Amelia is an extremely rare birth defect marked by the absence of one or more limbs. The term may be modified to indicate the number of legs or arms missing at birth, such as tetra-amelia for the absence of all four limbs. A related term is meromelia, which is the partial absence of a limb or limbs. Several older terms are no longer in use in international nomenclature because of their imprecision: phocomelia, peromelia, dysmelia, ectromelia, and hemimelia.
The complete absence of an arm or leg in amelia occurs when the limb formation process is either prevented or interrupted very early in the developing embryo: between 24 and 36 days following fertilization. Nearly 25% of all congenital limb defects are amelia. A single limb is involved about 60% of the time and symmetrical amelia is uncommon. The likelihood for upper versus lower limb absence varies with the syndrome.
Amelia may be present as an isolated defect, but more than 50% of the time it is associated with major malformations in other organ systems. The malformations most frequently seen with amelia include cleft lip and/or palate, body wall defects, malformed head, and defects of the neural tube, kidneys and diaphragm. Facial clefts may be accompanied by other facial anomalies such as abnormally small jaw, and missing ears or nose. The body wall defects allow internal organs to protrude through the abdomen. Head malformations may be minor to severe with a near absence of the brain. The diaphragm may be herniated or absent and one or both kidneys may be small or absent.
Other abnormalities associated with amelia include severe defects of the lungs, vertebrae, heart, internal and external genital system, and anus. There is usually a severe growth deficiency, both before and after birth, and mental retardation may be present in survivors. Benign facial tumors made up of clusters of blood vessels (hemangiomas) may be present.
Amelia was traditionally thought to be a sporadic anomaly with little risk of recurrence, or evidence of genetic origins. However, an estimated 20% of amelia cases can now be traced to probable genetic causes. These genetic conditions may be due to recessive or dominant mutations, or involve chromosomal aberrations where entire sections of chromosomes are deleted, duplicated or exchanged. The best defined of these genetic diseases is known as Roberts SC phocomelia or, pseudothalidomide syndrome, caused by an autosomal recessive mutation of unknown location. There is a great variability of expression of the disease, even within families. Classic signs of Roberts SC phocomelia include symmetrical defects of all four limbs including amelia, severe growth deficiency, head and face (craniofacial) abnormalities such as small head and cleft lip or palate, also sparse, silvery blond hair, and facial hemangiomas.
A very small group of genetically based amelia cases is referred to as "autosomal recessive tetra amelia" which consists of an absence of all four limbs, with small or absent lungs, cleft lip or palate, malformed head and other anomalies. A similar " X-linked tetra-amelia" is highly lethal to the fetus and involves the same set of abnormalities. The abnormal gene for X-linked tetra-amelia is assumed to be located on the X chromosome. Very few cases have been documented for either of these inherited conditions but the defective gene seems to be more prevalent in Arab populations of the Middle East or in small isolated cultures where consanguineous relationships (intermarriage within extended families) is more common. There is disagreement as to whether these conditions represent new syndromes or are severe cases of Roberts SC phocomelia.
Amelia is associated with various other genetic syndromes. It is seen in the autosomal recessive Baller-Gerold syndrome and Holt-Oram syndrome, an autosomal dominant condition that sometimes involves amelia. It has been proposed that many of the new, isolated cases of amelia are due to autosomal dominant mutations where only one copy of an abnormal gene on a non-sex chromosome is powerful enough to cause amelia to be displayed. Absent limbs have also been seen in chromosomal aberrations such as Trisomy 8 (three copies of chromosome 8) and a deletion of region 7q22 found on the long arm of chromosome 7.
Sporadic amelia may be the end result of various types of disturbances of limb development in the embryo. These disturbances can be vascular, mechanical, due to teratogens (substances that can cause birth
Mechanical disruption can be seen following rupture of the amnion (the thin but tough membrane surrounding the embryo) due to infection, direct trauma such as attempted abortion or removal of IUD, or familial predisposition to rupture. Strands of the collapsed amnion and adhesions (fibrous bands which abnormally connect tissue surfaces) may entangle and amputate developing limbs and cause a variety of other defects including facial clefts.
Various teratogens are well-established causes of amelia. A well-documented historic instance was due to thalidomide use by pregnant women from 1958 to 1963. Thalidomide was used as a sedative and anti-nausea drug but was found to cause a wide array of limb deficiencies, including amelia. It is estimated to have caused 5,800 cases of malformed fetuses, mostly in Europe, but also in North America and wherever it was available worldwide. The mechanism by which thalidomide causes birth defects is still not known but may involve disruption of nerve processes. Although thalidomide is again in use today to treat certain cancers, infections and arthritis, it should not be used by women of childbearing age.
Alcohol (ethanol) consumption by pregnant women, especially in the first trimester, has been documented by several surveys to cause limb deformities. The abnormalities range from frequent, minor defects such as shortened fingers to the much rarer amelia. It is hypothesized that alcohol interrupts the blood supply to the developing limb resulting in malformation or non-growth. Additional teratogens known to cause amelia include methotrexate, other chemotherapeutic agents and potent vasoconstrictive drugs such as epinephrine and ergotamine.
Maternal diabetes mellitus (non-gestational) has long been associated with congenital anomalies, rarely including amelia. There is a two to threefold risk for congenital abnormalities in children of diabetic mothers and limb defects of various types occur in about one percent of infants of these mothers. It is thought that either abnormal maternal carbohydrate metabolism, or vascular disease resulting in decreased oxygen flow to the fetus, might play a role in causing malformations.
Amelia is generally considered to be sporadic with scattered cases occurring infrequently. These rare events are presumably influenced by environmental factors, such as teratogenic drugs, maternal factors such as diabetes mellitus, and vascular accidents in the uterus. The role of genetics in causing this condition is still undetermined but two large epidemiological studies estimate that nearly 20% of amelia cases are of genetic origin. Mutations in more than one gene with different modes of transmission can lead to this severe limb deficiency.
Recurrence of amelia within families is the exception. When this occurs, it is most often associated with other malformations in autosomally recessive syndromes such as Roberts SC phocomelia, autosomal recessive amelia and X-linked amelia. Roberts SC phocomelia has a clearly identifiable genetic abnormality that can be seen during chromosome analysis. The abnormality is called either Premature Centromeric Separation (PCS) or Heterochromatin Repulsion (HR). The darkly staining heterochromatin of the chromosome can be seen puffing and splitting. The PCS test is positive in almost 80% of patients with Roberts SC phocomelia.
The rarity of amelia makes the study of it on a population level speculative. A few large-scale studies pooling decades of information from malformation registries in several countries do provide preliminary data. Amelia has an incidence of 11-15 cases per million live births and 790 cases per million stillbirths. The condition is probably under reported due to lack of documentation of some miscarriages, stillbirths, and neonatal deaths.
There is no significant difference between number of males and females affected except in the select, extremely rare cases of X-linked amelia, which are all male. Only men would be affected since the abnormal gene is inherited on the X chromosome and men only receive one copy of an X chromosome. Since females inherit two copies of the X chromosome, the normal copy of the gene on the second X chromosome can usually mask the more severe complications that would result if only the abnormal gene was expressed.
The disorder occurs worldwide and there are no geographic clusters except for two. Amelia resulting from the use of thalidomide occurred primarily in Europe and other areas where the drug was available. Autosomal recessive and X-linked amelia has mostly occurred in Arabic and Turkish families. This suggests ethnic differences for an abnormal recessive gene but is based on less than 20 cases. Such a recessive gene is likely to be
Signs and symptoms
Prior to clinical observation of absent limbs, certain signs in the pregnant mother may indicate a greater likelihood of amelia. Abnormal vaginal bleeding, diabetes mellitus, and toxemia (disturbed metabolism during pregnancy characterized by high blood pressure, swelling and protein in the urine) are all associated with amelia in the fetus. Alpha fetoprotein is a protein normally produced by the liver of the fetus which then circulates in the mother's blood. An increased alpha fetoprotein in the maternal blood may indicate neural tube defects that can accompany limb defects. Besides seeing missing limbs by ultra-sound, signs in the fetus accompanying amelia include breech and other non-cephalic presentations at birth (where the baby is not in the normal head-first, face-down delivery position), an increased frequency of only a single artery in the umbilical cord, low placental weight and extremely low birth weight, not accounted for by the lack of limbs. The average birth weight for an infant with amelia is less than the third percentile for its age.
Detection of an absent limb is generally simple. Clinical observation of the missing limb is either made at birth or prenatally by ultrasonography. However, more than 50% of amelia cases are accompanied by malformations of other organ systems, and in these cases, determination of a specific syndrome can be difficult. Defects overlap greatly between conditions. A family history including a pedigree chart to map other affected family members can be very helpful in detecting genetic causes. A prenatal history should include determination of maternal exposure to alcohol, thalidomide and other teratogenic drugs. Maternal diabetes mellitus should be considered a risk factor for congenital abnormalities.
Roberts SC phocomelia must be differentiated from other autosomal recessive or X-linked amelias. Genetic testing for PCS should be performed on cells from amniotic fluid. Darkly staining heterochromatin of the chromosome puffs out abnormally and splits in a positive test. The PCS test will be positive in nearly 80% of Roberts SC phocomelia cases but negative in the other syndromes. A positive PCS test along with some of the signs listed above, is diagnostic for Roberts SC phocomelia. Further chromosome studies should be done to detect gross chromosomal aberrations such as deletions or Trisomy 8.
Treatment and management
Preventive measures to avoid serious limb defects such as amelia include avoidance of thalidomide and other teratogens in women of childbearing years, avoidance of alcohol during pregnancy and comprehensive management of diabetes mellitus throughout pregnancy. A prenatal ultrasound that detects an absence of limbs can be followed by chromosome analysis and genetic counseling to make informed decisions regarding termination.
Children with amelia can be fitted with a prosthesis to substitute for the missing limb. Surgery is often performed to repair craniofacial defects. Minimal to full time care may be needed depending on the degree of mental retardation.
When amelia occurs as an isolated abnormality, prognosis is good. However, when amelia is combined with multiple other defects, the prognosis is grim. Abnormalities accompanying amelia may include cleft lip and/or palate, body wall defects, malformed head, and abnormalities of the neural tube, kidneys and diaphragm. Many infants die prior to birth. Sixty percent of newborns die within the first year, with half not surviving the first day. Mild cases of Roberts SC phocomelia are likely to survive past the first few years and reach adulthood. Patients with more severe forms of amelia, such as severe growth deficiency and craniofacial defects, do not live past the first few months.
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National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.
Marianne F. O'Connor, MT (ASCP), MPH