Term Paper on Kniest written By C. Birner in November 2002.
Please ask permission before citing or quoting.

Please click on a link or
read the paper straight through

Introduction to Skeletal Dysplasias
History, Incidence, and Genetics Of Kniest
Different Types And Functions Of Collagen
Specific Changes In Type II Collagen Which Cause Kniest Dysplasia
Diagnosis Of Kniest And Differential Diagnosis
Complications Associated With Kniest and Their Pathways
Advanced Maternal And Paternal Age
Genetics Of Kniest And Other Skeletal Dysplasias
Conclusion And Suggestions For Future Research

Table 1: Incidence of Skeletal Dysplasias


Questions? Contact us

Links to get to other sections of the web page

Introduction To Skeletal Dysplasias

A skeletal dysplasia is defined as a malformation in the development or growth of at least one bone in the body. Not all skeletal dysplasias cause short stature, though most lead to an adult height under 4'10". Skeletal dysplasia are caused by failures or defects in bone formation, either during fetal development or during childhood. Bone formation is a very complex process and there are many pathways that can lead to skeletal dysplasias. There are over 200 distinct forms of skeletal dysplasias. Table 1 illustrates the incidence, expected height ranges, and biochemical changes of the most common forms of skeletal dysplasias.

The study of skeletal dysplasias is important because it provides links between genetic defects and phenotypes. Some forms of skeletal dysplasias are lethal prenatally but most are quite compatible with life. Others present increased infant mortality but a normal life span thereafter.

In recent years, treatments for some of the disorders that cause short stature have been developed. Examples are synthetic growth hormone for persons with pituitary dwarfism and people with achondroplasia undertaking Elongated Limb Lengthening (ELL). The recent availability of ELL has been quite controversial in the dwarfism community. (Internet Resource 1).

Accurate diagnosis of skeletal dysplasia can also help alert medical providers to potentially severe side effects. For example, Type II collagen disorders are associated with retinal detachment and people with achondroplasia are at risk for hydrocephalus. Accurate diagnoses can also make parents feel more at ease about their children's future, since most disorders leave intellect unaffected and most people with skeletal dysplasias have average life spans.

Kniest dysplasia is caused by an error in the formation of Type II collagen. Like other Type II skeletal dysplasias, diagnosis of Kniest dysplasia is complicated by the considerable overlap in phenotypes of people with skeletal dysplasias. It is common for patients to receive multiple diagnoses before a definitive one is made. Not having a diagnosis can be frustrating for the people with the conditions. A correct diagnosis is helpful for medical management. Therefore, research to improve the speed and accuracy of diagnoses is important. (Spranger et al., 1994).

Other related skeletal dysplasias also show considerable overlap with Kniest Skeletal Dysplasia, further complicating diagnosis. Achondroplasia is the most common form of skeletal dysplasia and is caused by fibroblast growth factor receptor defects. There are conditions that look somewhat similar, such as achondroplasia and hypoachondroplasia, which have mutations very close to each other. People with achondroplasia, however, who pass on the mutation will always have a child with achondroplasia, and never hypoachondroplasia or another related form of dwarfism. (Francomano et al. 1996).

Back to top

History, Incidence, and Genetics Of Kniest

Kniest Skeletal Dyaplsia is a very rare skeletal dysplasia, occurring in fewer than one in a million live births. It is autosomal dominant and affects males and females equally. A dominant condition requires only one copy of the nonfunctioning gene to be inherited for the condition to be expressed.

Doctor Wilhelm Kniest first characterized this disorder in 1952. He described findings in a 3-year old girl who had had skeletal changes that were consistent with known dysplasias such a disproportionate short stature and kyphoscoliosis. There were also some distinguishing symptoms: very thick joints, progressively worsening joint problems, vision and hearing problems, and a flat and round mid-face. (Spranger et al., 1997). Please see Illustration I for a picture of Dr. Kniest and his patient.

People with Kniest have an average height of 100-140 CM (39-55 in). They have flat, round faces and a low nasal ridge. Please see Illustration 3 for a picture of the distinct facial features. They also have progressively severe kyphoscoliosis and swollen joints. Progressive joint contractures with limited range of motion are also frequently present. People with Kniest are unable to make a tight first. In addition to the skeletal dysplasia, there are very frequent eye problems (50%) and hearing problems (40%). Hearing and vision defects are due collagen deficiencies in the eyes and inner ears. (Spranger et al., 1997). These will be covered in more detail in detail in the Complications and Pathways section.

In a few cases, an excess of keratin sulphate has been detected in the urine of people with Kniest. It is interesting to note that this has also been found in some forms of the skeletal dysplasia Morquio Syndrome. (Maumenee and Traboulsi, 1985.)

Back to top

Different Types And Functions Of Collagen

Before understanding the mutations that can interfere with skeletal growth, it is important to understand the normal process. Collagen means 'glue' in Greek. Humans have at least 25 different types of collagen, and it is the most abundant protein in the human body. Type II collagen is found in cartilage, eyes, and inner ear. Other kinds of collagen are found in skin, blood vessels, and the vitreous layer of the eye. (Internet Resource 4).

Collagen is a main component of bone formation. Limb buds first appear in humans during the fourth week of development. Mesenchymal cells in the lateral mesoderm layer initiate development. Each limb bud is covered by ectoderm. They grow by proliferation of the mesenchyme cells. The location and patterning of the limbs is regulated by Homeobox genes. (Moore and Persaud, 1998).

The process of fetal bone development is called osteogenesis. There are two main stages of bone growth: formation and lengthening. Bone formation starts from the osteogenesis centers, which appear after the fifth week of gestation. Formation of the bones starts from the center of the bone and moves outwards as a collagen "template" of the new bone is formed. Once the initial shape of the bones is formed, the growth originates from growth plates at each end of the long bones in the epiphyseal layer. Collagen is turned into bone in the ossification centers starting in the twelfth week of gestation. The ossification happens in the metaphyseal layer. Muscle and nerve cells form parallel to, and at the same time as, the long bones. (Moore and Persaud, 1998).

During elongation, strands of collagen are ossified into bones in a very complex process. Type II collagen is made up of three identical polypeptide chains and is coded by the COL2A1 gene located on chromosome 12. Because of the tight spaces involved in the triple Type II collagen fibers, every third amino acid must be a Glycine, the smallest amino acid. Type II collagen is found in cartilage, the spine, and the vitreous layer in the eyes. (Cohen, 2000).

Back to top

Specific Changes In Type II Collagen Which Cause Kniest Dysplasia

There are a dozen known mutations that cause Kniest dysplasia. Most result from small deletions that lead to shortened Type II collagen fibers. All but one of the Kniest mutations is clustered between the COL2A1 exons 12 and 24 on chromosome 12. 90% of Kniest mutations have been shown to arise from small deletions in the locus that codes for Type II collagen, and the other 10% arise from point mutations that cause substitutions. One deletion mutation causes part of the exon to be skipped by interfering with a splice site. (Wilkin et al., 1999).

Two different substitutions errors leading to Arginine instead of Glycine have been found to cause Kniest. (Francomano et al. 1996). Similar substitutions have also been found to cause other skeletal dysplasias. In some of these substitution-induced disorders, the effects are fatal. For instance, substitution of Serine for Glycine in the skeletal dysplasia achondrogenesis leads to prenatal death. (Knowlton et al., 1998, Internet Resource 3). These skeletal dysplasias are rare and there have been too few cases studied on the molecular level to make genotype to phenotype generalizations. It has been shown that the more deformed Type II collagen is present, the more severe the symptoms are. (Mortier et. al 1995, 2000).

The abnormal protein disrupts the functioning of unaffected (normal) cells. People with Kniest have a characteristic 'Swiss Cheese' pattern in their collagen. The mechanism by which the mutant proteins are incorporated is complex and not yet fully understood. One study found that normal fibers loop outward and distend to accommodate the malformed Kniest fibers caused by protein substitutions. (Fernandes et al., 1998).

In addition to the 'looping out' process suggested by Fernandes, Weiss et all (1998) suggest that the triple helix cartilage matrix cuts off the longer normal sized collagen fibers to match the smaller ones truncated by Kniest deletions. No mutations that initiate unsolicited stop codons have been found to cause Kniest, although they have been found to cause other collagen-related skeletal dysplasias. (Francomano et al., 2000)

Collagen is the building block of bones and mutant collagen fibers cause multiple problems at the cellular level. The abnormal proteins do not fold correctly. They take longer to fold and the resulting tertiary structure is abnormal. They may also take longer to excrete and impair later modification of collagen fibers. They also decrease thermal stability, leading to more potential problems once the collagen and bone have formed. (Cohen, 2000).

Back to top

Diagnosis Of Kniest And Differential Diagnosis

Kniest can be diagnosed prenatally. Since some mutations for Kniest are known it is possible to diagnose it by amniocentesis or CVS. Parents with Kniest who wish to have children and obtain prenatal genetic testing need first to know which Kniest mutation they have. Therefore, it is recommended that they see a genetic counselor before becoming pregnant.

Ultrasounds will show disproportionate dwarfism in the second trimester. The most apparent signs will be slowed growth, polyhydramnios, and flared bone ends. The skull shows frontal flattening, maxillary hypoplasia, and shallow orbits. The ribs are short and there is delayed ossification in femoral heads and clubbed metaphyseal layers. The spine shows diffuse coronal clefts. The pelvis is also smaller. (Knowlton et al., Internet Resource 2)

At birth, the distinct facial features, short limbs, and other problems usually lead to consideration of a skeletal dysplasia. X-rays and blood tests to rule out other disorders are usually performed. X-rays will show the classic 'Swiss cheese' cartilage as well as low broad ilia, and short tubular bones with broad metaphyses and deformed large epiphyses. The vertebrae are ovoid shaped. The chest may be broad and round with a short neck. Eye problems and swollen joints may be apparent at birth. A cleft palate due to Pierre Robin Syndrome is common at birth. Clubfeet are also frequently seen. Blood work will be normal, though occasionally excess of keratin sulphate is detected in the urine.

As the child grows, back problems may increase and the torso appears to be shorter in comparison to the limbs. The flat vertebrae make the neck appear invisible and the head looks as if it rests on the torso. Cervical spine instability can occur because of malformations in the odontoid process. Motor development is usually delayed. Careful monitoring of cervical instability, eye, and joint problems need to be a regular part of medical care for children with Kniest. Many of the problems associated with these complications can be prevented if caught in time. (Internet Resource 3). Please see Illustration 2 for a picture if a young girl with Kniest.

Due to the considerable overlap among phenotypes of skeletal dysplasias, and especially between spondyloepiphyseal dyplasia and Kniest, differential diagnosis focuses on the specific clusters of bone malformations. In general, the tubular bones are shorter and the ends wider in people with Kniest than with SEDC. The bones in the hands are more affected in Kniest than in SEDC. Most people with SEDC have unaffected hands. (Spranger et al., 1994). Both conditions can cause severe short stature, shortened limbs, joint problems, eye and ear problems, progressive kyphoscoliosis, and a short torso. (Internet resource 3).

Back to top

Complications Associated With Kniest and Their Pathways

Pierre Robin Sequence
Due to a small jaw, the tongue does not always have enough room to form. This can in turn cause the tongue to locate in the wrong place and interfere with the palate closing, leading to a cleft palate. Until the cleft can be surgically repaired, an infant with Robin sequence may experience respiratory and feeding problems. About 20% of the cases are sporadic and the rest are associated with other disorders. The diagnosis of Robin sequence may take a few days, as the other genetic conditions need to be ruled out. (Singer and Sidoti, 1992).


It is not surprising that people with Kniest experience progressive joint problems. The collagen to form the joints is itself defective. The building blocks are the wrong shape. These faulty building blocks create malformed bones and joints. Abnormal kinesthetic movements then act on the joints, in some cases affecting development. There are also theories that the body's immune system attacks the deformed collagen because it is viewed as foreign. (Helfgott et. al, 1991).

For example, hip dysplasias are always present in people with Kniest. The hip joint relies partly on physical pressures from the femur from walking to develop correctly. Since the femur is too short, the femoral neck-shaft/hip joint connection is unable to make the angle of 120-135O required for the joint to function correctly. The hip being at less than 120O is called coxa vara and leads to a waddling gait.

Coxa vara is very rare in the general population, but common among people with skeletal dysplasias. As blood vessels, ligaments, and nerves grow to accommodate the malformed joint, corrective surgery becomes increasingly less effective. It is important that hip dysplasia be diagnosed in very early childhood so that corrective surgeries to pre-empt and minimize hip problems can be an option.

Scoliosis/ Respiratory Problems

The flat vertebrae make the spine less stable and more prone to curvature. Lack of exercise can also result in weaker abdominal muscles and further exaggerate the back problems. The combination of short trunk and severe curvature can interfere with breathing and the curvature may need to be repaired surgically.

Another urgent spine repair is fusion of the cervical spine. People with Kniest frequently have an underdeveloped odontoid process, which leads to cervical spine instability. Cervical instability can also develop later in life. It is recommended that people with Kniest have neck-flexion X-rays done every two years to monitor for cervical spine instability.

The very short and compressed torso occasionally leads to lung hypoplasia. The lung hypoplasia can lead to pulmonary hypoxia and hypotension, which can cause pulmonary vascular disease. These heart and lung problems can become chronic, lifelong disabilities.

Eye Problems

Eye problems are present in many skeletal diseases. Collagen is present in the lining of the eye and this is thought to contribute to the numerous eye problems in people with Kniest and other skeletal dysplasias. In Kniest, severe myopia, vitreoretinopathy, and retinal detachment are the main problems. Findings of cataracts, dislocation of lenses, and blepharoptosis (droopy eyelids) have also been reported. Since retinal detachments can be prevented if detected in time, this should be part of the standard care for people with Kniest. (Maumenee and Traboulsi, 1985.)


Hearing loss is progressive. The exact cause of the hearing problems associated with Kniest has not been identified. It is speculated that the deafness is conductive deafness or as a result of frequent ear infections (Internet Resource 3). There have been some suggestions that this gradual worsening has an autoimmune function, and that the body attacks the malformed collagen. People with Kniest should have their hearing tested regularly. (Helfgott et. al, 1991).


Pain management is a sensitive subject but must be addressed. Many people with skeletal dysplasias feel they need to 'suffer through.' Medications and lifestyle changes can greatly reduce pain and improve the quality of life. In addition, anti-inflammatory drugs may reduce joint wear-and-tear, in addition to decreasing pain.

Back to top


No teratogens have been associated with any skeletal dysplasias. Women with these skeletal dysplasias who have very shortened trunks are at a slightly higher risk of pre-term labor and are more prone to respiratory problems during pregnancy. (Yoshimura et al. 1998). Some teratogens may cause short stature, however. Thalidomide, for example, can cause micromelia or amelia of the legs leading to very reduced height. Many teratogens, such as alcohol, contribute to short stature, but not a height considered to be dwarfism.

Back to top

Advanced Maternal And Paternal Age

While there is an association of Advanced Paternal Age with achondroplasia, no associations have been made with other skeletal dysplasias. (Wilkin et al., 1998). Achondroplasia is much more common than Type II skeletal dysplasias (see chart 1). It is conceivable that there is an association with advanced paternal age, given that both are dominant, substitution mutations, but the data are not there yet. Just as women taking folic acid has been shown to dramatically decrease the incidence of spina biffida, there may be in the future proactive steps older men will be able take to insure healthier offspring.

Back to top

Genetics Of Kniest And Other Skeletal Dysplasias

Kniest is an autosomal dominant disorder located on chromosome 12. There have been no recorded cases of a person being born with two copies of Kniest mutations. However, it appears that having mutations for more than one major skeletal dysplasia can have very serious effects. For example, a baby born double dominant for achondroplasia rarely survives beyond the first year of life. (Internet Resource 3). It has been documented that being a double heterozygote for two different skeletal dysplasias can be worse than the combined symptoms of having each one separately. (Unger et al., 1991).

Back to top

Conclusion And Suggestions For Future Research

People with orphan diseases are frequently underserved in the research department because it is not economically feasible to invest in uncommon conditions. Understanding the rare genetic mutations such as Kniest can lead to a better understanding of human development. In addition, it may lead to clues to understanding adult-onset bone disorders such as arthritis and osteoporosis and autoimmune function.

Kniest dysplasia can be very disabling, though many people with the condition lead very active and satisfying lives. Please see Illustration 4 for pictures of children recovering from Kniest-related surgeries.

It is also possible that some people have substitutions in the Type II collagen and other collagens and are phenotypically normal. It would be interesting to look more at Cohen's suggestions on how malformed Type II collagens interact with other tissues in the body. (Cohen, 2000)

Some dwarfs feel comfortable with their height and it is an inseparable part of their being (Internet Resource 1) and resent even the idea of a search for a 'cure.' Like some deaf people after the invention of the cochlear implants, they view themselves as an endangered species. As pre-natal tests become increasingly available and affordable, non-directive counseling and informed choice will be vital to serving people affected with these conditions.

Back to top

Table 1: Incidence of Skeletal Dysplasias
(Internet Reference 3)






Height Range




1/26,000 - 40,000

Autosomal Dominant

Female: 48.6 in


Male: 51.8 in


Fibroblast Growth Factor Receptor 3 mutation





Type II Collagen associated defects


Autosomal Dominant and also Recessive



Type II collagen disruption





Kniest Dysplasia

Fewer than 1/1,000,000

Autosomal Dominant

39-55 in

Type II collagen defect





Diastrophic Dyplasia

1/100,000 births

Autosomal Recessive

Female: 3.7- 4.2 ft


Male: 3.4 - 4 ft


Problem with sulfate processing impairing collagen formation






Osteogenesis Imperfecta


Autosomal Dominant

Varies.Some types can have very short stature.

Type I collagen defect





Back to top


Cohen MM Jr. Merging the old skeletal biology with the new. II. Molecular aspects of bone formation and bone growth J Craniofac Genet Dev Biol Apr-Jun;20(2):94-106 (2000)

Fernandes RJ, Wilkin DJ, Weis MA, Wilcox WR, Cohn DH, Rimoin DL, Eyre DR. Incorporation of structurally defective type II collagen into cartilage matrix in kniest chondrodysplasia. Arch Biochem Biophys 355(2):282-90 (1998)

Francomano CA, McIntosh I, Wilkin DJ. Bone dysplasias in man: molecular insights. Curr Opin Genet Dev. Jun;6(3):301-8. Review. (1996)

Helfgott SM, Mosciscki RA, San Martin J, Lorenzo C, Kieval R, McKenna M, Nadol J, Trentham DE. Correlation Between Antibodies To Type II Collagen And Treatment Outcome In Bilateral Progressive Sensorineural Hearing Loss. The Lancet 16;337(8738):387-9 (1991).

Maumenee IH, Traboulsi EI. The ocular findings in Kniest dysplasia. Am J Ophthalmol Jul 15;100(1):155-60. (1985)

Mortier GR, Wilkin DJ, Wilcox WR, Rimoin DL, Lachman RS, Eyre DR, Cohn DH. A radiographic, morphologic, biochemical and molecular analysis of a case of achondrogenesis type II resulting from substitution for a glycine residue (Gly691-->Arg) in the type II collagen trimer. Hum Mol Genet.Feb;4(2):285-8. (1985)

Mortier GR, Weis M, Nuytinck L, King LM, Wilkin DJ, De Paepe A, Lachman RS, Rimoin DL, Eyre DR, Cohn DH. Report of five novel and one recurrent COL2A1 mutations with analysis of genotype-phenotype correlation in patients with a lethal type II collagen disorder. J. Med Genet 37(4):263-71 (2000).

Singer Lewis, Sidoti Eugene J. Pediatric Management of Robin Sequence Cleft Palate Craniofac J. May;29(3):220-3 (1992)

Spranger J, Winterpacht A, Zabel B. The Type II Collagenopathies: A Spectrum of Chondroplasias. Eur J. Pediatr 153:56-65 (1994)

Spranger J, Winterpacht A, Zabel B. Kniest Dysplasia: Dr. W. Kniest, His Patient, The Molecular Defect. Am J. of Med Gen 69:79-84 (1997)

Weis MA, Wilkin DJ, Kim HJ, Wilcox WR, Lachman RS, Rimoin DL, Cohn DH, Eyre DR. Structurally Abnormal Type II Collagen In A Severe Form Of Kniest Dysplasia Caused By An Exon 24 Skipping Mutation. J. Biol Chem 273:4761-4768 (1998)

Wilkin DJ, Szabo JK, Cameron R, Henderson S, Bellus GA, Mack ML, Kaitila I, Loughlin J, Munnich A, Sykes B, Bonaventure J, Francomano CA. Mutations in fibroblast growth-factor receptor 3 in sporadic cases of achondroplasia occur exclusively on the paternally derived chromosome. Am J Hum Genet Sep;63(3):711-6 (1998)

Unger S, Korkko J, Krakow D, Lachman RS, Rimoin DL, Cohn DH. Double heterozygosity for pseudoachondroplasia and spondyloepiphyseal dysplasia congenita. Am J Med Genet Nov 22;104(2):140-6 (2001)

Yoshimura T, Nakamura T, Ito M, Okamura H. Respiratory Difficulty Necessitated Early Delivery in a Woman with Spondyloepiphyseal Dysplasia. Journal Of Maternal-Fetal Investigation Sep;8(3):145-146 (1998)

Internet Resources

1) The LPA Medical Advisory Board's Position Paper On Extended Limb Lengthening Retrieved 10/15/2002 from

2) Sarah Knowlton MD, Cornelia Graves, MD, George E. Tiller, MD, PhD, Philippe Jeanty, MD, PhD Achondrogenesis. Retrieved 10/15/2002 from

3) The Greenberg Center for Skeletal Dysplasias at John Hopkins University Type II Collagen Conditions Clinical Summaries. Retrieved 10/15/2002 from

4) Online Mendelian Inheritance of Man 120140 Collagen Type II, Alpha-1; COL2A1 Retreived 10/11/2002 from


Moore & Persaud, The Developing Human 6th edition, W B Saunders Co publishers

Back to top


Thanks to the Kniest support group.
Thanks to Matt and Kathy for their editing help and suggestions.
Thanks to Dominique and her family for being such an inspiration.

This is a term Paper on Kniest written By C. Birner in November 2002.
Please ask permission before citing or quoting.

End of Kniest term paper



Valid XHTML 1.0 Strict     Valid CSS!

Top of Page

Home   |   Contact Us   |   What's New   |   Site Map   |   Advocacy   |   Medical Terms  |   Search Site

Where do I start?  |   Exercise and Alternative Therapies   |   Family Stories   |   Newsletters and Events

Medical Information   |   Do Your Own Research   |   Adaptive Equipment

©2005 Kniest SED Group