Clinical manifestations

Presentation and course

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).

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

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).

Epidemiology

The incidence of rhizomelic chondrodysplasia punctata is 1 in 100,000 (21). The exact incidence of the other specific types is unknown (03).

The X-linked dominant forms are seen predominantly in females but a small group of males have been identified in the literature with microscopic changes in the X-chromosome.

Prevention

Consanguinity is a risk factor for autosomal recessive rhizomelic chondrodysplasia punctata. Prenatal diagnosis using chorionic or amniotic tissue is available for future pregnancies after an index case with rhizomelic chondrodysplasia punctata (22). Structural changes seen on prenatal ultrasound may also aid early diagnosis (33).

Differential diagnosis

Confusing conditions

Although many publications categorize chondrodysplasia punctata based on Mendelian inheritance, others have used chondrodysplasia punctata as a phenotype for punctate epiphyses seen in other conditions (19). Peroxisomal disorders, such as Zellweger syndrome, and cholesterol metabolism disorders, such as Smith-Lemli-Opitz syndrome and Greenberg dysplasia, have been associated with punctate calcifications in long bones. Warfarin embryopathy or alcohol embryopathy are well-described conditions with a similar chondrodysplasia punctata phenotype caused by the disruption of vitamin K metabolism (31; 17). Trisomies such as Turner syndrome, Down syndrome, and trisomy 18 also present with the clinical features of chondrodysplasia punctata. Finally, maternal autoimmune factors, such as mothers with systemic lupus erythematosus and mixed connective tissue disease, have played a role in neonates presenting with a chondrodysplasia punctata phenotype. To date, 21 neonates have been reported (01) and the pathogenesis is thought to be maternal anti-RNP antibodies interfere with calcium-binding proteins (29).

Diagnostic workup

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.

Management

Management for all forms of chondrodysplasia punctata is supportive. Plastic surgery may be helpful for patients with severe nasal hypoplasia. 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 (24).

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 (13). 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 (12). This discovery creates promise for a possible enzyme replacement therapy and measurable clinical endpoints for therapeutic interventions in the near future.

Outcomes

Current 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.

Special considerations

Pregnancy

Maternal ingestion of warfarin or a maternal vitamin K deficiency can produce a phenocopy of genetic chondrodysplasia punctata (26).

Maternal infections with cytomegalovirus and rubella have also been linked to fetal development of chondrodysplasia punctata (01).

Anesthesia

Although not specifically described in the chondrodysplasia punctata, many skeletal dysplasias are associated with platybasia and with risks for spinal cord transection during intubation. In addition, one must be aware of possible cervical instability/cervical spine stenosis prior to hyperextension maneuvers during intubation.