Chondrodysplasia Punctata

We report a case of two and a half months old male child affected by chondrodysplasia punctata, a rare condition characterized by depressed nasal bridge, hypoplastic distal phalanges and epiphyseal stippling of the bones.


Introduction
C hondrodysplasia punctata is a group of dysplasias characterized by s ppled calcifi ca ons within the epiphyses in infancy and associated with short stature, dry and scaly skin, occasional heart defects, and cataracts.
The most common form of chondrodysplasia punctata is Conradi-Hünermann syndrome, which is inherited as an X-linked dominant trait (CDPX2), also known as Conradi-Hünermann-Happle syndrome, is seen in girls and is a result of a muta on in the emopamil-binding protein (EBP) gene. It is characterised by accumula on of calcium salts in long ends of bones, limb and joint shortening, fl at face, thick scales, fl aky skin, sparse coarse hair, alopecia, kyphosis and scoliosis.
A rarer autosomal recessive form, characterized by a rhizomelic pa ern of dwarfi sm, is o en fatal within the fi rst year of life. It results from a variety of muta ons in the PEX7 gene, which encodes the protein peroxin 7. This type of chondrodysplasia is gene cally a member of the family of peroxisomal disorders, which include Zellweger syndrome and infan le Refsum disease. This form of disease is characterised by systemic shortening of limbs(rhizomelia), recurrent respiratory tract infec ons, seizures and congenital cataracts.
The X-linked recessive form of chondrodysplasia (CDPX1) has been localized to the arylsulfatase E gene (ARSE gene lies in short arm of x chromosome).Abnormali es in the ARSE gene lead to defi ciency of a sulfatase enzyme that results in a high degree of sulfa on in the car lage matrix. This form occours exclusively in males and is characterized by deafness, skin and hair involvement, maxillary hypoplasia (fl at nose), short columella, short ends of fi nger ps and toes.

The Case
A two and a half months old male child presented to us with respiratory distress and oxygen dependency since soon a er birth. The baby was born preterm by normal vaginal delivery. He was third in birth order, with two elder sisters who were normal. There was no history of s ll births or abor ons. There was history of stridor along with one episode of cyanosis with respiratory distress soon a er birth. On examina on, the weight was appropriate for age. Bilateral air entry was equal and normal, subcostal recessions were present even on oxygen by nasal prongs.
On examina on baby had depressed nasal bridge due to hypoplasia of nasal bone and hypoplasia of distal phalanges of the hands, ichthyosis, irregular foci of alopecia, shortened neck, fl a ened facies with saddle nose, permanently fl exed knee and elbow joints, limbs shortening, microcephaly and micrognathia (Fig 1 and  2). No other features of chondrodysplasia punctata like congenital disloca on of hip, undue rigidity of the larynx or trachea were noted. Chest skiagram showed calcifi ca on of trachea and bronchi (Fig 3). Infantogram showed s ppled calcifi ca on of epiphyses of knee, hip, shoulder, wrist and vertebral bodies (Fig 4). There were no calcium deposits in the kidneys or the car lages of the ears and nose. CT scan chest also revealed calcifi ca on of trachea (     Biochemical inves ga ons like total and ionised serum calcium, phosphorus and alkaline phosphatase were within normal limits. Vitamin D levels were however below the normal levels.
It was possible, therefore, to exclude hypervitaminosis D or a general metabolic disorder, as a cause of ectopic calcifi ca on. Based on epiphyseal s ppling, distal phalangeal hypoplasia in hands, mid facial hypoplasia, a presump ve diagnosis of chondrodysplasia punctata was thought of and venous blood sample of baby was sent for karyotyping which was reported as normal.

Discussion
Bone dysplasias are characterized by changes in growth, car laginous and bone development, as well as in bone remodeling 1 , mainly the X-linked dominant (Conradi-Hünnermann syndrome) and autosomal recessive rhizomelic forms of the disease have been described.
The chondordysplasia punctata (CDP) dominant form is most frequent and is related to a defect in peroxisomal enzyme biosynthesis. The clinical picture may range from mild disease to an extremely severe condi on, with cataracts, asymmetrical shortening of long bones, scoliosis, ichthyo c-type skin lesions, and fl a ened facies with broad nasal bridge 2 . There is some life expectancy, although early fetal death can occur. Infants who survive beyond the fi rst year usually present normal life expectancy and mental development 3 .
The rhizomelic CDP is of autosomal recessive origin, characterized by a peroxisomal func onal defect resul ng in an enzyma c defi ciency where there is a decrease in the plasmalogen synthesis, decrease in phytanic acid oxida on and presence of a unprocessed (inac ve), the 3-oxacyl-CoA-thiolase 4 .
Currently this form of CDP is diagnosed through clinical features compa ble with the syndrome associated with biochemical fi ndings including serum phytanic acid levels, screening of plasmalogen synthesis on cultured fi broblasts 4 , as well as in erythrocytes, and plasma c level of fa y acids with long carbon chain 4,5 . The plasma level of phytanic acid is high, and the plasmalogen synthesis in fi broblast and erythrocytes is reduced usually, the serum level of fa y acids with long carbon chain is normal 5,6,7,8 . The chromosomal study demonstrates PEX7 muta on, 50% of them in the L292ter allele 4 . None of these biochemical or gene c tests has been performed in the present case.
This CDP variant is rare, with an es mated incidence of 1:100,000 and with only 72 cases reported in the literature up to 1995 2,9 .
The main characteris cs described in the literature are symmetric and severe rhizomelicmicromelia (proximal shortening of limbs), punctate calcifi ca ons and long bones metaphyseal and epiphyseal ossifi ca on changes, punctate calcifi ca ons and coronal cle s in vertebral bodies of the thoracic and lumbar spine, microcephaly and growth retarda on, psychomotor delay, spas city and precocious death 2,4,10 . The presence of vertebral cle s, radiotransparent longitudinal zone observed in the lateral view, previously described as invariable in cases of rhizomelic CDP has not been present in three of fi ve cases analyzed by Wardinsky et al and in other cases reported in the literature, and is not obligatorily necessary for the diagnosis 5 .
Other characteris cs have been described with a variable frequency like ichthyosis, cataracts, restricted joint mobility, sucking and deglu on diffi culty, alopecia, audi ve and visual difi ciencies, seizures, op c nerves hypoplasia, kyphoscoliosis and cle spine 3,4,11,12 . Pa ents usually present with fl a ened facies with micrognathia, malar hypoplasia, fl a ened nasal bridge and bulbous nose. In contrast to the other forms of CDP, the rhizomelic CDP presents a poor prognosis, with repe ve infec ons and death in the fi rst two years of life 2,4,5,6 .
Our pa ent presented ichthyosis, irregular foci of alopecia, shortened neck, fl a ened facies with saddle nose, permanently fl exed knee and elbow joints, microcephaly and micrognathia and history of deglu on diffi culty, clinical characteris cs corrobora ng the diagnosis of rhizomelic CDP. An usual characteris c of the rhizomelic CDP is the presence Auditory and/or visual difi ciencies have been observed, although being found with variable frequency in the referred literature. However, another typical fi nding in this type of chondrodysplasia is microcephaly, which has shown to be quite accentuated, considering the values very below than normal. Considering the exuberance of the clinical-radiological picture in the index case,a diagnosis of recessive CDP was made.
It is important to note that pa ents with diagnosis of rhizomelic CDP should undergo ambulatorial followup, as, in spite of the current inexistence of specifi c treatment, many clinical manifesta ons, like alopecia, ichthyosis and cataracts, might not be present at the moment of the diagnosis, showing up with the progress of the disease. Other manifesta ons, like punctate calcifi ca ons, tend to disappear with aging, without resul ng in bone deformi es. Presently, the pa ent is being kept in ambulatory follow-up in our ins tu on.
CDP is a very rare disorder with characteris c features. Some of the manifesta ons present later with progress of disease others like punctuate calcifi ca on tend to disappear with aging. Since no specifi c treatment is available these should be kept on regular follow up. Previously, antenatal diagnosis of this condi on was made by radiography. The prenatal diagnosis of chondrodysplasia punctata has been made with ultrasonography. The punctate calcifi ca ons can be seen in late pregnancy in the rhizomelic form, whereas limb shortening is apparent earlier, specifi cally s ppling of the proximal humerus, has permi ed us to iden fy the condi on in a fetus at 28 weeks' gesta on 14 . Amniocentesis has also been useful in diagnosing the rhizomelic form.

Conclusion
Chondrodysplasia Punctata is a rare disorder which could be missed in rou ne examina on of children. Since there is no treatment these children should be kept on a regular follow up because some of the manifesta ons could disappear with me. Defi ni ve diagnosis helps in planning future pregnancies from the point of view of antenatal diagnosis and gene c counseling.