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20087-06-16-21 Achondroplasia © Burmagina www.thefetus.net/
Achondroplasia

Yuliya Burmagina, MD; Ekaterina Kaloyanova, MD.

OB-Gyn. Dept., Dubai Hospital , Dubai, UAE.

 

 

 

Synonyms

 

Chondrodysplasia, micromelia, skeletal dysplasia, little people, achondroplastic, skeletal dysplasia, rhizomelic dwarfism, short-limb dwarfism, short-trunk dwarfism, chondrodystrophia fetalis, classic chondrodystrophy, dyschondroplasia fetalis.

 

Definition

 

The term "achondroplasia" is inaccurate because it denotes "lack of cartilage" instead of abnormal cartilage. More accurate are the terms "chondrodysplasia" or "chondrodystrophy" which imply abnormal cartilage tissue formation and sustenance but these terms apply to many other disorders in addition to achondroplasia. “Achondroplasia, hypochondroplasia, and metaphyseal chondrodysplasias are considered short-limb dwarfing conditions. Additional terms used to describe the segment of the limb are rhizomelic (proximal), mesomelic (middle), and acromelic (distal). In achondroplasia, the extremity involvement is rhizomelic, with the arms and thighs more severely involved than the forearms, legs, hands, and feet.[1]

 

Case report

 

Mrs. M., 34 years old, housewife, G7P5, with no consanguinity, was admitted at 33 weeks of gestation to antenatal ward for evaluation of fetus in view of tense polyhydramnios. Patients obstetric history was unremarkable except of c-section for breech in labor. Husband is healthy, 36 year old  clerk.  Ultrasound scan done by radiographer revealed discrepancy of fetal parameters (BPD>95th centile,  AC>95th  centile, FL and HL<5th  centile) along with polyhydramnios (max vertical pool 7.7cm). The patient was advised to have detailed fetal scan. At 36 weeks fetal parameters were as follow: BPD>95th  centile, AC>95th   centile, FL<5th centile. Polyhydramnios.  At 37 weeks the following features were depicted along with increased amount of the amniotic fluid (Fig. 10): frontal bossing with depressed nasal bridge (Fig. 1,2,3, 6, and 7) representing midfacial hypoplasia, brachycephaly with signs of craniosynostosis (Fig. 4 and 5), mild prefrontal edema, contracted scull base (Fig. 6,7) shortened long bones with humerus length (HL) and femur length (FL) <3rd  centile (Fig. 16,17,18, and 19), while biparietal diameter (BPD) and abdominal circumference (AC) >98th centile with no "bowing" (Fig. 4), "bell-shaped" thorax with narrow chest and distended abdomen (Fig. 8,9,11), no other abnormalities were detected (no kidneys anomalies - Fig.12,13, no polydactyly - Fig. 14,15,18).

 

The following indices were calculated:

 

  • FL/AC= 58.1/351.7=0.165 – indicating non-lethal nanism. (Normal FL/AC > 0.2, FL/AC = 0.16-0.19 - non-lethal nanism, FL/AC <0.16 - lethal nanism).[2]
  • Thoracic Circumference/AC= 256.0/ 359.7=0.713 - indicating skeletal dysplasia. (Normal TC/AC = 0.56-1.04).[2]

Fetus was  suspected to have skeletal dysplasia, with the most likely diagnosis of  achondroplasia. She had cesarean section and gave birth to alive baby girl weighing  3310 g with length = 44 cm (< 3rd  centile). Clinical examination and postnatal radiograph findings  were suggestive of achondroplasia (Fig. 20). The patient was advised to complete  the work-up by molecular study (FGFR3 mutation).

Sonographic findings

Figures 1, 2, 3. Note the frontal bossing that can be picked up even by 2D scan of fetal face.

  

Figures 4, 5. Abnormal head shape: brachycephaly with starting craniosynostosis.

 

Figures 6, 7. Characteristic profile and head shape (prefrontal edema, frontal bossing, typical appearance of nasal bridge (midface hypoplasia) and short cranial base).

 

Figures 8, 9. “Bell-shaped" trunk (narrow thorax and distended abdomen), frontal bossing. Note the polyhydramnios.

 

Figures 10, 11. Note the significant difference in circumferences of abdomen and thorax (along with relative cardiomegaly)

 

Figures 12, 13. Normal kidney size and sonographic pattern (enabling better differential diagnosis).

 

Figures 14, 15. Absence of polydactyly (helping to differentiate the condition).

 

Figures 16a, 16b, 17. Short femur length=581mm, <5centile, fibula & tibia. Humerus (=523mm, < 2centile).

  

Figures 18, 19. Note shortened arm (ulna=515 mm, <5 centile).

 

Figure 20. X-ray study few days after birth: Narrow chest, shortened long bones (no evidence of platyspondyly).

Discussion

Etymology

Greec. a = not, chondros = cartilage, plasis = a molding, and -ia = condition, i.e.  a failure of normal development of cartilage

History

The past perception of achondroplasia is reflected in art, beginning about 2000 B.C. Achondroplasia is thought to have provided a model for the representation of a series of figures including the Egyptian god Bes, the Greek teller of fables Aesop, and the Renaissance giant of fiction Morgante. It is believed that achondroplasia was perceived as a positive, not a negative, condition during at least part of the past four millennia. [27].

Prevalence

Achondroplasia occurs in one in 25,000 live births. No documented race predilection exists. Males and females are affected equally.[2]  

Etiology

Achondroplasia is caused by mutations in the gene for fibroblast growth factor receptor-3 (FGFR3). The gene has been mapped to band 4p16.3. Fibroblast growth factors are structurally related proteins associated with cell growth, migration, wound healing, and angiogenesis. Mutation causes enhancement in its function of limiting endochondral ossification. Mutation in FGFR3 in achondroplasia is due to transition of guanine to adenine (G to A) at nucleotide 1138 of complimentary DNA.[4,5]

Inheritance

This condition is inherited as an autosomal dominant trait with 100% penetrance, 90% of cases are sporadic ( i.e. result from a random new mutation)  with an increased risk correlated with paternal age (more than 36 years)  at the time of conception suggesting a de-novo and paternal origin of the mutation [6].
When both parents have achondroplasia, 50% of their offspring are heterozygous and affected, 25% are homozygous, which is ordinarily fatal in the first few months of life, and 25% are unaffected. When one parent has achondroplasia, the chance of transmitting this gene to each child is 50%.

Pathogenesis

The primary defect found in patients with achondroplasia is abnormal endochondral ossification. Tubular bones are short and broad, reflecting normal periosteal growth. The iliac crest apophyses (appositional growth) are normal, giving rise to large, square iliac wings. The growth of the triradiate cartilage (endochondral growth) is abnormal, giving rise to horizontal acetabular roofs. Thus, these patterns of defect help to explain many of the observed clinical and radiographic characteristics of achondroplasia.

Clinical features of achondroplasia

• non-proportional short stature (average adult height of 131cm for males and 123 cm for females);
• narrow thorax with prominent abdomen;
• rhizomelic (proximal) shortening of the limbs;
• redundant skin folds on the limbs;
• short fingers and toes;
• "trident" hand (separation between the middle and ring fingers);
• large head with frontal bossing;
• hypoplastic midface with a flattened nasal bridge ("saddle nose");
• maxillary hypoplasia with dental crowding and malocclusion;
• spinal kyphosis or lordosis;
• varus or valgus  deformities;
• ventriculomegaly or arrested  hydrocephalus;
• intelligence level is within normal limits;
• motor milestones may lag by 3-6 months;
• delayed speech acquisition in ~20%;
• leg pain, dysesthesia, paresthesia, paraparesis, incontinence, and neurogenic claudication ( in view of  stenosis of the spinal canal and intervertebral foramen);
• recurrent otitis media (due to poor drainage of the eustachian tubes from underdevelopment of the midface);
• sleep apnea  (due to narrowing of the foramen magnum compressing the cervicomedullary region).

Implications for targeted examinations

Despite the advance in prenatal ultrasonography, diagnosis of a specific skeletal dysplasia remains difficult, with the largest study reporting an accurate prenatal diagnosis by the referring physician in less than one third of cases [7]. Both false-positive and false-negative diagnoses may occur with antenatal ultrasonography of skeletal dysplasias.  It is extremely important to try and distinguish between those cases in which a primary bone dysplasia is present and those in which the findings of short limbs are secondary to intrauterine growth retardation or genetic syndromes that can mimic skeletal dysplasia on ultrasound [8]. This can be especially difficult when short limbs are detected in the third trimester. However, in growth-restricted fetuses, there is shortening of the long bones, but their appearance is usually normal. This is not the case in the osteochondrodysplasias because frequently diaphyseal, epiphyseal, and metaphyseal abnormalities can be seen, especially in the third trimester. Detailed surveillance of the appendicular and axial skeleton, in addition to other organ system involvement, may provide clues that will aid in differentiation of growth restriction from skeletal dysplasias, and help delineate a more precise differential diagnosis among the osteochondrodysplasias. It may not be possible to make a specific diagnosis antenatally, but it is important to attempt to find indicators that suggest a high probability of lethality. Such indicators include femur length–to–abdominal circumference ratio [9] small bell-shaped thorax, and decreased bone echogenicity [10]. Fetal ultrasonography should be performed in order  to evaluate skeletal anomalies and to measure the long bones for size, shape, bowing, symmetry, and quality of calcification.  In addition to that  fetal  the skull is to be evaluated  for size and shape. Serial ultrasonograms must be obtained at the beginning of the second trimester to plot the femoral length growth curves to distinguish individuals with homozygous (lethal) and heterozygous (nonlethal) achondroplasia from unaffected individuals, since the characteristic features of heterozygous achondroplasia may not manifest until the second trimester.
Krakow et al  found that  3D-imaging in the prenatal-onset diagnosis of skeletal dysplasia had advantages over the 2-dimensional (2D) imaging in the evaluation of facial dysmorphism, relative proportion of the appendicular skeletal elements, and the hands and feet. 3D images of the abnormal findings  are more readily appreciated than other images  which is helpful in patient counseling [11,16].  Recent reports suggest that  NT measurement  in the I trimester may be helpful in screening the high risk pregnancies.[12].

Radiological Studies

Radiographs of the skull, spine, and extremities in patients with achondroplasia reveal the characteristic features:

- midface hypoplasia;
- enlarged calvaria;
- frontal prominence ("bossing");
- shortening of the base of the skull;
- size of the foramen magnum is diminished;
- a lumbar spine (anteroposterior [AP]) view reveals distinct narrowing on the interpedicular distances from proximal to distal in L1-L5;
- lateral view reveals shortening of the pedicles and vertebral bodies with significant posterior scalloping;
- various degrees of thoracolumbar kyphosis;
- pelvis is typically broad and short, and the ilium has a square appearance;
- sacrosciatic notch is short, and the acetabular roof is horizontal;
- femoral neck is short with trochanteric overgrowth (coxa vara);
- long bones have metaphyseal flaring and are short and thick;
- sites of major muscle attachments, such as the deltoid and patellar tendon tuberosity, are prominent;
- distal femoral physes have an inverted-V (chevron) shaped configuration;
- bowing usually affects the tibia more than the femur;
- fibula is typically longer than the tibia;
- humerus is markedly shortened, and the radial head is frequently dislocated;
- ulna is typically short with an elongated styloid process;
- proximal and middle phalanges of the hand are broader, with greater shortening than the distal phalanges and metacarpals [15].

Differential diagnosis

Achondrogenesis - is an autosomal recessive and lethal dwarfism Short-limbed dwarfism is severe. The skull and rest of the skeleton is poorly ossified. Chest narrowing is marked, but the head may be enlarged relative to the trunk. Polyhydramnios is usually present.

Chondroectodermal dysplasia  (Ellis-van Creveld syndrome) - is autosomal recessive with variable expression. The ribs are severely shortened, associated with short limbs, narrow thorax, polydactyly, postaxial hexadactyly, and congenital heart disease. The size of thorax is particularly striking when compared with the abdomen and head [23].

Asphyxiating thoracic dystrophy  (Jeune syndrome) - is an autosomal recessive disorder. Patients present with an extremely narrow thorax, rhizomelic short-limb dwarfism, polydactyly, and renal dysplasia (renal cysts) [20,23].

Osteogenesis imperfecta - type IIa is a lethal autosomal dominant condition with a thin skull vault that may collapse and short limbs that are thickened and angulated because of multiple fractures. Osteogenesis Imperfecta types I, III, and IV are autosomal dominant or sporadic. Patients have normal body proportions and fractures with normal bone lengths [19].

Congenital hypophosphatasia - is an autosomal recessive disorder with severe demineralization of the bones is present. Sonography shows short-limbed dwarfism, thin delicate bones with reduced echogenicity. First-trimester chorionic sampling with alkaline phosphatase assay may establish the diagnosis [21].

Metatrophic dysplasia - with varied inheritance associated with a narrow thorax, kyphoscoliosis relatively long trunk, and a tail-like appendage over the sacrum [18].

Roberts syndrome (pseudothalidomide syndrome) - is autosomal recessive with variable expression, featuring tetraphocomelia and a midline facial cleft. Chromosomal analysis shows a classical abnormality with the centromere region being fluffy [23].

Diastrophic dysplasia - is an autosomal recessive disorder with multiple contractures and hitchhiker"s thumb (more muscle mass than arthrogryposis) [23].

Short rib-polydactyly syndrome types I, II, and III

  • Type I, or Saldino-Noonan disease: with severely shortened ribs and/or narrow thorax, short limbs, polydactyly, CVS and genital anomalies, polycystic kidney and pointed metaphysis

  • Type II, or Majewski disease: short limbs, narrow thorax, polydactyly, CVS anomalies, polycystic kidneys, genital anomalies disproportionately short tibia, and cleft lip and palate.

  • Type III, or Naumoff disease: short limbs, narrow thorax, polydactyly, and CVS and genital anomalies, wide metaphysic with marginal spurs [22,24].

Camptomelic dysplasia (Spondyloepiphyseal dysplasia congenital) - is autosomal dominant and associated with short and bowed femora, a short spine and trunk, anterior bowing of the long bones of the lower extremities, anomalies of cervical and thoracic spine with spinal scoliosis, and hypoplastic or absent scapulas [19].

Thanatophoric dysplasia - sporadic lethal skeletal dysplasia. About 14% with cloverleaf skull, marked narrowing of the thorax and marked micromelia, enlargement of the head (with a prominent forehead), occasional hydrocephalus, and polyhydramnios. The soft tissues of the limbs may be thickened [18,23].

Chondrodysplasia punctate (rhizomelic type) - is associated with severe micromelia of the humeri and femora, multiple joint contractures, and dorsal and ventral ossification of the vertebral body separated by a cartilaginous bar [17].

Kniest dysplasia -  is an autosomal dominant disease associated with kyphoscoliosis, short trunk, broad thorax, and widened metaphyses [23].

Mesomelic and acromesomelic dysplasia - are autosomal recessive or autosomal dominant conditions associated with micromelia of the middle or distal segments [18].

Hypochondroplasia - is characterized by phenotypic and genetic heterogeneity. Difficult to differentiate  from other conditions with disproportionate short stature. The crucial skeletal regions to focus on in the diagnosis of hypochondroplasia are the lumbar spine and legs [18].

Pseudoachondroplasia - (PSACH) is a spondyloepimetaphyseal dysplasia characterized by disproportionate short stature, generalized ligamentous laxity and precocious osteoarthritis.

Prognosis

The standardized mortality ratio is increased for all age groups by a factor of 2.27 over that of the general population [13].

Recurrence risk

The risk of the parents producing a second affected child is almost negligible. Recently, reports have estimated the risk of recurrence of achondroplasia in the siblings of an affected child with unaffected parents to be 1 in 443 [14]. This is because of gonadal mosaicism in the parents. Average-sized siblings have no increased risk of producing a child with achondroplasia.

Management

Fetuses with suspected achondroplasia should generally be delivered by cesarean section to reduce the risk of possible CNS complications associated with vaginal delivery. The typical appearance of achondroplastic dwarfism is apparent at birth.

Medical Care: Growth hormone is currently being used to augment the height of patients with achondroplasia. Therapy is initiated at young age (1-6 years) for maximum benefits [25,26].

Surgical Care: Craniocervical stenosis, thoracolumbar kyphosis, spinal stenosis, angular deformities of the lower extremities and lengthening of the short extremities are the orthopedic procedures commonly performed in achondroplasia [15].

Special considerations and pitfalls

• The diagnosis of achondroplasia in the fetus is made with certainty when one or both parents have this condition.
• In situations in which the parents have normal stature, the diagnosis may only be suspected based on the observation of disproportionately short limbs in the fetus when evaluated by ultrasound.
• In most cases, the specific diagnosis cannot be made with certainty until birth.
• Caution should be exercised when counseling the family.
• The diagnosis should be confirmed at birth using radiographic studies. The measurements, including arm span, occipital frontal circumference, body length, and upper-to-lower body ratio, should be documented.
• It is important to consult a physician with experience and expertise concerning achondroplasia early in the child"s development. Since pediatricians usually see the child first, a set of guidelines exists to assist them in caring for children with achondroplasia and their families [15].

Reference

1. "Achondroplasia" . Illustrated overview. – Medical Etymology- Pandora"s WordBox- W.     Wertelecki, M.D-.www.consultsos.com.
2. Antenatal Detection of Skeletal Dysplasias  Barbara V. Parilla, MD, Elizabeth A. Leeth, MS, Michelle P. Kambich, MS, Patricia Chilis, RDMS and Scott N. MacGregor, DO . Division of Maternal-Fetal Medicine, , Northwestern University Medical School, Evanston, Illinois USA. J Ultrasound Med 22:255-258 • 0278-4297.
3. Julia Wynn 1, Terri M. King 1, Michael J. Gambello 1, D. Kim Waller 2, Jacqueline T. Hecht 1 31Department of Pediatrics, University of Texas Health Science  Center at Houston, Houston, Texas. Mortality in achondroplasia study: A 42-year follow-up. American Journal of Medical Genetics Part A, Volume 143A, Issue 21, P.2502-2511.  
4. Rousseau, F., et al. Mutations in the gene encoding fibroblast growth factor receptor 3 in achondroplasia. Nature, volume 371, September 15, 1994, pages 252-254.
5. Shiang, R., et al. Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell, volume 78, July 29, 1994, pages 335-342.
6. Wilkin, D.J., Szabo, J.K., Cameron, R., Henderson, S., Bellus, G.A., Mack, M.L., Kaitila, I., Loughlin, J., Munnich, A., Sykes, B. et al. (1998) Mutations in fibroblast growth-factor receptor 3 in sporadic cases of achondroplasia occur exclusively on the paternally derived chromosome. Am. J. Hum. Genet., 63, 711–716..
7. Sharony, R, Browne C, Lachman RS, et al: Prenatal diagnosis of the skeletal dysplasias. Am J Obstet Gynecol 169:668-675, 1993. ,      Rimoin DL, Krakow D: Skeletal dysplasias, in New M (ed): Diagnosis and Treatment of the Unborn Child. Reddick, Fla, Idelson-Gnocchi,1999, pp 63-65.
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14. American Journal of Medical Genetics Volume 90, Issue 3, P.250-251. Recurrence risk for sibs of children with  " sporadic"  achondroplasia. Gabrielle Mettler 1 *, F. Clarke Fraser
15. Ali Nawaz Khan, King Fahad Hospital, Saudi Arabia. Sumaira Macdonald , Sheffield University Medical School; Endovascular Fellow, Sheffield Vascular Institute- Achondroplasia.-on-line article-
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