NORD gratefully acknowledges Shashikant Kulkarni, PhD, Director of CytoGenomics and Molecular Pathology, Director of Clinical & Molecular Cytogenetics, Department of Pathology, Washington University School of Medicine, for assistance in the preparation of this report.
Chromosome 4, Monosomy Distal 4q is a rare chromosomal disorder in which there is deletion (monosomy) of a portion of the 4th chromosome. Associated symptoms and findings may be variable, depending upon the specific length and location of the deleted portion of chromosome 4. However, characteristic features include growth deficiency after birth (postnatal growth retardation), varying degrees of mental retardation, malformations of the skull and facial (craniofacial) region, structural heart defects, abnormalities of the hands and feet, and/or other physical findings. Chromosome 4, Monosomy Distal 4q usually appears to result from spontaneous (de novo) errors very early during embryonic development that occur for unknown reasons (sporadically).
As mentioned above, the symptoms and physical findings associated with Chromosome 4, Monosomy Distal 4q may be variable. However, in many cases, the disorder is characterized by distinctive malformations of the skull and facial (craniofacial) region, structural malformations of the heart that are present at birth (congenital heart defects), abnormalities of the hands and feet, and/or other physical abnormalities. In addition, individuals with the disorder are typically affected by mild, moderate, or severe mental retardation and delays in the acquisition of skills requiring the coordination of mental and physical activities (psychomotor retardation).
Although the birth weight is usually normal in those with Chromosome 4, Monosomy Distal 4q, most affected infants have growth deficiency after birth (postnatal growth retardation). Some infants also have low muscle tone (hypotonia) and/or sudden episodes of uncontrolled electrical activity in the brain (seizures).
Characteristic craniofacial abnormalities associated with Monosomy Distal 4q may include a small head (microcephaly); a short nose with a low nasal bridge and upturned nostrils (anteverted nares); and/or low-set, pointed ears. In addition, many with the disorder have an abnormally small, receding lower jaw (microretrognathia) and incomplete closure of the roof of the mouth (cleft palate) that, in some cases, may be associated with downward displacement or retraction of the tongue (glossoptosis). The association of microretrognathia, cleft palate, and glossoptosis may be referred to as “Pierre-Robin syndrome” or “Robin malformation sequence.” The malformations associated with Pierre-Robin syndrome may lead to feeding and breathing difficulties in the newborn (neonatal) period. Associated abnormalities may include impaired sucking and swallowing, failure to grow and gain weight at the expected rate (failure to thrive), upper airway obstruction, sudden absence of spontaneous breathing (apnea), insufficient oxygen supply to body tissues (hypoxia), inflammation of the lungs due to entrance of food particles or other foreign matter into the lungs’ air passages (aspiration pneumonia), and/or other abnormalities.
Chromosome 4, Monosomy Distal 4q may also be associated with additional craniofacial malformations. These may include widely spaced eyes (ocular hypertelorism); upwardly slanting eyelid folds (palpebral fissures); vertical skin folds that may cover the eyes’ inner corners (epicanthal folds); and/or an abnormal groove in the upper lip (cleft lip). In addition, in some cases, the shape of the forehead may appear dissimilar from one side to the other (forehead asymmetry).
According to reports in the medical literature, over 60 percent of affected infants also have congenital heart (cardiac) defects. Most frequently, such cardiac defects include an abnormal opening in the partition (septum) that normally separates the lower chambers (ventricles) or the upper chambers (atria) of the heart (ventricular or atrial septal defects [VSDs or ASDs]). Additional cardiac defects reported in association with the disorder have included abnormal narrowing (stenosis) of the opening between the pulmonary artery and the right ventricle (pulmonary stenosis); abnormal narrowing of the aorta (aortic coarctation) or of the opening between the aorta and the left ventricle (aortic stenosis); patent ductus arteriosus (PDA); or tetralogy of Fallot. In PDA, the channel that is present between the pulmonary artery and the aorta during fetal development fails to close after birth. (The pulmonary artery transports oxygen-depleted blood from the right ventricle to the lungs, where the exchange of oxygen and carbon dioxide occurs. The aorta, the major artery of the body, arises from the left ventricle and supplies oxygen-rich blood to most arteries.) Tetralogy of Fallot refers to a combination of heart defects, including ventricular septal defect; pulmonary stenosis; displacement of the aorta, enabling oxygen-depleted blood to flow from the right ventricle to the aorta; and thickening (hypertrophy) of the heart muscle (myocardium) of the right ventricle. In those with cardiac defects, associated symptoms and findings may vary, depending upon the severity and combination of heart malformations present and other factors. For example, in some cases, such as those with small isolated VSDs, no symptoms may be apparent. However, in other instances, such as those with larger VSDs and/or other cardiac defects, associated symptoms and findings may include difficulties feeding, shortness of breath, failure to thrive, excessive sweating, irritability, bluish discoloration of the skin and mucous membranes (cyanosis), and/or other abnormalities. In some individuals with Monosomy Distal 4q, congenital heart disease and/or respiratory difficulties associated with certain craniofacial malformations (e.g., Pierre-Robin syndrome) may lead to potentially life-threatening complications during infancy or early childhood.
Chromosome 4, Monosomy Distal 4q may also be associated with distinctive abnormalities of the hands and feet. Such malformations may include abnormal bending (clinodactyly) and tapering of the “pinkies” (fifth fingers), with unusually pointed or duplicated fingernails; implanted thumbs and great toes (halluces); abnormal skin ridge patterns on the palms and the fifth fingers; overlapping toes; and/or deformities in which the feet are twisted out of shape or position (clubfeet). In some cases, additional musculoskeletal defects may also be present, such as limited extension of the elbows and/or dislocated hips.
In some affected individuals, the disorder may be associated with additional physical abnormalities, including genital, kidney (renal), gastrointestinal, and/or other malformations.
In individuals with Chromosome 4, Monosomy Distal 4q, there is deletion (monosomy) of all or a portion of the end (distal) region of the long arm (q) of chromosome 4. (“Distal” indicates away or farthest from a particular point of reference, meaning the chromosome’s centromere [described below].) Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p,” a long arm identified by the letter “q,” and a narrowed region at which the two arms are joined (centromere). Chromosomes are further subdivided into bands that are numbered outward from the centromere. For example, “4q31” refers to band 31 of the long arm of chromosome 4.
Evidence suggests that individuals with characteristic features of Monosomy Distal 4q have deletions beginning within band 4q31 (breakpoint) that extend to the end (or “terminal”) of chromosome 4q (i.e., 4q31-qter). (The distal region of 4q is sometimes referred to as “4q3” and includes bands 4q31 through 4q35, the latter of which is the terminal band of 4q.) Patients with deletions from band 4q32-qter appear to have symptoms and findings similar to those associated with deletions of 4q31-qter. However, some researchers indicate that deletions beginning within bands 4q33 or 4q34 to qter appear to be characterized by less severe clinical features.
In addition, evidence indicates that “interstitial” deletions within bands 4q31 to 4q34 that do not extend to qter may have many features typically associated with the syndrome. (Interstitial means situated between, such as between other regions of a chromosome.) According to some investigators, such findings suggest that characteristic features attributed to loss of 4q31-qter may primarily result from deletion of 4q31 to 4q33-q34.
In contrast, reports indicate that the clinical features associated with interstitial deletions of 4q that are “proximal” to 4q31 are generally more variable and less specific than–and may differ greatly from–those associated with distal deletions. However, such features typically include mental retardation and relatively mild craniofacial abnormalities. (Proximal, which is the opposite of the term distal, indicates closer to or nearest a particular point of reference [i.e., the centromere].)
In most cases, Chromosome 4, Monosomy Distal 4q appears to be caused by spontaneous (de novo) errors very early in embryonic development. In such instances, the parents of the affected child usually have normal chromosomes and a relatively low risk of having another child with the chromosomal abnormality.
Less commonly, the deletion may result from a “balanced translocation” in one of the parents. Translocations occur when portions of certain chromosomes break off and are rearranged, resulting in shifting of genetic material and an altered set of chromosomes. If a chromosomal rearrangement is balanced, meaning that it consists of an altered but balanced set of chromosomes, it is usually harmless to the carrier. However, such a chromosomal rearrangement may be associated with an increased risk of abnormal chromosomal development in the carrier’s offspring.
Chromosomal analysis and genetic counseling are typically recommended for parents of an affected child to help confirm or exclude the presence of a balanced translocation or other chromosomal rearrangement in one of the parents.
Chromosome 4, Monosomy Distal 4q appears to affect males and females in relatively equal numbers. Partial deletion of chromosome 4q was originally reported in a child in 1967. Chromosome 4, Monosomy Distal 4q was proposed as a distinct chromosomal syndrome with characteristic symptoms and findings in 1979. More than 30 patients with the syndrome have been reported in the medical literature.
In some cases, Chromosome 4, Monosomy Distal 4q may be suggested before birth (prenatally) by specialized tests such as ultrasound, amniocentesis, and/or chorionic villus sampling (CVS). During fetal ultrasonography, reflected sound waves create an image of the developing fetus, potentially revealing certain findings that suggest a chromosomal disorder or other developmental abnormalities. With amniocentesis, a sample of fluid that surrounds the developing fetus is removed and analyzed, while CVS involves the removal of tissue samples from a portion of the placenta. Chromosomal analysis performed on such fluid or tissue samples may reveal the presence of Monosomy Distal 4q.
The disorder is usually diagnosed or confirmed after birth (postnatally) based upon a thorough clinical evaluation, detection of characteristic physical findings, and chromosomal analysis. Various specialized tests, including advanced imaging techniques, may also be performed to help detect and/or characterize certain abnormalities that may be associated with the disorder (e.g., microretrognathia, cleft palate, etc.). In addition, a thorough cardiac evaluation may be advised to detect any heart abnormalities that may be present. Such evaluation may include a thorough clinical examination, evaluation of heart and lung sounds through use of a stethoscope, and specialized tests that enable physicians to evaluate the structure and function of the heart (e.g., x-ray studies, electrocardiography [EKG]), echocardiography).
The treatment of Chromosome 4, Monosomy Distal 4q is directed toward the specific symptoms and findings that are apparent in each individual. Such disease management may require the coordinated efforts of a team of medical professionals, such as pediatricians; surgeons; heart specialists (cardiologists); physicians who diagnose and treat disorders of the skeleton, muscles, joints, and related tissues (orthopedists); neurologists; and/or other health care professionals.
For newborns with feeding and respiratory difficulties, such as due to microretrognathia and cleft palate, possibly in association with downward displacement of the tongue (e.g., those with Pierre-Robin syndrome), recommended disease management may include keeping infants on their stomaches (prone positioning) and monitoring of breathing. In some cases, treatment may also require placement of a breathing tube via the nose or, if necessary, the performance of certain surgical procedures. These may include a procedure in which the tongue is temporarily joined to the lower lip (tongue-lip adhesion) to keep the tongue from blocking the airway or creation of an opening through the neck into the windpipe into which a tube is inserted (tracheostomy). Additional supportive measures may also be required to help improve feeding and ensure sufficient intake of nutrients, such as the use of modified artificial nipples or, in some cases, tube feeding (gavage feeding). In addition, surgical measures to correct cleft palate will be advised at the appropriate age during infancy or childhood in order to repair the abnormality and to help improve speech development. Physicians may also recommend surgical correction of additional, associated craniofacial malformations in some cases.
For infants and children with congenital heart defects, treatment with certain medications, surgical intervention, and/or other measures may also be required. In addition, in some cases, physicians may advise surgical repair or correction of additional skeletal, genital, and/or other malformations associated with Chromosome 4, Monosomy Distal 4q. The specific surgical procedures performed will depend upon the severity and location of the anatomical abnormalities, their associated symptoms, and other factors.
In individuals with seizures, anticonvulsant medications may be administered to help prevent, reduce, or control seizure episodes.
Early intervention may also be important in ensuring that affected children reach their potential. Special services that may be beneficial include special education, speech therapy, physical therapy, and/or other medical, social, and/or vocational services. Genetic counseling will also be of benefit for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
(Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder [e.g., craniofacial abnormalities, congenital heart defects, mental retardation, etc.].)
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