Chondrodysplasia punctata

Nagma Dalvi MD

Neurogenetic Disorders

Updated 02.24.2023
Released 02.03.1994
Expires For CME 02.24.2026

Chondrodysplasia punctata

Author: Nagma Dalvi MD

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Editor: Solomon L Moshé MD

Chondrodysplasia punctata

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Introduction

Overview

Over 100 distinct chondrodysplasias have been identified in humans.

Chondrodystrophy is a term that is often interchanged with chondrodysplasia. Chondrodystrophy is a broad term for conditions with impaired cartilage production, which leads to abnormal skeletal growth and formation.

Chondrodysplasia punctata is a group of inherited disorders that affect the skeletal system and the skin, eye, and brain organ systems. This group is characterized by shortened bones and punctate deposits calcium at the end of bones and in the cartilage (hallmark radiographic finding).

Individuals with certain forms of chondrodysplasia punctata have a significantly shortened lifespan and therapy has been predominantly supportive. Recent correlation of the importance of plasmalogens to the development of the central and peripheral nervous system provides a platform for therapeutic interventions that can overcome plasmalogen deficiency found in certain forms of chondrodysplasia.

Key points

	• There are over 100 distinct chondrodysplasias in humans.
	• The term chondrodystrophy is often interchanged to describe chondrodysplasia.
	• Chondrodysplasia punctata (CDP) is a group of inherited disorders that affect the skeletal system, the eyes, the brain, and the skin.
	• Chondrodysplasia presents with a vast phenotypic and genotypic heterogeneity.
	• Classification based on mendelian inheritance is divided into the autosomal recessive type, autosomal dominant type, X-linked recessive type, and X-linked dominant type.

Historical note and terminology

Patients with chondrodysplasia punctata were first described by Conradi in 1914 and Hünermann in 1931 (37). Spranger and associates published a landmark article documenting extreme phenotypic and genetic heterogeneity of chondrodysplasia punctata (34). The classification of chondrodysplasia punctata has evolved over the past 50 years using inheritance patterns, clinical features, pathogenesis, and genetic etiology. An international working group on Constitutional Diseases of Bone was formed in 1972 to help address this variability. The working group identified the importance of creating separate but parallel classification systems with one based on clinical characteristics and another based on molecular pathogenesis. The classification subtypes of chondrodysplasia punctata, based on Mendelian inherited groups, are autosomal recessive CDP, autosomal dominant CDP, X-linked recessive CDP, and X-linked dominant CDP (03). They each have varying clinical manifestations and molecular pathogenesis.

Clinical manifestations

Presentation and course

	• Chondrodysplasia punctata describes focal calcifications of infantile cartilage in the growing parts of the long bones (stippled epiphyses).
	• Autosomal recessive chondrodysplasia punctata is also known as rhizomelic chondrodysplasia punctata (RCDP) and is subdivided into three subtypes based on the genetic mutation involved.
	• The clinical neurologic presentation of patients at the severe end of the rhizomelic chondrodysplasia punctata spectrum includes profound epilepsy, contractures, and near-absent development.
	• Autosomal dominant chondrodysplasia punctata, or Sheffield-type CDP, is a symmetrical disorder that is milder than the recessive form with normal intellectual development.
	• X-linked recessive chondrodysplasia punctata is also known as CDPX1 and is found almost exclusively in males. These males have symmetric short stature. Intellectual development is normal.
	• X-linked dominant chondrodysplasia punctata, also known as CDPX2, is an asymmetric disorder with unilateral hemiatrophy and scoliosis that predominantly affects females. Hyperkeratotic skin lesions seen in whorls along lines of Blaschko can be observed. Intellectual development is preserved.

Chondrodysplasia punctata describes focal or punctate calcifications of infantile cartilage that occur primarily but not exclusively in the epiphyses. The epiphyses do not exhibit clinical abnormalities but appear stippled on x-ray imaging. This hallmark radiographic feature can resolve over time, making early suspicion and testing crucial for diagnosis.

Autosomal recessive chondrodysplasia punctata. Otherwise known as rhizomelic chondrodysplasia punctata (RCDP), autosomal recessive chondrodysplasia punctata is a disorder with symmetrically shortened proximal segments of the limbs. This form of chondrodysplasia punctata is extremely rare, with a total estimate of between 516 to 847 individuals, all under the age of 35 years old, in the United States and the five largest European countries (25). Researchers have described three types (RCDP type 1, RCDP type 2, and RCDP type 3) that are indistinguishable clinically but are subdivided based on the genetic mutation involved. These patients present in the neonatal period with microcephaly, unusual facies with frontal bossing, a shallow nasal bridge, and a small nose (45%), bilateral cataracts (80%), ichthyosis (50%), or alopecia (27%), seizures with median age at onset 2.5 years, cardiac defects (52%-64%), and contractures (48%). They are also observed to have frequent respiratory tract infections. Retinitis pigmentosa and peripheral neuropathy have also been reported (36; 02; 18; 10; 05).

Rhizomelic chondrodysplasia punctata

This photo shows an infant with rhizomelic chondrodysplasia punctata. (Contributed by Dr. Golder Wilson.)

A published case report has discovered a new GNPAT variant in RCDP type 2, which presents with prefrontal edema on fetal ultrasounds. This may be the first possible genotypic-phenotypic correlation for RCDP type 2 (06).

Metaphyseal and vertebral abnormalities, such as cervical stenosis, occur in addition to widespread stippling. They have severe growth and developmental delay that typically precede infantile death. There are occasional childhood survivors with severe intellectual disability seen with the milder forms of rhizomelic chondrodysplasia punctata. These individuals can walk (with or without assistance) and communicate verbally or via nonverbal mechanisms.

Autosomal dominant chondrodysplasia punctata. Also known as Sheffield-type CDP, autosomal dominant chondrodysplasia punctata is observed to have a mild phenotype with milder abnormal facial features (73%) and normal/mildly impaired mental development. Limb lengths are normal (symmetric) and eye (5%) and skin (13%) changes are much less frequent (37; 32). Stippling often occurs over the tarsus, with occasional involvement of the vertebrae. These patients exhibit rapid clinical improvement with resolution of radiographic stippling, which likely leads to underrecognized adults for this condition.

X-linked recessive chondrodysplasia punctata. also known as CDPX1, X-linked recessive chondrodysplasia punctata is exhibited almost exclusively by male patients with visible X chromosome deletions. These males have symmetric short stature with typical facial changes (shallow nasal bridge, short nose) and hypoplastic distal phalanges (37). Individuals typically have normal intelligence and a normal life expectancy. Less common features include skin and hair changes, hearing loss, vision abnormalities, and heart defects.

X-linked dominant chondrodysplasia punctata. X-linked dominant chondrodysplasia punctata is also known as CDPX2, and the more familiar Conradi-Hunermann-Happle syndrome, X-linked dominant chondrodysplasia punctata, has a broad spectrum of severity of symptoms. Patients exhibit unilateral scoliosis and hemiatrophy (100%), joint contractures (46%), cataracts (46%), short stature, and stippling of epiphyses. Ichthyosis (following lines of Blaschko) or erythroderma (95%) may occur in patches and whorls as predicted by random inactivation of normal and abnormal X chromosome alleles. Intellectual development is usually normal but some patients may die early due to respiratory and/or cardiac compromise from significant scoliosis. Females are predominantly affected (95%) but some affected males may have been observed (15; 20). Dykman and colleagues published a case describing novel findings of hypocalcemia and hypoparathyroidism in an infant with CDPX2 (11), and de Jesus and colleagues described a case presentation of a 12-year-old female with obsessive-compulsive disorder, illustrating the complexity of the clinical presentation (09).

Prognosis and complications

Patients with the most severe forms of chondrodysplasia punctata have a significantly shortened life expectancy, with many dying by two years of age. White and colleagues published the natural history of autosomal recessive chondrodysplasia punctata and showed that 90% of patients survive up to 1 year and 50% survive up to 6 years (36). Patients with the milder forms of chondrodysplasia punctata usually have minimal complications aside from short stature. Treatment involves a multidisciplinary approach for supportive care with specialists from orthopedics, cardiology, pulmonology, ophthalmology, and neurology.

Studies of a synthetic plasmalogen used in a mouse model of autosomal recessive chondrodysplasia punctata shows promise for a possible oral treatment. Further studies are needed to explore clinical utility (13).

Clinical vignette

A 10-month-old female presented for evaluation of short stature, scoliosis, ichthyosiform erythroderma that would change to ichthyosis with swirls of hyperkeratotic skin, bilateral lenticular cataracts, asymmetric limb shortening, and facial abnormalities including frontal bossing, shallow nasal bridge, and a short nose with hypoplastic alae nasae. Her mother was similarly affected with short stature (adult height of about 4 feet), ichthyosis, leg asymmetry, scoliosis, and cataracts. A skeletal survey on the child revealed punctate calcifications surrounding the spine, sternum, and lower limbs. Urinary pipecolic acid was elevated, and levels of fibroblast dihydroxyacetonephosphate acyltransferase were about 50% of normal. A diagnosis of X-linked dominant chondrodysplasia punctata was made.

Biological basis

	• Autosomal recessive chondrodysplasia punctata/rhizomelic chondrodysplasia punctata are classified as an intermediate form of peroxisomal biogenesis disorders and have three subclasses, with 80% associated with PEX7 gene mutation (type 1).
	• Defects in peroxisomal biogenesis leads to inability to produce plasmalogens that are crucial for Schwann cell development and differentiation.
	• Severe forms of rhizomelic chondrodysplasia punctata have little to no detectable serum plasmalogen levels.
	• The biological/genetic basis for autosomal dominant chondrodysplasia punctata is unknown.
	• Mutations found in X-linked recessive chondrodysplasia punctata causes deficiency in arylsulfatase E.
	• X-linked dominant chondrodysplasia punctata have mutations in emopamil-binding protein leading to cholesterol biosynthesis defects.
	• External factors that lead to chondrodysplasia punctata phenotype include infectious causes (cytomegalovirus, rubella), drug-induced (warfarin, phenytoin), vitamin K defects, and placental transference of autoimmune antibodies.

Etiology and pathogenesis

Clinical and biochemical characterization of chondrodysplasia punctata is dependent on pathogenesis of the genetic mutation.

Autosomal recessive chondrodysplasia punctata. Autosomal recessive chondrodysplasia punctata, is classified as peroxisomal biogenesis disorders (35). Three types of peroxisomal defects have been recognized: type 1 (classical rhizomelic chondrodysplasia punctata) is associated with mutations in the peroxin-7 (PEX7) gene located on 6q21-q22.2 (found in over 80% of patients), type 2 is associated with defects in the glyceronephosphate O-acyltransferase (GNPAT) gene located on 1q42, and type 3 is associated with mutations in alkylglycerone phosphate synthase (AGPS) gene located on 2q31(04; 27). Defects in these genes hinder the ability to produce plasmalogen (13). Plasmalogens are crucial for Schwann cell development and differentiation; defects impair radial sorting, myelination, and myelin structure (07). Hence, neurologic manifestations are seen in these patients, including seizures and peripheral neuropathy.

Autosomal dominant chondrodysplasia punctata. Autosomal dominant chondrodysplasia punctata does not have an identified genetic mutation leading to this milder form that affects males and females equally.

X-linked recessive chondrodysplasia punctata. X-linked recessive chondrodysplasia punctata (CDPX-1) has been mapped to the Xq22.3 region. Mutations in an arylsulfatase (ARSL) gene have been demonstrated in several patients (14; 30; 08; 16). This arylsulfatase is also inhibited by warfarin, perhaps explaining the phenocopy observed in warfarin embryopathy. The exact function of this enzyme is unknown.

X-linked dominant chondrodysplasia punctata. X-linked dominant chondrodysplasia punctata (CDPX-2) had mutations of the emopamil-binding protein (EBP) gene located on Xp11.23-p11.22. EBP functions as a sterol-8-isomerase enzyme and plays a role in cholesterol biosynthesis (03; 28; 23).

Of important consideration when evaluating for this condition is uniparental disomy as a rare cause of X-linked recessive conditions. Woods and colleagues published the first case of a female with CDPX-1 with a carrier parent (38).

Several case studies have shown an autoimmune association with chondrodysplasia punctata in the fetus in mothers who have systemic lupus erythematous, mixed connective tissue disorders, and Sjogren syndrome (first proposed by Curry and colleagues in 1993). Twenty-one neonates with chondrodysplasia punctata born to autoimmune mothers have been reported to date (01). One proposed pathophysiology is that maternal antibodies interfere with calcium-binding proteins. Pandita and colleagues suggest a correlation with high anti-RNP antibodies seen in multisystem autoimmune conditions as a possible biomarker for fetal development of chondrodysplasia punctata (29).

Diagnostic workup

	• Radiographs are most helpful to evaluate for punctate lesions; however, they resolve during childhood.
	• Skin biopsy and plasma phytanic and plasmalogen levels may support diagnosis of rhizomelic chrondrodysplasia punctata.
	• Molecular testing can help support diagnosis of autosomal recessive (PEX7), X-linked recessive (ARSL), and X-linked dominant (EBP) forms of chondrodysplasia punctata.

Radiographs are most helpful because they show punctate epiphyses together with other skeletal anomalies. Autosomal recessive chondrodysplasia punctata is associated with widespread stippling and unusual vertebral ossification centers. Autosomal dominant chondrodysplasia punctata is frequently associated with tarsal stippling. X-linked recessive chondrodysplasia punctata is associated with hypoplastic distal phalanges. X-linked dominant chondrodysplasia punctata is associated with scoliosis and asymmetry.

Aside from molecular genetic testing (mutations in PEX7, GNPAT, or AGPS genes), diagnosis of autosomal recessive chondrodysplasia punctata may be supported by skin biopsy for analysis of fibroblast peroxisomal enzymes and blood workup for analysis of plasma phytanic acid and erythrocyte plasmalogen levels. Diagnosis of X-linked recessive chondrodysplasia punctata is made through the identification of an affected male with typical clinical and radiographic findings and molecular genetic testing for ARSL pathogenic variant. Diagnosing a suspected female with X-linked dominant chondrodysplasia punctata may be supported with an increased concentration of 8(9)-cholestenol and 8-dehydrocholesterol in plasma, skin biopsy, and/or a heterozygous pathogenic variant in emopamil-binding protein identified by molecular genetic testing.

References

01: Alrukban H, Chitayat D. Fetal chondrodysplasia punctata associated with maternal autoimmune diseases: a review. Appl Clin Genet 2018;11:31-44. PMID 29720879
02: 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. PMID 24172221
03: Braverman N. Conradi Hunermann syndrome. National Organization for Rare Disorders, 2010.
04: Braverman N, Steel G, Obie C, et al. Human PEX7 encodes the peroxisomal PTS2 receptor and is responsible for rhizomelic chondrodysplasia punctata. Nat Genet 1997;15:369-76. PMID 9090381
05: Braverman NE, Steinberg SJ, Fallatah W, et al. Rhizomelic chondrodysplasia punctata type 1. 2001 Nov 16 [Updated 2020 Jan 30]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle, 2021. PMID 20301447
06: Cordisco A, Pelo E, Di Tommaso M, Biagiotti R. A new GNPAT variant of foetal rhizomelic chondrodysplasia punctata. Mol Genet Genomic Med 2021;9(8):e1733. PMID 34110102
07: da Silva TF, Eira J, Lopes AT, et al. Peripheral nervous system plasmalogens regulate Schwann cell differentiation and myelination. J Clin Invest 2014;124(6):2560-70. PMID 24762439
08: Daniele A, Parenti G, d'Addio M, Andria G, Ballabio A, Meroni G. Biochemical characterization of arylsulfatase E and functional analysis of mutations found in patients with X-linked chondrodysplasia punctata. Am J Hum Genet 1998;62:562-72. PMID 9497243
09: de Jesus S, Costa ALR, Almeida M, Garrido P, Alcafache J. Conradi-Hünerman-Happle Syndrome and obsessive-compulsive disorder: a clinical case report. BMC Psychiatry 2023;23(1):87. PMID 36747187
10: Duker AL, Niiler T, Eldridg, G, Brereton NH, Braverman NE, Bober MB. Growth charts for individuals with rhizomelic chondrodysplasia punctata. Am J Med Genet Part A 2017;173(1):108-13. PMID 27616591
11: Dykman M, Voller LM, Boull C. Conradi-Hünermann-Happle syndrome associated with severe hypocalcemia in a newborn. Pediatr Dermatol 2022;39(4):657-8. PMID 35355312
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13: Fallatah W, Smith T, Cui W, et al. Oral administration of a synthetic vinyl-ether plasmalogen normalizes open field activity in a mouse model of rhizomelic chondrodysplasia punctata. Dis Model Mech 2020;13(1):dmm042499. PMID 31862688
14: Franco B, Meroni G, Parenti G, et al. A cluster of sulfatase genes on Xp22.3: mutations in chondrodysplasia punctata (CDPX) and implications for warfarin embryopathy. Cell 1995;81:15-25. PMID 7720070
15: Happle R. X-linked dominant chondrodysplasia punctata/ichthyosis/cataract syndrome in males. Am J Med Genet 1995;57(3):493. PMID 7677158
16: He G, Yin Y, Zhao J, et al. Prenatal findings in a fetus with X-linked recessive type of chondrodysplasia punctata (CDPX1): a case report with novel mutation. BMC Pediatr 2019;19(1):250. PMID 31337364
17: Howe AM, Lipson AH, Sheffield LJ, et al. Prenatal exposure to phenytoin, facial development, and a possible role for vitamin K [review]. Am J Med Genet 1995;58(3):238-44. PMID 8533825
18: Huffnagel IC, Clur SA, Bams-Mengerink AM, et al. Rhizomelic chondrodysplasia punctata and cardiac pathology. J Med Genet 2013;50(7):419-24. PMID 23572185
19: Irving MD, Chitty LS, Mansour S, Hall CM. Chondrodysplasia punctata: a clinical diagnostic and radiological review. Clin Dysmorphol 2008;17(4):229-41. PMID 18978650
20: Kumble S, Savarirayan R, Adam MP, et al. Chondrodysplasia punctata 2, X-linked. 2011 May 31 [Updated 2020 Jan 9]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle, 2021. PMID 21634086
21: Landino J, Jnah AJ, Newberry, DM, Iben, SC. Neonatal rhizomelic chondrodysplasia punctata type 1. J Perinat Neonatal Nurs 2017;31(4):350-7. PMID 29068853
22: Lazarow PB, Moser HW. Disorders of peroxisome biogenesis. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic basis of inherited diseases. 7th edition. New York: McGraw-Hill, 1995:2287-324.
23: Liu Y, Wang L, Xu B, Yang Y, Shan D, Wu Q. X-linked dominant chondrodysplasia punctata with severe phenotype in a female fetus: a case report. Medicine (Baltimore) 2019;98(1):e13850. PMID 30608402
24: Lui JC, Colbert M, Cheung CSF, et al. Cartilage-targeted IGF-1 treatment to promote longitudinal bone growth. Mol Ther 2019;27(3):673-80. PMID 30765323
25: 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(1):300. PMID 34229749
26: Menger H, Lin AE, Toriello HV, Bernert G, Spranger JW. Vitamin K deficiency embryopathy: a phenocopy of the warfarin embryopathy. Am J Med Genet 1997;72:129-34. PMID 9382132
27: Ofman R, Hettema EH, Hogenhout EM, Caruso U, Muijsers AO, Wanders RJ. Acyl-CoA:dihydroxyacetonephosphate acyltransferase: cloning of the human cDNA and resolution of the molecular basis in rhizomelic chondrodysplasia punctata type 2. Hum Mol Genet 1998;7:847-53. PMID 9536089
28: Pacault M, Vincent M, Besnard T, et al. New splicing pathogenic variant in EBP causing extreme familial variability of Conradi Hünermann-Happle syndrome. Eur J Hum Genet 2018;26(12):1784-90. PMID 30135486
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30: Parenti G, Buttitta P, Meroni G, et al. X-linked recessive chondrodysplasia punctata due to a new mutation of the ARSE gene. Am J Med Genet 1997;73:139-43. PMID 9409863
31: Pauli RM, Lian JB, Mosher DF, Suttie JW. Association of congenital deficiency of multiple vitamin K-dependent coagulation factors and the phenotype of the warfarin embryopathy: Clues to the mechanism of teratogenicity of coumarin derivatives. Am J Hum Genet 1987;41:566-83. PMID 3499071
32: Rittler M, Menger H, Spranger J. Chondrodysplasia punctata, tibia-metacarpal (MT) type. Am J Med Genet 1990;37(2):200-8. PMID 2248286
33: Sastrowijoto SH, Vandenberghe K, Moerman P, Lauweryns JM, Fryns JP. Prenatal ultrasound diagnosis of rhizomelic chondrodysplasia punctata in a primigravida. Prenat Diag 1994;14:770-6.
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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Nagma Dalvi MD

Dr. Dalvi of Albert Einstein College of Medicine Montefiore Medical Center has no relevant financial relationships to disclose.
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Editor

Solomon L Moshé MD

Dr. Moshé of Albert Einstein College of Medicine has no relevant financial relationships to disclose.
See Profile

Former Authors

Golder N Wilson MD (original author) and Martha D Carlson MD PhD

Patient Profile

Age range of presentation: 0 month to 12 years
Sex preponderance: Rhizomelic chondrodysplasia punctata, type 1: no sex preponderance

Rhizomelic chondrodysplasia punctata, type 2: no sex preponderance

Rhizomelic chondrodysplasia punctata, type 3: no sex preponderance

Chondrodysplasia punctata, autosomal dominant: no sex preponderance

Chondrodysplasia punctata, X-linked recessive: male >females

Chondrodysplasia punctata, X-linked dominant: females > males
Heredity: autosomal dominant CDP

autosomal recessive CDP

X-linked dominant CDP

X-linked recessive CDP
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-10: Chondrodysplasia punctata: Q77.3
OMIM: Rhizomelic chondrodysplasia punctata, type 1: #215100

Rhizomelic chondrodysplasia punctata, type 2: #222765

Rhizomelic chondrodysplasia punctata, type 3: #600121

Chondrodysplasia punctata, autosomal dominant: 118650

Chondrodysplasia punctata, X-linked recessive: #302950

Chondrodysplasia punctata, X-linked dominant: #302960

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Chondrodysplasia punctata

Associated Disorders

Stippled epiphyses
Punctate epiphyseal calcifications
Chondrodystrophia calcificans

Differential Diagnosis

autosomal trisomies
warfarin embryopathy
skeletal dysplasias

Also Relevant

Disorders of peroxisome assembly
Hypothyroidism
Refsum disease
Smith-Lemli-Opitz syndrome

Clinical Categories

Neurogenetic Disorders

	• The overall incidence of rhizomelic chondrodysplasia punctata is 1 in 100,000 live births.
	• The incidence of each specific type of chondrodysplasia punctata is unknown.
	• X-linked dominant forms have been observed in males with microscopic changes found on the X-chromosome.

	• Consanguinity is a risk factor for recessive forms of inheritance.
	• Prenatal diagnosis can be done using chorionic or amniotic tissue sampling.
	• Prenatal ultrasounds may show structural changes such as scoliosis or mid facial hypoplasia, which may prompt additional testing.

	• Primary treatment is cosmetic and supportive.
	• Dietary modifications might play a role in milder forms of rhizomelic chondrodysplasia punctata.
	• Gene therapy to replete plasmalogen shows promise in mouse model studies.

Chondrodysplasia punctata

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Questions or Comment?

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