Cleidocranial dysostosis (CCD), also called cleidocranial dysplasia, is a

birth defect A birth defect, also known as a congenital disorder, is an abnormal condition that is present at birth regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can ...

that mostly affects the

bone A bone is a Stiffness, rigid Organ (biology), organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red blood cell, red and white blood cells, store minerals, provid ...

s and

teeth A tooth ( : teeth) is a hard, calcified structure found in the jaws (or mouths) of many vertebrates and used to break down food. Some animals, particularly carnivores and omnivores, also use teeth to help with capturing or wounding prey, tear ...

. The

collarbone The clavicle, or collarbone, is a slender, S-shaped long bone approximately 6 inches (15 cm) long that serves as a strut between the shoulder blade and the sternum (breastbone). There are two clavicles, one on the left and one on the right ...

s are typically either poorly developed or absent, which allows the shoulders to be brought close together. The front of the

skull The skull is a bone protective cavity for the brain. The skull is composed of four types of bone i.e., cranial bones, facial bones, ear ossicles and hyoid bone. However two parts are more prominent: the cranium and the mandible. In humans, the ...

often does not close until later, and those affected are often shorter than average. Other symptoms may include a prominent forehead, wide set eyes, abnormal teeth, and a flat nose. Symptoms vary among people; however, intelligence is typically unaffected. The condition is either inherited from a person's parents or occurs as a new

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...

. It is inherited in an

autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

manner. It is due to a defect in the

RUNX2 Runt-related transcription factor 2 (RUNX2) also known as core-binding factor subunit alpha-1 (CBF-alpha-1) is a protein that in humans is encoded by the ''RUNX2'' gene. RUNX2 is a key transcription factor associated with osteoblast differentia ...

gene which is involved in bone formation. Diagnosis is suspected based on symptoms and

X-rays An X-ray, or, much less commonly, X-radiation, is a penetrating form of high-energy electromagnetic radiation. Most X-rays have a wavelength ranging from 10 Picometre, picometers to 10 Nanometre, nanometers, corresponding to frequency, ...

with confirmation by

genetic testing Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...

. Other conditions that can produce similar symptoms include mandibuloacral dysplasia,

pyknodysostosis Pycnodysostosis (from Greek: πυκνός (puknos) meaning "dense", ''dys'' ("defective"), and ''ostosis'' ("condition of the bone")), is a lysosomal storage disease of the bone caused by a mutation in the gene that codes the enzyme cathepsin K. ...

osteogenesis imperfecta Osteogenesis imperfecta (; OI), colloquially known as brittle bone disease, is a group of genetic disorders that all result in bones that break easily. The range of symptoms—on the skeleton as well as on the body's other organs—may be mi ...

, and Hajdu-Cheney syndrome. Treatment includes

supportive measures A therapy or medical treatment (often abbreviated tx, Tx, or Tx) is the attempted remediation of a health problem, usually following a medical diagnosis. As a rule, each therapy has indications and contraindications. There are many different ...

such as a device to protect the skull and dental care. Surgery may be performed to fix certain bone abnormalities. Life expectancy is generally normal. It affects about one per million people. Males and females are equally commonly affected. Modern descriptions of the condition date to at least 1896. The term is from ''cleido'' meaning collarbone, ''cranial'' from the Greek κρανιὀς meaning skull, and ''dysostosis'' meaning formation of abnormal bone.

Signs and symptoms

Cleidocranial dysostosis is a general skeletal condition so named from the

(cleido-) and

cranium The skull is a bone protective cavity for the brain. The skull is composed of four types of bone i.e., cranial bones, facial bones, ear ossicles and hyoid bone. However two parts are more prominent: the cranium and the mandible. In humans, the ...

deformities which people with it often have. People with the condition usually present with a painless swelling in the area of the clavicles at 2–3 years of age. Common features are: *

Clavicle The clavicle, or collarbone, is a slender, S-shaped long bone approximately 6 inches (15 cm) long that serves as a strut between the shoulder blade and the sternum (breastbone). There are two clavicles, one on the left and one on the rig ...

s (collarbones) can be partly missing leaving only the medial part of the bone. In 10% of cases, they are completely missing. If the collarbones are completely missing or reduced to small vestiges, this allows hypermobility of the shoulders including ability to touch the shoulders together in front of the chest. The defect is bilateral 80% of the time. Partial collarbones may cause nerve damage symptoms and therefore have to be removed by surgery. * The mandible is prognathic due to hypoplasia of maxilla (

micrognathism Micrognathism is a condition where the jaw is undersized. It is also sometimes called mandibular hypoplasia. It is common in infants, but is usually self-corrected during growth, due to the jaws' increasing in size. It may be a cause of abnorma ...

) and other facial bones. * A soft spot or larger soft area in the top of the head where the

fontanelle A fontanelle (or fontanel) (colloquially, soft spot) is an anatomical feature of the infant human skull comprising soft membranous gaps ( sutures) between the cranial bones that make up the calvaria of a fetus or an infant. Fontanelles allow f ...

failed to close, or the fontanelle closes late. * Bones and joints are underdeveloped. People are shorter and their frames are smaller than their siblings who do not have the condition. * The

permanent teeth Permanent teeth or adult teeth are the second set of teeth formed in diphyodont mammals. In humans and old world simians, there are thirty-two permanent teeth, consisting of six maxillary and six mandibular molars, four maxillary and four mandibul ...

include

supernumerary teeth Hyperdontia is the condition of having supernumerary teeth, or teeth that appear in addition to the regular number of teeth (32 in the average adult). They can appear in any area of the dental arch and can affect any dental organ. The opposite ...

. Unless these supernumeraries are removed they will crowd the adult teeth in what already may be an underdeveloped jaw. If so, the supernumeraries will probably need to be removed to make space for the adult teeth. Up to 13 supernumerary teeth have been observed. Teeth may also be displaced. Cementum formation may be deficient. * Failure of eruption of

. * Bossing (bulging) of the

forehead In human anatomy, the forehead is an area of the head bounded by three features, two of the skull and one of the scalp. The top of the forehead is marked by the hairline, the edge of the area where hair on the scalp grows. The bottom of the fore ...

. * Open skull sutures, large

s. *

Hypertelorism Hypertelorism is an abnormally increased distance between two organs or bodily parts, usually referring to an increased distance between the orbits (eyes), or orbital hypertelorism. In this condition the distance between the inner eye corners as ...

. * Delayed

ossification Ossification (also called osteogenesis or bone mineralization) in bone remodeling is the process of laying down new bone material by cells named osteoblasts. It is synonymous with bone tissue formation. There are two processes resulting in t ...

of bones forming symphysis pubis, producing a widened

symphysis A symphysis (, pl. symphyses) is a fibrocartilaginous fusion between two bones. It is a type of cartilaginous joint, specifically a secondary cartilaginous joint. # A symphysis is an amphiarthrosis, a slightly movable joint. # A growing together ...

. *

Coxa vara Coxa vara is a deformity of the hip, whereby the angle between the head and the shaft of the femur is reduced to less than 120 degrees. This results in the leg being shortened and the development of a limp. It may be congenital and is commonly cau ...

can occur, limiting abduction and causing

Trendelenburg gait Trendelenburg gait, named after Friedrich Trendelenburg, is an abnormal gait. It is caused by weakness or ineffective action of the gluteus medius muscle and the gluteus minimus muscle. Gandbhir and Rayi point out that the biomechanical action in ...

. * Short middle fifth

phalanges The phalanges (singular: ''phalanx'' ) are digital bones in the hands and feet of most vertebrates. In primates, the thumbs and big toes have two phalanges while the other digits have three phalanges. The phalanges are classed as long bones. ...

, sometimes causing short and wide fingers. * Vertebral abnormalities. * On rare occasions,

brachial plexus The brachial plexus is a network () of nerves formed by the anterior rami of the lower four cervical nerves and first thoracic nerve ( C5, C6, C7, C8, and T1). This plexus extends from the spinal cord, through the cervicoaxillary canal in th ...

irritation can occur. *

Scoliosis Scoliosis is a condition in which a person's spine has a sideways curve. The curve is usually "S"- or "C"-shaped over three dimensions. In some, the degree of curve is stable, while in others, it increases over time. Mild scoliosis does not t ...

spina bifida Spina bifida (Latin for 'split spine'; SB) is a birth defect in which there is incomplete closing of the spine and the membranes around the spinal cord during early development in pregnancy. There are three main types: spina bifida occulta, me ...

and

syringomyelia Syringomyelia is a generic term referring to a disorder in which a cyst or cavity forms within the spinal cord. Often, syringomyelia is used as a generic term before an etiology is determined. This cyst, called a syrinx, can expand and elongate ...

have also been described. Other features are: parietal bossing,

basilar invagination Basilar invagination is invagination (infolding) of the base of the skull that occurs when the top of the C2 vertebra migrates upward. It can cause narrowing of the foramen magnum (the opening in the skull where the spinal cord passes through to t ...

( atlantoaxial impaction), persistent

metopic suture The frontal suture is a fibrous connective tissue, fibrous suture (joint), joint that divides the two halves of the frontal bone of the human skull, skull in infants and children. Typically, it completely fuses between three and nine months of ag ...

, abnormal

ear An ear is the organ that enables hearing and, in mammals, body balance using the vestibular system. In mammals, the ear is usually described as having three parts—the outer ear, the middle ear and the inner ear. The outer ear consists of ...

structures with

hearing loss Hearing loss is a partial or total inability to Hearing, hear. Hearing loss may be present at birth or acquired at any time afterwards. Hearing loss may occur in one or both ears. In children, hearing problems can affect the ability to Language ...

supernumerary Supernumerary means "exceeding the usual number". Supernumerary may also refer to: * Supernumerary actor, a performer in a film, television show, or stage production who has no role or purpose other than to appear in the background, more commonl ...

ribs The rib cage, as an enclosure that comprises the ribs, vertebral column and sternum in the thorax of most vertebrates, protects vital organs such as the heart, lungs and great vessels. The sternum, together known as the thoracic cage, is a semi- ...

hemivertebrae Congenital vertebral anomalies are a collection of malformations of the spine. Most, around 85%, are not clinically significant, but they can cause compression of the spinal cord by deforming the vertebral canal or causing instability. This condi ...

with

spondylosis Spondylosis is the degeneration of the vertebral column from any cause. In the more narrow sense it refers to spinal osteoarthritis, the age-related wear and tear of the spinal column, which is the most common cause of spondylosis. The degenera ...

, small and high

scapulae The scapula (plural scapulae or scapulas), also known as the shoulder blade, is the bone that connects the humerus (upper arm bone) with the clavicle (collar bone). Like their connected bones, the scapulae are paired, with each scapula on either ...

hypoplasia Hypoplasia (from Ancient Greek ὑπo- ''hypo-'' 'under' + πλάσις ''plasis'' 'formation'; adjective form ''hypoplastic'') is underdevelopment or incomplete development of a tissue or organ.illiac bones, absence of the

pubic bone In vertebrates, the pubic region ( la, pubis) is the most forward-facing ( ventral and anterior) of the three main regions making up the coxal bone. The left and right pubic regions are each made up of three sections, a superior ramus, inferior ...

, short / absent fibular bones, short / absent radial bones,

hypoplastic Hypoplasia (from Ancient Greek :wikt:ὑπό, ὑπo- ''hypo-'' 'under' + πλάσις ''plasis'' 'formation'; adjective form ''hypoplastic'') is underdevelopment or incomplete development of a tissue or organ.phalanges The phalanges (singular: ''phalanx'' ) are digital bones in the hands and feet of most vertebrates. In primates, the thumbs and big toes have two phalanges while the other digits have three phalanges. The phalanges are classed as long bones. ...

Genetics

CCD is usually

, but in some cases its cause is not known. The main mechanism is thought to involve

haploinsufficiency Haploinsufficiency in genetics describes a model of dominant gene action in diploid organisms, in which a single copy of the wild-type allele at a locus in heterozygous combination with a variant allele is insufficient to produce the wild-type ...

caused by mutations in CBFA1 (also known as Runx2), a

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

located on the short arm of

chromosome 6 Chromosome 6 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 6 spans more than 170 million base pairs (the building material of DNA) and represents between 5.5 and 6% of the total ...

( 6p21), which encodes a transcription factor required for the differentiation of

stem cells In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type o ...

into

osteoblast Osteoblasts (from the Greek language, Greek combining forms for "bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cell (biology), cells with a single Cell nucleus, nucleus that synthesize bone. However, in the p ...

s. This results in delayed ossification of midline structures of the body and ensuing defects in

membranous A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. ...

and

endochondral Endochondral ossification is one of the two essential processes during fetal development of the mammalian skeletal system by which bone tissue is produced. Unlike intramembranous ossification, the other process by which bone tissue is produced, ...

bone formation Ossification (also called osteogenesis or bone mineralization) in bone remodeling is the process of laying down new bone material by cells named osteoblasts. It is synonymous with bone tissue formation. There are two processes resulting in t ...

Diagnosis

Different features of the dysostosis are significant. Radiological imaging helps confirm the diagnosis. During gestation (pregnancy), clavicular size can be calculated using available nomograms.

Wormian bone Wormian bones, also known as intrasutural bones or sutural bones, are extra bone pieces that can occur within a suture (joint) in the skull. These are irregular isolated bones that can appear in addition to the usual centres of ossification of the ...

s can sometimes be observed in the skull. Diagnosis of CCD spectrum disorder is established in an individual with typical clinical and radiographic findings and/or by the identification of a heterozygous pathogenic variant in RUNX2 (CBFA1).

Treatment

Around 5 years of age, surgical correction may be necessary to prevent any worsening of the deformity. If the mother has dysplasia, caesarian delivery may be necessary. Craniofacial surgery may be necessary to correct skull defects. Coxa vara is treated by corrective femoral osteotomies. If there is brachial plexus irritation with pain and numbness, excision of the clavicular fragments can be performed to decompress it. In case of open fontanelle, appropriate headgear may be advised by the orthopedist for protection from injury.

Prognosis

Several studies have reported that life expectancy appears to be normal for people with CCD.

Epidemiology

Cleidocranial dysostosis affects about one per million people.

Notable cases

In 1987, a young girl named

Jessica McClure Jessica McClure Morales (born March 26, 1986; widely known as "Baby Jessica" in 1987) fell into a well in her aunt's backyard in Midland, Texas, on October 14, 1987, at the age of 18 months. Over the next 56 hours, rescuers worked to succes ...

fell down a narrow well pipe in her family's Texas property. Ron Short, a roofing contractor who was born without collarbones because of cleidocranial dysostosis and thus could collapse his shoulders to work in cramped corners, arrived at the site and offered to go down the shaft. The rescuers did not end up using him, though McClure was successfully recovered from the well. Actor

Gaten Matarazzo Gaetano John Matarazzo III (; ; born September 8, 2002) is an American actor. He began his career on the Broadway stage as Benjamin in '' Priscilla, Queen of the Desert'' (2011–12) and as Gavroche in ''Les Misérables'' (2014–15). Matara ...

was born with cleidocranial dysplasia, which is incorporated into his character Dustin Henderson's storyline on ''

Stranger Things ''Stranger Things'' is an American science fiction horror drama television series created by the Duffer Brothers, who also serve as showrunners and are executive producers along with Shawn Levy and Dan Cohen. Produced by Monkey Massacre Prod ...

''. Sibling actress-singers Milly and Abby Shapiro were born with cleidocranial dysplasia, a trait they share with their mother.

References

External links

* {{Transcription factor deficiencies Congenital disorders of musculoskeletal system Transcription factor deficiencies Rare diseases Wikipedia medicine articles ready to translate