Amelia
Definition
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.
Description
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, 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 tetraamelia 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 a defective 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 cause birth defects),
or accompany other disease processes such as diabetes. An example of vascular
disturbance would be hemorrhage in the embryo causing lack of blood and oxygen
flow to surrounding tissue. The type and number of resulting defects would
depend on the location of the hemorrhage and the point of embryo development
when the bleed took place. Defects in limbs and the body wall tend to result
from this type of disturbance.
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.
Genetic
profile
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
about 80% of patients with Roberts SC phocomelia.
Demographics
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
homozygous (meaning two copies of the abnormal gene need to be inherited for
amelia to result), and thus expressed in malformation more often in any culture
that tends to be isolated and has more intermarriage from a limited gene
pool .
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 ultrasound, 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
positon), 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.
Diagnosis
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
Prognosis
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. Infants with severe growth deficiency
and craniofacial defects from Roberts SC phocomelia and amelia do not live past
the first few months.
