Fetal Skeletal dysplasia,

Skeletal dysplasias, also known as osteochondrodysplasias, constitute a group of approximately 450 disorders that affect both bone and cartilage. The newest (tenth version) “Nosology and Classification of Genetic Skeletal Disorders” comprises 461 different diseases that are classified into 42 groups based on their clinical, radiographic, and/or molecular phenotypes. Remarkably, pathogenic variants affecting 437 different genes have been found in 425/461 (92%) of these disorders. Many of these disorders result from new (de novo) dominant mutations, and for the autosomal recessive disorders, many occur in families with no history of a skeletal dysplasia.

The prevalence of skeletal dysplasias is estimated to be approximately 2.4 per 10,000 births. Due to high perinatal mortality, the overall prevalence in perinatal deaths is much higher at 9 per 1,000. Although the occurrence of each individual skeletal dysplasia may be rare, as a group they account for a significant number of newborns with congenital anomalies. The presence of a skeletal dysplasia is not always evident at the time of the fetal anatomical survey, and in particular, some non-lethal skeletal dysplasias may only become apparent in the third trimester.

The fetal skeleton develops relatively early, thus the suspicion of a skeletal dysplasia may be possible as early as the first trimester. The appendicular and axial skeleton undergo a programmed pattern of endochondral ossification, whereas the calvarium and portions of the clavicle and pubis ossify via membraneous ossification. Ossification occurs at relatively early gestational ages: the clavicle and mandible at 8 weeks, the appendicular skeleton, ilium, and scapula by 12 weeks, and the metacarpals and metatarsals by 12–16 weeks. The secondary ossification centers become visible later in gestation, beginning with the calcaneus at 20 weeks, the distal femoral epiphysis after 32 weeks, and the proximal tibial epiphysis after 37 weeks.

Prenatal ultrasound has only a 65–68% accuracy rate for diagnosis of a particular skeletal dysplasia. Thus, many skeletal dysplasias remain undiagnosed until the neonatal period. However, with the use of both two and three-dimensional ultrasound, abnormal skeletal elements may be identified. A differential diagnosis may be achieved with a systematic approach that requires analysis of a constellation of findings. These diagnoses can be applied to counseling patients with regards to options for optimal management and calculation of recurrence risk.

Suspicion of a fetal skeletal dysplasia is often prompted by identification of long bone shortening on sonography. Thus, it is important to review the various terms used to describe varying degrees of long bone shortening.

  • rhizomelia-proximal shortening (humerus, femur)
  • mesomelia: shortening of the middle segment of the limb (radius/ulna or tibia/fibula)
  • acromelia: small hands &/or feet
  • micromelia: all segments shortened

Table 1 illustrates these concepts.

 

 

APPROACH TO DIAGNOSIS

There is no one universal approach that is used to diagnose a skeletal dysplasia. With a myriad of conditions and multiple findings that may overlap, determining the exact diagnosis may be extremely difficult. However, establishing a differential diagnosis is just as valuable. One approach is to attempt to answer the following questions, beginning with evaluation of the long bones.

 

1. Are the long bones short?

 

2. If short, what type of shortening?

  • Is the shortening rhizomelic, mesomelic, acromelic or micromelic?
  • All long bones should be assessed.

TIP: micromelia is more common in the more severe, often lethal skeletal dysplasias.

3. Is the long bone morphology normal? This includes answering the following:

  • Are the bones undermineralized (underossified)?
  • Are fractures present?
  • Is the bone shape normal?
    • Are the bones bowed/angulated?

TIP: If the bones are undermineralized and there are fractures, osteogenesis imperfecta (OI) type II is a leading diagnosis. Undermineralization may also be seen in hypophosphatasia and achondrogenesis. Undermineralization of the spine is a particular feature of achondrogenesis that is not seen in OI type II. If the limbs are bowed without evidence of fracture, the differential includes thanatophoric dysplasia (TD), camptomelic dysplasia (CD), atelosteogenesis, achondrogenesis or homozygous achondroplasia.

4. When in gestation is the skeletal dysplasia suspected?

  • Limb shortening in the first or second trimester is likely to be a skeletal dysplasia and more likely to be lethal
  • Mild limb shortening noted later in pregnancy (late second to third trimester) may be a normal variation, familial, associated with fetal growth restriction or achondroplasia, which is the most common nonlethal skeletal dysplasia

TIP: It is common for achondroplasia to be suspected in the third trimester.

5. Is the spine normal?

  • Is there platyspondyly (flattening of the vertebral bodies with increased space between the vertebrae)?
  • Is there kyphosis (abnormal curvature in the sagittal plane) or scoliosis (abnormal curvature in the coronal plane)?
  • Is the spine normally ossified?

TIP: If the spine is completely unossified (figure 1), achondrogenesis type IA is a highly likely diagnosis.

Figure 1. Achondrogenesis type IB. Radiograph demonstrating a lack of skull ossification (straight arrows), wavy ribs (curved arrow) and lack of spine ossification (open arrow). Underossification of the spine is a hallmark of achondrogenesis, a lethal skeletal dysplasia.

6. Is the calvarium normal?

  • Is the shape normal? If not, craniosynostosis (premature closure of sutures) may be present. A cloverleaf shape deformity is consistent with TD type II.
  • Is there evidence of undermineralization? The differential diagnosis of underossificaion of the skull includes OI type II, achondrogenesis types IA, IB and II, and autosomal recessive perinatal lethal hypophosphatasia.

TIP: When the skull is underossified, pressure by the ultrasound transducer may appear to cause a “deformity”, as if the skull was being indented. Underossification of the skull may result in intracranial structures that are seen “too well” (figure 2).

Figure 2. Axial view of the fetal head. The skull is underossified that results in the intracranial structures visualized “too well”. The underossification of the skull also results in a “deformity” (red circle) due to pressure from the ultrasound transducer.

7. Does the face appear normal?

  • frontal bossing?
  • midface hypoplasia?
  • depressed nasal bridge?
  • micrognathia?

TIP: mild frontal bossing identified in the third trimester is often consistent with achondroplasia. Micrognathia is a feature of CD.

8. Is the thorax small?

  • Best appreciated in a sagittal view
  • Is there appearance of a “shelf” (figure 3), the connection between a small chest and protuberant abdomen? If so, this is often seen in lethal skeletal dysplasias and predictive of pulmonary hypoplasia.
  • What is the shape of the chest?

TIP: A small and bell-shaped chest should warrant consideration of TD as a possible diagnosis; a milder bell-shaped chest may be seen in CD.

Figure 3. Image of a fetus at 24 weeks showing a very small thorax. The arrow suggests the appearance of a “shelf” that connects the small thorax to a protuberant abdomen. This finding is a feature of many lethal skeletal dysplasias and results in pulmonary hypoplasia.

9. Are the ribs normal?

  • Are they short?
  • Are there fractures which cause a beading appearance (figure 4)?
  • Do the ribs appear wavy?

TIP: fractured or beaded ribs are seen in OI type II and achondrogenesis type IA. Ribs that are straight with a long and narrow chest may be seen in the short rib-polydactyly syndromes.

Figure 4. Osteogenesis imperfecta type II (perinatal lethal form). Image of ribs with a “beading” appearance indicative of multiple fractures with subsequent callus formation.

10. Are the hands and feet normal?

  • Is there evidence of brachydactyly (short digits) or a trident hand?
  • Is there polydactyly (extra digits) or syndactyly (fused digits)?
  • Are the feet clubbed?
  • What is the femur to foot ratio? A ratio of 1 is normal irrespective of gestational age, and a ratio <1 is suggestive of a skeletal dysplasia.
  • Are there joint contractures?
  • Is there an ulnar deviated thumb (also referred to as a hitchhiker thumb, figure 5)

TIP: The differential diagnoses for a hitchhiker thumb includes diastrophic dysplasia, achondrogenesis type IB, and atelosteogenesis type 2.

Figure 5. “Hitchhiker thumb”. Arrow points to abducted position of the thumb. This finding may be seen in diastrophic dysplasia, atelosteogenesis type 2 and achondrogenesis type IB.

11. What about the scapula and clavicles?

  • In campomelic dysplasia, the scapula may be hypoplastic or absent.
  • In cleidocranial dysplasia, the clavicles may be hypoplastic or absent.

12. Is there hydrops present? If yes, consider short rib-polydactyly syndrome or achondrogenesis type I.

13. Are there any other structural anomalies present?

  • Orofacial clefts, cardiac defects, genitourinary abnormalities, cystic hygroma

TIP: A finding of ambiguous genitalia (along with other long bone findings) is suspicious for CD.

DETERMINING THE LETHALITY OF A SKELETAL DYSPLASIA

The most common lethal skeletal dysplasias include TD, OI type II, achondrogenesis, atelosteogenesis, short rib polydactyly and perinatal lethal hypophosphatasia. Additionally, homozygous achondroplasia and CD. Some of these conditions will be discussed in more detail in this narrative.

Once a skeletal dysplasia is suspected, an important next step is to determine if the condition is lethal. Of note, the earlier in gestation a skeletal dysplasia is suspected, the greater the chance it is lethal. The primary cause of death in most lethal skeletal dysplasias is a small thorax that results in pulmonary hypoplasia. Specific ultrasound findings that may suggest a lethal skeletal dysplasia include the following:

  • chest-to-abdominal circumference ratio less than 0.6
  • femur length-to-abdominal circumference ratios less than 0.16
  • fractures of long bones
  • severe bowing of long bones
  • undermineralization of the skull and/or long bones
  • presence of fetal hydrops (abnormal fluid accumulation in two or more extravascular body compartments)

Some other key concepts with respect to lethal skeletal dysplasias include the following:

  • the prediction of lethality by small thoracic circumference and abnormal sagittal contour in the second-trimester is very accurate
  • the primary cause of death in a lethal skeletal dysplasia is a small chest circumference that results in pulmonary hypoplasia
  • not all skeletal dysplasias associated with small thoracic circumferences are associated with immediate lethality
  • conversely, some disorders with normal-appearing thoracic size are still lethal

SPECIFIC CONDITIONS

Thanatophoric Dysplasia (TD)

Thanatophoric (Greek for “death bearing”) dysplasia is the most common lethal skeletal dysplasia, its name derived from the Greek word thanatophoros, which means “bearing death.” TD is divided into two types. In both types, severe micromelia is present, as well as a small thorax, short broad ribs and flattened vertebral bodies with relative enlargement of the disc spaces, referred to as platyspondyly.

Type I TD, more common than type II is characterized by femurs that are short and bowed with a “telephone receiver” appearance (figure 6). In TD type II, the femurs are usually straight. The “cloverleaf” skull deformity, also known as kleeblattschädel (figure 7) is also a feature of TD type II and is due to premature closure of the cranial sutures. Platyspondyly tends to be more severe in TD type I.

Polyhydramnios is present in almost 50% of cases. Death occurs in early infancy (within the first few hours to days of life) in the majority of cases due to respiratory insufficiency from pulmonary hypoplasia. Both types of TD are due to mutations in the fibroblast growth factor receptor 3 (FGFR3) gene that resides on the short (p) arm of chromosome 4 at position 16.3 (4p16.3). FGFR3 mutations are known as gain-of-function mutations that are associated with an increase in one or more normal functions of a protein. FGFR3 mutations are also the etiology for other skeletal dysplasias, including hypochondroplasia, SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans) and achondroplasia.

Figure 6. Image of “telephone receiver” femur that is characteristic of thanatophoric dysplasia type I.

Figure 7.Thanatophoric dysplasia type II. Note the “cloverleaf” shaped skull, also referred to as Kleeblattschädel.

Achondroplasia

Achondroplasia is the most common skeletal dysplasia with a prevalence of 1 in 10,000 births. As noted above, achondroplasia (similar to TD) is due to a mutation within the FGFR3 gene. Most mutations are classified as autosomal dominant new mutations, which implies they occur without a family history. Individuals with achondroplasia have only one copy of the mutation, referred to as heterozygous achondroplasia.

Homozygous achondroplasia is a lethal disorder that occurs in 25% of offspring when both parents are affected with achondroplasia. In homozygous achondroplasia, the long bone shortening is significantly more severe than noted in heterozygous achondroplasia, and as is the case with most lethal skeletal dysplasias, pulmonary hypoplasia is the explanation for the lethality.

Achondroplasia is characterized by many features including:

  • rhizomelic limb shortening
  • mild limb bowing
  • midface hypoplasia
  • large head (macrocephaly)
  • frontal bossing-prominent forehead with depression of the nasal bridge, best demonstrated in the sagittal plane
  • trident hand (figure 8)-short and stubby fingers, referred to as brachydactyly and a gap between the middle and ring fingers
  • platyspondyly
  • prominent thoracolumbar kyphosis
  • increased proximal femoral diaphyseal-metaphyseal angle (usually greater than 130 degrees, figure 9).
  • mildly increased amniotic fluid volume (polyhydramnios)

TIP: It is important to note that the fetal anatomical survey usually performed at 18-20 weeks’ gestation is often normal as limb shortening often manifests between 21-27 weeks.

Figure 8. Image of trident hand. Note the fingers appear short and stubby (brachydactyly) with a gap between the middle and ring finger. This finding may be noted in both thanatophoric dysplasia and achondroplasia.

Figure 9. Proximal femoral diaphyseal-metaphyseal angle. The normal angle at 22 weeks’ gestation is 98.5+/-6.8 degrees and at 32 weeks’ gestation, 105.6 +/- 7.3 degrees. In cases of achondroplasia, this angle is usually greater than 130 degrees as noted in this case.

Although frontal bossing is usually a consistent finding seen in achondroplasia, other syndromes associated with frontal bossing include TD, achondrogenesis, craniosynostosis syndromes (Crouzon, Pfeiffer) and craniofrontonasal dysplasia

The majority of individuals with achondroplasia have normal intelligence, a normal lifespan, and lead independent and productive lives. The mean final height in achondroplasia is 130 cm for men and 125 cm for women, and specific growth charts have been developed to document and track their linear growth, head circumference, and weight.

Campomelic Dysplasia (CD)

The term “campomelic” comes from the Greek word for “bent limb.” CD is a rare skeletal dysplasia that is usually lethal, although there are occasional long-term survivors.

Features of CD include the following:

  • severe angulation of the femur, tibia and fibula (figure 10)
  • anterolateral bowing especially common
  • normal bone ossification without evidence of fractures
  • small bell-shaped chest
  • kyphoscoliosis
  • preterm skin dimpling
  • cystic hygroma
  • cardiac anomalies
  • clubfeet
  • hydrocephalus
  • hydronephrosis
  • polyhydramnios
  • absent or hypoplastic scapula (figure 11)
  • 60%-70% of genetically male (XY) patients have sex reversal (appear phenotypically female) or ambiguous genitalia
  • micrognathia

Hypoplastic scapulae, nonmineralized thoracic pedicles and vertically narrow iliac bones are unique to CD. In addition, the bony changes in CD are usually confined to the legs, which again is often not the case with other skeletal dysplasias. The thorax in CD is often small but usually not as visually impressive as other lethal skeletal dysplasia.

Figure 10. Campomelic dysplasia. Note the mild bowing of the femurs bilaterally (yellow arrows) and anterolateral angulation of the tibiae (red circles).

Figure 11. Campomelic dysplasia. Radiograph of a term infant demonstrating hypoplastic scapulae bilaterally (circles). This finding is a distinguishing feature, noted in greater than 95% of infants with campomelic dysplasia.

Campomelic dysplasia is caused by mutations within the SOX9 gene, located on the long (q) arm of chromosome 17 at position 24.3 (17q24.3). This gene provides instructions for making a protein that plays a critical role during embryonic development. The SOX9 protein is especially important for development of the skeleton and plays a key role in the determination of sex before birth. Mutations within this gene prevent the production of the SOX9 protein or result in a protein with impaired function. More than 70 mutations involving the SOX9 gene have been found to cause CD.

Osteogenesis Imperfecta (OI) Type II

The prevalence of OI is reported as 1/10,000-1/20,000 births. There are at least 19 recognized forms of osteogenesis imperfecta, designated type I through type XIX. More recently, the nomenclature has been revised to further subdivide the types based on different phenotypes. For our purposes, we are most concerned with the perinatal lethal form, also referred to as OI type II.

The presence of long bone fractures is a hallmark feature of OI type II that distinguishes it from other skeletal dysplasias. Features of OI type II include:

  • long bone shortening
  • long bone fractures resulting in callus formation that gives a “crumpled” appearance
  • small chest
  • multiple rib fractures giving a “beaded” appearance
  • undermineralization of the long bones
  • undermineralization of the skull that results in brain structures seen “too well” on ultrasound and skull deformation from normal ultrasound transducer pressure
  • relatively normal hands and feet

The majority of OI cases (90%) are due to abnormalities in type I collagen as a result of mutations in either the COL1A1 or COL1A2 gene. Inheritance is usually autosomal dominant, with 60% of mutations occurring de novo in cases of mild OI. The COL1A1 gene, located on the long arm of chromosome 17 at position 21.33 (17q21.33), provides instructions for making part of a large molecule called type I collagen, the most abundant form of collagen in the human body.

Collagens are a family of proteins that strengthen and support many tissues in the body, including cartilage, bone, tendon, skin, and the white part of the eye (the sclera). Mutations in the COL1A1 gene are responsible for other conditions such as Ehlers-Danlos syndrome and Caffey disease. Of note, for the perinatal lethal form of OI, an autosomal recessive pattern of inheritance has recently been identified involving three genes, namely CRTAP, P3H1 and PPIB that correspond to OI type VII, VIII and IX, respectively. Advanced paternal age may increase the risk of OI type II.

Achondrogenesis

Achondrogenesis is a group of lethal osteochondrodysplasias that is due to failure of cartilaginous matrix formation. It is the second most common lethal short-limb chondrodysplasia, with a prevalence of 1/40,000-1/50,000 births. Main features include severe micromelia, a disproportionately large skull with poor ossification of the skull, and either poor or complete lack of spine ossification.

The lack of spine ossification is a feature that distinguishes this condition from many other skeletal dysplasias. Although there are reports of some infants who live for a short time in the postnatal period, most die either in-utero or soon after birth from respiratory failure. Severe polyhydramnios may be seen. It is not uncommon to encounter hydrops, which is noted in approximately 1/3rd of cases. There are three main subtypes, with type II accounting for 80% of cases.

Type IA (also referred to as the Houston-Harris type)

  • poorly ossified skull
  • complete lack of spine ossification
  • short ribs with multiple fractures
  • proximal femurs have a metaphyseal spike
  • arched ilium with hypoplastic ischium
  • encephalocele may be seen occasionally

Type IB (also referred to as the Parenti-Fraccaro type)

  • poorly ossified skull
  • short ribs but no fractures
  • only posterior pedicles of spine are underossified
  • distal femurs have metaphyseal irregularities

Type II (also referred to as the Langer-Saldino type0

  • normal skull ossification
  • poorly ossified spine
  • hypoplastic ilium with medial spike
  • abnormalities seen occasionally include micrognathia, cleft soft palate, microtia (small ears), cystic hygroma and heart defects (atrial septal defects and atrioventricular septal defects)

Without genetic testing, it may be difficult to distinguish among these subtypes. Types IA and IB are inherited in an autosomal recessive fashion and thus carry a recurrence risk of 25%. At least nine mutations in the TRIP11 gene, located on the long (q) arm of chromosome 14 at position 32.12 (14q32.12) have been found to cause achondrogenesis type IA. The TRIP11 gene provides instructions for making a protein known as Golgi microtubule-associated protein 210 (GMAP-210).

This protein is found in the Golgi apparatus, a cell structure in which newly produced proteins are modified so they can carry out their functions. Studies suggest that the GMAP-210 protein helps to maintain the structure of the Golgi apparatus, and it may also be involved in the transport of certain proteins out of cells.

Mutations in the SLC26A2 gene have been implicated in achondrogenesis type IB The SLC26A2 gene is also known as the DTDST (diastrophic dysplasia sulfate transporter) gene and is located on the long (q) arm of chromosome 5 at position 32 (5q32). It provides instructions for making a protein that transports charged molecules (ions), particularly sulfate ions, across cell membranes.

This protein appears to be active in many of the body’s tissues, including developing cartilage. Cartilage is a tough, flexible tissue that makes up much of the skeleton during early development. Most cartilage is later converted to bone, except for the cartilage that continues to cover and protect the ends of bones and is present in the nose and external ears.

Achondrogenesis type II is inherited in an autosomal dominant fashion. The etiology of achondrogenesis type II has been attributed to mutations in the COL2A1 gene, located on the long (q) arm of chromosome 12 at position 13.11 (12q13.11). The COL2A1 gene provides instructions for making one component of type II collagen, called the pro-alpha1(II) chain. Type II collagen adds structure and strength to the connective tissues that support the body’s muscles, joints, organs, and skin. Thus, achondrogenesis is classified as a type II collagenopathy, in contrast to OI type II where type I collagen is defective.

Spondylothoracic Dysplasia

Spondylothoracic dysplasia (STD) is a rare disorder in which there are malformations affecting the spine and ribs (figure 12). Features of this condition include a small and shortened thorax, hemivertebrae (where only one side of the vertebral body develops, resulting in deformation of the spine, multiple vertebral body fusion causing irregular shortened spine, indistinct or joined ribs posteriorly and a small thorax.

On an x-ray this gives the thorax a crab-like shape. The limbs tend to be of normal length. This condition is often lethal due to the small thorax resulting in pulmonary insufficiency. Jarcho-Levin syndrome is often another name of STD, although may researchers believe the widespread, inconsistent use of Jarcho-Levin syndrome has rendered the term obsolete and that its use should be discontinued. For a time, spondylocostal dysplasia was used interchangeable with STD, but these are now thought to be two distinct entities.

Figure 12. Spondylothoracic Dysplasia. Ultrasound image showing disorganization of the spine

The prevalence of STD is estimated at 1in 200,000 and is thought to be more common in people of Puerto Rican ancestry, affecting approximately one in 12,000 people. It is inherited in an autosomal recessive manner. At least three mutations in the MESP2 gene have been found to cause STD. The MESP2 gene is located on the long (q) arm of chromosome 15 at position 26.1(15q26.1) and provides instructions for making a transcription factor, which is a protein that binds to specific regions of DNA and helps control the activity of particular genes.

The MESP2 protein controls the activity of genes in the Notch pathway, an important pathway in embryonic development. The Notch pathway plays a critical role in the development of the vertebral bones. Specifically, the MESP2 protein and the Notch pathway are involved in separating future vertebrae from one another during early development.

Perinatal Lethal Hypophosphatasia

Hypophosphatasia is a rare inherited disorder of bone metabolism. There are three subtypes referred to as the perinatal lethal form, infantile form and late onset (adult) form. Features of the perinatal lethal form include undermineralization of the bones and calvarium and severe micromelia. Unlike OI type II, fractures are uncommon. Bones may appear “moth eaten” later in gestation. The long bones may be bowed and angulated (figure 13) with spurs along the midshaft. As in the case of OI type II, undermineralization of the calvarium may result in intracranial structures seen “too well” (figure 14) and a deformity when pressure is applied by the transducer.

Figure 13. Perinatal Lethal Hypophosphotasia. Ultrasound image showing an angulated femur characteristic of this condition

Figure 14. Perinatal Lethal Hypophosphotasia. Ultrasound image showing brain structures “too well” due to undermineralization of the calvarium. Undermineralization of the calvarium is also noted in OI type II and achondrogenesis type 1A.

The prevalence of the perinatal lethal type is reported as 1 in 100,000. Mutations in the ALPL gene are responsible for this condition. The ALPL gene is located on the short (p) arm of chromosome 1 at position 36.12 (1p36.12) and provides instructions for making an enzyme called tissue-nonspecific alkaline phosphatase (TNSALP).

This enzyme plays an important role in the growth and development of bones and teeth. It is also active in many other tissues, particularly in the liver and kidneys. Mutations in the ALPL that result in the perinatal lethal type of hypophosphatasia are known as loss-of-function mutations in that they result in the complete elimination of TNSALP activity. Milder forms of hypophosphatasia may be inherited an either an autosomal recessive or autosomal dominant pattern. However, the perinatal lethal form is inherited in an autosomal recessive manner.

Asphyxiating Thoracic Dystrophy

Asphyxiating thoracic dystrophy (ATD), also known as Jeune syndrome may be classified as a short rib-polydactyly syndrome. Diagnostic clues include a triad of features namely micromelia, polydactyly and short horizontal ribs with a long and narrow thorax (figure 15). Perinatal lethality is common and due to pulmonary insufficiency. Childhood survivors may develop liver or kidney disease. The prevalence of ATD is reported at 1 in 100,000 to 1 in 130,000 and the inheritance pattern is autosomal recessive.

Figure 15. Asphyxiating Thoracic Dysplasia. Three-dimensional rendered ultrasound image demonstrating a narrow bell-shaped thorax with short ribs reaching approximately halfway around the thorax.

This condition comprises a group of disorders known as skeletal ciliopathies or ciliary chondrodysplasias, all of which are caused by problems with cilia and involve bone abnormalities. Mutations in at least 11 genes, including IFT80 and DYNC2H1 have been implicated as a cause of ATD. Both of these genes provide instructions for making proteins that are found in cell structures called cilia. Cilia are microscopic, finger-like projections that stick out from the surface of cells.

The proteins are involved in a process called intraflagellar transport (IFT), by which materials are carried to and from the tips of cilia. IFT is essential for the assembly and maintenance of these cell structures. Cilia play central roles in many different chemical signaling pathways. Mutations in the genes associated with asphyxiating thoracic dystrophy impair IFT, which disrupts the normal assembly or function of cilia. As a result, cilia are missing or abnormal in many different kinds of cells. The IFT80 gene is located on the long (q) arm of chromosome 3 at position 25.33 (3q25.33) and the DYNC2H1 gene is location on the long (q) arm of chromosome 11 at position 22.3 (11q22.3).

REFERENCES

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United States National Library of Medicine. Genetics Home Reference.

Steve Ramsey, PhD- Public Health

Natural health consultant, MSc medical ultrasound, BSc diagnostic imaging – Charles sturt university – Australia

Diplomas in Radiology , sonography an natural health – Canada

Pharmacy /Radiology – Baghdad .

Okotoks, Alberta 

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