Daily Archives: 22/12/2021

Thanatophoric Dysplasia (TD)

TD is the most common lethal skeletal dysplasia in fetuses and neonates. It is caused by generalized disruption of the growth plate resulting from new autosomal dominant mutations in FGFR3. It is characterized by extreme rhizomelia, a normal trunk length with a narrow thorax, and a large head with a prominent forehead. Two subtypes have been identified:

–     Type 1: severe rhizomelia, typical bowed “telephone receiver” femurs, narrow thorax, a relatively large head and absent cloverleaf skull.

–     Type 2: severe cloverleaf skull and short and straight long bones.

Prenatal diagnosis with DNA analysis is currently possible.

Incidence: 1 in 4000-15,000 births, relatively increased with paternal age.

Sonographic findings:

Fig 1, Fig 2, Fig 3, Fig 4, Fig 5, Fig 6

• Normal bone echodensity.
• Severe micromelia with typical telephone receiver femurs (type I).
• Long bones may grow slowly and steadily at first and stop in late pregnancy.
• Short and straight long bones (type II).
• Short and broad tubular bones in hands and feet.
• Relatively large calvarium with a prominent forehead.
• Cloverleaf skull in about 14% of cases (all cases of type II).
• Platyspondylosis may be documented in some cases.
• Polyhydramnios is nearly always present, especially in the third trimester.
• Ventriculomegaly in some cases.
• Increased NT in the late first trimester in some cases.
• The main differential diagnoses include all short-limbed dwarfism with normal echodensity such as short rib polydactyly syndrome, homozygous achondroplasia, and asphyxiating thoracic dysplasia (slight shortening of long bones and normal vertebrae).
• 3D ultrasound is helpful in providing more details such as the relative proportion of the appendicular skeletal elements and the hands and feet.
• Pitfalls: A normal sonographic appearance in the late first trimester can not exclude the possibility of TD.
• Usually diagnosed after the first trimester.

Fig 1:  Micromelia in Thanatophoric dysplasia  Severe shortenings of humerus (arrow) but normal ossification

Fig 2:  Thanatophoric dysplasia   Cross-sectional scan of the skull: Cloverleaf skull; prominent parietal bone

Fig 3:  Large head   Cross-sectional scan of the abdomen and skull: disproportion in size of the trunk and head of the fetus with Thanatophoric dysplasia

Fig 4:  Micromelia in Thanatophoric dysplasia   Severe shortenings of humerus (arrow) but normal ossification

Fig 5:  Platyspondylosis   Oblique sagittal scan of the spine: relatively flattened vertebra (arrow) in case of Thanatophoric dysplasia

Fig 6:  Small thorax in Thanatophoric dysplasia   Coronal scan of fetal trunk: disproportionately small thorax, compared to the abdomen

Associations: Hydrocephalus in some cases.

Management: Termination of pregnancy can be offered.

Prognosis: Lethal; in the report of one survivor, mental and bone maturation were severely retarded.

Recurrence risk: The majority of cases are caused by new mutations, therefore, the recurrence risk is rare.

Achondrogenesis

Achondrogenesis is a lethal chondrodystrophy characterized by severe micromelia, short trunk, absent vertebral bodies ossification, and macrocrania. It has been classified into two types:

–     Type I: autosomal recessive type, the more severe form, accounting for 20% of cases, characterized by severe hypoossification and severe micromelia, and thin ribs with fractures (type IA) or not (type IB). Type 1B is associated with mutation in the gene for the DTDST gene on chromosome 5, the same gene identified in the cause of diastrophic dysplasia.

–     Type II (Langer-Saldino, autosomal dominant), accounting for 80% of cases, has relatively normal ossification, less severe micromelia, and thicker ribs without fractures. Type II is caused by a new mutation in the COL2A1 gene on chromosome 12, or inherited via germline mosaicism of the healthy parents.

Incidence: About 1 per 4000 births.

Sonographic findings:

Fig 1, Fig 2, Fig 3, Fig 4, Fig 5

• Decreased mineralization of all or many vertebral bodies, sacrum and ischium. The absence of vertebral body ossification may be the unique finding of type II.
• Severe micromelia with bowing, however, it can be found with normally developed extremities in rare cases.
• Enlarged calvarium with poor ossification in type I but relatively normal ossification in type II.
• Thin ribs (type I) with or without fractures.
• Polyhydramnios is common.
• Redundancy and edema of the subcutaneous tissues (pseudohydrops) or nuchal edema even in the first trimester.
• 3D ultrasound is helpful in providing more details such as facial dysmorphism, the relative proportion of the appendicular skeletal elements and the hands and feet.
• The main differential diagnosis includes thanatophoric dysplasia, achondroplasia, and short-rib polydactyly syndrome, all of which may have underdeveloped vertebral bodies, but none of these also have calvarial underossification. Severe hypophosphatasia may result in severe calvarial and spinal underossification, but hypophosphatasia usually has diffuse underossification of the spinal ossification centers or focal loss of the neural arch ossification centers as opposed to focal lack of vertebral body ossification that is seen in achondrogenesis.
• Pitfalls: Normally developed extremities can be seen in type II. Therefore, complete examination of the vertebral body is very important.
• First diagnosable in the late first trimester, but mostly in the second trimester.

Fig 1:  Spinal poor ossification   Mid-sagittal scan of the cervical spine: very sonolucent spine (arrow) in association with achondrogenesis

Fig 2:  Long bone shortening   Longitudinal scan of the thigh and leg: shortening of thigh and leg, compared with foot (achondrogenesis)

Fig 3:  Sonolucent and shortened arm   Longitudinal scan of the arm: Sonolucent and shortened humerus (*) in case of achondrogenesis

Fig 4:  Poor ossification of hand   Sonolucency of the hand bones as well as short fingers

Fig 5:  Poor ossification   Sonolucency of the hand bones as well as short fingers (left) and short humerus (right)

Associations: Rare, cephalocele, cystic hygroma, and polydactyly in some cases.

Management: Termination of pregnancy can be offered.

Prognosis: Lethal.

Recurrence risk: Type IB is autosomal dominant, and carries a theoretical recurrence risk of 25%. The recurrence risk of type II, new mutations, is rare.

Congenital Hypophosphatasia

Congenital hypophosphatasia is a rare autosomal recessive inherited disorder characterized by demineralization of bones with low alkaline phosphatase in serum and other tissues. It is related to the numerous tissue non-specific alkaline phosphatase genes on chromosome 1. Prenatal diagnosis may be made using ultrasound and by assaying alkaline phosphatase in tissue obtained from chorionic villous samplings or in blood from cordocentesis, and can also be made by DNA analysis.

Incidence: 1 per 100,000 births.

Sonographic findings:

Fig 1, Fig 2, Fig 3, Fig 4, Fig 5, Fig 6

• Variable hypomineralization, boneless appearance in some cases.
• Compressible skull with complete absence of acoustic shadow, and probably so severe that the normally-difficult-to-visualize near-field brain is easily seen.
• Ossification centers in both the vertebral bodies and neural arches may be absent, or there may be preservation of some vertebral body ossification centers, unlike achondrogensis in which the vertebral body ossification centers are absent with preserved neural arch ossification centers.
• Severe micromelia.
• Thin or delicate or seemingly absent long bones.
• Spurs along the midshaft of long bones and at the knees and elbows.
• The main differential diagnosis is OI type II, in particular type IIC which involves similarly thin bones. All three forms of OI type II have multiple fractures and wavy or wrinkled bones that should help distinguish them from hypophosphatasia.
• Increased nuchal translucency thickness during late first trimester.
• Pitfalls: It is probably indistinguishable from OI type II and achondrogenesis. However, they have the same lethal prognosis.
• Extremely low levels of alkaline phosphatase in the cord blood can confirm the diagnosis.
• Usually diagnosed in the second half of pregnancy, but possible as early as the late first trimester.

Fig 1:  Hypophosphatasia    Longitudinal scan of the forearm and hand: poorly ossified radius and ulna as well as hand bones and clubhand

Fig 2:  Sonolucent spine   Sagittal scan of the fetus at 14 weeks: sonolucent vertebrae of the fetus with hypophosphatasia

Fig 3:  Hypophosphatasia  Oblique sagittal scan of the spine: poorly ossified spine (arrow), only 3 vertebral bodies are ossified

Fig 4:  Hypophosphatasia   Cross-sectional scan of the spine: poorly ossified posterior ossification centers but normally ossified anterior center (arrow)

Fig 5:  Hypophosphatasia   Cross-sectional scan of skull: thin and sonolucent calvarium (arrow = falx cerebri)

Fig 6:  Hypophosphatasia   Longitudinal scan of long bones: shortened and poorly ossified bones

Associations: Rare.

Management: Termination of pregnancy can be offered.

Prognosis: Lethal, though successful treatment with high-dose pyridoxal phosphate in some non-lethal cases has been reported.

Recurrence risk: 25%, an autosomal recessive disorder.

Osteogenesis Imperfecta (OI)

OI is genetically a heterogeneous disorder consisting of both autosomal dominant and autosomal recessive entities caused by mutations in one or two structural genes for type I procollagen. The clinical heterogeneity is due to the different mutations in the genes: COL1A1 and COL1A2. OI is divided into four types as follows:

• Type I (autosomal dominant) is characterized by bone fragility, blue sclera, hearing loss, and normal calvarium, with fractures ranging from none to multiple. DNA-based analysis is possible for early prenatal diagnosis.
• Type II (new dominant mutations and autosomal recessive in <5%) is a perinatal lethal variety characterized by almost no ossification of the skull, beaded ribs, shortened crumpled long bones and multiple fractures in utero.
• Type III (autosomal recessive, rare) is a non-lethal variety characterized by blue sclera (becoming white with time) and multiple fractures present at birth.
• Type IV (autosomal dominant) is the mildest form (mild to moderate osseous fragility). Long bones and sclera are normal.

Incidence: 0.4 per 10,000 births for OI, and 0.2 per 10,000 births for OI type II.

Sonographic findings (OI type II) :

Fig 1, Fig 2, Fig 3, Fig 4, Fig 5, Fig 6

• Variable hypomineralization, which may result in complete absence of acoustic shadow and may be so severe that the normally-difficult-to-visualize near-field brain is easily seen.
• Micromelia (type IIB and IIC may be less severe).
• Fractures of long bones.
• Thickened long bones due to frequent fractures and secondary callus formation.
• Small bell-shaped thorax with multiple rib fractures or beaded ribs.
• Increased nuchal translucency thickness in the first trimester in some cases.
• MRI complemented sonography may be helpful in further differentiating clinical and sonographic findings.
• Sonographic features are variable among the three subtype as follows:
  • Type IIA: thick bones, multiple fractures, hypomineralization, beaded ribs
  • Type IIB: thick bones, multiple fractures, less beading of ribs; lower extremities are affected more than upper extremities
  • Type IIC: thin bones, multiple fractures, thin beaded ribs.
• Pitfalls: Variable short limb lengths without fractures may be the only clue in the mild form.
• Usually diagnosed in the second and third trimesters but possible in the late first trimester.

Fig 1:  Sonolucent and compressible skull   Poorly ossified and compressible cranium (arrow), cerebral sulci and gyri could easily be seen

Fig 2:  Rib fractures   Multiple rib fractures with poor ossification in the fetus with osteogenesis imperfecta type IIA

Fig 3:  Micromelia   Irregularity and severe shortening of long bone (arrowhead)

Fig 4:  Fracture in utero   Longitudinal scan of upper extremity: poorly ossified and fracture in osteogenesis imperfecta type IIA

Fig 5:  Osteogenesis imperfecta type IIA   Longitudinal scan of lower extremity: shortened and irregular ossified long bones

Fig 6:  Fracture of long bones   Longitudinal scan of rib and humerus: fracture rib (arrow) and humerus (arrowhead) with moderate ossification

Associations: Rare, though concurrent anencephaly has been reported.

Management: Termination of pregnancy can be offered. For term pregnancy, cesarean delivery does not decrease fracture rates at birth in infants with non-lethal forms of OI.

Prognosis: OI type II is lethal.

Recurrence risk: Unlikely because OI type II is due to new mutations in most cases and there are only a few reports of autosomal recessive inheritance.

Spinal Dysraphism

Spinal dysraphism, splaying of the posterior ossification centers of the spine, usually indicates spina bifida resulting from failure of closure of the posterior neuropore. However, spinal dysraphism can be due to other abnormalities as follows:

Fig 1, Fig 2, Fig 3

Major differential diagnoses

• Spina bifida
  • meningocele
  • meningomyelocele
  • myeolochisis
• Arnold-Chiari malformation type II
• Pseudodysraphism: technical pitfalls (described previously)

Minor differential diagnoses

• Diastematomyelia: a splitting of the spinal cord
• Lipomyelomeningocele: asymmetric lesion of lipoma originating in the spinal cord or cauda equina
• etc.

Fig 1:  Spina bifida   Cross-sectional scan of the lumbar and thoracic spine: separation of posterior ossification centers at the lumbar region with small protrusion of the overlying tissue

Fig 2:  Spina bifida   Coronal scan of the lumbosacral spine: separation of the ossification centers of the spine (arrow)

Fig 3:  Spina bifida  Cross-sectional scan of the lumbar and thoracic spine: separation of posterior ossification centers at the lumbar region with small protrusion of the overlying tissue (arrow)

Masses on the Back

Lumbosacral masses can be caused by a number of specific anomalies, especially meningomyelocele, which is the most common cause. The differential diagnosis for lumbosacral mass can be summarized as follows:

Fig 1, Fig 2, Fig 3

Major differential diagnoses

Meningomyelocele (most common)

• spinal dysraphism
• solid-cystic mass located at the lumbosacral spine in most cases
• associated cranial signs of spina bifida, such as lemon sign, banana sign, and ventriculomegaly

Sacrococcygeal teratoma (SCT) (uncommon)

• solid-cystic, solid predominantly in most cases but entirely cystic in 15% of cases
• high vascularization
• intra-abdominal components in most cases with a displacement effect on internal structures
•  usually located in the sacrococcygeal area

Limb-body wall complex (uncommon)

• solid-cystic asymmetric mass
• abnormal spinal curvature
• no specific location
• severe abdominal wall defects
•  limb defects
• no or very short umbilical cord

Amniotic band syndrome (uncommon)

• solid-cystic asymmetric mass
• no specific location
• associated limb reduction/constriction defects
• amniotic band in the amniotic cavity.

Minor differential diagnoses

• Artifacts: extrafetal mass, such as chorioangioma attached to the fetal back
• Rare tumors: lipomas, lipomyelomeningocele, and large hemangioma.

Fig 1:  Sacrococcygeal teratoma   Sagittal scan of the spine: abnormal complex solid mass (*) beneath the sacral spine

Fig 2:  Large meningomyelocele   Scan of lower spine: large solid mass with heterogeneous echodensity (solid circle) (arrow = sacrum)

Fig 3:  Lumbar meningocele   Sagittal scan of the spine: small solid mass protruding from lumbar region

Abnormal Spinal Curvature

These abnormalities include kyphoscoliosis, hemivertebrae, angulations or disorganized vertebral structures. Scoliosis, an abnormal lateral deflection of the spinal column, is the most common in this category.

Fig 1, Fig 2, Fig 3, Fig 4

Sonographic differential diagnosis:

• Normal
• Meningomyelocele (common)
• LBWC (uncommon)
• Amniotic band syndrome (uncommon)
• Skeletal dysplasia
• VATER or VACTERL associations (rare)
• Isolated hemivertebrae
• Iniencephaly (very rare)
• Caudal regression syndrome

Note:

• Hemivertebrae are an example of congenital scoliosis resulting from failure of segmentation, which is mostly associated with other anomalies.
• The normal flexible skeleton can be subject to strong deformation forces in utero resulting in transient scoliosis.
• Gross skeletal defects, including absent ribs or hemivertebrae, associated with lateral spinal deflection probably represent truly pathologic scoliosis.

Fig 1:  Scoliosis   Coronal scan of the spine: scoliosis of spine at the thoracic region (arrow)

Fig 2:  Angulation of spine   Coronal scan of the spine: angulation of spine at the thoraco-lumbar region (arrow)

Fig 3:  VATER associations   Coronal scan of the spine: scoliosis

Fig 4:  Disorganized spine :   Coronal scan of the spine: scoliosis and disorganized

Abnormal Hands and Feet

Hands and feet should be examined to exclude polydactyly, brachydactyly, abnormal hand posture, sandal gap, clinodactyly, Rocker-bottom foot, clubfoot, etc. These abnormalities are commonly part of several syndromes.

Polydactyly Fig 1

Polydactyly is the presence of an additional digit, which can be postaxial (on the ulnar or fibular side) or preaxial (on the radial or tibial side) and with a central form. This extra digit may range from a fleshy nubbin to a complete digit. Postaxial polydactyly is the most common form and is inherited autosomal dominantly as an isolated finding in most cases. However, it is significantly related to some syndromes, especially trisomy 13 or short-rib polydactyly syndrome. Preaxial polydactyly, especially a triphalangeal thumb, is most likely to be part of a syndrome.

The major differential diagnoses for polydactyly include

• Isolated polydactyly
• Chromosome abnormalities, especially trisomy 13
• Meckel Gruber syndrome
• Asphyxiating thoracic dystrophy
• Short-rib polydactyly syndrome
• Achondroectodermal dysplasia (Ellis-Van Creveld syndrome)
• Smith-Lemli-Opitz syndrome.

Fig 1:  Polydactyly

Clubfoot Fig 2

A clubfoot is one of the most common congenital anomalies, occurring in 1:250 to 1 in 1000 births. In 95% of cases, the sole is turned medially (talipes equinovarus). This can be caused by external compression in the case of oligohydramnios or by internal factors including abnormal bone formation, spina bifida, muscular defects or genetic causes (15% have a family history of clubfoot). Most clubfeet are found in otherwise normal infants. However, about 10% of cases are associated with several syndromes including Pena-Shokier phenotype, trisomy 18 and 13, etc.

Rocker bottom foot Fig 3

Vertical talus, or eversion of the planar arch, produces a rocker-bottom (convex outward) appearance of the bottom of the foot. This is most often associated with chromosomal abnormalities, particularly trisomy 13 and 18, although it may also be seen as an isolated anomaly, with caudal dysplasia sequence, neural tube defects, and neuromuscular disorders, and as part of the Potter sequence

Fig 2:  Clubfoot  Longitudinal scan of the lower leg: plantar view of the foot seen in the same plane of longitudinal view of tibia and fibula

Fig 3:  Rocker bottom foot   Prominent calcaneous bone (arrow) associated with trisomy 13

Abnormal hand posture Fig 4, Fig 5, Fig 6

Fetal hand malformation may be isolated or associated with chromosomal abnormalities, limb reduction defect, a neuromuscular disorder, or skeletal dysplasia. Ultrasound evaluation of the fetal hand requires assessment of the number and configuration of the fingers, the presence and position of the thumb, and the relationship of the thumb and fingers to each other and to the hand and wrist. The phalanges should be evaluated in the long-axis rather than the short-axis view. Short-axis views may represent the metacarpals rather than the phalanges. The normal fetal hand is most often in a resting position with loosely curled fingers, which the fetus periodically opens. Sonographic assessment requires skill on the part of the examiner in following the movement of the hand and documenting the extended fingers and thumb should the hand open during the examination.

Clenched hands Fig 7, Fig 8

Clenched hands or abnormal hand postures are often related to other abnormalities and more than half of cases have aneuploidy, predominantly trisomy 18 (88% of aneuploid fetuses).

Fig 4:  Pena-Shokier phenotype  Fixed flexion of both elbow and wrist joint (arrow) as well as persistent mouth opening (*)

Fig 5:  VATER associations  Longitudinal scan of forearm: absent radius with abnormal hand posture

Fig 6:  Hitchhiker thumbs   Abnormal posture and wide separation of the thumb (arrow) in the fetus with diastrophic dysplasia (25 weeks)

Fig 7:  Clenched hand   Overlapping fingers of the fetus with trisomy 18

Fig 8: Clenched hand   Overlapping fingers of the fetus with trisomy 18

Clinodactyly Fig 9, Fig 10

Clinodactyly is the permanent curvature or deflection of one or more fingers. It is frequently associated with abnormal chromosomes especially trisomy 21.

Syndactyly

Syndactyly is the fusion of digits and may consist of bony or soft tissue fusion. This may also be difficult to detect sonographically, especially those cases consisting of soft tissue fusion. Syndactyly is associated with a number of syndromes. It may be seen in the SRPD syndromes with the characteristics of polydactyly, and it may be seen in triploidy or Down’s syndrome.

Fig 9: Clinodactyly   Curved-in position of the fifth finger (arrow) of the fetus with trisomy 21

Fig 10:  Clinodactyly  Scan of the hand: disproportionately small middle phalange of the fifth finger (arrow)

Limb Reduction Defects

Limb reduction deformities, presenting alone or as part of a specific syndrome, occur in approximately 0.5 per 10,000 births. Half of them are simple transverse reduction deficiencies of one forearm or hand without associated anomalies and the remaining half have additional anomalies.

Fig 1, Fig 2, Fig 3

Isolated limb reduction:

• isolated limb deficiency more commonly occurs in the upper extremities rather than the leg, which generally occurs within the context of a syndrome, as do bilateral amputations or reduction of all limbs
• sporadic occurrence in most cases with negligible risk of recurrence

Limb reduction associated amniotic band:

• secondary to entanglement with mesodermic bands derived from the chorionic surface of the amnion after the latter has separated from the chorion
• isolated or multiple limb reductions, with or without other defects

Phocomelia:

• typically hands and feet are present, but the intervening arms and legs are absent
• main differential diagnoses include Robert’s syndrome, variants of TAR syndrome, and Grebe’s syndrome
• can be caused by exposure to thalidomide but this is only of historical interest

Radial ray defects: radial clubhand may be part of

• TAR syndrome (thrombocytopenia with absent radius)
• Fanconi’s syndrome: an autosomal recessive disorder consisting of pancytopenia anemia, leukopenia and thrombocytopenia and skeletal anomalies, especially radial clubhand
• Aase’s syndrome: an autosomal recessive disorder characterized by hypoplastic anemia and radial clubhand with bilateral triphalangeal thumb and a hypoplastic radius
• Holt-Oram syndrome: an autosomal dominant disorder characterized by congenital heart defects, radial hypoplasia and triphalangeal or absent thumb
• VATER association: a sporadic disorder resulting from defective mesodermal development during embryogenesis consisting of vertebral segmentation (70%), anal atresia (80%), tracheoesophageal fistula (70%), esophageal atresia, and radial (65%) and renal defects (53%)
• Goldenhar’s syndrome: characterized by hemifacial microsomia, hypoplasia of the malar and maxillary or mandibular region, vertebral anomalies, and radial defects
• Klipple-Feil syndrome
• Chromosomal abnormalities, particularly trisomy 18 and 21.

Fig 1:  Transverse limb reduction  Scan of the foot: absent distal end of foot

Fig 2:  Absent radius syndrome  Longitudinal scan of upper limb (15 weeks): short ulna (arrow) without radius with fixed flexion of wrist joint (arrowhead)

Fig 1:  Limb reduction   Longitudinal scan of lower limb: absent tibia and fibula, abnormal foot (*) arising from femur (arrow) in the fetus with VATER association

Long Bone Bowing

The degree of long-bone curvature should be examined. Campomelic (bent-bow) dysplasia is characterized by ventral bowing of the long bones. Thanatophoric dysplasia and osteogenesis imperfecta also have bowed extremities.

Fig 1, Fig  2

The major differential diagnoses are as follows:

• Campomelic dysplasia (bowing but no shortening)
• Osteogenesis imperfecta type II (related to fracture and callus formation)
• Thanatophoric dysplasia (severe shortened long bones)
• Achondrogenesis
• Hypophosphatasia

Fig 1:  Campomelic dysplasia   Longitudinal scan of tibia: anterior bowing of well ossified tibia

Fig 2:  Osteogenesis imperfecta type IIB  Irregular and angular fracture of long bones (arrow) but rather well-ossified