Last updated:
11/30/2023
Years published: 2023
NORD gratefully acknowledges Kevin McMahon and Greg Cichon, MD candidates, Creighton University School of Medicine, Adrea Schelhaas, MS, CGC, LCGC, Nemour Children’s Health, and Wedad Fallatah, MD, MAS, PhD, Department of Neurology, Kennedy Krieger Institute, Peroxisomal Disease Laboratory, Johns Hopkins University School of Medicine, for the preparation of this report.
Summary
Rhizomelic chondrodysplasia punctata (RCDP) is a rare disorder associated with a deficiency of ether-type lipids called plasmalogens that affect the development of many parts of the body. RCDP is characterized by disproportionately short stature which is most noticeable in the upper arms and legs (rhizomelia). Individuals with RCDP often have limited or decreased movement of their joints (contractures). They have distinctive facial features which may include prominence of the forehead, widely set eyes and underdevelopment of the middle of the face. Other clinical features include intellectual impairment, clouding of the lenses of the eyes (cataracts), seizures, heart defects and respiratory concerns.
Introduction
RCDP is in a group of peroxisomal disorders characterized by the failure of the peroxisomes to function properly and produce plasmalogens. Peroxisomes are small sacs in the gel-like fluid (cytoplasm) of cells that play a vital role in numerous biochemical processes in the body. Peroxisomes help with the breakdown of fats and formation of different molecules such as plasmalogen. Deficiency of plasmalogen affects bone growth, red blood cells and nerves.
RCDP is caused by changes (variants) in genes that affect the production of plasmalogens. Currently, there are 5 types of RCDP that are classified based on the associated genes. The most common type is RCDP1 which is caused by variants in the PEX7 gene. Regardless of type or gene involved, all 5 types of RCDP are due to impairment in the peroxisomal steps of plasmalogen biosynthesis. Inheritance is autosomal recessive.
RCDP is a complex medical condition and when first discovered more than 50 years ago, children with this condition often did not survive beyond infancy or early childhood. Those who did survive had significant physical disabilities and cognitive impairment. Now, due to the availability of patient registries and patient organizations, as well as early diagnosis and management, individuals with this condition are living longer. Several resources about RCDP are currently available to assist families (listed below).
RCDP1 is the most common and best understood type. However, RCDP regardless of type may be categorized as “classic” which has more severe features and lower plasmalogen levels or “nonclassic” which has relatively mild features and higher plasmalogen levels.
Classic (severe) RCDP1
Affected individuals often have significant lung disease requiring long-term oxygen use and have frequent lung infections. Individuals also have skeletal and joint abnormalities including shortened arm and leg bones, tight joints (contractures) and narrowing of the spinal canal (spinal stenosis). These abnormalities may make it difficult or impossible to walk and may cause pinching of the spinal cord resulting in pain, tingling, weakness or poor bladder control. Vision is also affected, and most children are diagnosed with cataracts in the first six months of life. Facial features typical of RCDP include an upturned nose, underdevelopment of the midface and widely set eyes. Baby teeth may appear late and recurrent ear infections may occur thus increasing the risk of hearing loss. These children are likely to fall behind on growth curves compared to unaffected children due to feeding difficulties. People with RCDP have intellectual disability and may develop seizures ranging in type and severity. Most do not progress beyond the early infant milestones of a 6-month-old child but are still able to learn to smile, recognize familiar faces and laugh. Other common symptoms of RCDP include heart defects and eczema. Respiratory problems due to infection and underdevelopment of the lungs are currently the most common cause of death in children with classic RCDP1.
Nonclassic (mild) RCDP1
Affected individuals often have skeletal abnormalities, cataracts, intellectual disability and growth restriction, but these are significantly less severe and/or present later in life (compared to classic RCDP1) leading to a delayed diagnosis. Birthweight and height are often close to normal and as these children grow, they fall behind but not as quickly as children with classic RCDP1. Diagnosis is often in early childhood. Symptoms such as developmental delays, joint contractures and cataracts appear by two years of age. Limb shortening, if present, is often milder but is still associated with deformities of joints and contractures which most often affect the elbows, hips and/or knees. Children with mild RCDP1 often learn to walk and develop basic verbal and nonverbal communication skills but may have learning difficulties and behavioral issues such as ADHD or autism. Seizures and cardiac abnormalities also frequently occur but are often less severe and may occur later in life.
Children with RCDP1 RCDP2 and RCDP3 have identical symptoms and features. Children with RCDP4 have similar features such as severe intellectual disability, early-onset seizures, congenital cataracts and growth restriction but do not have shortening of limb bones (rhizomelia) or abnormal calcification of bones and cartilage (chondrodysplasia punctata). Children with RCDP5 typically have symptoms similar to other types, but these are often less severe (like those seen in milder or nonclassic forms). In RCDP5, skeletal abnormalities are less pronounced, epilepsy onset is later, growth delay is less significant and intellectual disability is not as severe.
RCDP is caused by changes (variants) in several different genes. These variants affect the function of peroxisomes, which are sac-like structures in cells associated with breakdown of fatty acids and synthesis of different molecules. These gene variants affect the production of plasmalogens, resulting in low plasmalogen levels. RCDP1 is also associated with the accumulation of phytanic acid which does not occur in other types. Individuals with classic RCDP have lower plasmalogen levels and are more severely affected than those with the nonclassic form.
Each type of RCDP is characterized by variants in different genes as listed below:
RCDP1 = PEX7 gene variants
RCDP2 = GNPAT gene variants
RCDP3 = AGPS gene variants
RCDP4 = FAR1 gene variants
RCDP5 = PEX5 gene variants
RCDP follows autosomal recessive inheritance. Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the mutated gene and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
RCDP is an ultra-rare condition that occurs in people of all racial or ethnic groups, but most reported patients are from northern Europe such as the UK, Germany, France, Italy, Spain or the Netherlands. In the United States and Western Europe, RCDP affects less than 1 in 100,000 livebirths.
RCDP may be suspected in a newborn baby based on physical features such as development of early-onset cataracts, relative shortening of the proximal limbs (rhizomelia), characteristic facial features or when imagining tests show characteristic skeletal abnormalities. RCDP is definitively diagnosed by biochemical and molecular testing.
Individuals with nonclassic RCDP may not be diagnosed until later in childhood when significant developmental delays and/or cataracts are apparent. Genetic and/or biochemical testing can help determine whether the individual has the classic or nonclassic form of RCDP.
Clinical Testing and Workup
It may be possible to predict when seizures are likely to occur in people with RCDP. Serial EEGs (tests that measure brain electrical activity) and brain imaging may show abnormal electrical activity in the brain that progresses over time and decreased white matter.
Treatment
RCDP is a disease that affects many body systems. Treatment depends on the patient’s age as well as the type and severity of the disease. It generally involves social, educational, communication, physical therapy and occasionally surgery. The main goals of treatment are to prevent complications, improve quality of life and support the patient and family. There is currently no known cure for RCDP and treatment is focused on specific symptoms.
Some of the common treatments for RCDP are:
– Feeding tubes, lung function monitoring and chest physiotherapy for recurrent aspiration and poor feeding
– Cataract surgery for vision loss
– Physical therapy and orthopedic surgeries for contractures and deformities
– Specialized education and occupational therapy for intellectual disability
– Low phytanic acid diet to prevent accumulation and cell damage (for RCDP1)
– Yearly measurement of phytanic acid (for RCDP1) and plasmalogen levels (all types) to monitor disease progression
Some of the important evaluations and interventions for RCDP are:
– Growth, nutritional status and developmental needs assessment
– Spine and brain imaging for structural abnormalities
– Skeletal imaging for abnormal bone formation and calcification
– Eye exams for cataracts and near-sightedness
– Ear exams and hearing testing for ear infections and hearing loss
– Developmental assessments for motor, cognitive, adaptive and speech/language skills
– Speech and language evaluation for communication challenges and alternative/assistant devices
– Neurology consults and brain activity measurement for evaluation of seizure risk and treatment
– Gastroenterology and speech therapy consults for feeding difficulties and tube feeds
– Cardiology consults and heart ultrasounds for heart structure and function
– Lung evaluation for neurologic compromise, restrictive lung disease, aspiration/choking risk and oxygen need
– Dermatology consults for eczema management or skin rashes
– Regular medications and vaccinations to prevent or reduce infections
– Nephrology consults for kidney or kidney tract abnormalities
– Social worker or care facility referral for patient and family support
– Genetic counseling for parents to assess recurrence risk
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
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Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
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 Jul 6;16(1):300. doi: 10.1186/s13023-021-01889-z.
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 Jul;44(4):1021-1038. doi: 10.1002/jimd.12349.
Duker AL, Niiler T, Kinderman D, Schouten M, Poll-The BT, Braverman N, Bober MB. Rhizomelic chondrodysplasia punctata morbidity and mortality, an update. Am J Med Genet A. 2020 Mar;182(3):579-583. doi: 10.1002/ajmg.a.61413.
Samanta D. Rhizomelic chondrodysplasia punctata: Role of EEG as a biomarker of impending epilepsy. eNeurologicalSci. 2019 Dec 4;18:100218. doi: 10.1016/j.ensci.2019.100218.
Landino J, Jnah AJ, Newberry DM, Iben SC. Neonatal rhizomelic chondrodysplasia punctata type 1: weaving evidence into clinical practice. J Perinat Neonatal Nurs. 2017 Oct/Dec;31(4):350-357. doi: 10.1097/JPN.0000000000000282.
Bams-Mengerink AM, Koelman JH, Waterham H, Barth PG, Poll-The BT. The neurology of rhizomelic chondrodysplasia punctata. Orphanet J Rare Dis. 2013 Oct 30;8:174. doi: 10.1186/1750-1172-8-174.
White AL, Modaff P, Holland-Morris F, Pauli RM. Natural history of rhizomelic chondrodysplasia punctata. Am J Med Genet A. 2003 May 1;118A(4):332-42. doi: 10.1002/ajmg.a.20009.
Wanders RJA, Jansen GA, Skjeldal OH. Refsum Disease, Peroxisomes and Phytanic Acid Oxidation: A Review. J Neuropathol Exp Neurol. 2001; 60(11): p.1021-1031. doi: 10.1093/jnen/60.11.1021.
Purdue PE, Skoneczny M, Yang X, Zhang JW, Lazarow PB. Rhizomelic chondrodysplasia punctata, a peroxisomal biogenesis disorder caused by defects in Pex7p, a peroxisomal protein import receptor: a minireview. Neurochem Res. 1999 Apr;24(4):581-6. doi: 10.1023/a:1023957110171.
Agamanolis DP, Novak RW. Rhizomelic chondrodysplasia punctata: report of a case with review of the literature and correlation with other peroxisomal disorders. Pediatr Pathol Lab Med. 1995 May-Jun;15(3):503-13. doi: 10.3109/15513819509026986.
Wardinsky TD, Pagon RA, Powell BR, McGillivray B, Stephan M, Zonana J, Moser A. Rhizomelic chondrodysplasia punctata and survival beyond one year: a review of the literature and five case reports. Clin Genet. 1990 Aug;38(2):84-93. doi: 10.1111/j.1399-0004.1990.tb03554.
INTERNET
Rhizomelic Chrondrodysplasia Punctata, Type 5; RCDP5. Online Mendelian Inheritance in Man (OMIM). June 30, 2021. https://www.omim.org/entry/616716 Accessed November 28, 2023
Braverman NE, Steinberg SJ, Fallatah W, et al. Rhizomelic Chondrodysplasia Punctata Type 1. 2001 Nov 16 [Updated 2020 Jan 30]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1270/ Accessed Nov 29, 2023.
Steinberg SJ, Raymond GV, Braverman NE, et al. Zellweger Spectrum Disorder. 2003 Dec 12 [Updated 2020 Oct 29]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1448/ Accessed Nov 29, 2023.
Rhizomelic chondrodysplasia punctata. MedlinePlus. July 1, 2010. https://medlineplus.gov/genetics/condition/rhizomelic-chondrodysplasia-punctata/ Accessed Nov 29, 2023.
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