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Rhizomelic chondrodysplasia punctata type 1(RCDP1)

MedGen UID:
347072
Concept ID:
C1859133
Disease or Syndrome
Synonyms: Chondrodysplasia punctata rhizomelic form; Chondrodystrophia calcificans punctata; PEROXISOME BIOGENESIS DISORDER 9; RCDP1
SNOMED CT: Rhizomelic chondrodysplasia punctata type 1 (1003862001)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): PEX7 (6q23.3)
 
Monarch Initiative: MONDO:0008972
OMIM®: 215100
Orphanet: ORPHA309789

Disease characteristics

Excerpted from the GeneReview: Rhizomelic Chondrodysplasia Punctata Type 1
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. [from GeneReviews]
Authors:
Nancy E Braverman  |  Steven J Steinberg  |  Wedad Fallatah, et. al.   view full author information

Additional descriptions

From OMIM
Rhizomelic chondrodysplasia punctata (RCDP) is a peroxisomal disorder characterized by disproportionately short stature primarily affecting the proximal parts of the extremities, a typical facial appearance including a broad nasal bridge, epicanthus, high-arched palate, dysplastic external ears, and micrognathia, congenital contractures, characteristic ocular involvement, dwarfism, and severe mental retardation with spasticity. Biochemically, plasmalogen synthesis and phytanic acid alpha-oxidation are defective. Most patients die in the first decade of life. RCDP1 is the most frequent form of RCDP (summary by Wanders and Waterham, 2005). Individuals with RCDP1, carrying mutations in the PEX7 gene, have cells of peroxisome biogenesis disorder (PBD) complementation group 11 (CG11, equivalent to CGR). For information on the history of PBD complementation groups, see 214100. Genetic Heterogeneity of Rhizomelic Chondrodysplasia Punctata RCDP2 (222765) is caused by mutation in the gene encoding acyl-CoA:dihydroxyacetonephosphate acyltransferase (GNPAT; 602744) on chromosome 1q42. RCDP3 (600121) is caused by mutation in the gene encoding alkyldihydroxyacetonephosphate synthase (alkyl-DHAP synthase) (AGPS; 603051) on chromosome 2q31. RCDP5 (616716) is caused by mutation in the gene encoding peroxisomal biogenesis factor-5 (PEX5; 600414) on chromosome 12p13. Whereas RCDP1 is a peroxisomal biogenesis disorder (PBD), RCDP2 and RCDP3 are classified as single peroxisome enzyme deficiencies (Waterham and Ebberink, 2012).  http://www.omim.org/entry/215100
From MedlinePlus Genetics
Rhizomelic chondrodysplasia punctata is a condition that impairs the normal development of many parts of the body. The major features of this disorder include skeletal abnormalities, distinctive facial features, intellectual disability, and respiratory problems.\n\nRhizomelic chondrodysplasia punctata is characterized by shortening of the bones in the upper arms and thighs (rhizomelia). Affected individuals also have a specific bone abnormality called chondrodysplasia punctata, which affects the growth of the long bones and can be seen on x-rays. People with rhizomelic chondrodysplasia punctata often develop joint deformities (contractures) that make the joints stiff and painful.\n\nDistinctive facial features are also seen with rhizomelic chondrodysplasia punctata. These include a prominent forehead, widely set eyes (hypertelorism), a sunken appearance of the middle of the face (midface hypoplasia), a small nose with upturned nostrils, and full cheeks. Additionally, almost all affected individuals have clouding of the lenses of the eyes (cataracts). The cataracts are apparent at birth (congenital) or develop in early infancy.\n\nResearchers have described three types of rhizomelic chondrodysplasia punctata: type 1 (RCDP1), type 2 (RCDP2), and type 3 (RCDP3). The types have similar features and are distinguished by their genetic cause.\n\nRhizomelic chondrodysplasia punctata is associated with significantly delayed development and severe intellectual disability. Most children with this condition do not achieve developmental milestones such as sitting without support, feeding themselves, or speaking in phrases. Affected infants grow much more slowly than other children their age, and many also have seizures. Recurrent respiratory infections and life-threatening breathing problems are common. Because of their severe health problems, most people with rhizomelic chondrodysplasia punctata survive only into childhood. It is rare for affected children to live past age 10. However, a few individuals with milder features of the condition have lived into early adulthood.  https://medlineplus.gov/genetics/condition/rhizomelic-chondrodysplasia-punctata

Clinical features

From HPO
Flared metaphysis
MedGen UID:
337976
Concept ID:
C1850135
Finding
The presence of a splayed (i.e.,flared) metaphyseal segment of one or more long bones.
Rhizomelia
MedGen UID:
357122
Concept ID:
C1866730
Congenital Abnormality
Disproportionate shortening of the proximal segment of limbs (i.e. the femur and humerus).
Severe short stature
MedGen UID:
3931
Concept ID:
C0013336
Congenital Abnormality
A severe degree of short stature, more than -4 SD from the mean corrected for age and sex.
Severe failure to thrive
MedGen UID:
343373
Concept ID:
C1855514
Finding
Rhizomelia
MedGen UID:
357122
Concept ID:
C1866730
Congenital Abnormality
Disproportionate shortening of the proximal segment of limbs (i.e. the femur and humerus).
Sensorineural hearing impairment
MedGen UID:
9164
Concept ID:
C0018784
Disease or Syndrome
A type of hearing impairment in one or both ears related to an abnormal functionality of the cochlear nerve.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Seizures
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterised by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
A broad category of disorders characterized by an impairment to the intelligence an individual possesses. These impairments can result from trauma, birth, or disease and are not restricted to any particular age group.
Delayed CNS myelination
MedGen UID:
867393
Concept ID:
C4021758
Anatomical Abnormality
Delayed myelination in the central nervous system.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Cerebral cortical atrophy
MedGen UID:
1646740
Concept ID:
C4551583
Disease or Syndrome
Atrophy of the cortex of the cerebrum.
Micrognathia
MedGen UID:
44428
Concept ID:
C0025990
Congenital Abnormality
Developmental hypoplasia of the mandible.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Frontal bossing
MedGen UID:
67453
Concept ID:
C0221354
Congenital Abnormality
Bilateral bulging of the lateral frontal bone prominences with relative sparing of the midline.
Flexion contracture
MedGen UID:
83069
Concept ID:
C0333068
Anatomical Abnormality
A flexion contracture is a bent (flexed) joint that cannot be straightened actively or passively. It is thus a chronic loss of joint motion due to structural changes in muscle, tendons, ligaments, or skin that prevents normal movement of joints.
Kyphoscoliosis
MedGen UID:
154361
Concept ID:
C0575158
Anatomical Abnormality
An abnormal curvature of the spine in both a coronal (lateral) and sagittal (back-to-front) plane.
Coronal cleft vertebrae
MedGen UID:
320483
Concept ID:
C1834954
Finding
Frontal schisis (cleft or cleavage) of vertebral bodies.
Flared metaphysis
MedGen UID:
337976
Concept ID:
C1850135
Finding
The presence of a splayed (i.e.,flared) metaphyseal segment of one or more long bones.
Malar flattening
MedGen UID:
347616
Concept ID:
C1858085
Anatomical Abnormality
Underdevelopment of the malar prominence of the jugal bone (zygomatic bone in mammals), appreciated in profile, frontal view, and/or by palpation.
Epiphyseal stippling
MedGen UID:
349104
Concept ID:
C1859126
Finding
The presence of abnormal punctate (speckled, dot-like) calcifications in one or more epiphyses.
Calcific stippling of infantile cartilaginous skeleton
MedGen UID:
395186
Concept ID:
C1859135
Finding
Rhizomelia
MedGen UID:
357122
Concept ID:
C1866730
Congenital Abnormality
Disproportionate shortening of the proximal segment of limbs (i.e. the femur and humerus).
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Respiratory insufficiency
MedGen UID:
11197
Concept ID:
C0035229
Pathologic Function
Impairment of gas exchange within the lungs secondary to a disease process, neoplasm, or trauma, possibly resulting in hypoxia, hypercarbia, or both, but not requiring intubation or mechanical ventilation. Patients are normally managed with pharmaceutical therapy, supplemental oxygen, or both.
Abnormality of metabolism/homeostasis
MedGen UID:
867398
Concept ID:
C4021768
Finding
Micrognathia
MedGen UID:
44428
Concept ID:
C0025990
Congenital Abnormality
Developmental hypoplasia of the mandible.
Frontal bossing
MedGen UID:
67453
Concept ID:
C0221354
Congenital Abnormality
Bilateral bulging of the lateral frontal bone prominences with relative sparing of the midline.
Upslanted palpebral fissure
MedGen UID:
98390
Concept ID:
C0423109
Finding
The palpebral fissure inclination is more than two standard deviations above the mean for age (objective); or, the inclination of the palpebral fissure is greater than typical for age.
Depressed nasal bridge
MedGen UID:
373112
Concept ID:
C1836542
Finding
Posterior positioning of the nasal root in relation to the overall facial profile for age.
Flat face
MedGen UID:
342829
Concept ID:
C1853241
Finding
Absence of concavity or convexity of the face when viewed in profile.
Malar flattening
MedGen UID:
347616
Concept ID:
C1858085
Anatomical Abnormality
Underdevelopment of the malar prominence of the jugal bone (zygomatic bone in mammals), appreciated in profile, frontal view, and/or by palpation.
Cleft palate
MedGen UID:
756015
Concept ID:
C2981150
Congenital Abnormality
Cleft palate is a developmental defect of the palate resulting from a failure of fusion of the palatine processes and manifesting as a separation of the roof of the mouth (soft and hard palate).
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Alopecia
MedGen UID:
7982
Concept ID:
C0002170
Finding
A noncongenital process of hair loss, which may progress to partial or complete baldness.
Ichthyosis
MedGen UID:
7002
Concept ID:
C0020757
Disease or Syndrome
A group of inherited or acquired skin disorders characterized by a dry, thickened, and scaly skin. The skin changes range from mild to severe.
Developmental cataract
MedGen UID:
3202
Concept ID:
C0009691
Congenital Abnormality
A cataract that occurs congenitally as the result of a developmental defect, in contrast to the majority of cataracts that occur in adulthood as the result of degenerative changes of the lens.

Term Hierarchy

Follow this link to review classifications for Rhizomelic chondrodysplasia punctata type 1 in Orphanet.

Recent clinical studies

Etiology

Masih S, Moirangthem A, Phadke SR
Am J Med Genet A 2021 May;185(5):1504-1508. Epub 2021 Feb 14 doi: 10.1002/ajmg.a.62110. PMID: 33586206
Mathijssen IB, Henneman L, van Eeten-Nijman JM, Lakeman P, Ottenheim CP, Redeker EJ, Ottenhof W, Meijers-Heijboer H, van Maarle MC
Eur J Med Genet 2015 Mar;58(3):123-8. Epub 2015 Jan 30 doi: 10.1016/j.ejmg.2015.01.004. PMID: 25641760
Ro M, Park J, Nam M, Bang HJ, Yang J, Choi KS, Kim SK, Chung JH, Kwack K
J Child Neurol 2012 Oct;27(10):1270-5. Epub 2012 Feb 28 doi: 10.1177/0883073811435507. PMID: 22378669

Diagnosis

Masih S, Moirangthem A, Phadke SR
Am J Med Genet A 2021 May;185(5):1504-1508. Epub 2021 Feb 14 doi: 10.1002/ajmg.a.62110. PMID: 33586206
Landino J, Jnah AJ, Newberry DM, Iben SC
J Perinat Neonatal Nurs 2017 Oct/Dec;31(4):350-357. doi: 10.1097/JPN.0000000000000282. PMID: 29068853
Mathijssen IB, Henneman L, van Eeten-Nijman JM, Lakeman P, Ottenheim CP, Redeker EJ, Ottenhof W, Meijers-Heijboer H, van Maarle MC
Eur J Med Genet 2015 Mar;58(3):123-8. Epub 2015 Jan 30 doi: 10.1016/j.ejmg.2015.01.004. PMID: 25641760
Oswald G, Lawson C, Raymond G, Golden WC, Braverman N
Am J Med Genet A 2011 Dec;155A(12):3160-3. Epub 2011 Nov 3 doi: 10.1002/ajmg.a.34331. PMID: 22052861
Motley AM, Brites P, Gerez L, Hogenhout E, Haasjes J, Benne R, Tabak HF, Wanders RJ, Waterham HR
Am J Hum Genet 2002 Mar;70(3):612-24. Epub 2002 Jan 7 doi: 10.1086/338998. PMID: 11781871Free PMC Article

Therapy

Dranchak PK, Di Pietro E, Snowden A, Oesch N, Braverman NE, Steinberg SJ, Hacia JG
J Cell Biochem 2011 May;112(5):1250-8. doi: 10.1002/jcb.22979. PMID: 21465523Free PMC Article

Prognosis

Landino J, Jnah AJ, Newberry DM, Iben SC
J Perinat Neonatal Nurs 2017 Oct/Dec;31(4):350-357. doi: 10.1097/JPN.0000000000000282. PMID: 29068853
Oswald G, Lawson C, Raymond G, Golden WC, Braverman N
Am J Med Genet A 2011 Dec;155A(12):3160-3. Epub 2011 Nov 3 doi: 10.1002/ajmg.a.34331. PMID: 22052861
Motley AM, Brites P, Gerez L, Hogenhout E, Haasjes J, Benne R, Tabak HF, Wanders RJ, Waterham HR
Am J Hum Genet 2002 Mar;70(3):612-24. Epub 2002 Jan 7 doi: 10.1086/338998. PMID: 11781871Free PMC Article

Clinical prediction guides

Wood PL, Khan MA, Smith T, Ehrmantraut G, Jin W, Cui W, Braverman NE, Goodenowe DB
Lipids Health Dis 2011 Oct 18;10:182. doi: 10.1186/1476-511X-10-182. PMID: 22008564Free PMC Article
Dranchak PK, Di Pietro E, Snowden A, Oesch N, Braverman NE, Steinberg SJ, Hacia JG
J Cell Biochem 2011 May;112(5):1250-8. doi: 10.1002/jcb.22979. PMID: 21465523Free PMC Article
Motley AM, Brites P, Gerez L, Hogenhout E, Haasjes J, Benne R, Tabak HF, Wanders RJ, Waterham HR
Am J Hum Genet 2002 Mar;70(3):612-24. Epub 2002 Jan 7 doi: 10.1086/338998. PMID: 11781871Free PMC Article

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