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1992-10-13-13 Campomelic dysplasia © Valcamonico www.thefetus.net/

Campomelic dysplasia 

Adriana Valcamonico, MD, Philippe Jeanty, MD, PhD 

 Address correspondence to Adriana ­Valcamonico, MD, Vanderbilt University, De­partment of Radiology, 31st and Garland, Nashville, TN 37232-5316, Ph: 615-343-0595, Fax: 615-343-4890

Synonyms: Camptomelic dysplasia, campomelic syndrome, campomelic dwarfism, congenital bowing of the limbs1.

 Definition: Campomelia is a syndrome featuring angulation of the long bones such as femur and tibiae2. Some authors have classified the disease into two varieties: “long limbed” and “short limbed,” depending on the type of limbs involved in the pathological process3.

Etymology: from campo = bent, and melia = limb.

Prevalence: 0.02:10,000 live births4. Sex reversal occurs in some karyotypic males with lack the H-Y antigen. Phenotypic sex ratio is approximately M1:F2.3, karyotypic sex ratio is approximately M2:F11.

Etiology: Autosomal recessive inheritance. Most cases are sporadic1.

Recurrence risk: 25%5.

Pathogenesis: Different pathogenetic factors have been proposed: 1) mechanical stress due to faulty fetal position within the uterus6; 2) primary muscle imbalance and shortening, particularly of the calf muscles causing secondary bending of the tibia7; 3) intrauterine fracture with subsequent healing8; 4) abnormal vascular and cellular elements of perichondrium9; 5) developmental disturbance in the cartilagineous phase of bone formation10.

Associated anomalies: High forehead with prominent occiput, low-set ears, micrognathia, hyper­te­lo­rism, cleft of the soft palate, small and bell-shaped chest, short limbs, hypoplastic fibulae, eleven pairs of ribs, hypoplasia of the scapulae, scoliosis or kyphoscoliosis with hypoplasia of the midthoracic vertebral bodies, high and narrow pelvis, dislocation of the hips, talipes equinovarus and cutaneous dimpling, soft and reduced tracheobronchial cartilages. Central nervous system, cardiac and renal abnormalities have been reported in some cases11.

Differential diagnosis: Osteogenesis imperfecta type I and II, hypophosphatasia, unclassifiable varieties of congenital bowing  of the long bones12, thanatophoric dysplasia, mesomelic dysplasia (Reinhart variety)2.

Prognosis: Almost all result in neonatal or infant death. Some survivors,  including a boy alive at 17 years, have been reported13.

Management: Before viability, the option of termination of pregnancy should be offered. After viability, standard obstetrical management is not altered, and respiratory function in the newborn must be supported.

MESH Dwarfism-diagnosis, Osteochondrodysplasia-diagnosis BDE 0122 MIM 211970 ICD9 754.4 CDC 754.425

Introduction

Campomelic dysplasia is a disorder which presents with congenital bowing of the long bones, particularly tibiae and femurs. Because of several extraskeletal anomalies, some authors prefer to  refer to campomelic syndrome rather than campomelic dysplasia11.

Khajavi et al.3 distinguished two different types of this syndrome. A “long-limbed” type with bent bones of normal width but slightly shortened and rarely involving the upper limbs, and a “short-limbed” type in which the bent bones are short and wide. Neonatal death is the expected outcome, almost always due to respiratory distress. However, some survivors have been described (one alive at 17 years of age)11.

Case report

A 27-year-old woman G5P2002 was referred to our institution after a routine ultrasound scan at 18 weeks that revealed a discrepancy in the fetal measurements. The gestational age derived from the head measurement was 18 weeks, but it was only 14 weeks when derived from the long bone measurements. The anamnesis of the patient was unremarkable except for congenital absence of the left forearm in her mother.

Our scan revealed multiple anomalies including significant limb shortening and bowing (fig. 1-2), short ribs, an omphalocele (fig. 3) with ascites and chest hypoplasia. Ossification of the bones appeared within normal limits. A percutaneous umbilical blood sampling revealed a normal female karyotype.

The pregnancy was terminated with Prostin induction at 20 weeks of gestation. A 330g girl fetus was delivered. The radiograms of the whole body showed bilateral ulnar bowing, mild bilateral femoral bowing and bilateral shortening of the tibiae. Ossification of the fibulae was absent bilaterally. All the extremities were shortened in proportion to the trunk, and the thorax was hypoplastic, with the ribs demonstrating a horizontal alignment. Both scapulae were dysplastic, and the pelvis demonstrated a trident-like spur. Cleft lip, cleft palate and omphalocele were noted. Macroscopic and microscopic examination of the different organs were unremarkable.

 Figure 1: The curvature of the femur is visible.

 

Figure 2: The curvature of the ulna is visible.

Figure 3: A small omphalocele is also present.

Discussion

Etiopathogenesis

The genesis of the long bones bowing and shortening, characteristic of campomelic dysplasia, is still obscure. Many different mechanisms are postulated to explain the very typical skeletal anomaly of this syndrome:

·         Bain and Barrett suggest that the underlying defect is an abnormality in the vascular and cellular elements of perichondrium9.

·         Lee describes a developmental disturbance in the cartilaginous phase of bone formation10.

·         Middleton reports that during fetal life, as a result of primary shortness of calf muscles, a strain is applied to the tibial bones which, being still cartilaginous, bend in the region of least resistance, which is the junction between the middle and the lower third7.

·         Lazjuk proposes that the pathogenesis of bone curvature in the lower limbs is multifactorial and is the result of primary focal shaft dysplasia and defective length of the posterior muscles of the femora and crus15.

·         A Japanese study based on morphological observation and biochemical analysis of glycosaminoglycans, showed increased amounts and differences in composition of glycosaminoglycans in the diaphyseal bone of the concave side, suggesting the existence of bone with maturity retardation16.

·         A transient exogenous teratogen or toxic agent could be another etiologic factor to explain the abnormality of cartilage anlage formation in campomelic dysplasia17.

Associated anomalies

Many extraskeletal anomalies have been described in association with bowing of the long bones. They include dolichoce­phaly with high forehead and prominent occiput, cleft of the soft palate, micrognathia, low-set ears,  narrow and bell-shaped chest with hypoplastic scapulae and often 11 pairs of ribs, hypo­plasia of the mid-thoracic vertebral bodies with absent mineralization of the pedicles, dislocation of the hips, and talipes equi­no­varus. Central nervous sytem abnormalities, including absence of olfactory bulbs and nerves, are found in about half of the autopsied cases, often with dilatation of the lateral ventricles (hydrocephalus has been reported in only 23% of cases). Hydronephrosis with unilateral or bilateral urethral dilation is seen in about 30% of patients. In 25% of cases, a congenital heart defect is diagnosed, most commonly a patent ductus arteriosus or foramen ovale11. In the respiratory system, the most characteristic finding is the deficiency of tracheobronchial cartilages, which may be reduced in number, fused and fenestrated anteriorly, incomplete posteriorly, soft, easily collapsible and totally absent in smaller bronchi18.

Almost half of the cases present sex reversal, which means a female phenotype with a male 46XY chromosomal constitution and H-Y antigen negative11.

Polyhydramnios is commonly described (Table 1). 

Table 1: Review of the literature. 

Case

Prenatal findings

Postnatal findings

Neonatal outcome

120

Dilatation of the posterior horns of the lateral ventricles and of the third ventricle; bilateral cystic renal mass; bowing of the left tibia; polyhydramnios.

Large cranium with small mid-face, down- slanting eyes, low-set malformed ears; small bell-shaped thorax; bilateral bowing of the tibiae and fibulae; scapular hypoplasia; hypoplastic pelvis; skin dimpling;bilateral talipes equinovarus

Died 2 hours after birth of respiratory failure.

219

Large BPD and discrepancy between upper and lower limbs diaphysis length, flattened nose, high forehead.

Bowing of the lower limbs, clubfeet, cleft palate, micrognathia, soft larynx and trachea, VSD, hypoplasia of the scapulae, iliac bones and fibulae, 11 pair of ribs.

Termination of pregnancy at 20 weeks

312

Bowing and shortness of the lower extremities, hypoplasia of fibulae and scapulae, talipes equinovarus, bell-shaped chest, micrognathia, flat nasal bridge.

Brachycephaly, hypertelorism, low-set ears, pretibial dimples, narrow iliac wings.

Termination of pregnancy at 26 weeks

421

Short and curved femora, bowing of both tibiae and fibulae, polyhydramnios.

Bell-shaped thorax, hypoplasia of the mid- thoracic vertebral bodies, scapulae and several ribs, narrowing of the iliac wings, dislocation of both femora.

Died at six days of life for respiratory insufficiency.

522

Shortness and bowing of one femur and one humerus. Small chest, large kidneys, severe oligohydramnios.

Short and bowed bones of extremities, tibial dimples, 13 thoracic vertebrae, the 3rd with no ribs and no pedicles, equinus deformity of the foot, generalized edema, large and deformed head. Autopsy: polycystic dysplasia of the kidneys, liver and pancreas, very short small and  large bowel, atresia of the cecum and polysplenia, absence of the olfactory bulbs.

Onset of labor at 27 weeks: the baby died during labor.

Present case

Limb shortening and bowing, short ribs, omphalocele with ascites, chest hypoplasia

Dysplastic scapulae, trident-like spur of the pelvis, cleft lip and palate.

Termination of pregnancy

at 20 weeks.

Differential diagnosis 

The presence of bowing of the long bone is quite typical of campomelic dysplasia, even though a few other skeletal anomalies present this finding. They are:

·         osteogenesis imperfecta, in which the bones are shortened, fractured and angulated. A callus is often visible at the apex of the angle;

·         hypophosphatasia, characterized by marked demineralization of the calvarium and long bones which are often fractured;

·         unclassifiable varieties of congenital bowing of the long bones12,

·         thanatophoric dysplasia, in which the extreme rhizomelia is often associated with a hypo­plastic thorax and cloverleaf skull;

·         mesomelic dysplasia (Reinhardt variety), characterized by meso­melic shortening of the upper extremities, bowing of the forearm bones, ulnar deviation of the arm and hypoplastic fibula2.

Variants

In 1989, Macpherson et al.14 reported two cases of infants with respiratory distress showing all the clinical and radiological stigmata of the campomelic dysplasia except campomelia itself.

Prognosis

Campomelic syndrome is usually fatal within days. Respiratory failure is the most common cause of death18. The small bell-shaped thoracic cage in combination with soft, easily collapsible and reduced tracheobronchial cartilages produce serious inspiratory and expiratory obstruction in these infants that lead rapidly to the development of respiratory failure and death.

However, several survivors are reported with initially normal neurologic status and psychomotor development.

In 1971 Maroteaux reported a case of campomelic syndrome in a boy alive at 17 years of age with an IQ of 45 and hearing loss13. Gillerot 19 presented a case of campomelic dysplasia in a 5-year-old girl, and Houston reported 4 cases of babies with campomelic dysplasia all alive at 1, 2, 12 and 30 months, respectively11.

Management

Since campomelic dysplasia is almost always a fatal anomaly, the option of pregnancy termination should be offered before viability. At birth, the neonate usually presents with respiratory distress and requires ventilatory assistance. However, in spite of many efforts to ventilate these babies, most of them die within days or weeks because of the severe degree of laryngotracheobroncho­malacia which is typical of this disease.

References

1. Buyse ML. Birth defects encyclopedia. Dover, MA. Blackwell Scientific Publications, pp 252-253, 1990.

2. Romero R, Pilu G, Jeanty P. et al. Prenatal diagnosis of congenital anomalies. Appleton and Lange, Norwalk, Connecticut, 1988.

3. Khajavi A, Lachman R, Rimoin N, et al. Heterogeneity in the campomelic syndromes. Long and short bone varieties. Radiology 120:641-647;1976.

4. Urioste M, Arroyo A, Martinez-Frias ML. Campomelia, polycystic dysplasia and cervical lymphocele in two sibs. Am J Med Genet 41:475-477;1991.

5. Hall BD, Spranger JW. Campomelic dysplasia: further elucidation of a distinct entity. Am J Dis Child 134:285-289;1980.

6. Caffey J. Prenatal bowing and thickening of tubular bones with multiple cutaneous dimples in arms and legs: a congenital syndrome of mechanical origin. Am J Dis Child 74:543-562;1947.

7. Middleton DS. Studies of prenatal lesions of striated muscle as a cause of congenital deformities. Edinburgh Med J 41:401-442;1934.

8. Snure H. Intrauterine fracture. Radiology 13:362-365;1929.

9. Bain AD, Barrett HS. Congenital bowing of the long bones: report of a case. Arch Dis Child 34:516-524;1959.

10. Lee FA, Isaacs H, Strauss J. The “campomelic” syndrome. Am J Dis Child 124:485-496;1972.

11. Huston CS, Opiz JM, Spranger JW, et al. The campomelic syndrome: review, report of 17 cases, and follow-up on the currently 17-year-old boy first reported by Maroteaux et al. in 1971. Am J Med Genet 15:3-28;1983.

12. Cordone M, Lituania M, Zampatti C, et al. In utero ultrasonographic features of campomelic dysplasia. Prenat Diagn 9:745-750;1989.

13. Maroteaux P, Spranger J, Opiz JM, et al. Le syndrome campomelique. Presse Med 79:1157-1162;1971.

14.Macpherson RI, Skinner SA, Donnenfeld AE. Acampomelic campomelic dysplasia. Pediatr Radiol 20:90-93;1989.

15. Lazjuk GI, Shved IA, Cherstvoy ED, et al. Campomelic syndrome: concepts of the bowing and shortening in lower limbs. Teratology 35:1-8;1987.

16. Nogami H, Oohira A, Kuroyanagi M, et al. Congenital bowing of long bones: clinical and experimental study. Teratology 33:1-7;1986.

17. Roth SI, Jimenez JF, Husted S et al. The histopathology of camptomelia (bent limbs). Clin Ortop Relat Res 167:152-159;1982.

18. Grad R, Sammut PH, Britton JR, et al. Bronchoscopic evaluation of airway obstruction in campomelic dysplasia. Pediatr Pulmonol 3:364-367;1987.

19. Gillerot Y, Vanheck CA, Foulon M, et al. Campomelic syndrome: manifestations in a 20 week fetus and case history of a 5 years old child. Am J Med Genet 34:589-592;1989.

20. Slater CP, Ross J, Nelson MM, et al. The campomelic syndrome - prenatal ultrasound investigations. South Afr Med J 67:863-866;1985.

21. Balcar I, Bieber FR Sonographic and radiological findings in campomelic dysplasia. AJR 141:481-2;1983.

22. Cumming WA, Ohison A, Ali A. Brief clinical report: campomelia, cervical limphocele, polycystic dysplasia, short gut, polisplenia. Am J Med Genet 25:783-790;1986.

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