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).
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).
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.