Craniofacial is a medical term that relates to the bones of the skull and face. Craniofacial abnormalities are birth defects of the face or head. Some, like cleft lip and palate, are among the most common of all birth defects. Others are very rare. Most of them affect how a person's face or head looks. These conditions may also affect other parts of the body.

Treatment depends on the type of problem. Plastic and reconstructive surgery may help the person's appearance.

Cleft lip and cleft palate are birth defects that occur when a baby's lip or mouth do not form properly. They happen early during pregnancy. A baby can have a cleft lip, a cleft palate, or both.

A cleft lip happens if the tissue that makes up the lip does not join completely before birth. This causes an opening in the upper lip. The opening can be a small slit or a large opening that goes through the lip into the nose. It can be on one or both sides of the lip or, rarely, in the middle of the lip.

Children with a cleft lip also can have a cleft palate. The roof of the mouth is called the "palate." With a cleft palate, the tissue that makes up the roof of the mouth does not join correctly. Babies may have both the front and back parts of the palate open, or they may have only one part open.

Children with a cleft lip or a cleft palate often have problems with feeding and talking. They also might have ear infections, hearing loss, and problems with their teeth.

Often, surgery can close the lip and palate. Cleft lip surgery is usually done before age 12 months, and cleft palate surgery is done before 18 months. Many children have other complications. They may need additional surgeries, dental and orthodontic care, and speech therapy as they get older. With treatment, most children with clefts do well and lead a healthy life.

Cleft lip with or without cleft palate is among the most common of birth defects. The Centers for Disease Control and Prevention (CDC) estimates that in the United States:

• About 1 in every 1,600 babies is born with cleft lip with cleft palate.
• About 1 in every 2,800 babies is born with cleft lip without cleft palate.
• About 1 in every 1,700 babies is born with cleft palate.

In the earliest days of a baby’s development in the womb, there is normally a split (called a cleft) between the right and left sides of the lip and the roof of the mouth (called the palate). Sometime during the 6^th to 11^th week of pregnancy, this split comes together to form the lips and mouth. If the tissue doesn’t join, it can cause a cleft lip or a cleft palate.

The opening in a cleft lip can be a small slit or a large split that extends from the lip into the nose. The cleft can be on one side or both sides of the lip, or in the middle. The opening in a cleft palate may affect the front, or back, or both parts of the palate.

A baby may be born with only a cleft lip or a cleft palate, but some babies are born with both.

Children with a cleft lip or a cleft palate, depending on the size of the openings, may have problems eating and breathing. As they grow older, they may also have speech and language delays. Children with cleft lip or palate are also more likely to have ear infections, hearing loss, and problems with their teeth.

The lip forms between the fourth and seventh weeks of pregnancy. As a baby develops during pregnancy, body tissue and special cells from each side of the head grow toward the center of the face and join together to make the face. This joining of tissue forms the facial features, like the lips and mouth. A cleft lip happens if the tissue that makes up the lip does not join completely before birth. This results in an opening in the upper lip. The opening in the lip can be a small slit or it can be a large opening that goes through the lip into the nose. A cleft lip can be on one or both sides of the lip or in the middle of the lip, which occurs very rarely. Children with a cleft lip also can have a cleft palate.

The roof of the mouth (palate) is formed between the sixth and ninth weeks of pregnancy. A cleft palate happens if the tissue that makes up the roof of the mouth does not join together completely during pregnancy. For some babies, both the front and back parts of the palate are open. For other babies, only part of the palate is open.

• About 1 in every 1,600 babies is born with cleft lip with cleft palate in the United States.
• About 1 in every 2,800 babies is born with cleft lip without cleft palate in the United States.
• About 1 in every 1,700 babies is born with cleft palate in the United States.

During embryonic development, the right and left maxilla bones come together at the midline to form the upper jaw. At the same time, the muscle and skin overlying these bones join together to form the upper lip. Inside the mouth, the palatine processes of the maxilla bones, along with the horizontal plates of the right and left palatine bones, join together to form the hard palate. If an error occurs in these developmental processes, a birth defect of cleft lip or cleft palate may result.

Cleft lip is a common development defect that affects approximately 1:1000 births, most of which are male. This defect involves a partial or complete failure of the right and left portions of the upper lip to fuse together, leaving a cleft (gap).

A more severe developmental defect is cleft palate, which affects the hard palate. The hard palate is the bony structure that separates the nasal cavity from the oral cavity. It is formed during embryonic development by the midline fusion of the horizontal plates from the right and left palatine bones and the palatine processes of the maxilla bones. Cleft palate affects approximately 1:2500 births and is more common in females. It results from a failure of the two halves of the hard palate to completely come together and fuse at the midline, thus leaving a gap between them. This gap allows for communication between the nasal and oral cavities. In severe cases, the bony gap continues into the anterior upper jaw where the alveolar processes of the maxilla bones also do not properly join together above the front teeth. If this occurs, a cleft lip will also be seen. Because of the communication between the oral and nasal cavities, a cleft palate makes it very difficult for an infant to generate the suckling needed for nursing, thus leaving the infant at risk for malnutrition. Surgical repair is required to correct cleft palate defects.

Treacher Collins syndrome is a condition that affects the development of bones and other tissues of the face. The signs and symptoms of this disorder vary greatly, ranging from almost unnoticeable to severe. Most affected individuals have underdeveloped facial bones, particularly the cheek bones, and a very small jaw and chin (micrognathia). Some people with this condition are also born with an opening in the roof of the mouth called a cleft palate. In severe cases, underdevelopment of the facial bones may restrict an affected infant's airway, causing potentially life-threatening respiratory problems.

People with Treacher Collins syndrome often have eyes that slant downward, sparse eyelashes, and a notch in the lower eyelids called an eyelid coloboma. Some affected individuals have additional eye abnormalities that can lead to vision loss. This condition 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 three small bones in the middle ear, which transmit sound, or by underdevelopment of the ear canal. People with Treacher Collins syndrome usually have normal intelligence.

Craniofacial microsomia is a term used to describe a spectrum of abnormalities that primarily affect the development of the skull (cranium) and face before birth. Microsomia means abnormal smallness of body structures. Most people with craniofacial microsomia have differences in the size and shape of facial structures between the right and left sides of the face (facial asymmetry). In about two-thirds of cases, both sides of the face have abnormalities, which usually differ from one side to the other. Other individuals with craniofacial microsomia are affected on only one side of the face. The facial characteristics in craniofacial microsomia typically include underdevelopment of one side of the upper or lower jaw (maxillary or mandibular hypoplasia), which can cause dental problems and difficulties with feeding and speech. In cases of severe mandibular hypoplasia, breathing may also be affected.

People with craniofacial microsomia usually have ear abnormalities affecting one or both ears, typically to different degrees. They may have growths of skin (skin tags) in front of the ear (preauricular tags), an underdeveloped or absent external ear (microtia or anotia), or a closed or absent ear canal; these abnormalities may lead to hearing loss. Eye problems are less common in craniofacial microsomia, but some affected individuals have an unusually small eyeball (microphthalmia) or other eye abnormalities that result in vision loss.

Abnormalities in other parts of the body, such as malformed bones of the spine (vertebrae), abnormally shaped kidneys, and heart defects, may also occur in people with craniofacial microsomia.

Many other terms have been used for craniofacial microsomia. These other names generally refer to forms of craniofacial microsomia with specific combinations of signs and symptoms, although sometimes they are used interchangeably. Hemifacial microsomia often refers to craniofacial microsomia with maxillary or mandibular hypoplasia. People with hemifacial microsomia and noncancerous (benign) growths in the eye called epibulbar dermoids may be said to have Goldenhar syndrome or oculoauricular dysplasia.

Craniofacial-deafness-hand syndrome is characterized by distinctive facial features, profound hearing loss, and hand abnormalities.

The distinctive facial features of people with craniofacial-deafness-hand syndrome result from a variety of developmental abnormalities involving the skull (cranium) and face. Affected individuals often have underdeveloped or absent nasal bones resulting in a small nose, thin nostrils, and a flattened mid-face with a flat nasal bridge. Individuals with this condition typically also have widely spaced eyes (ocular hypertelorism), narrowed openings of the eyes (narrowed palpebral fissures), a small upper jaw (hypoplastic maxilla), and a small mouth with pursed lips.

People with this condition also have profound hearing loss that is caused by abnormalities in the inner ear (sensorineural deafness). Hearing loss in these individuals is present from birth.

In affected individuals, a common abnormality of the muscles in the hand is a malformation in which all of the fingers are angled outward toward the fifth finger (ulnar deviation). People with craniofacial-deafness-hand syndrome may also have permanently bent third, fourth, and fifth fingers (camptodactyly), which can limit finger movement and lead to joint deformities called contractures. Contractures in the wrist can further impair hand movements.

Crouzon syndrome is a genetic disorder characterized by the premature fusion of certain skull bones (craniosynostosis). This early fusion prevents the skull from growing normally and affects the shape of the head and face.

Many features of Crouzon syndrome result from the premature fusion of the skull bones. Abnormal growth of these bones leads to wide-set, bulging eyes and vision problems caused by shallow eye sockets; eyes that do not point in the same direction (strabismus); a beaked nose; and an underdeveloped upper jaw. In addition, people with Crouzon syndrome may have dental problems and hearing loss, which is sometimes accompanied by narrow ear canals. A few individuals with Crouzon syndrome have an opening in the lip and the roof of the mouth (cleft lip and palate). The severity of these signs and symptoms varies among affected people. Individuals with Crouzon syndrome usually have normal intelligence.

Burn-McKeown syndrome is a disorder that is present from birth (congenital) and involves abnormalities of the nasal passages, characteristic facial features, hearing loss, heart abnormalities, and short stature.

In people with Burn-McKeown syndrome, both nasal passages are usually narrowed (bilateral choanal stenosis) or completely blocked (bilateral choanal atresia), which can cause life-threatening breathing problems in infancy without surgical repair. Typical facial features include narrow openings of the eyelids (short palpebral fissures); a gap (coloboma) in the lower eyelids; widely spaced eyes (hypertelorism); a prominent bridge of the nose; a short space between the nose and the upper lip (philtrum); a small opening of the mouth (microstomia); and large, protruding ears.

Some people with Burn-McKeown syndrome have congenital hearing loss in both ears which varies in severity among affected individuals. The hearing loss is described as mixed, which means that it is caused by both changes in the inner ear (sensorineural hearing loss) and changes in the middle ear (conductive hearing loss).

Other features that can occur in Burn-McKeown syndrome include mild short stature and congenital heart defects such as patent ductus arteriosus (PDA). The ductus arteriosus is a connection between two major arteries, the aorta and the pulmonary artery. This connection is open during fetal development and normally closes shortly after birth. However, the ductus arteriosus remains open, or patent, in babies with PDA. If untreated, this heart defect causes infants to breathe rapidly, feed poorly, and gain weight slowly; in severe cases, it can lead to heart failure. Intelligence is unaffected in Burn-McKeown syndrome.

Pfeiffer syndrome is a genetic disorder characterized by the premature fusion of certain skull bones (craniosynostosis). This early fusion prevents the skull from growing normally and affects the shape of the head and face. Pfeiffer syndrome also affects bones in the hands and feet.

Many of the characteristic facial features of Pfeiffer syndrome result from premature fusion of the skull bones. Abnormal growth of these bones leads to bulging and wide-set eyes, a high forehead, an underdeveloped upper jaw, and a beaked nose. More than half of all children with Pfeiffer syndrome have hearing loss; dental problems are also common.

In people with Pfeiffer syndrome, the thumbs and first (big) toes are wide and bend away from the other digits. Unusually short fingers and toes (brachydactyly) are also common, and there may be some webbing or fusion between the digits (syndactyly).

Pfeiffer syndrome is divided into three subtypes. Type 1, also known as classic Pfeiffer syndrome, has symptoms as described above. Most individuals with type 1 Pfeiffer syndrome have normal intelligence and a normal life span. Types 2 and 3 are more severe forms of Pfeiffer syndrome that often involve problems with the nervous system. The premature fusion of skull bones can limit brain growth, leading to delayed development and other neurological problems. In addition, individuals with type 2 or 3 can have fusion of the bones (ankylosis) in the elbow or other joints, limiting mobility, and abnormalities of the face and airways, which can cause life-threatening breathing problems. Type 2 is distinguished from type 3 by the presence of a cloverleaf-shaped head, which is caused by more extensive fusion of bones in the skull.

Rubinstein-Taybi syndrome is a condition characterized by short stature, moderate to severe intellectual disability, distinctive facial features, and broad thumbs and first toes. Additional features of the disorder can include eye abnormalities, heart and kidney defects, dental problems, and obesity. These signs and symptoms vary among affected individuals. People with this condition have an increased risk of developing particular types of noncancerous brain and skin tumors.

Cherubism is a disorder characterized by abnormal bone tissue in the jaw. Beginning in early childhood, both the lower jaw (the mandible) and the upper jaw (the maxilla) become enlarged as bone is replaced with painless, cyst-like growths. These growths give the cheeks a swollen, rounded appearance and often interfere with normal tooth development. In some people the condition is so mild that it may not be noticeable, while other cases are severe enough to cause problems with vision, breathing, speech, and swallowing. Enlargement of the jaw usually continues throughout childhood and stabilizes during puberty. The abnormal growths are gradually replaced with normal bone in early adulthood. As a result, many affected adults have a normal facial appearance.

Most people with cherubism have few, if any, signs and symptoms affecting other parts of the body. Rarely, however, this condition occurs as part of another genetic disorder. For example, abnormal jaw growth, like that in cherubism, can occur in Ramon syndrome, which also involves short stature, intellectual disability, and overgrowth of the gums (gingival fibrosis). Additionally, cherubism-like growths have been reported in rare cases of Noonan syndrome (a developmental disorder characterized by unusual facial characteristics, short stature, and heart defects), fragile X syndrome (a condition primarily affecting males that causes learning disabilities and cognitive impairment), and neurofibromatosis type 1 (a condition primarily characterized by multiple skin tumors).

Cleidocranial dysplasia is a condition that primarily affects development of the bones and teeth. Signs and symptoms of cleidocranial dysplasia can vary widely in severity, even within the same family.

Individuals with cleidocranial dysplasia usually have underdeveloped or absent collarbones, also called clavicles ("cleido-" in the condition name refers to these bones). As a result, their shoulders are narrow and sloping, can be brought unusually close together in front of the body, and in some cases can be made to meet in the middle of the body. Delayed maturation of the skull (cranium) is also characteristic of this condition, including delayed closing of the growth lines where the bones of the skull meet (sutures) and larger than normal spaces (fontanelles) between the skull bones that are noticeable as "soft spots" on the heads of infants. The fontanelles normally close in early childhood, but they may remain open throughout life in people with this disorder. Some individuals with cleidocranial dysplasia have extra pieces of bone called Wormian bones within the sutures.

Affected individuals are often shorter than other members of their family at the same age. Many also have short, tapered fingers and broad thumbs; flat feet; knock knees; short shoulder blades (scapulae); and an abnormal curvature of the spine (scoliosis). Typical facial features include a wide, short skull (brachycephaly); a prominent forehead; wide-set eyes (hypertelorism); a flat nose; and a small upper jaw.

Individuals with cleidocranial dysplasia often have decreased bone density (osteopenia) and may develop osteoporosis, a condition that makes bones progressively more brittle and prone to fracture, at a relatively early age. Women with cleidocranial dysplasia have an increased risk of requiring a cesarean section when delivering a baby, due to a narrow pelvis preventing passage of the infant's head.

Dental abnormalities are very common in cleidocranial dysplasia and can include delayed loss of the primary (baby) teeth; delayed appearance of the secondary (adult) teeth; unusually shaped, peg-like teeth; misalignment of the teeth and jaws (malocclusion); and extra teeth, sometimes accompanied by cysts in the gums.

In addition to skeletal and dental abnormalities, people with cleidocranial dysplasia may have hearing loss and are prone to sinus and ear infections. Some young children with this condition are mildly delayed in the development of motor skills such as crawling and walking, but intelligence is unaffected.

Costello syndrome is a rare disorder that affects many parts of the body. This condition is characterized by delayed development, loose folds of skin (which are especially noticeable on the hands and feet), unusually flexible joints, heart problems, short stature, and distinctive facial features.

Children with Costello syndrome are often delayed in reaching developmental milestones, such as speaking, sitting, and walking. Affected individuals may also have intellectual disabilities that can vary in severity.

Distinctive facial features in people with Costello syndrome typically include a prominent forehead, full cheeks, and full lips. Infants with Costello syndrome may be larger than average at birth, but most have difficulty eating and grow more slowly than other children. Affected individuals may have gastrointestinal problems that include constipation or a backflow of stomach acids into the esophagus (gastroesophageal reflux or GERD). People with this condition have short stature compared to their family and peers and may have reduced growth hormone levels.

Heart problems are common, including an abnormal heartbeat (arrhythmia), structural heart defects, and a type of heart disease that enlarges and weakens the heart muscle (hypertrophic cardiomyopathy). Neurological problems in people with Costello syndrome include seizures, weak muscle tone (hypotonia), and a structural abnormality of the brain called a Chiari I malformation. Costello syndrome can cause vision problems, such as nearsightedness (myopia), farsightedness (hyperopia), or eyes that do not point in the same direction (strabismus). Hearing loss may also occur.

Other signs and symptoms of Costello syndrome can include tight Achilles tendons (which connect the calf muscles to the heel), recurrent respiratory infections, dry and thickened skin, skeletal abnormalities, and dental problems.

Beginning in early childhood, people with Costello syndrome have a higher risk of developing certain cancerous and noncancerous tumors compared to the general population. The most common noncancerous tumors associated with this condition are papillomas, which are small, wart-like growths that usually develop around the nose and mouth or near the anus. The most common cancerous tumor associated with Costello syndrome is a childhood cancer called rhabdomyosarcoma, which begins in muscle tissue. Neuroblastoma, a tumor that arises in developing nerve cells, has also been reported in children and adolescents with this syndrome. In addition, some teenagers with Costello syndrome have developed transitional cell carcinoma, a form of bladder cancer that is usually seen in older adults.

The signs and symptoms of Costello syndrome overlap significantly with those of two other genetic conditions, cardiofaciocutaneous syndrome (CFC syndrome) and Noonan syndrome. In affected infants, it can be difficult to tell the three conditions apart based on their physical features. However, the conditions can be distinguished by their genetic causes and by the specific patterns of signs and symptoms that develop later in childhood.

Noonan syndrome is a condition that affects many areas of the body. It is characterized by mildly unusual facial features, short stature, heart defects, bleeding problems, skeletal malformations, and many other signs and symptoms.

People with Noonan syndrome have distinctive facial features such as a deep groove in the area between the nose and mouth (philtrum), widely spaced eyes that are usually pale blue or blue-green in color, and low-set ears that are rotated backward. Affected individuals may have a high arch in the roof of the mouth (high-arched palate), poor teeth alignment, and a small lower jaw (micrognathia). Many children with Noonan syndrome have a short neck, and both children and adults may have excess neck skin (also called webbing) and a low hairline at the back of the neck.

Between 50 and 70 percent of individuals with Noonan syndrome have short stature. At birth, they are usually a normal length and weight, but growth slows over time. Abnormal levels of growth hormone, a protein that is necessary for the normal growth of the body's bones and tissues, may contribute to the slow growth.

Individuals with Noonan syndrome often have either a sunken chest (pectus excavatum) or a protruding chest (pectus carinatum). Some affected people may also have an abnormal side-to-side curvature of the spine (scoliosis).

Most people with Noonan syndrome have some form of critical congenital heart disease. The most common heart defect in these individuals is a narrowing of the valve that controls blood flow from the heart to the lungs (pulmonary valve stenosis). Some have hypertrophic cardiomyopathy, which enlarges and weakens the heart muscle.

A variety of bleeding disorders have been associated with Noonan syndrome. Some affected individuals have excessive bruising, nosebleeds, or prolonged bleeding following injury or surgery. Rarely, women with Noonan syndrome who have a bleeding disorder have excessive bleeding during menstruation (menorrhagia) or childbirth.

Adolescent males with Noonan syndrome typically experience delayed puberty. They go through puberty starting at age 13 or 14 and have a reduced pubertal growth spurt that results in shortened stature. Most males with Noonan syndrome have undescended testes (cryptorchidism), which may contribute to infertility (inability to father a child) later in life. Females with Noonan syndrome can experience delayed puberty but most have normal puberty and fertility.

Noonan syndrome can cause a variety of other signs and symptoms. Most children diagnosed with Noonan syndrome have normal intelligence, but a few have special educational needs, and some have intellectual disability. Some affected individuals have vision or hearing problems. Affected infants may have feeding problems, which typically get better by age 1 or 2 years. Infants with Noonan syndrome may be born with puffy hands and feet caused by a buildup of fluid (lymphedema), which can go away on its own. Older individuals can also develop lymphedema, usually in the ankles and lower legs.

Some people with Noonan syndrome develop cancer, particularly those involving the blood-forming cells (leukemia). It has been estimated that children with Noonan syndrome have an eightfold increased risk of developing leukemia or other cancers over age-matched peers.

Noonan syndrome is one of a group of related conditions, collectively known as RASopathies. These conditions all have similar signs and symptoms and are caused by changes in the same cell signaling pathway. In addition to Noonan syndrome, the RASopathies include cardiofaciocutaneous syndrome, Costello syndrome, neurofibromatosis type 1, Legius syndrome, and Noonan syndrome with multiple lentigines.

Noonan syndrome is a disorder that involves unusual facial characteristics, short stature, heart defects present at birth, bleeding problems, developmental delays, and malformations of the bones of the rib cage.

What is Noonan Syndrome?

Noonan syndrome is a disorder that involves unusual facial characteristics, short stature, heart defects present at birth, bleeding problems, developmental delays, and malformations of the bones of the rib cage.

Noonan syndrome is caused by changes in one of several autosomal dominant genes. A person who has Noonan syndrome may have inherited an altered (mutated) gene from one of his or her parents, or the gene change may be a new change due to an error carried by the egg or sperm or occurring at conception. Alterations in four genes - PTPN11, SOS1, RAF1 and KRAS - have been identified to date.

Noonan syndrome is present in about 1 in 1,000 to 1 in 2,500 people.

What are the symptoms of Noonan Syndrome?

Symptoms of Noonan syndrome may include the following:

• A characteristic facial appearance.

• Short stature.

• Heart defect present at birth (congenital heart defect).

• A broad or webbed neck.

• Minor eye problems such as strabismus in up to 95 percent of individuals.

• Bleeding problems such as a history of abnormal bleeding or bruising.

• An unusual chest shape with widely-spaced and low set nipples.

• Developmental delay of varying degrees, but usually mild.

• In males, undescended testes (cryptorchidism).

How is Noonan syndrome diagnosed?

The diagnosis of Noonan syndrome is based on the person's clinical symptoms and signs. The specialist examines the person looking for the specific features of Noonan syndrome.

Individuals who have Noonan syndrome have normal chromosome studies. Four genes - PTPN11, SOS1, RADF1and KRAS - are the only genes that are known to be associated with Noonan syndrome. Approximately 50 percent of individuals with Noonan syndrome have mutations in the PTPN11 gene. Twenty percent of those with Noonan Syndrome have mutations in the SOS1. Mutations in the RAF1 gene account for between 10 and 15 percent of Noonan syndrome cases. About 5 percent of people with Noonan syndrome have mutations in the KRAS gene and usually have a more severe or atypical form of the disorder. The cause of Noonan syndrome in the remaining 10 to 15 percent of people with this disorder is not yet known. .

Symptoms of Noonan syndrome may include the following:

• A characteristic facial appearance.

• Short stature.

• Heart defect present at birth (congenital heart defect).

• A broad or webbed neck.

• Minor eye problems such as strabismus in up to 95 percent of individuals.

• Bleeding problems such as a history of abnormal bleeding or bruising.

• An unusual chest shape with widely-spaced and low set nipples.

• Developmental delay of varying degrees, but usually mild.

• In males, undescended testes (cryptorchidism).

What is the treatment for Noonan syndrome?

Treatment for individuals who have Noonan syndrome is based on their particular symptoms. Heart problems are treated in the same way as they are for individuals in the general population. Early intervention programs are used to help with developmental disabilities, when present. Bleeding problems that can be present in Noonan syndrome may have a variety of causes and are treated according to their cause. Growth problems may be caused by lack of growth hormone and may be treated with growth hormone treatment. Symptoms such as heart problems are followed on a regular basis.

Is Noonan syndrome inherited?

Noonan syndrome is inherited in families in an autosomal dominant pattern. This means that a person who has Noonan syndrome has one copy of an altered gene that causes the disorder. In about one-third to two-thirds of families one of the parents also has Noonan syndrome. The parent who has Noonan syndrome has a 1 in 2 (50 percent) chance to pass on the altered gene to a child who will be affected; and a 1 in 2 (50 percent) chance to pass on the normal version of the gene to a child who will not have Noonan syndrome. In many individuals who have Noonan syndrome, the altered gene happens for the first time in them, and neither of the parents has Noonan syndrome. This is called a de novo mutation. The chance for these parents to have another child with Noonan syndrome is very small (less than 1 percent).

Noonan syndrome with multiple lentigines (formerly called LEOPARD syndrome) is a condition that affects many areas of the body. As the condition name suggests, Noonan syndrome with multiple lentigines is very similar to a condition called Noonan syndrome, and it can be difficult to tell the two disorders apart in early childhood. However, the features of these two conditions differ later in life. The characteristic features of Noonan syndrome with multiple lentigines include brown skin spots called lentigines that are similar to freckles, heart defects, widely spaced eyes (ocular hypertelorism), a sunken chest (pectus excavatum) or protruding chest (pectus carinatum), and short stature. These features vary, however, even among affected individuals in the same family. Not all individuals with Noonan syndrome with multiple lentigines have all the characteristic features of this condition.

The lentigines seen in Noonan syndrome with multiple lentigines typically first appear in mid-childhood, mostly on the face, neck, and upper body. Affected individuals may have thousands of small dark brown skin spots by the time they reach puberty. Unlike freckles, the appearance of lentigines has nothing to do with sun exposure. In addition to lentigines, people with this condition may have lighter brown skin spots called café-au-lait spots. Café-au-lait spots tend to develop before the lentigines, appearing within the first year of life in most affected people.

Of the people with Noonan syndrome with multiple lentigines who have heart defects, about 80 percent have hypertrophic cardiomyopathy, which is a thickening of the heart muscle that forces the heart to work harder to pump blood. The hypertrophic cardiomyopathy most often affects the lower left chamber of the heart (the left ventricle). Up to 20 percent of people with Noonan syndrome with multiple lentigines who have heart problems have a narrowing of the artery from the heart to the lungs (pulmonary stenosis).

People with Noonan syndrome with multiple lentigines can have a distinctive facial appearance. In addition to ocular hypertelorism, affected individuals may have droopy eyelids (ptosis), thick lips, and low-set ears. Affected individuals also usually have an abnormal appearance of the chest; they either have pectus excavatum or pectus carinatum.

At birth, people with Noonan syndrome with multiple lentigines are typically of normal weight and height, but in some, growth slows over time. This slow growth results in affected individuals being shorter than average, although less than half of people with Noonan syndrome with multiple lentigines have significantly short stature.

Other signs and symptoms of Noonan syndrome with multiple lentigines include hearing loss caused by abnormalities in the inner ear (sensorineural deafness), mild intellectual disability, and extra folds of skin on the back of the neck. Affected males often have genital abnormalities, which can include undescended testes (cryptorchidism) and a urethra that opens on the underside of the penis (hypospadias). These abnormalities may reduce the ability to have biological children (decreased fertility). Females with Noonan syndrome with multiple lentigines may have poorly developed ovaries and delayed puberty.

Noonan syndrome with multiple lentigines is one of a group of related conditions collectively known as RASopathies. These conditions all have similar signs and symptoms and are caused by changes in the same cell signaling pathway. In addition to Noonan syndrome with multiple lentigines, the RASopathies include Noonan syndrome, cardiofaciocutaneous syndrome, Costello syndrome, neurofibromatosis type 1, and Legius syndrome.

Megalencephaly (also known as macrencephaly) is a condition in which an infant or child has a large, heavy, and potentially malfunctioning brain. By definition, the brain weight is greater than average for the age and biological sex of the child. Head enlargement may be evident at birth or the head may become larger in the early years of life.

Megalencephaly is thought to be related to a disturbance in the regulation of cell production in the brain. Neuron proliferation, or the process through which nerve cells divide to form new generations of cells, is generally regulated so that the correct number of cells is produced in the proper place at the appropriate time. In a megalencephalic brain, too many cells are produced either during development or progressively as part of another disorder, such as one of the neurofibromatoses or leukodystrophies.

Symptoms of megalencephaly include:

• Delayed development
• Seizures
• Corticospinal (brain cortex and spinal cord) dysfunction

Megalencephaly affects males more often than females. Unilateral megalencephaly or hemimegalencephaly is a rare condition that is characterized by the enlargement of one side of the brain. Children with this disorder may have a large, asymmetrical head accompanied by seizures, partial paralysis, and impaired cognitive development. Megalencephaly is different from macrocephaly (also known as megacephaly or megalocephaly), which describes a big head, and which doesn't necessarily indicate abnormality. Large head size can be passed down through the generations in some families.

Osteoglophonic dysplasia is a condition characterized by abnormal bone growth that leads to severe head and face (craniofacial) abnormalities, short stature, and other features. The term osteoglophonic refers to the bones (osteo-) having distinctive hollowed-out (-glophonic) areas that appear as lesions or holes on x-ray images. These lesions typically affect the long bones of the arms and legs.

In people with osteoglophonic dysplasia, bones in the skull often fuse together too early (craniosynostosis). The craniosynostosis seen in people with this disorder may give the head a flat appearance or a "cloverleaf" shape, depending on which bones fuse first. Characteristic facial features in people with osteoglophonic dysplasia include a prominent forehead, widely spaced eyes (hypertelorism) that are prominent (proptosis), low-set ears, a flattening of the bridge of the nose and the middle of the face (midface hypoplasia), a protruding jaw (prognathism), a high arch in the roof of the mouth (a high-arched palate), and a short neck. People with this condition usually have no visible teeth because the teeth never emerge from the jaw (clinical anodontia). In addition, the gums are often overgrown (hypertrophic gingiva).

Most people with osteoglophonic dysplasia have hollowed lesions in the long bones. These lesions are likely non-ossifying fibromas, which are benign (noncancerous) bone tumors made up of fibrous tissue that does not harden into bone. The lesions appear early in life and gradually increase in size and number during childhood. Later in life, the lesions may get smaller or go away once the bones have stopped growing. Individuals with osteoglophonic dysplasia can also have short, bowed legs and arms. They also have flat feet; overlapping toes; and short, broad hands and fingers.

Infants with osteoglophonic dysplasia often experience failure to thrive, which means they do not gain weight and grow at the expected rate. Affected individuals can experience episodes of increased body temperature and excessive sweating.

Some people with osteoglophonic dysplasia develop pyloric stenosis, which is a narrowing of the opening from the stomach into the small intestines. Others can develop inguinal hernia, in which the contents of the abdomen causes a soft out-pouching through the lower abdominal wall.

The life expectancy of people with osteoglophonic dysplasia depends on the extent of the craniofacial abnormalities. People with abnormalities that obstruct the air passages and affect the mouth and teeth may have respiratory problems and difficulty eating and drinking. Despite the skull abnormalities, intelligence is generally not affected in people with this disorder, but speech delays can occur.