buds are first seen by ultrasound at about the 8th week of gestation; the
femur and humerus are seen from 9 weeks, the tibia/fibula and radius/ulna
from 10 weeks and the digits of the hands and the feet from 11 weeks. All
long bones are consistently seen from 11 weeks. Body movements (wiggling)
are seen at 9 weeks and, by 11 weeks, limbs move about readily. The lengths
of the humerus, radius/ulna, femur and tibia/fibula are similar and increase
linearly with gestation. At the 18–23-week scan, the three segments of each
extremity should be visualized, but it is only necessary to measure the length
of one femur.
of leg and foot should also be assessed to rule out clubfoot.
- 2D Ultrasound
- 3D Ultrasound (rendering mode)
a 190K clip of club foot
dysplasia is found in about 1 per 4000 births; about 25% of affected fetuses
are stillborn and about 30% die in the neonatal period. The birth prevalences
of the most common dysplasias are shown in the Table on the next page.
existing nomenclature for skeletal dysplasias is complicated. Some disorders
are referred to by eponyms (such as Ellis–Van Creveld syndrome), by Greek
terms describing a salient feature of the disease (diastrophic or twisted,
metatrophic or changeable) or by a term related to the presumed pathogenesis
of the disease (such as osteogenesis imperfecta). The fundamental problem
with any classification of skeletal dysplasias is that the pathogenesis of
these diseases is largely unknown and, therefore, the current system relies
on purely descriptive findings of either clinical or radiological nature.
According to the International Nomenclature for Skeletal Dysplasias, the diseases
are subdivided into three different groups:
Osteochondrodysplasias (abnormalities of cartilage and / or bone growth and
Disorganized development of cartilaginous and fibrous components of the skeleton;
to prenatal diagnosis
is a wide range of rare skeletal dyplasias, each with a specific recurrence
risk, dysmorphic expression, and implications for neonatal survival and quality
of life. Our knowledge of the in utero expression of these syndromes
is based on a few case reports and, therefore, in attempting to perform prenatal
diagnosis of individual conditions in at-risk families, extrapolation of findings
from the perinatal period is often necessary. The incidental discovery of
a skeletal dysplasia on routine ultrasound screening, in a pregnancy not known
to be at risk of a specific syndrome, necessitates a systematic examination
to arrive at the correct diagnosis. All limbs must be evaluated (see Figure
17, p. 97) as to their length, shape, mineralization and movement, and associated
abnormalities in other systems, particularly the head, thorax and spine, should
of long bones
of the extremities can involve the entire limb (micromelia, such as achondrogenesis,
short-rib polydactyly syndrome, diastrophic dysplasia osteogenesis imperfecta
type II), the proximal segment (rhizomelia, such as achondroplasia), the intermediate
segment (mesomelia, such as mesomelic dysplasia) or the distal segment (acromelia,
such as Ellis–Van Creveld syndrome). The diagnosis of rhizomelia or mesomelia
requires comparison of the dimensions of the bones of the leg and forearm
with those of the thigh and arm. The femur, however, is abnormally short even
in mesomelic dwarfism and, therefore, in our routine fetal abnormality screening,
we tend to confine limb measurements to that of the femur. When dealing with
pregnancies at risk for a skeletal dysplasia, both segments of all limbs are
severe limb reductions associated with osteogenesis imperfecta type II, achondrogenesis
and thanatophoric, diastrophic, and chondroectodermal dysplasias can be detected
by a single measurement of the femur length at 16–18 weeks of gestation. In
the case of achondroplasia, however, the diagnosis may not become obvious
until 22–24 weeks and, therefore, serial measurements are necessary; homozygous
achondroplasia, which is usually lethal, manifests in abnormally short limbs
earlier than the heterozygous form.
minor degree of lateral curvature of the femur is commonly seen in normal
fetuses. Pronounced bowing, however, is observed in association with campomelic
dysplasia, thanatophoric dwarfism, autosomal dominant osteogenesis imperfecta,
achondrogenesis and hypophosphatasia. In the latter, fractures and callus
formation may also be detected. Reduced echogenicity of bones, suggestive
of hypomineralization, is seen in such disorders as hypophosphatasia, osteogenesis
imperfecta and achondrogenesis. The virtual absence of ossification of the
spine, characteristic of achondrogenesis, may lead to the erroneous diagnosis
of complete spinal agenesis. Similarly, the pronounced clarity with which
the cerebral ventricles are imaged, as a result of the poorly mineralized
globular cranium in cases of hypophosphatasia, may result in the misdiagnosis
of hydrocephalus. Care must be exercised, however, because lesser degrees
of hypomineralization may not be detectable.
limb reduction deformities, such as amelia (complete absence of extremities),
acheiria (absence of the hand), phocomelia (seal limb) or aplasia–hypoplasia
of the radius or ulna, are often inherited as part of a genetic syndrome (Holt–Oram
syndrome, Fanconi pancytopenia, thrombocytopenia with absent radii syndrome)
and are readily diagnosible by ultrasonography in an at-risk fetus. Other
causes of focal limb loss include the amniotic band syndrome, thalidomide
exposure and caudal regression syndrome.
of hands and feet
fingers and toes can be seen, and, with meticulous examination, abnormalities
of numbers, shape, movement and attitudes can be recognized. Several skeletal
dysplasias feature alterations of the hands and feet. Polydactyly refers to
the presence of more than five digits. It is classified as postaxial if the
extra digits are on the ulnar or fibular side and preaxial if they are located
on the radial or tibial side. Syndactyly refers to soft tissue or bony fusion
of adjacent digits. Clinodactyly consists of deviation of a finger(s). Disproportion
between hands and feet and the other parts of the extremity may also be a
sign of a skeletal dysplasia.
of fetal movements
perception of fetal movements is usually decreased in fetuses with skeletal
dysplasias, such as achondrogenesis and thanatophoric dysplasia. Ultrasonography
can aid in the diagnosis of conditions characterized by limitation of flexion
or extension of the limbs, such as arthrogryposis and multiple pterygium syndrome.
of thoracic dimensions
skeletal dysplasias are associated with a small thorax, and chest restriction
leads to pulmonary hypoplasia, which is the common cause of death in these
conditions. The appropriateness of thoracic dimensions can be assessed by
measuring the thoracic circumference at the level of the four-chamber view
of the heart and examining the thoracic-to-abdominal circumference ratio,
the thoracic-to-head circumference ratio, or the thoracic-to-cardiac circumference
dysplasias associated with a long narrow thorax include asphyxiating thoracic
dysplasia (Jeune), chondroectodermal dysplasia (Ellis–Van Creveld), campomelic
dysplasia, Jarcho–Levin syndrome, achondrogenesis and hypophosphatasia. Dysplasias
with a short thorax include osteogenesis imperfecta (type II), Kniest’s dysplasia
(metatrophic dysplasia type II) and Pena–Shokeir syndrome. Hypoplastic thorax
is found in short-rib polydactyly syndrome (type I, type II), thanatophoric
dysplasia, cerebrocostomandibular syndrome, cleidocranial dysostosis syndrome,
homozygous achondroplasia, Melnick–Needles syndrome (osteodysplasty), fibrochondrogenesis
and otopalatodigital syndrome type II.
of the fetal head
skeletal dysplasias are associated with defects of membranous ossification
and, therefore, affect skull bones. The face should also be examined for the
diagnosis of hypertelorism, micrognathia, short upper lip, and abnormalities
of the ears.
tests complementary to sonography
or postnatal evaluation includes chromosomal studies, biochemical investigations
(e.g. hypophosphatasia) and DNA analysis for an increasing number of the osteochondrodysplasias.
Postnatally, examination of skeletal radiographs is of particular importance,
since the classification of skeletal dysplasias is largely based upon radiographic
is the most common lethal skeletal dysplasia with a birth prevalence of about
1 in 10 000. The term derives from the Greek, meaning death-bearing and the
characteristic features are severe shortening of the limbs, narrow thorax,
normal trunk length and large head with prominent forehead. In type I, which
is sporadic, the femurs are curved (telephone receiver) and in type II, which
is autosomal recessive, the femurs are straight but the skull is cloverleaf-shaped.
is a lethal skeletal dysplasia with a birth prevalence of about 1 in 40 000.
The characteristic features are severe shortening of the limbs, narrow thorax,
short trunk and large head. In achondrogenesis type I, which is autosomal
recessive, there is poor mineralization of both the skull and vertebral bodies
as well as rib fractures. In type II, which is sporadic (new autosomal dominant
mutations), there is hypomineralization of the vertebral bodies but normal
mineralization of the skull, and there are no rib fractures.
a 200K clip of achondrogenesis
imperfecta is a genetically heterogeneous group of disorders presenting with
fragility of bones, blue sclerae, loose joints and growth deficiency. The
underlying defect is a dominant negative mutation affecting COL1A1 or COL1A2
alleles, which encode the proA1(I) and proa2(I) chains of type I collagen,
a protein of paramount importance for normal skin and bone development. The
mutations result in the production of abnormal quantity (OI type I) or quality
(types II, III and IV) of collagen.
are four clinical subtypes. In type I, which is an autosomal dominant condition
with a birth prevalence of about 1 in 30 000, affected individuals have fragile
bones, blue sclerae and progressive deafness, but life expectancy is normal.
Prenatal diagnosis is available by DNA analysis. Ultrasonography in
the second and third trimesters may demonstrate fractures of long bones.
type II, which is a lethal disorder with a birth prevalence of about 1 in
60 000, most cases represent new dominant mutations (recurrence is about 6%).
The disorder is characterized by early prenatal onset of severe bone shortening
and bowing due to multiple fractures affecting all long bones and ribs, and
poor mineralization of the skull.
III is a progressively deforming condition characterized by multiple fractures,
usually present at birth, resulting in scoliosis and very short stature. Bowing
of the femur has been described in these cases in utero. Both autosomal dominant
and recessive modes of inheritance have been reported.
IV is an autosomal dominant condition with variable expressivity. Severely
affected individuals may have deformities of the long bones due to fractures.
Prenatal diagnosis of types III and IV can be made by chorion villous sampling
and DNA analysis, or by demonstration of abnormal collagen production in cultured
lethal, autosomal recessive condition, with a birth prevalence of about 1
in 100 000, is characterized by severe shortening of the long bones, small
thorax, hypomineralization of the skull and long bones. There is absence of
liver and bone isoenzymes of alkaline phosphatase, and first-trimester diagnosis
is made by measurement of alkaline phosphatase isoenzymes in chorion villous
samples. The diagnosis can also be made by DNA studies.
autosomal dominant syndrome has a birth prevalence of about 1 in 26 000, but
the majority of cases represent new mutations. The characteristic features
of heterozygous achondroplasia include short limbs, lumbar lordosis, short
hands and fingers, macrocephaly with frontal bossing and depressed nasal bridge.
a 200K clip of achondroplasia
and life expectancy are normal. Prenatally, limb shortening and typical
usually become apparent only after 22 weeks of gestation. In the homozygous
state, which is a lethal condition, short limbs are associated with a narrow
thorax. Achondroplasia is due to a specific mutation within the fibroblast
growth factor receptor type 3 gene (FGFR3) and can now be diagnosed by DNA
analysis of fetal blood or amniotic fluid obtained in cases of suspicious
sonographic findings. In cases where both parents have achondroplasia, there
is a 25% chance that the fetus is affected by the lethal type and the diagnosis
can be made by first-trimester chorion villous sampling.
lethal, autosomal recessive syndrome with a birth prevalence of 1 in 200 000
is characterized by shortening and bowing of the long bones of the legs, narrow
chest, hypoplastic scapulae, and large calvarium with disproportionately small
face. Some of the affected genetically male individuals show a female phenotype.
Patients usually die in the neonatal period from pulmonary hypoplasia.
is a heterogeneous disorder, characterized by vertebral and rib abnormalities
(misalignment of the cervical spine and ribs). An autosomal recessive type
is characterized by a constricted short thorax and respiratory death in infancy.
Another autosomal recessive and an autosomal dominant type are associated
with a short stature and are compatible with survival to adult life but with
some degree of physical disability.
thoracic dysplasia (Jeune syndrome)
is an autosomal recessive condition with a birth prevalence of about 1 in
70 000. The characteristic features are narrow chest and rhizomelic limb shortening.
There is a variable phenotypic expression and, consequently, the prognosis
varies from neonatal death, due to pulmonary hypoplasia, to normal survival.
Limb shortening is mild to moderate and this may not become apparent until
after 24 weeks of gestation.
dysplasia (Ellis–Van Creveld syndrome)
rare, autosomal recessive condition is characterized by acromelic and mesomelic
shortness of limbs, postaxial polydactyly, small chest, ectodermal dysplasia,
and congenital heart defects in more than 50% of cases.
limb polydactyly syndromes
group of lethal disorders is characterized by short limbs, narrow thorax and
postaxial polydactyly. Associated anomalies are frequently found, including
congenital heart disease, polycystic kidneys, and intestinal atresia. Four
different types have been recognized. Type I (Saldino–Noonan) has narrow metaphyses;
type II (Majewski) has cleft lip and palate and disproportionally shortened
tibiae; type III (Naumoff) has wide metaphyses with spurs; type IV (Beemer–Langer)
is characterized by median cleft lip, small chest with extremely short ribs,
protuberant abdomen with umbilical hernia and ambiguous genitalia in some
autosomal recessive condition is characterized by severe shortening and bowing
of all long bones, talipes equinovarus, hand deformities with abducted position
of the thumbs (‘hitchhiker thumb’), multiple joint flexion contractures and
scoliosis. There is a wide spectrum in phenotypic expression and some cases
may not be diagnosable in utero. This disease is not lethal and neurodevelopment
DEFICIENCY OR CONGENITAL AMPUTATIONS
of an extremity or a segment of an extremity is referred to as ‘limb deficiency’
or ‘congenital amputation’. The prevalence of limb reduction deformities is
about 1 per 20 000 births. In about 50% of cases, there are simple transverse
reduction deficiencies of one forearm or hand without associated anomalies.
In the other 50% of cases, there are multiple reduction deficiencies and,
in 25% of these, there are additional anomalies of the internal organs or
craniofacial structures. In general, limb deficiency of the upper extremity
is an isolated anomaly, whereas congenital amputation of the leg or bilateral
amputations or reductions of all limbs are usually part of a genetic syndrome.
amputation of an extremity can be due to amniotic band syndrome, exposure
to a teratogen or a vascular accident. There is an association between chorion
villous sampling before 10 weeks of gestation and transverse limb defects.
Syndromes associated with limb deficiencies include the aglossia–adactylia
syndrome (transverse amputations of the limbs ranging from absent digits to
severe deficiencies of all four extremities, micrognathia, and vestigial tongue
or ankylosis of the tongue to the hard palate, the floor of the mouth or the
lips), and the Moebius sequence (facial anomalies attributed to paralysis
of the 6th and 7th cranial nerves, leading to micrognathia and ptosis with
upper limb defects, ranging from transverse amputations to absent digits).
Both syndromes are sporadic.
reduction defects associated with other anomalies include the CHILD syndrome
(congenital hemidysplasia with ichthyosiform erythroderma and limb defects).
This is characterized by strict demarcation of the skin lesions to one side
of the mid-line and limb deficiencies, which are unilateral, varying from
hypoplasia of phalanges to complete absence of an extremity. The condition
is also associated with heart defects and unilateral hydronephrosis or renal
phocomelia, the extremities resemble those of a seal. Typically, the hands
and feet are present (these may be normal or abnormal), but the intervening
arms and legs are absent. Phocomelia can also be caused by exposure to thalidomide,
but this is only of historical interest. Three syndromes must be considered
in the differential diagnosis of phocomelia: Roberts syndrome (autosomal recessive
disorder characterized by the association of tetraphocomelia and facial clefting
defects or hypoplastic nasal alae), some varieties of thrombocytopenia with
absent radius (TAR syndrome) and Grebe syndrome (autosomal recessive condition,
described in the inbred Indian tribes of Brazil, characterized by marked hypomelia
of upper and lower limbs, increasing in severity from proximal to distal segments
– in contrast to Roberts syndrome, the lower limbs are more affected than
the upper extremities).
short femur has been classified into five groups: type I, simple hypoplasia
of the femur; type II, short femur with angulated shaft; type III, short femur
with coxa vara (the most common); type IV, absent or defective proximal femur;
and type V, absent or rudimentary femur. One or both femurs can be affected
but the right femur is more frequently involved. Femoral hypoplasia–unusual
facies syndrome, which is sporadic, consists of bilateral femoral hypoplasia
and facial defects, including short nose with broad tip, long philtrum, micrognathia
and cleft palate.
the defect is unilateral, it may correspond to the femur–fibula–ulna or femur–tibia–radius
complex. These two syndromes have different implications for genetic counseling;
the former is non-familial, while the second has a strong genetic component.
HAND AND FOOT SYNDROME
term ‘split hand and foot’ syndrome refers to a group of disorders characterized
by splitting of the hand and foot into two parts; other terms include lobster-claw
deformity and ectrodactyly. The conditions are classified into typical and
atypical varieties. The typical variety (found in 1 per 90 000 births and
usually inherited with an autosomal dominant pattern) consists of absence
of both the finger and the metacarpal bone, resulting in a deep V-shaped central
defect that clearly divides the hand into an ulnar and a radial part. The
atypical variety (found in 1 per 150 000 births) is characterized by a much
wider cleft formed by a defect of the metacarpals and the middle fingers;
the cleft is U-shaped and wide, with only the thumb and small finger remaining.
hand and foot deformities can occur as isolated anomalies, but more commonly
they are part of a more complex syndrome. Ectrodactyly–ectodermal dysplasia–cleft
lip/palate syndrome (EEC syndrome), which is autosomal dominant, involves
the four extremities with more severe deformities of the hands; the spectrum
of ectodermal defects is wide, including dry skin, sparse hair, dental defects
and defects of the tear duct. Other syndromes include split foot and triphalangeal
thumb, split foot and hand and central polydactyly, Karsch–Neugebauer syndrome
(split hand/foot with congenital nystagmus), acrorenal syndrome and mandibulofacial
dysostosis (Fontaine syndrome).
deformities are classified into two main categories: radial and ulnar. Radial
clubhand includes a wide spectrum of disorders that encompass absent thumb,
thumb hypoplasia, thin first metacarpal and absent radius. Ulnar clubhand,
which is less common, ranges from mild deviations of the hand on the ulnar
side of the forearm to complete absence of the ulna. While radial clubhand
is frequently syndromatic, ulnar clubhand is usually an isolated anomaly.
deformities are often found in association with chromosomal abnormalities
(such as trisomy 18), hematological abnormalities (such as Fanconi’s pancytopenia,
TAR syndrome and Aase syndrome), or genetic syndromes with cardiac defects
(such as Holt–Oram syndrome, or the Lewis upper limb–cardiovascular syndrome).
Radial clubhand is also associated with congenital scoliosis. The three syndromes
that should be considered part of the differential diagnosis include the VATER
association (vertebral segmentation, ventricular septal defect, anal atresia,
tracheoesophageal fistula, radial and renal defects, and single umbilical
artery), Goldenhar syndrome and the Klippel–Feil syndrome.
is the presence of an additional digit, which may range from a fleshy nubbin
to a complete digit with controlled flexion and extension. Postaxial polydactyly
(the most common form) occurs on the ulnar side of the hand and fibular side
of the foot. Preaxial polydactyly is present on the radial side of the hand
and the tibial side of the foot. The majority of conditions are isolated with
an autosomal dominant mode of inheritance. Some of them are part of a syndrome,
usually an autosomal recessive one. Preaxial polydactyly, especially triphalangeal
thumb, is most likely to be part of a multisystem syndrome. Central polydactyly,
which consists of an extra digit (usually hidden between the long and the
ring finger), is often bilateral and is associated with other hand and foot
malformations; it is inherited with an autosomal mode of inheritance.
AKINESIA DEFORMATION SEQUENCE (FADS)
is a heterogeneous group of conditions with a birth prevalence of about 1
in 3000. Neurological, muscular, connective tissue, and skeletal abnormalities
result in multiple joint contractures, including bilateral talipes and fixed
flexion or extension deformities of the hips, knees, elbows and wrists.
a 500K clip of akinesia
sequence includes congenital lethal arthrogryposis, multiple pterygium and
Pena–Shokeir syndromes. The deformities are usually symmetric and, in most
cases, all four limbs are involved. The severity of the deformities increases
distally in the involved limb, with the hands and feet typically being the
most severely affected. The condition is commonly associated with polyhydramnios
(usually after 25 weeks), narrow chest, micrognathia and nuchal edema (or
increased nuchal translucency at 10–14 weeks).
2000, Pilu, Nicolaides, Ximenes & Jeanty