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NIH Genetics Database
Craniofacial Chromosomal Mutations

Genetics Overview 

The field of genetics includes the study of how human characteristics, or phenotypes, are passed from one's parents to their children. Genetics defines how traits as simple as eye or hair color or as complex as a predisposition to diseases, deformity, and sicknesses that are passed in families. 


Genes are units, made up of complex strings of amino acids that code for proteins.  Proteins play a significant role in the structural support, storage, communication between cells, digestion and the transport of substances around the body. The genetic code for a given protein can either be properly or improperly coded (mutations), causing the protein to either to have a normal function or if improperly coded or transcribed render a protein incapable of proper interaction and function.  A genetic mutation, subsequent error in coding for a given protein, is the protagonist for deformity   Genetic heredity (code) is passed from parents to offspring and are contained in every single person's cells.  An individual human cell contains about 20 000 to 25000 genes. Genes vary greatly from person to person and influence disposition, intellect, physical appearance, and other traits to a certain degree.  However, importantly learning and environmental exposure plays important roles as well. A genetic coding error (mutation) can lie dormant, or never be presented as deleterious until environmental factors "trigger" the misread sequence to initiate a disease state. 


In the case of cleft and craniofacial syndromes, an inherited, mutated gene, improperly coding for a given protein in utero, (in the womb), leads to a  displayed physical characteristic or deformity.  Until promising science, such as in vitro gene editing is widely accepted and viable, the only recourse is surgical treatment.  The following addresses the specific genetic mutations responsible for the syndromes that The cleft and Craniofacial Center Utah addresses through the operative procedure.

Craniofaical Genetics

Genetics Definitions 

Genetics Terminology


DNA (deoxyribonucleic acid) is the chemical inside a gene that carries genetic instructions for making living things. DNA is made of 2 long; twisting molecules called the double helix.


Chromosomes are packets of genes in a cell. Humans have 23 pairs (46 total). One member of each pair of chromosomes is inherited from the mother and the other from the father. Two of the 46 chromosomes (X and Y) are sex chromosomes that determine whether offspring will be male or female. Individuals with a pair of X chromosomes are female and those with an X chromosome and a Y chromosome are male.


A genome is an entire system of genes. Genomics is the study of how genes interact and influence the biology and physical characteristics of living things.


Mutations are changes in DNA. These changes are sometimes passed on to offspring.


Genetic disorders are diseases or disorders caused by gene mutations or chromosomal defects.


Genetic disorders and inheritance


Heritability is the degree to which a characteristic is determined by a person's genes. Many diseases have a genetic cause. Types of genetic disorders are described below.


Familial disorders are those that affect more than 1 person in a family. There are times, however, when a child is born with an unexpected genetic disorder without a known family history of the disorder.


Chromosome abnormalities can cause some genetic disorders, which occur when a child is born with an abnormal number of chromosomes or extra or missing pieces of chromosomes.


Unifactorial diseases can occur when certain defects in a gene or a pair of genes are present. Sickle cell anemia and cystic fibrosis are 2 examples of unifactorial diseases.


Multifactorial diseases are those that involve some different genes that, combined with environmental factors, can cause disorders such as asthma and diabetes.


If you or your partner is concerned about a disorder that seems to run in either of your families, you may want to see a genetic counselor before having children. You can often be tested to see if your or your partner's genes carry certain disorders.


Companies such as Invitae provide preconception genetic testing. 

Preconception Genetic Screening

Cleft Lip and Palate

Orofacial clefts, notably cleft lip (CL) and cleft palate (CP), are the most common craniofacial birth defects in humans.  Clefts affect approximately 1 in 700 individuals, affected individuals initially face difficulties feeding and also experience speech, hearing, and dental problems. Although clefts can be surgically repaired, patients often undergo multiple craniofacial and dental surgeries, as well as speech and hearing therapy. Despite these interventions, patients can experience lifelong psychosocial effects from the malformation. In fact, individuals born with a cleft have increased incidences of mental health problems and higher mortality rates at all stages of life]. Clefting is also associated with a higher risk of various cancer types, including breast, brain, and colon cancers, in the individual with a cleft as well as their family members


The cleft lip and palate represents a complexity in genetics that is convoluted at best.  The following table demonstrates the various genetic mutations that show causal relationships to the vast variance in cleft lip and palate phenotypes (deformities).   Importantly environmental causes show a strong correlation in the onset of these mutations, with smoking during pregnancy being responsible for nearly 20% of all cases.  Additionally, alcohol use during pregnancy has demonstrated mixed causal results.  Exposure to heavy metals and carcinogenic substances also shows a relationship.  During the Vietnam War, the use of Agent Orange greatly increased the number of children born with various birth defects, including cleft lip and palate following exposure to Agent Orange or Dioxin. 



If you believe you are at high risk we encourage preconception genetic screening. 

Genes Associated with Cleft Lip and Palate

Cleft Lip and Palate Genetics
Cleft Lip and Palate Genetics

Elizabeth J. Leslie,

Am. J. Med. Genetics 2013


The overall prevalence of craniosynostosis has been estimated at between 1 in 2100 and 1 in 2500 births


Craniosynostosis is defined as the premature fusion of one or more of the cranial sutures. It leads not only to secondary distortion of skull shape but to various complications including neurologic, ophthalmic and respiratory dysfunction. Craniosynostosis is very complicated in the direct genetic causal relationship and in terms of its origins, appearance, and management. Both environmental factors and genetic factors are associated with the development of craniosynostosis.


Nonsyndromic craniosynostosis accounts for more than 70% of all cases. Nonsyndromic cases are difficult to associate with specific known induction of the syndrome and can be environmental, mutation-based, associated with cell defects in the sutures that induce early fusion, or even irregular position of the fetus in the womb, placing pressure on the head, thereby pushing bone plates together inducing fusion.  Syndromic, or gene-specific craniosynostosis with an identified genetic cause is more likely to involve multiple sutures or bilateral coronal sutures.  Whereas nonsyndromic craniosynostosis usually presents in elongation of the skull, as in the most common form, sagittal craniosynostosis.


FGFR2, FGFR3, FGFR1, TWIST1 and EFNB1 genes are major causative genes of genetic syndromes associated with craniosynostosis. Although most of the syndromic craniosynostosis show autosomal dominant inheritance, approximately half of patients are de novo cases. De novo mutations are an alteration in a gene that is present for the first time in one family member as a result of a mutation in a germ cell (egg or sperm) of one of the parents or in the fertilized egg itself. Apert syndrome, Pfeiffer syndrome, Crouzon syndrome, and Antley-Bixler syndrome are related to mutations in FGFR family (especially in FGFR2), and mutations in FGFRs can be overlapped between different syndromes. Compared to the other types of craniosynostosis, single gene mutations can be more frequently detected, in one-third of coronal synostosis patients. 



If you believe you are at high risk we encourage preconception genetic screening. 

Genes Associated Craniosynostosis Phenotypes

D. Johnson,

Craniosynostosis Mutations

FGFR2, FGFR3, and TWIST1 Mutaions, and Associated Syndromes

FGFR2 Genetics Craniofacial

D. Johnson,

European Journal of Human Genetics 2016

Apert syndrome 

Apert syndrome (AS) is characterized by craniofacial malformations including bicoronal synostosis and severe symmetrical syndactyly of fingers and toes.  Syndactyly is a characteristic feature of AS that permits distinction from the other FGFR2-related syndromes and shows a complex fusion leading to 'mitten hand' deformity in both hands and feet.


Apert Syndrome occurs in 6–15 out of 1000000 live births. This syndrome is caused by a genetic mutation in the FGFR2 gene, and approximately 98% of all patients have specific missense mutations of FGFR2 located in the linker between the IgII and IgIII domains, either p.Ser252Trp (66%) or p.Pro253Arg (32%).



Facial manifestations include a flat forehead and retracted midface, proptosis, hypertelorism, and low-set ears. Narrow pharynx and retracted midface frequently result in airway compromise. The other associated anomalies are skeletal malformations, poor joint mobility, eye and ear problems, cleft palate, and orthodontic and other dental problems. Most of the patients with AS arise from de novo mutations, which are mainly originated from the sperms of their father.

Crouzon syndrome

Crouzon syndrome (CS) is the representative craniofacial dysostosis syndrome, showing a prevalence of 16 in 1000000 live births. 


Craniofacial characteristics of CS are a tall and flat forehead, proptosis, and midface hypoplasia. However, the severity of facial deformity is milder than that of AS, and cleft palate is rarely associated with CS. In opposition to AS or PS, CS has normal intelligence, hands, and feet. Most (94%) of CS is caused by mutations in FGFR2, although a specific mutation in FGFR3 has been identified in patients with CS further complicating isolation of the specific causal relationships.

Pfeiffer Syndrome

Pfeiffer Syndrome affects about 1 in 100000 live births.


The characteristic features of Pfeiffer syndrome (PS) are broad, radially deviated thumbs and/or big toes along with craniosynostosis. Partial syndactyly on hands and feet can be accompanied in some patients. Other phenotypes including hydrocephalus, proptosis, ankylosed elbows, visceral anomalies, and delayed neuropsychological development may be found.


Craniofacial severity is variable among PS patients, and PS can be classified into three clinical subtypes based on the severity of clinical phenotypes. Type 1 has the 'classic' phenotypes with brachycephaly, midface hypoplasia, finger and toe abnormalities, and normal intelligence with a generally good outcome. Type 2 and 3 show more severe phenotypes including cloverleaf skull (very rare) severe proptosis, elbow ankylosis or synostosis, developmental delay with neurological complications.


Mutations in both FGFR2 and FGFR1 cause PS and FGFR2 mutations found in PS overlap those in Crouzon syndrome. Differentiation between PS and Crouzon syndrome rely on the presence or absence of hands and feet anomalies.  Again, however, we find multiple mutations across the FGFR family in concert. 

Jung Min Ko MD Ph.D.,

J. Neurological Society 2016

Treacher Collins syndrome

Treacher Collins affects an estimated 1 in 50,000 people.


Treacher Collins syndrome is a disorder that affects the development of bones and tissues of the face. The signs and indicators of this syndrome vary greatly, ranging from almost unremarkable to severe. Most affected persons have underdeveloped facial bones, predominantly the cheekbones, and a very small jaw and chin (micrognathia). In some instances, those affected are also born with a cleft palate.


 In severe cases, underdevelopment of the facial bones may limit an affected infant's airway, causing potentially life-threatening respiratory difficulties.  Additionally, persons with Treacher Collins syndrome often have eyes that angle downward, scant eyelashes, and a notch in the lower eyelids called an eyelid coloboma. Some affected individuals experience vision loss. This disorder is also characterized by absent, small, or unusually formed ears. Hearing loss occurs in about half of all affected individuals; hearing loss is caused by defects of the bones in the middle ear, or by underdevelopment of the ear canal. Individuals with Treacher Collins syndrome typically have normal intelligence.


Mutations in the TCOF1, POLR1C, or POLR1D gene have a causal effect in the demonstration of  Treacher Collins syndrome. TCOF1gene mutations are the most common cause of the disorder, accounting for 81 to 93 percent of all cases

POLR1C and POLR1D gene mutations cause an additional 2 percent of cases. In individuals without an identified mutation in one of these genes, the genetic cause of the condition is unknown.

The proteins produced from these genes all play important roles in the early development of bones and other tissues of the face.


When Treacher Collins syndrome results from mutations in the TCOF1 or POLR1D gene, it is considered an autosomal dominant condition.  Realizing that only one copy of the altered gene is sufficient to cause the disorder. About 60 percent of these cases result from new mutations in the gene and occur in people with no history of the disorder. The remaining autosomal dominant cases, Treacher Collins syndrome is presented through the inherited altered gene from an affected parent.


When Treacher Collins syndrome is caused by mutations in the POLR1C gene, the condition has an autosomal recessive pattern of inheritance. Autosomal recessive inheritance means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.  In the case of Treacher Collins, preconception screening is vital to understanding possible risk. 

More on Genetic Syndromes -Visit the National Institute for Health NIH

National Institute for Health Genetic Syndromes

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