Chondrodysplasia Punctata

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Chondrodysplasia punctata


Chondrodysplasia punctata is a group of inherited disorders affecting the skeletal system, skin, eyes, and mental functioning.


Chondrodysplasia punctata is characterized by shortened bones, punctated or dot-like calcification deposits in the cartilage, and abnormal peroxisomes. Peroxisomes are structures within cells that help remove toxins from the body.

There are three main variations of chondrodysplasia punctata: rhizomelic chondrodysplasia punctata , nonrhizomelic chondrodysplasia punctata, and Sheffield type. Within these variations, there are different syndromes characterized by distinct anomalies and modes of transmission.

Rhizomelic chondrodysplasia punctata is characterized by shortened long bones in the arms and legs, abnormalities of the spine, stippled or dotted appearance to the cartilage, scaling of the skin, cataract, and profound mental retardation. This type of chondrodysplasia punctata is caused by a single-gene mutation. Most fetuses with rhizomelic chondrodysplasia punctata die in utero or shortly after birth. Those that survive usually die within the first 10 years of life.

Non-rhizomelic chondrodysplasia punctata, sometimes called Conradi Hunermann disease, encompasses several distinct syndromes with unique characteristics and modes of transmission. Happle's chondrodysplasia is one type of non-rhizomelic chondrodysplasia characterized by asymmetry of the arms and legs, distinctive skin sores or scales, and cataract often affecting only one eye. Intelligence is usually normal. This type predominantly affects women and is usually lethal in males, generally resulting in miscarriage of male fetuses.

Another type of non-rhizomelic chondrodysplasia is brachytelephalangic chondrodysplasia punctata, which is characterized by severe facial abnormalities, abnormalities of the cartilage in the trachea and larynx, calcifications in the feet and legs, and hypoplastic, or small, little fingers and little toes. The abnormal facial features of this syndrome are called Binder's maxillonasal dystosis and include abnormalities of the upper jaw, flat nose, cleft palate, smooth or absent philtrum, and small teeth. These facial malformations and anomalies of the trachea and larynx can cause serious breathing difficulties for newborns. Infants with brachytelephalangic chondrodysplasia punctata often require respiratory therapy. This syndrome primarily affects boys and may cause mental retardation.

Sheffield type of chondrodysplasia punctata is a mild form of the disorder affecting males and females equally. It is characterized by the abnormal dotted cartilage formations, flattened facial features, and mental retardation. This is considered a milder form of the disorder. The inheritance has not been determined, and the genetic mutation responsible has not been identified.

Genetic profile

The genetic cause of rhizomelic chondrodysplasia punctata is well documented. Many of the anomalies result from abnormalities of the perisomes and the resulting inability of the body to process and remove toxic enzymes and proteins. Perisomes are structures found within cells that remove toxins from cells and therefore from the body. Researchers have identified a genetic mutation of the peroxisome biogenesis factor 7 (PEX7) as causing these perisomal abnormalities. This mutation is transmitted as an autosomal recessive trait. Autosomal recessive conditions are carried on a chromosome that is not involved in determining sex and must be present in both parents to be transmitted to a child. In the case of rhizomelic chondrodysplasia, the PEX7 gene is found on chromosome 4 in the 4p16 locus.

Non-rhizomelic chondrodysplasia is an X-linked disorder, which means the mutations responsible for causing it are located on the X chromosome. There are two types of X-linked transmission: dominant and recessive. In X-linked dominant traits, the condition will manifest if only one copy of the genetic mutation is present. For this reason, many X-linked dominant conditions are milder in females than in males. Genetic material on the second X chromosome can reduce the effects of the mutation. X-linked dominant mutations can have more severe effects in females and may be lethal in males. Happle's chondrodysplasia is an X-linked dominate condition resulting from mutations in the emopamil binding protein (EBP) gene.

In X-linked recessive traits, the genetic mutation is recessive, meaning the characteristics of the mutation will be seen only when another normal copy of the gene is not present. For this reason, X-linked recessive mutations most frequently affect males. Females must have two mutated copies of the same gene to demonstrate the abnormalities the mutation causes. It is rare for females to be affected by X-linked recessive genetic mutations, but they may be carriers, passing the gene on to their offspring. Brachytelephalangic chondrodysplasia punctata is an X-linked recessive condition caused by a mutation of the arylsulfatase E (ARSE) gene and a deletion of the short arm of X chromosome.


Chondrodysplasia punctata is a very rare condition. The exact prevalence is unknown.

The rhizomelic type of chondrodysplasia punctata is an autosomal recessive condition affecting males and females equally. In the non-rhizomelic types of the disorder, Happle's chondrodysplasia punctata affects females almost exclusively and is generally lethal to males. Brachytelephalangic chondrodysplasia punctata is seen more frequently in males; however, it may be seen in females. The milder form of the disorder, Sheffield type, affects females and males equally.

Signs and symptoms

The symptoms of chondrodysplasia punctata may involve the skeletal system, cartilage, face, eyes, and intellectual functioning. The specific signs and symptoms of this disorder depend on which type is present.

The symptoms of rhizomelic chondrodysplasia punctata can include:

  • abnormal hair loss
  • cataract
  • cartilage abnormalities
  • curvature of the spine
  • facial abnormalities
  • ichthyosis (scaly skin)
  • mental retardation
  • microcephaly
  • short stature or dwarfism

The symptoms of non-rhizomelic chondrodysplasia punctata can include:

  • abnormalities of the eye
  • abnormalities of the cartilage in the larynx and trachea
  • asymmetry of the body
  • cartilage abnormalities
  • dwarfism
  • hearing impairment
  • heart defects
  • mental retardation
  • mid-face abnormalities
  • kidney malformations
  • prematurity
  • punctate vertebrae (dotted appearance in x rays)
  • short and in-curving fingers
  • shortened limbs


For parents who know that they are carriers of the X-linked type of chondrodysplasia punctata, there is a prenatal procedure and test called preimplantation genetic diagnosis (PGD). After in vitro fertilization (IVF), PGD can test for genetic abnormalities, as well as gender before an embryo is implanted.

Prenatal ultrasound may be helpful in diagnosing chondrodysplasia punctata in the fetus. A second trimester ultrasound may detect the characteristic punctated calcifications of the spine and feet. Combined with evidence of shortened limbs, a diagnosis may be made. However, in milder cases of the disorder, the defects may be too subtle for detection by a routine prenatal ultrasound.

A physical examination may diagnose the external features of this disorder, including the facial abnormalities, shortened limbs, curvature of the spine, and ichthyosis.

A definitive diagnosis may be made by x ray of the limbs and spine. In children of one year or younger, punctated calcifications may be seen in the long bone and the feet in the areas of cartilage at the ends of growing bones. This cartilage disappears after the first year of age and is replaced with growth plates. These plates appear normal on x ray. In adults and older children, the diagnosis is based on shortened bones in the arms and legs and the presence of other physical characteristics of the disorder.

Treatment and management

The treatment and management of chondrodysplasia punctata is primarily orthopedic and dermatologic. The characteristic stippling or dotted cartilage will disappear as the child ages; however, shortened arms and legs and curvature of the spine require orthopedic treatment. In some cases, surgery may be necessary to help patients whose legs are different lengths.

In some individuals, bone growth may be induced by a surgical bone-lengthening procedure. This procedure involves several surgeries and an extensive recovery period. The bone to be lengthened is cut. Leaving a narrow gap between the two pieces of bone, metal pins are inserted into the bone and the skin is closed. An external frame is attached to the pins. Gradually, the bone is pulled apart just enough to provide a small gap for the bone to grow into. As the bone grows, the space is widened and more bone grows. After the bone has healed, the pins are surgically removed.

Spinal abnormalities, such as spinal cord compression and scoliosis , may be treated surgically. A spinal column fusion can relieve the stress on the spinal cord caused by malformations of the spinal column. In a spinal fusion, two or more vertebrae are fused together using bone grafts or metal rods.

Ichthyosis is often most severe at birth and can resolve completely as the child ages. However, in some individuals, the skin lesions may be extensive and long lasting, leading to recurrent skin infections. Management of ichthyosis involves topical treatment and, in severe cases, bandaging to help prevent infection.


Prognosis of chondrodysplasia punctata depends on the type. The rhizomelic form of this disorder has a very poor prognosis. Most individuals with this type of chondrodysplasia punctata do not survive the fetal period or die shortly after birth. Of those that do survive, life expectancy is 10 years or less. Along with the skeletal anomalies, profound mental retardation is common as well.

The non-rhizomelic type, also known as Conradi Hunermann disease, can have a better prognosis. Though the condition is extremely rare, a range of outcomes has been reported from death to mildly affected adults. The X-linked dominant type, or Happle's type, is usually lethal to males, and they generally do not survive past the second trimester of pregnancy. However, females with this type usually survive and may have normal intelligence.

The X-linked recessive type called brachytelephalangic chondrodysplasia punctata can have a range of possible prognoses. Because a component of this type is a flat mid-face, small nose, and cartilage abnormalities of the larynx and trachea, these children may have breathing difficulties and may die shortly after birth. If these anomalies are not present or are mild, the prognosis is much better. Individuals with this type of the disorder usually have normal intelligence.



Rimoin, David, Ralph Lachman, and Shelia Unger. "Chrondfrodysplasia." In Emery and Rimion's Principles and Practice of Medical Genetics, 4th edition, edited by David L. Rimoin, J. Michael Connor, Reed Pyeritz, and Bruce R. Korf. London: Churchull Livingstone, 2002.


Has, Cristina, Leena Bruckner-Tuderman, Dietmar Muller, et al. "The Conradi-Hunerman-Happle Syndrome (CDPX2) and Emopamil Binding Protein: Novel Mutations, and Somatic and Gonadal Mosaicism." Human Molecular Genetics 9, no 13(2000): 1951–1955.

Unger, Sheila. "A Genetic Approach to the Diagnosis of Skeletal Dysplasia." Clinical Orthopedics and Related Research 401 (2002): 32–38.


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Deborah L. Nurmi, MS