Clinical characteristics.

PEX7-related rhizomelic chondrodysplasia punctata (PEX7-RCDP), a peroxisome biogenesis disorder (PBD), has a classic (severe) form and a nonclassic (mild) form. 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. Birth weight, length, and head circumference are often at the lower range of normal; postnatal growth deficiency is profound. Intellectual disability is severe, and most children develop seizures. Most affected children do not survive the first decade of life; a proportion die in the neonatal period. 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.

Diagnosis/testing.

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.

Management.

Treatment of manifestations: In those with classic (severe) PEX7-RCDP, management is supportive and limited by the severe health issues present at birth and poor outcome. Dietary restriction of phytanic acid to avoid the consequences of phytanic acid accumulation over time may benefit individuals with mild PEX7-RCDP. Physical therapy to improve contractures; orthopedic procedures may improve function in some individuals; consider need for positioning and mobility devices; spinal decompression with or without fusion depending on region of compression and myelopathic signs; cataract extraction may restore and/or preserve vision; community vision services through early intervention or school district; poor feeding and recurrent aspiration may necessitate placement of a gastrostomy tube; developmental and educational support; standard treatment of seizures by an experienced neurologist; good pulmonary clearance and attention to respiratory function; influenza vaccine, RSV monoclonal antibody, and other interventions to prevent lung disease; management of congenital heart disease per cardiologist; dermatologist management of skin manifestations; management of kidney and urinary tract anomalies per nephrologist and/or urologist; social work and care coordination as needed.

Surveillance: Annual measurement of phytanic acid levels in children with non-classic (mild) PEX7-RCDP; musculoskeletal assessment, assessment for kyphosis and scoliosis, and neurologic exam with assessment for seizures at each visit; vision assessment every three months until cataracts are detected and then as recommended by ophthalmologist; assessment of growth, nutritional status, safety of oral intake, development, behavior, and respiratory function at each visit; cardiac exam, echocardiogram, and EKG with frequency per treating cardiologist; urine and imaging studies to assess for kidney stones as needed; assessment for skin issues and family needs at each visit.

Genetic counseling.

PEX7-RCDP is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a PEX7 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting both pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. 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.

Suggestive Findings

PEX7-related rhizomelic chondrodysplasia punctata (PEX7-RCDP) should be suspected based on the individual's age and the severity of clinical and skeletal/radiographic findings.

Classic (Severe) PEX7-RCDP (the majority of affected individuals)

Neonatal period

• Congenital cataracts
• Skeletal/radiographic findings
  • 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 (see Figure 1).
  • Radiolucent coronal clefts of the vertebral bodies on lateral spine radiographs that represent unossified cartilage (See Figure 2.)

Figure 1.

Radiograph of a newborn with classic (severe) PEX7-RCDP showing rhizomelia and chondrodysplasia punctata (CDP) (arrows).

Figure 2.

Lateral Infant spine showing vertebral coronal clefting (arrow)

Childhood

• Cataracts (usually apparent by age 6 months)
• Severe intellectual disability
• Profound postnatal growth restriction
• Evolution of skeletal/radiographic findings:
  • Resolution of the punctate calcifications leaving abnormal epiphyses and flared and irregular metaphyses after ages one to three years (See Figure 3a.)
  • Possible calcification of the intervertebral discs (See Figure 3b.)
  • Frontal bossing and a short, concave nasal bridge resulting from cartilaginous involvement (See Figure 4.)

Figure 3

a. Progression of radiographic changes in a child with classic (severe) PEX7-RCDP showing metaphyseal flaring (red closed arrows) and epiphyseal abnormalities (white open arrow) b. Calcification of intervertebral discs (blue arrows)

Figure 4.

Characteristic facial features of classic (severe) PEX7-RCDP showing frontal bossing, short concave nasal bridge, hypoplastic midface, upturned nose, and short-appearing neck. Note also rhizomelia and profound growth deficiency (children in the photos (more...)

Nonclassic (Mild) PEX7-RCDP

• Congenital or childhood cataracts
• CDP or, infrequently, chondrodysplasia manifesting as mild epiphyseal changes only (See Figure 5.)
• Joint contractures
• Developmental delays and learning disability
• Milder growth restriction than classic PEX7-RCDP
• Behavioral issues

Figure 5.

Radiographs of nonclassic (mild) PEX7-RCDP. Shoulders show CDP (arrows) at the proximal humerus without metaphyseal changes or rhizomelia.

Biochemical Testing

The finding of deficiency of plasmalogens in red blood cells (RBC), increased plasma concentration of phytanic acid (when diet includes phytanic acid sources), and normal plasma concentration of very long-chain fatty acids (VLCFA) has consistently predicted the PEX7 receptor defect in PEX7-RCDP [Braverman et al 2002, Motley et al 2002]. These assays are extremely specialized and are reliably performed in a limited number of laboratories worldwide.

Plasmalogen levels are valuable in distinguishing between classic and milder PEX7-RCDP: RBC plasmalogen levels are around 10- to 30-fold higher in individuals with milder PEX7-RCDP than in those with classic PEX7-RCDP [Braverman et al 2002, Bams-Mengerink et al 2013, Duker et al 2016, Fallatah et al 2021].

Plasmalogens are a unique class of ether glycerophospholipids (GPs) containing a fatty alcohol with a vinyl ether bond at the sn-1 position, and enriched in polyunsaturated fatty acids at the sn-2 position of the glycerol backbone.

Plasmalogens were traditionally measured in RBC by gas chromatography-mass spectrometry (GC-MS), which detects the relative amounts of C16:0, C18:0, and C18:1 plasmalogens as dimethyl acetal derivatives of the ether-linked alkenes [Steinberg et al 2008]. Overall, the GC-MS method provides highly sensitive plasmalogen values; however, it cannot specifically identify the molecular species of plasmalogens.

Recently, the GC-MS method was expanded to utilize dried blood spots in addition to RBC [Wegwerth et al 2023]. Moreover, quantification of plasmalogen species in RBC using liquid chromatography-tandem mass spectrometry (LC-MS/MS) showed utility in diagnosis of RCDP. The same study also reported age-specific reference values for plasmalogen species that provide insights about plasmalogen levels in different age groups [De Biase et al 2023].

Establishing the Diagnosis

The diagnosis of PEX7-RCDP is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in PEX7 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic PEX7 variants of uncertain significance (or of one known PEX7 pathogenic variant and one PEX7 variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

Nonclassic (Mild) PEX7-RCDP

This group is defined clinically by the ability to walk with or without support and the ability to use verbal or nonverbal types of communication [Bams-Mengerink et al 2013, Fallatah et al 2021]. Most individuals with nonclassic (mild) PEX7-RCDP presented in early childhood with bilateral cataracts, multiple joint contractures, and developmental delays [Braverman et al 2002, Bams-Mengerink et al 2006, Fallatah et al 2021]. Overall life expectancy is considerably longer than that of classic PEX7-RCDP, with survival to adulthood [Bams-Mengerink et al 2013, Huffnagel et al 2013]; in one study 11 of 12 affected individuals survived to adulthood [Duker et al 2020].

Skeletal. About 50% of individuals with mild PEX7-RCDP have limited joint mobility due to flexion contractures of the elbows, knees, and hips. Joint contractures, particularly at the knees, are progressive leading to restricted movement and a need for assistive devices. Hip deformities (coxa valga, coxa vara, or hip dysplasia) are common and usually require surgical intervention to improve activities of daily living (see Figure 6). In a cohort of 16 individuals, CDP was detected in skeletal radiographs in 56% of individuals with mild PEX7-RCDP at the time of diagnosis; however, asymmetrical rhizomelia was reported in only 18% [Fallatah et al 2021].

Figure 6.

Girl age five years with nonclassic PEX7-RCDP showing better growth than classic PEX7-RCDP and absence of rhizomelia. Radiographs of the hips show coxa vara of the femoral head (arrows). Femoral osteotomy was performed to improve mobility.

Eye abnormalities. Most individuals with mild PEX7-RCDP have bilateral cataracts noted in the first two years of life. In some instances, bilateral cataracts were the only clinical finding prompting the diagnosis of PEX7-RCDP. Other abnormalities found in a single individual include unilateral strabismus, myopic astigmatism, horizonal nystagmus, and lacrimal duct obstruction. Bilateral pigmentary retinopathy in late childhood or early adulthood was reported in two individuals with mild PEX7-RCDP [Braverman et al 2002, Fallatah et al 2021].

Growth of individuals with mild PEX7-RCDP can be within normal ranges at birth. Postnatal growth rates are better than in children with classic PEX7-RCDP. Growth curves based on four individuals with mild PEX7-RCDP have been published [Duker et al 2017].

Intellect and development. Individuals with mild PEX7-RCDP show a wide range of developmental delays. Some had normal gross and fine motor skills and required minimal educational support during school years. Others manifested significant developmental delays particularly in fine motor skills and verbal communication. These individuals needed special education and speech therapy. A few showed prominent global delays in acquiring gross motor skills (such as walking) and fine motor skills and were mainly using nonverbal communication [Fallatah et al 2021].

Neurologic features. Late-onset seizures (range: age 4-24 years) occur in individuals with mild PEX7-RCDP. The most common seizure types were absence and tonic-clonic seizures. Brain MRI was either normal or showed white matter signal abnormalities [Fallatah et al 2021].

Congenital heart disease. Cardiac defects including atrial septal defect, patent foramen ovale, patent ductus arteriosus, and ventricular septal defect are frequently reported in individuals with mild PEX7-RCDP. Two of the sixteen individuals with mild PEX7-RCDP reported developed heart block and mitral valve prolapse, possibly indicating degenerative cardiac changes [Fallatah et al 2021, Dorninger et al 2023].

Behavior disorders. Attention-deficit/hyperactivity, autism spectrum, and obsessive-compulsive disorders are frequently reported in school-aged children with mild PEX7-RCDP. Sleep disturbances and anxiety symptoms have also been documented. These behavioral problems could interfere with learning and often require medical treatment [Fallatah et al 2021].

Other abnormalities. Vitamin D deficiency, eczema, or mild ichthyosis are documented in 25% of individuals. Endocrine abnormalities including episodes of hypoglycemia and hypothyroidism have been reported in a single individual [Fallatah et al 2021].

Genotype-Phenotype Correlations

Correlations between the predicted severity of PEX7 pathogenic variants and PEX7-RCDP phenotype include the following:

• All individuals homozygous for the p.Leu292Ter pathogenic variant studied to date have had classic PEX7-RCDP.
• In individuals who are compound heterozygotes for p.Leu292Ter and another pathogenic variant, the effect of the other allele is important in determining the phenotype. Several PEX7 variants that are associated with a milder PEX7-RCDP phenotype or adult Refsum disease have been identified. It is predicted that these encode either residual amounts of a normal peroxisomal targeting signal 2 receptor protein (the protein encoded by PEX7) or a defective protein with residual function [Braverman et al 2002, Motley et al 2002, van den Brink et al 2003, Fallatah et al 2021].
• The hypomorphic variant p.His285Arg is the most frequent PEX7 variant associated with a mild phenotype [Bams-Mengerink et al 2013, Fallatah et al 2021].

Nomenclature

PEX7-RCDP is one of two groups of peroxisome biogenesis disorders (PBD); the other group is Zellweger spectrum disorder. Although individuals with PEX7-RCDP have a perturbation in matrix protein import consistent with a peroxisomal assembly defect, they have a biochemical, cellular, and clinical phenotype distinct from Zellweger spectrum disorder.

In the 2023 revision of the Nosology of Genetic Skeletal Disorders [Unger et al 2023], PEX7-RCDP is referred to as PEX7-related rhizomelic CDP.

Prevalence

The birth prevalence of PEX7-RCDP is estimated to be lower than 1:100,000. Using allele frequencies (extracted from TopMed and gnomAD) and RCDP survival analyses [Duker et al 2020], the birth and disease prevalence for PEX7-RCDP was further refined to 0.5 cases in 100,000 births and 190 living affected individuals in the United States [Luisman et al 2021], with slightly higher projections in Europe.

The high frequency of the p.Leu292Ter pathogenic variant is secondary to a founder effect in individuals of northern European descent [Braverman et al 2000]. This variant was identified in high frequency in a genetically isolated community in the Netherlands, where the carrier frequency among tested individuals was around 6% [Mathijssen et al 2015] (see Table 6).

The hypomorphic variant p.His285Arg is the most frequent PEX7 variant associated with a mild phenotype, and is proposed to be a founder variant in individuals of Dutch origin [Bams-Mengerink et al 2013, Fallatah et al 2021].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with PEX7-RCDP, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

In classic (severe) PEX7-RCDP, management is supportive because of the severe health issues present at birth and poor outcome. In children with nonclassic (mild) PEX7-RCDP, supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 4).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended.

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Anecdotal reports of natural plasmalogen precursor (alkylglycerol) supplementation in a few individuals with classic PEX7-RCDP have not indicated dramatic clinical benefit; however, alkylglycerol supplementation in humans has not yet been studied in a systematic fashion. A synthetic plasmalogen precursor was recently trialed in healthy adults for safety, tolerability, and pharmacokinetics [Smith et al 2025].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

PEX7-related rhizomelic chondrodysplasia punctata (PEX7-RCDP) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for a PEX7 pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a PEX7 pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for a PEX7 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting both pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. To date, individuals with classic PEX7-RCDP are not known to reproduce.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a PEX7 pathogenic variant.

Carrier Detection

Molecular genetic carrier testing for at-risk relatives requires prior identification of the PEX7 pathogenic variants in the family.

Note: Carriers cannot be identified by biochemical methods.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of known carriers, particularly if both partners are of the same ancestry (see Prevalence).

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the PEX7 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Ultrasound examination. Rhizomelia and punctate calcifications have been noted on ultrasound examination as early as 17 to 19 weeks' gestation [Krakow et al 2003, Zwijnenburg et al 2010, Landino et al 2017, Gerami & Barkhordari 2023]. Others have reported these findings along with bilateral cataracts at 32 weeks' gestation, and epiphyseal stippling shown four weeks later [Başbuğ et al 2005]. Homozygosity of the p.Leu292Ter and p.Cys86Tyr variant in PEX7 was verified in the Zwijnenburg et al [2010] and Gerami & Barkhordari [2023] reports, respectively.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

PEX7-related rhizomelic chondrodysplasia punctata (PEX7-RCDP) is a disorder of peroxisome biogenesis, caused by defects in PEX7. PEX7 encodes peroxisomal targeting signal 2 receptor, a receptor for peroxisomal matrix enzymes that contain a PTS2 targeting sequence. The enzymes include:

• AGPS (required for plasmalogen synthesis)
• PHYH (required for phytanic acid oxidation)
• ACAA1 (involved in fatty acid B oxidation, but not required)

Peroxisomal targeting signal 2 receptor (PEX7) binds to these enzymes and has a second binding site for the PEX5-encoded peroxisomal targeting signal 1 receptor (which binds PTS1-targeted enzymes; PEX5) in the cytosol to carry its cargo to the peroxisome membrane, where the enzymes are translocated inside. Subsequently, the import complex is disassembled, and PEX7 and other proteins of the complex 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 and requires the coordinated action of multiple PEX proteins. Defects in any one of 13 of these cause the peroxisome biogenesis disorder Zellweger spectrum, whereas PEX7-related rhizomelic chondrodysplasia punctata (PEX7-RCDP) is caused by defects in PEX7 or, rarely, in the PEX7 binding region of PEX5. See Kunze et al [2011], Waterham & Ebberink [2012], and Waterham et al [2016] for details of PEX genes, peroxisome biogenesis, and disorders of peroxisome deficiency.

Mechanism of disease causation. Pathogenic variants in PEX7 impair the import of PTS2-targeted peroxisome matrix enzymes resulting in deficient activity of these enzymes; however, other peroxisomal functions remain intact, such as import of PTS1-targeted proteins by PEX5 and peroxisome membrane assembly. In vitro assays in fibroblasts show that the PTS2-targeted peroxisomal matrix enzymes remain cytosolic and are degraded in individuals with PEX7-RCDP. There is no evidence to support gain of function as a cause of PEX7-RCDP.

Variants associated with a milder PEX7-RCDP phenotype or adult Refsum disease are either:

• Missense variants located on the surface of PEX7 and, thus, unlikely to disrupt its structural integrity (p.Ser25Phe, p.His285Arg, p.Thr14Pro, p.Ile245Phe, p.Ser116Ile, p.Tyr40Cys, p.Asp177Glu) [Braverman et al 2002, van den Brink et al 2003, Fallatah et al 2021, Masih et al 2021];
• "Leaky" alleles, potentially able to generate residual amounts of normal PEX7 protein (c.-45C>T, c.340-10A>G), to reinitiate translation in-frame (p.His18ArgfsTer35), or located at a downstream methionine residue (p.Gly7ValfsTer51) [Braverman et al 2002, Motley et al 2002, van den Brink et al 2003, Fallatah et al 2021].

PEX7-specific laboratory technical considerations. Technical considerations in sequencing PEX7 include reviewing the 5' UTR and intron 3 for known PEX7 pathogenic variants (see Table 6).

Author History

Michael B Bober, PhD, MD (2020-2025)
Nancy E Braverman, MS, MD (2001-present)
Ricki Carroll, MD, MBE (2025-present)
Angela Duker, MS, CGC (2020-2025)
Wedad Fallatah, MD, MAS (2020-present)
Mahim Jain, MD, PhD (2025-present)
Ann B Moser, BA; Kennedy Krieger Institute (2001-2020)
Candace Muss, PA-C, LCGC (2025-present)
Steven K Steinberg, PhD (2001-2025)

Revision History

• 7 August 2025 (sw) Comprehensive update posted live
• 30 January 2020 (bp) Comprehensive update posted live
• 13 September 2012 (me) Comprehensive update posted live
• 2 March 2010 (me) Comprehensive update posted live
• 18 July 2006 (me) Comprehensive update posted live
• 13 February 2004 (me) Comprehensive update posted live
• 16 November 2001 (me) Review posted live
• 10 June 2001 (nb) Original submission

Literature Cited

• Abousamra O, Kandula V, Duker AL, Rogers KJ, Bober MB, Mackenzie WG. Cervical spine deformities in children with rhizomelic chondrodysplasia punctata. J Pediatr Orthop. 2019;39:e680–e686. [PubMed: 31503224]
• 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]
• Bams-Mengerink AM, Koelman JH, Waterham H, Barth PG, Poll-The BT. The neurology of rhizomelic chondrodysplasia punctata. Orphanet J Rare Dis. 2013;8:174. [PMC free article: PMC4228450] [PubMed: 24172221]
• 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]
• Başbuğ M, Serin IS, Ozçelik B, Guneş T, Akçakuş 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]
• Bose M, Anglade TC, Donlon CI, Kerrihard AL, Berger HF, Berkowitz AS, Ritchie SA, Smith TM. Development and evaluation of RhizoQOL, a quality-of-life caregiver-reported survey for rhizomelic chondrodysplasia punctata, a rare peroxisomal disorder. Orphanet J Rare Dis. 2025;20:147. [PMC free article: PMC11956500] [PubMed: 40165314]
• 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]
• 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]
• Braverman NE, Moser AB. Functions of plasmalogen lipids in health and disease. Biochim Biophys Acta. 2012;1822:1442–52. [PubMed: 22627108]
• De Biase I, Yuzyuk T, Cui W, Zuromski LM, Moser AB, Braverman NE. Quantitative analysis of ethanolamine plasmalogen species in red blood cells using liquid chromatography tandem mass spectrometry for diagnosing peroxisome biogenesis disorders. Clin Chim Acta. 2023;542:117295. [PubMed: 36914043]
• Dorninger F, Kiss A, Rothauer P, Stiglbauer-Tscholakoff A, Kummer S, Fallatah W, Perera-Gonzalez M, Hamza O, König T, Bober MB, Cavallé-Garrido T, Braverman NE, Forss-Petter S, Pifl C, Bauer J, Bittner RE, Helbich TH, Podesser BK, Todt H, Berger J. Overlapping and Distinct Features of Cardiac Pathology in Inherited Human and Murine Ether Lipid Deficiency. Int J Mol Sci. 2023;24:1884. [PMC free article: PMC9914995] [PubMed: 36768204]
• Duker AL, Eldridge G, Braverman NE, Bober MB. Congenital heart defects common in rhizomelic chondrodysplasia punctata. Am J Med Genet A. 2016;170A:270–2. [PubMed: 26408048]
• Duker AL, Niiler T, Eldridge G, Brereton NH, Braverman NE, Bober MB. Growth charts for individuals with rhizomelic chondrodysplasia punctata. Am J Med Genet A. 2017;173:108–13. [PubMed: 27616591]
• Duker AL, Niiler T, Schouten M, Poll-The BT, Braverman NE, Bober MB. Rhizomelic chondrodysplasia punctata morbidity and mortality, an update. Am J Med Genet A. 2020;182:579–83. [PubMed: 31769196]
• Fallatah W, Schouten M, Yergeau C, Di Pietro E, Engelen M, Waterham HR, Poll-The BT, Braverman N. Clinical, biochemical, and molecular characterization of mild (nonclassic) rhizomelic chondrodysplasia punctata. J Inherit Metab Dis. 2021;44:1021-38. [PubMed: 33337545]
• Fryburg JS, Kelly TE. Chondrodysplasia punctata, humero-metacarpal type: a second case. Am J Med Genet. 1996;64:493–6. [PubMed: 8862628]
• Gerami R, Barkhordari S. Antenatal ultrasonographic diagnosis of rhizomelic chondrodysplasia punctata. J Ultrasound. 2023;26:539-42. [PMC free article: PMC10247581] [PubMed: 36315400]
• Huffnagel IC, Clur SA, Bams-Mengerink AM, Blom NA, Wanders RJ, Waterham HR, Poll-The BT. Rhizomelic chondrodysplasia punctata and cardiac pathology. J Med Genet. 2013;50:419–24. [PubMed: 23572185]
• Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519–22. [PubMed: 28959963]
• 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]
• Krakow D, Williams J 3rd, 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]
• Kunze M, Neuberger G, Maurer-Stroh S, Ma J, Eck T, Braverman N, Schmid JA, Eisenhaber F, Berger J. Structural requirements for interaction of peroxisomal targeting signal 2 and its receptor PEX7. J Biol Chem. 2011;286:45048–62. [PMC free article: PMC3247985] [PubMed: 22057399]
• Landino J, Jnah AJ, Newberry DM, Iben SC. Neonatal rhizomelic chondrodysplasia punctata type 1: weaving evidence into clinical practice. J Perinat Neonatal Nurs. 2017;31:350–7. [PubMed: 29068853]
• Luisman T, Smith T, Ritchie S, Malone KE. Genetic epidemiology approach to estimating birth incidence and current disease prevalence for rhizomelic chondrodysplasia punctata. Orphanet J Rare Dis. 2021;16:300. [PMC free article: PMC8258949] [PubMed: 34229749]
• Masih S, Moirangthem A, Phadke SR. Twins with PEX7 related intellectual disability and cataract: Highlighting phenotypes of peroxisome biogenesis disorder 9B. Am J Med Genet A. 2021;185:1504-8. [PubMed: 33586206]
• Mathijssen IB, Henneman L, van Eeten-Nijman JM, Lakeman P, Ottenheim CP, Redeker EJ, Ottenhof W, Meijers-Heijboer H, van Maarle MC. Targeted carrier screening for four recessive disorders: high detection rate within a founde population. Eur J Med Genet. 2015;58:123–8. [PubMed: 25641760]
• 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]
• Oswald G, Lawson C, Raymond G, Golden WC, Braverman N. Rhizomelic chondrodysplasia punctata type 1 and fulminant neonatal respiratory failure, a case report and discussion of pathophysiology. Am J Med Genet A. 2011;155A:3160–3. [PubMed: 22052861]
• 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]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Smeitink JA, Beemer FA, Espeel M, Donckerwolcke RA, Jakobs C, Wanders RJ, Schutgens RB, Roels F, Duran M, Dorland L, Berger R, Poll-The BT. Bone dysplasia associated with phytanic acid accumulation and deficient plasmalogen synthesis: a peroxisomal entity amenable to plasmapheresis. J Inher Metab Dis. 1992;15:377–80. [PubMed: 1405474]
• Smith T, Knudsen KJ, Ritchie SA. First-In-Human Safety, Tolerability, and Pharmacokinetics of PPI-1011, a Synthetic Plasmalogen Precursor. Clin Transl Sci. 2025;18:e70195. [PMC free article: PMC11906485] [PubMed: 40083139]
• Steinberg S, Jones R, Tiffany C, Moser A. Investigational methods for peroxisomal disorders. Curr Protoc Hum Genet. 2008 Jul;Chapter 17:Unit 17.6. [PubMed: 18633975]
• Unger S, Ferreira CR, Mortier GR, Ali H, Bertola DR, Calder A, Cohn DH, Cormier-Daire V, Girisha KM, Hall C, Krakow D, Makitie O, Mundlos S, Nishimura G, Robertson SP, Savarirayan R, Sillence D, Simon M, Sutton VR, Warman ML, Superti-Furga A. Nosology of genetic skeletal disorders: 2023 revision. Am J Med Genet A. 2023;191:1164-209. [PMC free article: PMC10081954] [PubMed: 36779427]
• 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]
• Waterham HR, Ebberink MS. Genetics and molecular basis of human peroxisome biogenesis disorders. Biochim Biophys Acta. 2012;1822:1430–41. [PubMed: 22871920]
• Waterham HR, Ferdinandusse S, Wanders RJ. Human disorders of peroxisome metabolism and biogenesis. Biochim Biophys Acta. 2016;1863:922–33. [PubMed: 26611709]
• 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]
• Yu TW, Chahrour MH, Coulter ME, Jiralerspong S, Okamura-Ikeda K, Ataman B, Schmitz-Abe K, Harmin DA, Adli M, Malik AN, D'Gama AM, Lim ET, Sanders SJ, Mochida GH, Partlow JN, Sunu CM, Felie JM, Rodriguez J, Nasir RH, Ware J, Joseph RM, Hill RS, Kwan BY, Al-Saffar M, Mukaddes NM, Hashmi A, Balkhy S, Gascon GG, Hisama FM, LeClair E, Poduri A, Oner O, Al-Saad S, Al-Awadi SA, Bastaki L, Ben-Omran T, Teebi AS, Al-Gazali L, Eapen V, Stevens CR, Rappaport L, Gabriel SB, Markianos K, State MW, Greenberg ME, Taniguchi H, Braverman NE, Morrow EM, Walsh CA. Using whole exome sequencing to identify inherited causes of autism. Neuron. 2013;77:259–73. [PMC free article: PMC3694430] [PubMed: 23352163]
• Wegwerth PJ, White AL, Stoway SD, Loken PR, Oglesbee D, Matern D, Tortorelli S, Raymond KM, Braverman NE, Gavrilov DK. A new test method for biochemical analysis of plasmalogens in dried blood spots and erythrocytes from patients with peroxisomal disorders. J Inherit Metab Dis. 2023;46:1159-69. [PubMed: 37747296]
• Zwijnenburg PJ, Deurloo KL, Waterham HR, Meijers-Heijboer EJ, van Vugt JM, Tan-Sindhunata MB. Second trimester prenatal diagnosis of rhizomelic chondrodysplasia punctata type 1 on ultrasound findings. Prenat Diagn. 2010;30:162–4. [PubMed: 20014169]