About craniocarpotarsal dystrophy (dysplasia)

What is craniocarpotarsal dystrophy (dysplasia)?

Freeman-Sheldon syndrome is a rare inherited disorder characterized by multiple contractures (i.e., restricted movement around two or more body areas) at birth (congenital), abnormalities of the head and face (craniofacial) area, defects of the hands and feet, and skeletal malformations. Craniofacial abnormalities may consist of characteristic facial features that cause the individual to appear to be whistling. These features include an extremely small puckered mouth (microstomia); a "full" forehead appearance, unusually prominent cheeks; and thin, pursed lips. Affected infants may also have an unusually flat middle portion of the face, a high roof of the mouth (palate), an unusually small jaw (micrognathia), an abnormally small tongue (microglossia), and/or a raised, scar-like mark in the shape of an "H" or a "V" extending from the lower lip to the chin. Affected infants often have abnormalities affecting the eyes including widely-spaced deep-set eyes, crossed eyes (strabismus), and/or downslanting eyelid folds (palpebral fissures). Malformations of the hands and feet are also characteristic of Freeman-Sheldon syndrome. Children with Freeman-Sheldon syndrome may also exhibit speech impairment; swallowing and eating difficulties; vomiting; failure to grow and gain weight at the expected rate (failure to thrive); and/or respiratory problems that may result in life-threatening complications. Freeman-Sheldon syndrome can be inherited as an autosomal dominant genetic trait. However, most cases occur randomly with no apparent cause (sporadically).

What are the symptoms for craniocarpotarsal dystrophy (dysplasia)?

Abnormal chin symptom was found in the craniocarpotarsal dystrophy (dysplasia) condition

Certain problems are required to be present for diagnosis of FSS. All persons with FSS have the following problems: very small mouth (microstomia), whistling-face appearance (pursed lips), “H” or “V” shaped chin dimple and very obvious crease from the nostril to the corners of the mouth (nasolabial creases). Classically, persons also have Restricted movement in joints (contractures) of two or more body areas, often hands and feet, with fingers and toes frequently overlapping.

Many additional problems have been associated with FSS, especially problems of the face, including: over-crowded teeth (dental crowding), poorly aligned teeth (class II malocclusion), very high roof of the mouth (vaulted or highly arched palate), extra distance between the nose and upper lip (long philtrum), bulging ridges above the eyes (prominent superciliary ridges or frontal bossing), very small tongue (microglossia), drooping eyelids (blepharoptosis), cross-eyed problem (strabismus), extra inner skin-fold of the eye next to the nose (epicanthal folds), down-slanting eyelid folds (palpebral fissures), very small eyelid opening (blepharophimosis), sunken appearance of eyes (enophthalmos), widely spaced eyes (ocular hypertelorism), low set and tilted ears, mild to moderate hearing impairment, under-developed chin (microgenia), under-developed (micrognathia) and recessed (retrognathia) jaw, wide nasal bridge, small nose, under-developed nostrils (hypoplastic alae nasi), long face and flat mid-face (mid-face hypoplasia). Skull bones may come together too early (craniosynostosis) and a small skull (microcephaly).

Hand or Foot deformities may be present on both (bilateral) or only one (unilateral) side. Fingers (phalanges) may be tightly bent (camptodactyly) and pointed outward from the thumb (ulnar deviation or windmill vane appearance). The thumb (pollex) may be tightly bent into the palm (adducted or thumb-in-palm deformity). The wrist often has limited movement and is frequently bent up (dorsoflexed or cock-up deformity). Feet often resemble a golf club (Talipes equinovarus or club foot condition) and may have a rocker bottom appearance (vertical talus), with toes (phalanges) tightly bent (camptodactyly) and turned inward (metatarsus varus). Sometimes there is overriding of fingers or toes shortly after birth that improves spontaneously or with mild therapy.

Different deformities of the back, ribs, and chest have been observed. Many persons with FSS have humpback (kyphosis), swayback (lordosis) or sideways (scoliosis) curves in the back bones. If the abnormalities in the curves of the spine and breastbone are significant, they can restrict internal organs of the chest and abdomen and cause gastrointestinal, lung, and heart problems. In people with FSS, the muscles between the ribs (intercostal muscles) often are non-functional, making breathing and coughing difficult (reduced respiratory effort and tussive ability) and rarely causing harm to the lungs (pulmonary hypertension) and heart (right heart strain and cor pulmonale). Not being able to breathe deeply and cough well also can make it difficult to recover from lower respiratory infections. When present, the combination of severely abnormal curves of the backbone and non-functional muscles between the ribs (intercostal muscles) may result in chronic lung problems (reduced intrathoracic volume, impaired thoracic cage compliance, impaired exercise tolerance, reduced ventilation of oxygen, and restrictive pulmonary disease). Notably, there is no evidence of FSS directly causing lung or heart problems. Some of the indirect or secondary lung and heart problems that persons with FSS may experience because of non-functional muscles between the ribs and possibly other areas of the chest can resolve or have improvement with exercise and medical treatment. Less frequently, some people may have deformities of the ribs and breastbone (sternum) cartilage, causing either a sunken (pectus excavatum) or jutted out (pectus carinatum) appearance of the chest. Rarely, persons may have small openings in the spinal bones (spina bifida occulta).

Persons with FSS often have a short neck that does not move well and may have extra skin, giving a “webbed” appearance (pterygium colli). Hips and knees and, less frequently, shoulders and elbows may have limited movement (contractures) and dislocations. The knee cap (patella) may repeatedly partially dislocate (habitual subluxation). Joints with limited or no movement (contractures) may have decreased or absent reflexes (deep tendon reflexes). Some patients have experienced abdominal hernias (inguinal, epigastric).

Under-development of the jaw (micrognathia) may contribute to swallowing (dysphagia) and breathing problems (lower airway obstruction), but typically, patients have a very small tongue (microglossia), preventing breathing problems caused by the tongue that happen in patients with other conditions involving under-development of the jaw. Mouth breathing is caused by very thin (hypoplastic) nasal cartilages and narrowed nasal passages (nasopharynx). Poor coughing (tussive) ability and swallowing problems (dysphagia) may put the person with FSS at greater risk for airway obstruction and inhalation (aspiration) of food, saliva or vomit into the lungs, which may cause lower respiratory infections (bronchitis and pneumonia). Mouth breathing, which causes inhalation of unconditioned air and potentially aerosol droplets from people with contagious respiratory infections, may further complicate the potential respiratory risk for patients with FSS. Upper respiratory infections may progress more often to bronchitis or pneumonia infections, as well. Mouth breathing, swallowing problems (dysphagia), and the not uncommon need for a high calorie diet can also cause persons with FSS to be more at risk for developing dental cavities (caries). Persons may be more at-risk for middle ear infections, which can lead to hearing loss. Persons with FSS may also experience sinus infections and frontal Headaches more often because of deformities of the skull.

While severe swallowing problems (dysphagia) may reduce eating efficiency—slowing growth in infancy and childhood, swallowing problems (dysphagia) typically improve spontaneously with age. Rarely, dysphagia may not improve. Persons with FSS typically have difficulty creating a suction with the lips and mouth because of ineffective facial muscles. Persons with FSS are typically short and may be thin into early adulthood, while others are normal weight or overweight as adults. There are some reports of persons with FSS experiencing more chronic constipation, vomiting, and gastroesophageal reflux, suggesting that gut (visceral) muscle may be secondarily affected. A few persons with FSS seem to use energy at higher rates and require high calorie foods, but the cause is unknown.

Speech problems (dysphasia), which typically include both a nasal voice (hyponasality) and articulation problems, are caused by multiple structural and functional problems, specifically problems with regional muscles; a very small tongue (microglossia); highly arched roof of the mouth (hard palate); very thin (hypoplastic) nasal cartilages; narrowed nasal passages (nasopharynx); and under-developed facial bones (midface hypoplasia).

Except those who have had severe respiratory complications and not enough oxygen reached the brain, persons with FSS have normal intelligence. Most persons have developmental delays that are caused by physical deformities.

Because of head, neck, throat (pharynx) and mouth problems, it is challenging for healthcare providers to protect the airway of persons with FSS who are unconscious. It is also difficult for healthcare providers to access blood vessels to draw blood or give medicine or fluid. These problems seriously complicate anesthesia, sedation and surgery planning for persons with FSS.

What are the causes for craniocarpotarsal dystrophy (dysplasia)?

There is no known link between FSS and environmental or parental factors, such as exposure to illnesses, toxins, drugs or harsh substances.

Though the cause remains uncertain for a small percentage of people, FSS can be caused by a change (mutation or allelic variation) in the embryonic myosin heavy chain (MYH3) gene, which is located on band 13.1 of the short arm (p) of chromosome 17 (a locus of 17p13.1). FSS is believed to impair muscle development in the embryo and disrupt muscle function throughout life by causing the energy [adenosine triphosphate (ATP)] needed for muscles to tense (muscle contraction) and relax properly to have difficulty attaching to the myosin, one of the main parts of muscles fibers. This may happen because of reduced activity of enzymes that break the ATP bonds to the myosin (ATPase) that could be caused by mechanical problems with actin, the other main part of muscle fibers. When muscles cannot function normally, deformities in the bones, joints, and other areas can result.

Most patients with FSS are born to normal healthy parents, and in this situation, FSS is not inherited but arises from a new change in the gene (new mutation). When FSS is inherited, almost all of the time one of the parents has FSS and passes on one copy of the gene to a child (autosomal dominant inheritance). In extremely rare situations, however, a parent may be healthy but have a MYH3 gene variant only in their reproductive cells (germline mosaicism). In this case, still only one copy of the changed gene is needed to cause FSS in a child.

Dominant means that only a single copy of a changed gene is necessary to cause the condition. Autosomal means the changed gene is not located on one of the gender determining chromosomes, and the risk of an affected parent of either biologic gender passing the changed gene in an autosomal dominant condition like FSS to an offspring is 50% for each pregnancy.

Except for women with FSS considering using in vetro fertilization to avoid an FSS pregnancy, determining if there is a change in the MYH3 gene or possibly another gene is not needed for diagnosis and does not affect or improve treatment. Diagnosis is based on the strict criteria of physical findings, which has strong agreement with genetic testing. While FSS severity differs greatly between individuals, each person affected has the same basic types of problems, and treatments have similar outcomes.

What are the treatments for craniocarpotarsal dystrophy (dysplasia)?

The underlying cause of the problems in persons with FSS is not fully understood, and treatment targets specific, functional problems. Since FSS is primarily a condition of the face and skull (craniofacial), overall care is best provided and coordinated by a craniofacial surgeon. Patients with FSS who receive overall care from a doctor in another speciality may have poorer outcomes. Doctors from other specialities may not have the training or experience to understand how the patient’s face and skull problems can affect their general health and psychosocial functioning.

Treatment includes physical, occupational, and speech therapy; and limited, specific use of surgery, especially oral-maxillofacial (dental and mouth problems) and plastic surgery (face, head, and hand problems). Surgery may be used to extend benefits gained in physical, occupational, and speech therapy. Abnormal muscle function sometimes limits surgical options and causes unfavorable surgical outcomes. It should be expected that surgeries will need to be repeated periodically because of the abnormalities of the muscle. Follow-up surgeries target the muscles to release the abnormal areas to reduce tension and allow greater movement.

To gain the greatest functional benefit and lessen psychosocial consequences, any face and skull reconstructive surgery deemed feasible should occur before early school years. Failure to operate on the face and skull early in the child’s life reduces treatment options later to improve speech, ability to breathe through the nose, access to the mouth to allow dental care, and facial appearance, as facial deformities can be a significant burden to the child throughout their life, impacting all areas of interpersonal interaction. If the eyelids cause obstruction of vision, failure to operate early can result in blindness. For patients with FSS, the ability to improve the appearance of the face is, however, limited.

Deformities of the hands, feet, and spine are best treated with aggressive physical therapy and without surgery. Braces and splints may be helpful to maintain the corrections gained by physical and occupational therapy. While physical therapy for the hands is best done soon after birth and in early childhood, it may be possible to do some corrective physical therapy into early adulthood. Generally, surgery for deformities of the feet should not be attempted, as the feet present a very poor surgical risk in most patients with FSS. Failure of surgery on the feet can result in non-functional feet or loss of one or both feet. For patients whose foot deformities cannot be corrected with physical therapy and braces, prosthetics (without need for amputation) can be used to transfer the weight-bearing to the knee and leg and allow the person to walk comfortably.

With appropriate therapy, including limited use of surgery, prognosis can be very good for most persons with FSS. Early diagnosis, aggressive physical therapy and maintaining a healthy, active lifestyle is associated with the best outcomes and minimizes the impact of physical problems on development.

What are the risk factors for craniocarpotarsal dystrophy (dysplasia)?

Crouzon syndrome affects males and females. Some articles in the medical literature report that males are affected more often than females. Crouzon syndrome is estimated to affect about 1.6 in 100,000 people in the general population. All forms of craniosynostosis are estimated to affect about 1 in 2,000-2,5000 live births.

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