Rhizomelic Chondrodysplasia Punctata Type 1
Summary
Clinical characteristics.
Rhizomelic chondrodysplasia punctata type 1 (RCDP1), a peroxisome biogenesis disorder (PBD) has a classic (severe) form and a nonclassic (mild) form. Classic (severe) RCDP1 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 the majority of children develop seizures. Most affected children do not survive the first decade of life; a proportion die in the neonatal period. Nonclassic (mild) RCDP1 is characterized by congenital or childhood cataracts, CDP or infrequently, chondrodysplasia manifesting only as mild epiphyseal changes, variable rhizomelia, and milder intellectual disability and growth restriction than classic RCDP1.
Diagnosis/testing.
The diagnosis of RCDP1 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: Classic (severe) RCDP1: Management is supportive and limited by the multiple handicaps present at birth and poor outcome. Poor feeding and recurrent aspiration may necessitate placement of a gastrostomy tube; attention to respiratory function and good pulmonary toilet. Cataract extraction may restore some vision. Physical therapy to improve contractures; orthopedic procedures may improve function in some individuals. Management of developmental delay/intellectual disability as per standard of care.
Prevention of primary manifestations: Dietary restriction of phytanic acid to avoid the consequences of phytanic acid accumulation over time may benefit individuals with mild RCDP1.
Surveillance: Frequent monitoring of growth, nutritional status, and developmental and educational needs; regular assessments for evidence of aspiration, respiratory insufficiency, seizure control, vision, hearing, contractures, and orthopedic complications.
Genetic counseling.
RCDP1 is inherited in an autosomal recessive manner. If each parent is 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 unaffected carrier, and a 25% chance of inheriting both normal alleles. Molecular genetic carrier testing of at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible once the PEX7 pathogenic variants have been identified in an affected family member.
Diagnosis
Suggestive Findings
Rhizomelic chondrodysplasia punctata type 1 (RCDP1) should be suspected based on the individual's age and the severity of clinical and skeletal/radiographic findings.
Classic (Severe) RCDP1 (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.
X-ray of a newborn with classic (severe) 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: infant and older children with classic RCDP1.)
Figure 3
a. Progression of radiographic changes in a child with classic (severe) RCDP1 showing metaphyseal flaring (red closed arrows), epiphyseal abnormalities (white open arrow) b. Calcification of intervertebral discs (blue arrows)
Figure 4.
Characteristic facial features of classic (severe) RCDP1 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 range (more...)
Nonclassic (Mild) RCDP1
- Congenital or childhood cataracts
- Chondrodysplasia punctata (CDP) or infrequently, chondrodysplasia manifesting as mild epiphyseal changes only (See Figure 5.)
- Variable rhizomelia
- Milder intellectual disability and growth restriction than classic RCDP1
Figure 5.
X-rays of nonclassic (mild) RCDP1: 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, 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 RCDP1 [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 RCDP1: erythrocyte plasmalogen levels are around 10- to 30-fold higher in milder RCDP1 than in classic RCDP1 [Braverman et al 2002, Bams-Mengerink et al 2013, Duker et al 2016].
Establishing the Diagnosis
The diagnosis of RCDP1 is established in a proband with suggestive findings and biallelic pathogenic variants in PEX7 identified by molecular genetic testing (see Table 1).
Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing or genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings of classic RCDP1 described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with the less specific findings of nonclassic (mild) RCDP1 are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
A chondrodysplasia punctata multigene panel that includes PEX7 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the diagnosis of RCDP1 is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is an option. Exome sequencing is the most commonly used genomic testing method; genome sequencing is also possible.
If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Rhizomelic Chondrodysplasia Punctata Type 1
| Gene 1 | Method | Proportion of Pathogenic Variants 2 Detectable by Method |
|---|---|---|
| PEX7 | Sequence analysis 3 | 97% 4 |
| Gene-targeted deletion/duplication analysis 5 | Unknown 6 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Sequence analysis of PEX7 coding and flanking intronic regions in 133 individuals with RCDP1 from the United States and the Netherlands identified 97% of pathogenic variants [Braverman et al 2002, Motley et al 2002]. Note: In all individuals with biochemically confirmed RCDP1, at least one pathogenic PEX7 variant was identified. See Table 6.
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
Exon and multiexon PEX7 deletions have been identified [N Braverman, unpublished].
Clinical Characteristics
Clinical Description
Classic (Severe) RCDP1
The characteristic clinical features of classic RCDP1 are skeletal abnormalities, cataracts, growth restriction, and intellectual disability. Life expectancy is shortened: the majority of children do not survive beyond the first decade of life and a proportion die in the neonatal period. Of 35 affected children older than age one month, 90% survived to age one year, 55% to age five years, and approximately 20% to age 12 years [White et al 2003]. In a separate review of 66 patients with RCDP1, 80% survived to age five years, 45% to age 12 years, and 35% to adulthood [Duker et al 2019]. Most deaths in these cohorts were secondary to respiratory complications. Some infants may die in the neonatal period; this number is not known. Clinical experience suggests that neonatal deaths were associated with congenital heart disease or lung hypoplasia [Oswald et al 2011].
Skeletal findings. Infants with RCDP1 have bilateral shortening of the humerus and to a lesser degree the femur. They typically have contractures and stiff, painful joints, causing irritability in infancy.
In a study of the MRIs of children with classic RCDP1, all patients had cervical stenosis. More global spinal stenosis, cervical kyphosis, and thoracolumbar kyphosis were seen, but with less frequency. Tethered cord was also identified [Khanna et al 2001, Bams-Mengerink et al 2013, Abousamra et al 2017].
Cataracts. Bilateral cortical cataracts develop in virtually all affected individuals. They are usually present at birth or appear in the first few months of life and are progressive.
Growth restriction. Whereas birth weight, length, and head circumference are often at the lower range of normal, profound postnatal growth deficiency is evident throughout the life span [Duker et al 2017]. At age three years, height, weight and head circumference are around the 50th percentile for a child age 4-6 months. Rate of weight gain is slow, dropping to 5 g/day at age six months, and <2 g/day expected after age three years. RCDP1 height, weight, and head circumference growth charts are available as well as height-for-weight charts and charts showing rate of weight gain over time [Duker et al 2017].
Intellectual disability. Developmental quotients are below 30. Early developmental skills such as smiling and recognizing voices are achieved by most children with RCDP1, but at delayed ages. Skills achieved in typically developing children after age six months are never seen in children with RCDP1 [White et al 2003, Bams-Mengerink et al 2013].
Seizures. The majority of children develop seizures [White et al 2003, Bams-Mengerink et al 2013]. Myoclonic jerks are the most frequent type of seizure reported, but seizure frequency and types are variable. The median age at seizure onset was 2.5 years [Bams-Mengerink et al 2013].
Recurrent respiratory tract infections. Most children with RCDP1 have recurrent respiratory tract infections caused by a combination of neurologic compromise, aspiration, immobility, and a small chest with restricted expansion. Plasmalogen deficiency may also play a role in the chronic respiratory disease as these lipids are enriched in lung tissues and an integral component of surfactant [Oswald et al 2011, Braverman & Moser 2012, Duker et al 2019].
Congenital heart disease. Cardiac malformations have been identified in 52% and 64% of individuals with RCDP1 in the Dutch and North American cohorts respectively [Huffnagel et al 2013, Duker et al 2016]. Septal defects, tetralogy of Fallot, and peripheral pulmonary stenosis were most commonly reported. Mitral valve prolapse was also noted in several patients.
Other. Eczema, mild ichthyosis, and skin rashes were noted in around 50% of individuals in the cohort studied by White et al [2003].
Other malformations observed in one affected individual include: ureteropelvic junction (UPJ) obstruction [Khanna et al 2001], cleft palate, diaphragmatic hernia, hypospadias, and cryptorchidism [White et al 2003].
Routine brain imaging is normal or shows cerebral and cerebellar atrophy with enlargement of the ventricles and CSF spaces [Powers et al 1999]. Cerebellar atrophy is progressive [Bams-Mengerink et al 2006]. MRI and MR spectroscopy have shown delayed myelinization, signal abnormalities in supratentorial white matter, decreased choline-to-creatine ratios, and increased levels of mobile lipids, thought to reflect the deficiency of plasmalogens, which are substantial components of myelin [Alkan et al 2003, Bams-Mengerink et al 2006, Bams-Mengerink et al 2013].
Nonclassic (Mild) RCDP1
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]. The majority of individuals with nonclassic (mild) RCDP1 have presented in early childhood with bilateral cataracts, multiple joint contractures, and developmental delays [Braverman et al 2002, Bams-Mengerink et al 2006]. A few individuals manifest cataracts within the first two years, no skeletal findings, and behavioral disorders that develop at school age [Braverman et al 2002, Yu et al 2013]. Overall life expectancy is considerably longer than that of classic RCDP1, with survival to adulthood [Bams-Mengerink et al 2013, Huffnagel et al 2013]; in a recent study 11 of 12 affected individuals survived to adulthood [Duker et al 2019].
Skeletal. Most individuals with mild RCDP1 have limited joint mobility due to flexion contractures of the elbows, knees, and hips. While the radiographic finding of CDP (chondrodysplasia punctata) is commonly noted at the time of RCDP1 diagnosis, rhizomelic limb shortening is uncommon in this group. Deformities in hip joints including coxa vara and small femoral heads have been reported (see Figure 6) [Barth et al 1996, Bams-Mengerink et al 2013]. Many of these individuals required orthopedic surgeries over time to improve mobility and activities of daily living [Barth et al 1996].
Figure 6.
Girl age five years with nonclassic RCDP1 showing better growth than classic RCDP1 and absence of rhizomelia. X-rays of the hips show coxa vara of the femoral head (arrows). Femoral osteotomy was performed to improve mobility. All images provided by authors. (more...)
Cataract. Most individuals with mild RCDP1 have bilateral cataracts diagnosed in the first two years of life.
Growth of individuals with mild RCDP1 can be within normal ranges at birth. Postnatal growth rates are also better than those in classic RCDP1. Growth curves based on four individuals with nonclassic RCDP1 have been published [Duker et al 2017].
Intellect. Most individuals with mild RCDP1 have had developmental delays and learning disabilities. However, they were able to achieve gross and fine motor skills never achieved in individuals with classic RCDP1. All individuals with mild RCDP1 were able to walk and most can communicate verbally; all required some degree of special education. Brain MRI was normal in all three individuals with nonclassic RCDP1 reported by Bams-Mengerink et al [2006].
Seizures. In one cohort, three of four individuals with mild RCDP1 developed seizures in late childhood (age range 7-21 years). The type of seizures more commonly seen in this group were absence and tonic-clonic seizures [Bams-Mengerink et al 2013].
Congenital heart disease. In six individuals with mild RCDP1, cardiac defects including atrial septal defects were reported in two individuals, one of whom also had first-degree heart block. Two individuals developed mitral valve prolapse, possibly indicating degenerative cardiac changes [Huffnagel et al 2013].
Behavior disorders, usually identified at school age in the limited number of individuals described with mild RCDP1, included attention-deficit/hyperactivity disorder and autism spectrum disorder (ASD) [Bams-Mengerink et al 2013, Yu et al 2013].
In one family, two sibs with the PEX7 variant p.Ser25Phe had congenital cataract. One sib had ASD, intellectual disability, and epilepsy; the other had normal intellect with attention-deficit disorder. Elevated blood phytanic acid was observed on an unrestricted diet.
In another family, two sibs had the PEX7 variant p.Trp75Cys and ASD, intellectual disability, epilepsy, and cataracts.
Retinitis pigmentosa and peripheral neuropathy. An individual with the PEX7 variant c.-45C>T had developmental delays and poor growth in childhood; retinitis pigmentosa and peripheral neuropathy developed in adolescence [Braverman et al 2002]. Cataracts were not reported.
Genotype-Phenotype Correlations
Correlations between the predicted severity of PEX7 pathogenic variants and RCDP1 phenotype include the following:
- All individuals homozygous for the p.Leu292Ter pathogenic variant studied to date have had classic RCDP1.
- 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 RCDP1 phenotype or adult Refsum disease have been identified. It is predicted that these encode either residual amounts of a normal PEX7 protein or a defective protein with residual function [Braverman et al 2002, Motley et al 2002, van den Brink et al 2003].
Nomenclature
RCDP1 is one of two groups of peroxisome biogenesis disorders (PBD); the other group is Zellweger spectrum disorder.
Although individuals with RCDP1 have a perturbation in matrix protein import consistent with a peroxisomal assembly defect, they have a biochemical, cellular, and clinical phenotype distinct from Zellweger spectrum disorder.
Prevalence
The prevalence of RCDP1 is estimated to be lower than 1:100,000. The disorder is pan ethnic.
The high frequency of the p.Leu292Ter variant is secondary to a founder effect in individuals of northern European descent [Braverman et al 2000]. The p.Leu292Ter allele was recently 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.
Differential Diagnosis
Table 2.
Genes of Interest in the Differential Diagnosis of Rhizomelic Chondrodysplasia Punctata Type 1 (RCDP1)
| Gene(s) | Disorder | MOI | Clinical Features of Differential Diagnosis Disorder | |
|---|---|---|---|---|
| Overlapping w/RCDP1 | Distinguishing from RCDP1 | |||
| GNPAT | RCDP2 1, 2 (OMIM 222765) | AR | Clinically identical | None |
| AGPS | RCDP3 1, 2 (OMIM 600121) | AR | Clinically identical | None |
| FAR1 | Peroxisomal fatty acyl-CoA reductase 1 disorder (OMIM 616154) | AR |
| Absence of rhizomelia & CDP |
| PEX5 | RCDP5 3 (OMIM 616716) | AR | Clinically identical | None |
| ARSE 4, 5 | X-linked chondrodysplasia punctata 1 | XL | CDP |
|
| EBP | X-linked chondrodysplasia punctata (Conradi-Hünermann syndrome) 6 | XL | In severely affected infants findings are bilateral & resemble those of RCDP1. |
|
| GGCX VKORC1 | Combined deficiency of vitamin K-dependent clotting factors (OMIM PS277450) | AR | CDP |
|
AD = autosomal dominant; AR = autosomal recessive; CDP = chondrodysplasia punctata; MOI = mode of inheritance; XL = X-linked
- 1.
RCDP2 and RDCP3 are caused by deficiency of dihydroxyacetone phosphate acyltransferase and alkyldihydroxyacetonephosphate synthase, respectively (both are peroxisomal enzymes involved in plasmalogen biosynthesis).
- 2.
Exhaustive classifications of CDP have been published [Irving et al 2008].
- 3.
PEX5 pathogenic variants that cause RCDP5 are located in the PEX5 domain that is known to bind PEX7.
- 4.
Contiguous gene deletions involving ARSE result in more complex phenotypes, including ichthyosis and corneal opacities resulting from steroid sulfatase deficiency.
- 5.
X-linked recessive chondrodysplasia punctata is caused by arylsulfatase E deficiency, a vitamin K-dependent enzyme.
- 6.
X-linked dominant chondrodysplasia punctata is caused by defects in sterol-Δ8-isomerase, which catalyzes an intermediate step in the conversion of lanosterol to cholesterol.
Other disorders to consider in the differential diagnosis of RCDP1
- Chondrodysplasia punctata, tibia-metacarpal type (OMIM 118651) and humero-metacarpal type [Fryburg & Kelly 1996] are inherited in an autosomal dominant manner. The gene(s) in which pathogenic variants are causative are unknown. Affected individuals have short metacarpals with shortening of various long bones. No cataracts or skin changes are present.
- Warfarin embryopathy and other fetal vitamin K deficiencies (including vitamin K epoxide reductase deficiency; see Table 4) show CDP, but are distinguished clinically from RCDP1 by nasomaxillary hypoplasia, brachytelephalangy, and absence of rhizomelia and cataracts. With the exception that males and females are affected, this phenotype is similar to X-linked chondrodysplasia punctata 1 (CDPX1).
- Maternal systemic lupus erythematosus (SLE) (OMIM 152700) and other maternal autoimmune diseases can cause CDP in the offspring, but are distinguished from RCDP1 by nasomaxillary hypoplasia, brachytelephalangy and absence of rhizomelia and cataracts. With the exception that males and females are affected, this phenotype is similar to CDPX1.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with rhizomelic chondrodysplasia punctata type I (RCDP1), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Table 3.
Recommended Evaluations Following Initial Diagnosis in Individuals with Rhizomelic Chondrodysplasia Punctata Type 1
| Organ/Concern | Evaluation | Comment |
|---|---|---|
| Constitutional | Measure height, weight, head circumference. | Growth restriction is seen in 100% of individuals w/classic (severe) RCDP1. |
| Biochemical | Measure erythrocyte plasmalogen levels if not already performed. | To help differentiate between classic & nonclassic (mild) RCDP1, to set appropriate growth, medical, & developmental expectations |
| Neurology | MRI of the entire spine (incl flexion & extension views of the cervical spine for cervical stenosis) should be strongly considered. 1 | Spinal cord compression may occur at any level & can co-occur w/upper cervical movement; tethered cord can also be present. |
| MRI of the brain (could be done at the time of the spinal MRI) | To evaluate for atrophy, myelin abnormalities | |
| Musculoskeletal | Orthopedics / physical medicine and rehabilitation / PT / OT evaluation | To incl assessment of:
|
| Skeletal survey to incl: AP/lateral spine, AP bilateral lower extremities in 1 view, AP bilateral upper extremities, & flexion/extension cervical spine | Document extent of skeletal dysplasia & chondrodysplasia punctata | |
| Eyes | Ophthalmologic examination | For evidence of congenital cataracts |
| Development & behavior | Developmental assessment | To incl motor, adaptive, cognitive & speech/language evaluation. |
| Seizures | EEG | Evaluation of various seizure types |
| Gastrointestinal/ Feeding | Gastroenterology / nutrition / feeding team evaluation |
|
| Cardiovascular | Echocardiogram to evaluate for congenital heart defects | To incl evaluation for septal defects, tetralogy of Fallot, mitral valve prolapse |
| Respiratory | Evaluation for respiratory insufficiency | Due to neurologic compromise, aspiration, immobility, restrictive lung disease, & small chest |
| Renal | Evaluation for congenital anomalies | Ureteropelvic junction obstruction has been observed. |
| Miscellaneous/ Other | Consultation w/clinical geneticist &/or genetic counselor | To incl genetic counseling. |
| Family supports/resources | Assess:
|
OT = occupational therapy; PT = physical therapy
- 1.
Abousamra et al [2017]