      11.
  - reference: PMID:9090382
    reference_title: Rhizomelic chondrodysplasia punctata is a peroxisomal protein targeting disease caused by a non-functional PTS2 receptor.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These findings prove that mutations in PEX7 cause RCDP, CG11.
    explanation: >-
      Functional rescue and segregation evidence confirm that PEX7 variants
      cause RCDP1.
- name: Prenatal Genetic Testing
  description: >-
    Prenatal testing can be offered in an affected family after the familial
    PEX7 pathogenic variants have been identified.
  diagnosis_term:
    preferred_term: prenatal genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:20301447
    reference_title: PEX7-Related Rhizomelic Chondrodysplasia Punctata.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Once the PEX7 pathogenic variants have been identified in an affected
      family member, molecular genetic carrier testing of at-risk relatives and
      prenatal/preimplantation genetic testing are possible.
    explanation: >-
      GeneReviews supports prenatal genetic testing when familial PEX7 variants
      are known.
- name: Preimplantation Genetic Testing
  description: >-
    Preimplantation genetic testing is possible for families once the familial
    PEX7 pathogenic variants have been identified.
  diagnosis_term:
    preferred_term: preimplantation genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:20301447
    reference_title: PEX7-Related Rhizomelic Chondrodysplasia Punctata.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Once the PEX7 pathogenic variants have been identified in an affected
      family member, molecular genetic carrier testing of at-risk relatives and
      prenatal/preimplantation genetic testing are possible.
    explanation: >-
      GeneReviews supports preimplantation genetic testing when familial PEX7
      variants are known.
treatments:
- name: Dietary Phytanic Acid Restriction
  description: >-
    Dietary restriction of phytanic acid may benefit individuals with mild
    (nonclassic) RCDP1 by limiting progressive phytanic acid accumulation.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_phenotypes:
  - preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:20301447
    reference_title: PEX7-Related Rhizomelic Chondrodysplasia Punctata.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dietary restriction of phytanic acid to avoid the consequences of phytanic
      acid accumulation over time may benefit individuals with mild PEX7-RCDP.
    explanation: >-
      GeneReviews supports dietary phytanic acid restriction in mild RCDP1.
- name: Supportive and Rehabilitative Care
  description: >-
    Management is supportive: physical therapy and orthopedic procedures for
    contractures, and cataract extraction to preserve vision.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Joint contracture
    term:
      id: HP:0034392
      label: Joint contracture
  - preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: PMID:20301447
    reference_title: PEX7-Related Rhizomelic Chondrodysplasia Punctata.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Physical therapy to improve contractures; orthopedic procedures may improve
      function in some individuals
    explanation: >-
      GeneReviews supports physical therapy and orthopedic management of
      contractures.
- name: Cataract Extraction
  description: >-
    Surgical removal of cataracts can restore and/or preserve vision.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_phenotypes:
  - preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: PMID:20301447
    reference_title: PEX7-Related Rhizomelic Chondrodysplasia Punctata.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      cataract extraction may restore and/or preserve vision
    explanation: >-
      GeneReviews supports cataract extraction to preserve vision in RCDP1.
differential_diagnoses:
- name: Zellweger Spectrum Disorders
  disease_term:
    preferred_term: Zellweger spectrum disorders
    term:
      id: MONDO:0019609
      label: Zellweger spectrum disorders
  description: >-
    ZSD results from generalized peroxisomal matrix-import failure affecting both
    PTS1 and PTS2 cargo, producing VLCFA accumulation alongside plasmalogen and
    bile-acid abnormalities. RCDP1 spares PTS1-dependent VLCFA beta-oxidation,
    so VLCFA levels are typically normal.
  distinguishing_features:
  - >-
    RCDP1 has a selective PTS2-import defect with normal VLCFA beta-oxidation;
    ZSD has generalized import failure with elevated VLCFA.
- name: Rhizomelic Chondrodysplasia Punctata Types 2-5
  description: >-
    RCDP types 2-5 phenocopy RCDP1 through direct deficiency of individual
    plasmalogen-biosynthesis enzymes (e.g., GNPAT, AGPS, FAR1) rather than
    through the PEX7 PTS2 import receptor, with preserved phytanic acid
    alpha-oxidation in the single-enzyme forms.
  distinguishing_features:
  - >-
    RCDP1 is a PEX7 biogenesis/import-receptor defect causing combined
    plasmalogen and phytanic-oxidation deficiency; RCDP2-5 are single-enzyme
    plasmalogen-synthesis defects.