Robinow syndrome is an extremely rare inherited disorder characterized by mild to moderate short stature due to growth delays after birth (postnatal growth retardation); distinctive abnormalities of the head and facial (craniofacial) area; additional skeletal malformations; and/or genital abnormalities. The facial features of infants with Robinow syndrome resemble those of an eight-week-old fetus; within the medical literature, this condition is often referred to as "fetal face." Characteristic craniofacial features may include an abnormally large head (macrocephaly) with a bulging forehead (frontal bossing); widely spaced eyes (ocular hypertelorism) that are abnormally prominent; a small, upturned nose with nostrils that are flared forward (anteverted); and/or a sunken (depressed) nasal bridge. Skeletal malformations may include forearm bones (radius and ulna) that are unusually short (forearm brachymelia), abnormally short fingers and toes, permanent fixation of the fifth fingers in a bent position (clinodactyly), unusually small hands with broad thumbs, malformation of the ribs, abnormal side-to-side curvature of the spine (scoliosis), and/or underdevelopment of one side of the bones in the middle (thoracic) portion of the spinal column (hemivertebrae). Genital abnormalities associated with Robinow syndrome may include an abnormally small penis (micropenis) and failure of the testes to descend into the scrotum (cryptorchidism) in affected males and underdevelopment (hypoplasia) of the clitoris and the outer, elongated folds of skin on either side of the vaginal opening (labia majora) in affected females. The range and severity of symptoms vary from case to case.
In some cases, Robinow syndrome has autosomal dominant inheritance; in other cases, the disorder may have an autosomal recessive mode of inheritance. According to the medical literature, individuals with the recessive form of Robinow syndrome may have more numerous abnormalities of the ribs and the bones of the spinal column (vertebrae) than in the dominant form of the disorder. In addition, the symptoms and physical findings associated with the recessive form tend to be more severe.
Robinow syndrome is an extremely rare inherited disorder characterized by short stature; characteristic facial features; skeletal malformations; and/or genital abnormalities. The range and severity of symptoms associated with Robinow syndrome vary from case to case.
In most cases, infants with Robinow syndrome experience growth delays (i.e., growth retardation and delayed bone age) after birth (postnatally). Growth delays continue during childhood, resulting in slight to moderate short stature. In rare cases, individuals with the dominant form of Robinow syndrome may reach normal adult height. In approximately 20 percent of cases, affected children may exhibit mental retardation, delays in reaching developmental milestones, and/or delays in developing language skills.
In most infants with Robinow syndrome, the facial features resemble those of an eight-week-old fetus, a condition often termed “fetal face” within the medical literature. Characteristic abnormalities of the head and facial (craniofacial) area may include an abnormally large head (macrocephaly) with a bulging forehead (frontal bossing) and underdevelopment of the middle portion of the face (midface hypoplasia). Affected infants may also have widely spaced eyes (ocular hypertelorism) that are abnormally prominent; unusually wide, downwardly slanting eyelid folds (palpebral fissures); a small, upturned nose with nostrils that are flared forward (anteverted); a sunken (depressed) nasal bridge; and/or abnormally positioned (i.e., posteriorly rotated) ears. In addition, in some cases, affected infants may have an abnormally broad, triangularly-shaped downwardly turned mouth with an abnormally long groove (philtrum) in the center of the upper lip; a small chin; an unusually small jaw (micrognathia); and/or abnormally overgrown gums (gingival hyperplasia). Dental abnormalities may also be present including misaligned teeth, crowding of the back (posterior) teeth, and/or delayed eruption of the secondary (permanent) teeth. In some cases, a certain soft-tissue structure at the back of the throat (uvula) may be underdeveloped or abnormally divided (bifid). In addition, affected infants may also have incomplete closure of the roof of the mouth (cleft palate), an abnormal vertical groove in the upper lip, and/or restricted movements of the tongue (ankyloglossia). In some affected infants and children, ankyloglossia may contribute to delays in language skill development. In most cases, the facial abnormalities associated with Robinow syndrome become less pronounced as affected children age.
In many cases, infants with Robinow syndrome may also have skeletal abnormalities including forearm bones (radius and ulna) that are abnormally short and underdeveloped (forearm brachymelia); abnormal deviation of the thumb side of the forearm (radius) due to shortening of the radius (Madelung deformity of the wrist); unusually short fingers (brachydactyly); permanent fixation of the fifth fingers in a bent position (clinodactyly); and/or abnormally small hands with broad thumbs. In some cases, the end bones (terminal phalanges) of the thumbs and great toes may be abnormally divided (bifid) and/or the bones (phalanges) of the fingers and toes may be underdeveloped (hypoplastic). Additional abnormalities may include dislocation of the hips, limited extension of the elbows, abnormal fusion or absence of certain ribs, abnormal side-to-side curvature of the spine (scoliosis), underdevelopment of one side of the bones (vertebrae) in the middle (thoracic) portion of the spinal column (hemivertebrae), and/or fusion of certain vertebrae. In addition, affected infants may exhibit abnormal depression of the bone forming the center of the chest (“funnel chest” or pectus excavatum). In some cases, infants with Robinow syndrome may also have malformed (dysplastic) nails and/or abnormalities of the skin ridge patterns (dermatoglyphics) on the fingers and palms.
In most cases, infants with Robinow syndrome also have abnormalities of the genitals. In some cases, affected infants may have external genitals that are not distinctly male or female (ambiguous genitalia). However, in such cases, gender can be properly determined during early infancy. In females, the clitoris and the outer, elongated folds of skin on either side of the vaginal opening (labia majora) may be underdeveloped (hypoplastic). In males, the penis may be abnormally small (micropenis) and may be hidden under the surrounding skin; in addition, one or both of the testes may fail to descend into the scrotum (cryptorchidism). In rare cases, affected males may have abnormally low levels of testicular function (partial primary hypogonadism); however, in such cases, affected males experience normal development of secondary sexual characteristics (e.g., deepening of the voice, characteristic hair growth patterns, sudden increase in growth and development of the testes and scrotum, etc.) with the exception of the persistence of micropenis. According to the medical literature, sexual function is possible in many affected males, and male reproduction has been reported repeatedly in those with the dominant form of the disorder. However, reproduction in males with the recessive form of Robinow syndrome has not yet been reported. In most cases, affected females exhibit normal function of the ovaries (normal gonadal function) and normal fertility.
In some cases, individuals with Robinow syndrome may have additional physical abnormalities such as duplication of the kidneys, unusual accumulation of urine in the kidney (hydronephrosis), protrusion of portions of the large intestine through an abnormal opening in the muscular lining of the abdominal cavity (inguinal hernia), and/or protrusion of portions of the large intestine through the abdominal wall near the navel (umbilical hernia). In addition, approximately 13 percent of infants with Robinow syndrome have heart (cardiac) defects that are present at birth (congenital heart defects). In such cases, the most common heart defect has been “right ventricular outlet obstruction,” in which the flow of blood from the lower chamber of the heart (ventricle) was obstructed due to abnormal narrowing (stenosis) or closure (atresia) of the vessel that arises from the ventricle (pulmonary trunk) and divides into the left and right pulmonary arteries. Symptoms associated with this heart defect vary greatly depending upon the size and location of the obstruction. In some infants with Robinow syndrome, other cardiac abnormalities may be present including complex congenital heart defects that may lead to life-threatening complications. In addition, in rare cases, infants and children with Robinow syndrome may be prone to repeated infections of the lungs (pneumonia). In rare, severe cases, without appropriate treatment, pneumonia may result in life-threatening complications.
The dominant and recessive forms of Robinow syndrome share many of the same symptoms and physical findings (e.g., craniofacial abnormalities, short stature, skeletal malformations, and genital hypoplasia). However, in most cases, the symptoms and physical findings associated with the recessive form tend to be more severe. Researchers suggest that, infants with the recessive form of Robinow syndrome exhibit more numerous rib abnormalities (e.g., abnormal displacement, fusion, and/or absence of certain ribs) and defects affecting bones of the spinal column (vertebrae) than those infants with the dominant form of the disorder. In addition, short stature, underdevelopment of the forearm bones (radioulnar hypoplasia), and abnormalities of the fingers are more severe. In most cases, affected individuals exhibit dislocation of the head of one of the forearm bones (radial head dislocation), an abnormality rarely seen in individuals with the dominant form of Robinow syndrome. Individuals with the recessive form may also tend to have a more triangularly-shaped mouth.
Robinow syndrome may have autosomal dominant or recessive inheritance. The medical literature is unclear as to which inheritance pattern tends to occur more often. In approximately 20 percent of cases, classification into recessive and dominant forms cannot be determined.
Genetic diseases are determined by two genes, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%.
Some cases of Robinow syndrome have had parents who were related by blood (consanguineous). All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
Investigators have determined that autosomal recessive Robinow syndrome occurs due to disruption or changes (mutations) in the ROR2 gene located on chromosome 9 (9q22). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 9q22” refers to band 22 on the long arm of chromosome 9. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Robinow syndrome is thought to affect males and females in equal numbers. However, affected males may be diagnosed and reported more frequently due to the presence of distinct genital abnormalities (e.g., micropenis) associated with the disorder. According to the medical literature, there is approximately one case of Robinow syndrome in every 500,000 births or about six new cases recognized per year in the United States. More than 100 cases have been reported in the medical literature since M. Robinow originally described the disorder in 1969. The autosomal recessive form of Robinow syndrome occurs with greater frequency in Turkey. In most cases, the physical abnormalities associated with Robinow syndrome are apparent at birth (congenital).
In some cases, Robinow syndrome may be detected before birth (prenatally) based upon specialized testing (ultrasonography). During fetal ultrasonography, reflected sound waves create an image of the developing fetus, potentially revealing characteristic findings suggestive of Robinow syndrome.
A diagnosis of Robinow syndrome may be confirmed after birth (postnatally) based upon a thorough clinical evaluation, identification of characteristic physical features (e.g., craniofacial, digital, forearm, genital, and/or other malformations), and advanced imaging techniques. Specialized x-ray studies may confirm the presence and/or extent of certain observed craniofacial and skeletal abnormalities. For example, such imaging tests may confirm abnormal smallness of the jaw (micrognathia) and underdevelopment of bones of the fingers and/or forearms. In addition, x-ray studies may reveal abnormalities of the vertebrae and rib cage. In rare cases, after puberty in some affected males, blood tests may reveal the presence of elevated levels of follicle-stimulating hormone (FSH), suggesting partial primary hypogonadism.
Because the autosomal recessive form of Robinow syndrome has been linked to mutations of the ROR2 gene, gene analysis may become available to confirm a diagnosis in the future.
The treatment of Robinow syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists who treat skeletal abnormalities (orthopedists), surgeons, specialists who diagnose and treat heart problems (cardiologists), physical therapists, and/or other health care professionals may need to systematically and comprehensively plan an affected child's treatment.
In affected infants who have ambiguous genitalia, gender may be properly determined by clinical examination during the newborn period. In some cases, surgery may be performed and/or other measures may be taken to correct cryptorchidism and/or other genital abnormalities.
In some cases, braces, casts, special exercises, and/or surgery may be beneficial in treating certain vertebral abnormalities. In some cases, surgery may also be performed to correct inguinal hernias, certain craniofacial abnormalities, and/or other malformations. Use of braces, dental surgery, and/or other supportive techniques may be used to help correct misalignment of the teeth and/or other dental abnormalities.
In addition, infants and children with Robinow syndrome should receive thorough medical evaluations to ensure prompt detection and immediate appropriate treatment of heart (cardiac) abnormalities that may be potentially associated with the disorder. Affected infants and children should also be carefully monitored to help prevent and/or immediately detect infections of the lungs (pneumonia) and to ensure prompt, appropriate treatment.
Early intervention is important to ensure that children with Robinow syndrome reach their potential. Special services that may be beneficial to affected children may include special remedial education, special social support, physical therapy, and/or other medical, social, and/or vocational services.
Genetic counseling will be of benefit for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive.
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