Chondrodysplasia punctata

Alex Manlapaz-Mann DO

Neurogenetic Disorders

Updated 03.26.2026
Released 02.03.1994
Expires For CME 03.26.2029

Chondrodysplasia punctata

Author: Alex Manlapaz-Mann DO

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Editor: Solomon L Moshé MD

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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 of calcium at the ends 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. 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 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 (49). Spranger and associates published a landmark article documenting extreme phenotypic and genetic heterogeneity of chondrodysplasia punctata (45). 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, autosomal dominant, X-linked recessive, and X-linked dominant chondrodysplasia punctata (05). 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 five 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.
	• A PEX7-related rhizomelic chondrodysplasia punctata is a peroxisomal disorder ranging from severe (rhizomelia, cataracts, profound disability, early mortality) to milder forms with less severe skeletal, cognitive, and growth abnormalities.
	• 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 a 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 in whorls along the lines of Blaschko may be observed. Intellectual development is preserved.

Chondrodysplasia punctata is a group of skeletal dysplasias marked by abnormal endochondral ossification and epiphyseal stippling. It refers to focal calcifications of infant cartilage, primarily in the epiphyses. Although the epiphyses may appear clinically normal, they show a characteristic stippled pattern on x-ray. This radiographic feature can resolve over time, making early recognition and evaluation essential 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 an estimated total of between 516 and 847 individuals, all under the age of 35 years old, in the United States and the five largest European countries (33). Five subtypes of RCDP (RCDP1-5) have been reported, each caused by a mutation in a separate gene. The most common form is RCDP1, caused by pathogenic variants in the PEX7 gene. 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 a median age at onset of 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 (48; 02; 24; 13; 07).

PEX7-related rhizomelic chondrodysplasia punctata. PEX7-related rhizomelic chondrodysplasia punctata (PEX7-RCDP), a peroxisome biogenesis disorder, has a classic (severe) form and a non-classic (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), 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. Non-classic (mild) PEX7-RCDP is characterized by congenital or childhood cataracts, chondrodysplasia punctata or, infrequently, chondrodysplasia manifesting only as mild epiphyseal changes, joint contractures, neurobehavioral abnormalities, and milder intellectual disability and growth restriction than classic PEX7-RCDP (06).

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 (09).

Compound heterozygous variants in the PEX10 gene were identified in a two-generation nonconsanguineous Han-Chinese pedigree, including a novel splicing variant (c.113-2A> G) and a previously reported substitution (c.890T> C, p.Leu297Pro) (23).

Metaphyseal and vertebral abnormalities, such as cervical stenosis, occur in addition to widespread stippling. They have severe growth and developmental delay that typically precedes 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 characterized by a mild phenotype with milder facial abnormalities (73%) and normal or mildly impaired mental development. Limb lengths are normal (symmetric), and eye (5%) and skin (13%) changes are much less frequent (49; 41). 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 this condition being underrecognized in adults.

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 (49). 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 or cardiac compromise from significant scoliosis. Females are predominantly affected (95%), but some affected males may have been observed (20; 26). Dykman and colleagues published a case describing novel findings of hypocalcemia and hypoparathyroidism in an infant with CDPX2 (14), 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 (12). Qiao and colleagues reported a case of X-linked chondrodysplasia punctata type 2 with a novel missense mutation, expanding the mutation spectrum and highlighting the value of exome sequencing for diagnosis (40).

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 (48). 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 show promise for a possible oral treatment. Further studies are needed to explore clinical utility (17).

Clinical vignette

A 10-month-old female presented for evaluation of short stature, scoliosis, ichthyosiform erythroderma that progressed 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 nasi. 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 dihydroxyacetone phosphate acyltransferase were about 50% of normal. A diagnosis of X-linked dominant chondrodysplasia punctata was made.

Biological basis

	• Autosomal recessive chondrodysplasia punctata and rhizomelic chondrodysplasia punctata are classified as intermediate forms of peroxisomal biogenesis disorders and have five subclasses, with 80% associated with PEX7 gene mutation (type 1).
	• Defects in peroxisomal biogenesis lead to an 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 has mutations in the 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 depends on the pathogenesis of the genetic mutation.

Autosomal recessive chondrodysplasia punctata. Autosomal recessive chondrodysplasia punctata is classified as a peroxisomal biogenesis disorder (46). Five subtypes of RCDP (RCDP1-5) have been reported, each caused by a mutation in a separate gene. The most common form is RCDP1, caused by pathogenic variants in the PEX7 gene, which encodes the PEX7 receptor, responsible for importing alkylglycerone phosphate synthase into the peroxisome. Three subtypes are caused by mutations in genes encoding peroxisomal enzymes at the beginning of the plasmalogen biosynthesis pathway: glycerophosphate O-acyltransferase (GNPAT, RCDP2), (AGPS, RCDP3), and fatty alcohol reductase 1 (FAR1, RCDP4). Additionally, RCDP5 results from a specific mutation in the PEX5 gene that causes pathogenic changes in the long isoform of the PEX5 protein, impairing its ability to recognize the PEX7 receptor, thereby preventing its targeting to the peroxisome (04).

In a study by Sankhe and colleagues, PEX7-deficient mice (RCDP1) exhibit profound lipid metabolism changes in the brain, involving multiple lipid classes, including phosphatidylethanolamines, phosphatidylcholines, acylcarnitines, and sphingomyelins, which are largely absent in plasma, suggesting plasma profiling underestimates CNS lipid alterations (42).

Fibroblasts from patients with type 1 rhizomelic chondrodysplasia punctata, who lack functional PEX7, did not exhibit peroxisomal HMGCR, highlighting the role of PEX7 in the regulation of HMGCR in cholesterol metabolism (47).

Defects in these genes hinder the ability to produce plasmalogen (17). Plasmalogens are crucial for Schwann cell development and differentiation; defects impair radial sorting, myelination, and myelin structure (10). Hence, neurologic manifestations are seen in these patients, including seizures and peripheral neuropathy.

Autosomal dominant chondrodysplasia punctata. Autosomal-dominant chondrodysplasia punctata lacks a defined genetic mutation, and this milder form 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 the arylsulfatase (ARSL) gene have been demonstrated (18; 38; 11; 21; 03; 51). ARSL encodes an arylsulfatase that is localized to the Golgi apparatus membrane (18). This arylsulfatase is also inhibited by warfarin, perhaps explaining the phenocopy observed in warfarin embryopathy. The exact function of this enzyme is unknown. There is also an association between ARSL variants and intrauterine complications like intracranial hemorrhage, which can lead to fetal death or stillbirth (08; 30).

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 (05; 36; 31). A case study by Shi and colleagues reported a heterozygous point mutation, c.204G>A (p.Trp68Ter), in the EBP gene, in which about 100 mutations have been identified (44). In this particular whole-exome sequence result, there is a substitution from guanine to adenine at nucleotide position 204, resulting in a premature termination codon at amino acid position 68 (p.Trp68 Ter).

An important consideration when evaluating for this condition is uniparental disomy as a rare cause of X-linked recessive conditions. Woods and colleagues reported the first case of a female with CDPX-1 with a carrier parent (50).

Several case studies have shown an autoimmune association with chondrodysplasia punctata in the fetus in mothers who have systemic lupus erythematosus, mixed connective tissue disorders, and Sjögren 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 (37).

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 the diagnosis of rhizomelic chondrodysplasia punctata.
	• Molecular testing can help support the 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 (35). 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. Recognition of stippled patterns with rhizomelia and facial dysmorphism is key to early diagnosis and management. Although genetic testing can confirm the condition, radiologic imaging remains essential, especially when such testing is unavailable (35).

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 the 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, or a heterozygous pathogenic variant in emopamil-binding protein identified by molecular genetic testing.

Management

	• 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.

Management for all forms of chondrodysplasia punctata is supportive. Plastic surgery may be helpful for patients with severe nasal hypoplasia. Balloon angioplasty can be a feasible and effective treatment for peripheral pulmonary artery stenosis (19). Tracheal dilation is feasible and should be considered as an initial surgical intervention but may not obviate the eventual need for tracheostomy (15; 29). Orthopedic management of spine and limb deformities is indicated, as is ophthalmologic evaluation for cataracts. In 2019, Lui and colleagues proposed using cartilage-targeted insulin-like growth factor-1 treatment to promote longitudinal bone growth (32).

Restriction of dairy products high in phytanic acid and experimental therapy to replete plasmalogens have been considered in milder rhizomelic or X-linked dominant patients with dihydroxyacetone phosphate acyltransferase and phytanic acid oxidase deficiencies.

An oral synthetic plasmalogen was tested in a rhizomelic chondrodysplasia punctata mouse model and shown to improve plasmalogen levels and augment hyperactivity (17). Fallatah’s group further showed evidence of a genotype-phenotype correlation between the severity of Pex7 deficiency and the degree of hyperactivity behavior and the level of neurotransmitters in their mouse models (16). This discovery creates promise for a possible enzyme replacement therapy and measurable clinical endpoints for therapeutic interventions in the near future.

Outcomes

Approved treatments are supportive. The vast majority of deaths are secondary to respiratory problems. Milder phenotypes have variable rhizomelia and have better growth and developmental outcomes and ultimately better survival.

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51: Zhou L, Peng Y, Chen J, et al. A novel frameshift deletion variant of ARSL associated with X-linked recessive chondrodysplasia punctata 1: a case report and literature review of prenatal, confirmed cases. BMC Med Genomics 2024;17(1):253. PMID 39425194

Contributors

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

Author

Alex Manlapaz-Mann DO

Dr. Manlapaz-Mann of Montefiore Medical Center/Albert Einstein College of Medicine 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.
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Former Authors

Golder N Wilson MD
Martha D Carlson MD PhD
Nagma Dalvi MD

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
ICD-11: Chondrodysplasia punctata: LD24.04
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 one 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 midfacial hypoplasia, which may prompt additional testing.

Chondrodysplasia punctata

Cite this article

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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