84 In 1955, Jeune et al. described familial asphyxiating tho- racic dystrophy (ATD) in a pair of siblings with severely nar- row thoraxes. This condition is also known as Jeune syndrome.
Incidence is estimated at 1 per 100,000–130,000 live births.
Jeune syndrome, a potentially lethal congenital dwarfism, is a rare autosomal recessive disorder characterized by typical skeletal dysplasias, such as a narrow thorax and micromelia, with respiratory and renal manifestations. Respiratory manifes- tations vary widely from respiratory failure and infantile death to a latent phenotype without respiratory symptoms.
GENETICS/BASIC DEFECTS
1. Inheritance: autosomal recessive 2. The gene for ATD
a. Mapped to chromosome 15q13
b. Families with both mild and severe forms of ATD mapped to 15q13
c. Five consanguineous families sharing a 1.2 cm region of homozygosity between D15S165 and D15S1010 d. No pathogenic mutations detected in two candidate
genes, GREMLIN and FORMIN, by mutation analysis
CLINICAL FEATURES
1. Wide phenotypic variability 2. Classification of ATD
a. Lethal form b. Severe form c. Mild form d. Latent form 3. Short-limbed dwarfism 4. Growth retardation 5. Respiratory distress
a. Respiratory distress secondary to a small thorax i. Motionless thorax
ii. Abdominal respiration
iii. Considerable supraclavicular, suprasternal, and intercostal space retraction on inspiration b. Severe dyspnea and extreme cyanosis in severe cases c. Some infants with only respiratory symptoms in con-
junction with infection
d. Some individuals lack respiratory symptoms in infancy or childhood
6. Chest deformity of varying degrees
a. A long, narrow, and abnormally small thorax with reduced thoracic cage capacity
b. Lung hypoplasia and respiratory distress, usually leading to early death
c. The symptoms of small thorax usually improves with age for those who survive early childhood
7. Limbs
a. Variable micromelia and short digits with bulbous ter- minal phalanges
b. Occasional postaxial polydactyly of the hands and feet
8. Eyes: occasional retinal degeneration 9. Occasional intestinal malabsorption
10. Renal failure developing during infancy, early adoles- cence, or second decade of life
11. Polyuria, polydipsia, and hypertension occur during the second or third year of life
12. Occasional involvement of the liver a. Prolonged neonatal jaundice b. Polycystic liver disease c. Hyperplasia of the bile ducts d. Congenital hepatic cirrhosis 13. Occasional involvement of the heart
a. Cardiac failure secondary to increased pulmonary vascular resistance, thoracic constriction, and alveolar hypoplasia
b. Possible intrinsic myocardial disease
14. Cystic changes of pancreatic ducts and pancreatic exocrine insufficiency occur in long-term survivors 15. Occasional involvement of the teeth, nails, and other
organs 16. Prognosis
a. Difficult to predict in each individual case because frequent pulmonary complications and cystic renal lesions are not always directly related to severity of skeletal changes
b. The skeletal dysplasia of this entity is compatible with life, though respiratory failure and infections are often fatal during infancy
c. Considerable variation in the severity of thoracic con- striction: For those patients who survive infancy, the thorax tends to revert to normal with improving respi- ratory function. This suggests that the lungs have a normal growth potential and the respiratory problems are secondary to restricted rib cage deformity d. Renal failure: Renal involvement is the major prognos-
tic factor in those patients who survive the respiratory insufficiency during infancy
e. Short stature in survivors 17. Morbidity and mortality
a. Alveolar hypoventilation
i. The most common and prominent clinical pres- entation
ii. Caused by impaired chest expansion as a result of short, horizontally placed ribs
b. Bilateral microcystic renal disease gradually progress- ing to tubular atrophy and renal failure
c. Most patients (approximately 60–70%) dying from respiratory failure in early infancy and early child- hood
d. Chronic renal failure ensuing in survivors e. Few patients reaching adolescence or adulthood
DIAGNOSTIC INVESTIGATIONS
1. Laboratory studies a. Urinalysis
i. Hematuria ii. Proteinuria
iii. Defective urine concentrating capacity
b. Arterial blood gas (ABG): hypoxia and hypercarbia in room air reflecting severe restrictive lung disease 2. Imaging studies
a. Newborn and infant radiography
i. Small and bell-shaped thorax with reduced trans- verse and anterior-posterior diameter
ii. Abnormal clavicles (“bicycle handlebar shaped”) iii. Short and horizontally oriented ribs with irregu- lar costochondral junctions and bulbous and irregular anterior ends
iv. Abnormal pelvis
a) Short squared iliac wings
b) Trident appearance of acetabular margin v. Short limbs relative to trunk
vi. Variable limb-shortening
vii. Short phalanges, metacarpals, or metatarsals with or without polydactyly
viii. Premature ossification of the capital femoral epi- physes
b. Childhood radiology
i. Relatively larger thorax with growth of ribs com- pared to infancy
ii. Short ilium with normal flaring of iliac wings iii. Striking cone-shaped epiphyses and early fusion
between the epiphyses and metaphyses of the distal and middle phalanges
iv. Short distal and middle phalanges
v. Varying shortening of extremities relative to trunk
c. Subtypes of ATD
i. Type I: irregular metaphyseal ends ii. Type II: smooth metaphyseal ends
3. Pulmonary function test to detect severe restrictive lung disease
4. Histology
a. Lungs: Hypoplastic due to a marked reduction in the number of alveolar ducts and alveoli (hypoplasia of alveoli)
b. Cartilages: retarded endochondral ossification in both types
i. ATD type I: irregular cartilage-bone junction with patchy distribution of physeal growth zone of chondrocytes
ii. ATD type II: smooth cartilage bone junctions c. Kidneys
i. Cystic renal dysplasia and hypoplasia ii. Nephronophthisis or interstitial nephritis
a) Diffuse interstitial and periglomerular fibrosis b) Round-cell lymphocytic infiltration
c) Hyalinized glomeruli d) Pericapsular thickening e) Thickened basement membrane f) Dilated or atrophic tubules iii. Pyelonephritis with scarring
iv. Distortion of renal parenchyma d. Liver
i. Periportal hepatic fibrosis ii. Bile duct proliferation iii. Early cirrhosis
GENETIC COUNSELING
1. Recurrence risk a. Patient’s sib: 25%
b. Patient’s offspring: usually lethal, not surviving to reproductive age
2. Prenatal diagnosis by ultrasonography
a. Detection of affected second- and third-trimester fetuses of at-risk families
b. Characteristic ultrasonographic findings i. Narrow thorax
ii. Short hypoplastic ribs iii. Short tubular bones
iv. Renal cystic changes c. Other ultrasonographic findings
i. Polyhydramnios
ii. Absent or feeble fetal respiratory movements iii. Increased nuchal translucency
iv. With or without polydactyly v. Ventriculomegaly
vi. A single umbilical artery 3. Management
a. Medical care i. Supportive care ii. Mechanical ventilation
a) Urgently required in the most severe cases, those when respiratory distress develops immediately after birth
b) Less-severe cases gradually progressing to respiratory failure as a result of multiple recurrent pulmonary infections
iii. Treat respiratory infections vigorously with antibiotics, endotracheal suctioning, and pos- tural drainage
iv. Nasogastric or gastrostomy feedings, if needed v. Ursodeoxycholic acid used to control the pro-
gression of the hepatic dysfunction b. Surgical care
i. Surgery indicated only in the most severe cases in which failure to intervene will result in progressive pulmonary damage and eventual death. No data are currently available on long-term follow-up care of patients who have been surgically treated ii. Expansion thoracoplasty utilizing various surgi-
cal techniques
a) Splitting the sternum or the rib cage and maintaining the separation with methacrylate
b) Rib grafts
c) Homologous bone grafts
d) Lateral rib cage expansion using staggered superiosteal rib osteotomies and rigid tita- nium miniplate and screw augmentation and stabilization
e) Modified bailey rib approximator to provide a calibrated dynamic separation for the ster- num after the primary procedure of midster- notomy and methylmethacrylate sternoplasty iii. Dialysis and renal transplantation indicated for renal failure. Recently, cadaver renal transplanta- tion was successful in a 10-year-old boy with Jeune syndrome type 2
iv. Surgical complications a) Pneumothorax
b) Mucous plugging of a bronchus c) Repeated infections
d) Progressive herniation of lung through ster- nal defect
e) Cardiac insufficiency
REFERENCES
Allen AW, Moon JB, Hovland KR, et al.: Ocular findings in thoracic-pelvic- phalangeal dystrophy. Arch Ophthalmol 97:489–492, 1979.
Amirou M, Bourdat-Michel G, Pinel N, et al.: Successful renal transplantation in Jeune syndrome type 2. Pediatr Nephrol 12:293, 294, 1998.
Aronson DC, Van Nierop JC, Taminiau A, et al.: Homologous bone graft for expansion thoracoplasty in Jeune’s asphyxiating thoracic dystrophy. J Pediatr Surg 34:500–503, 1999.
Aurora P, Wallis CE: Jeune syndrome (asphyxiating thoracic dystrophy) asso- ciated with Hirschsprung disease. Clin Dysmorphol 8:259–263, 1999.
Bard LA, Bard PA, Owens GW, et al.: Retinal involvement in thoracic-pelvic- phalangeal dystrophy. Arch Ophthalmol 96:278–281, 1978.
Barnes ND, Hull D, Milner AD, et al.: Chest reconstruction in thoracic dystro- phy. Arch Dis Child 46:833–837, 1971.
Bernstein J, Brough AJ, McAdams AJ: The renal lesion in syndromes of mul- tiple congenital malformations. Cerebrohepatorenal syndrome; Jeune asphyxiating thoracic dystrophy; tuberous sclerosis; Meckel syndrome.
Birth Defects Orig Artic Ser 10:35–43, 1974.
Borland LM: Anesthesia for children with Jeune’s syndrome (asphyxiating tho- racic dystrophy). Anesthesiology 66:86–88, 1987.
Chen CP, Lin SP, Liu FF, et al.: Prenatal diagnosis of asphyxiating thoracic dys- plasia (Jeune syndrome). Am J Perinatol 13:495–498, 1996.
Chen H: Asphyxiating thoracic dystrophy (Jeune syndrome). Emedicine, 2004.
http://www.emedicien.com
Cortina H, Beltran J, Olague R, et al.: The wide spectrum of the asphyxiating thoracic dysplasia. Pediatr Radiol 8:93–99, 1979.
Copeland-Fields LD, Singleton KA, Racela C, et al.: Discharge planning: pedi- atric case study of Jeune’s asphyxiating thoracic dystrophy. Crit Care Nurse 5:61–70, 1985.
Das BB, Nagaraj A, Fayemi A, et al.: Fetal thoracic measurements in prenatal diagnosis of Jeune syndrome. Indian J Pediatr 69:101–103, 2002.
Davis JT, Ruberg RL, Leppink DM, et al.: Lateral thoracic expansion for Jeune’s asphyxiating dystrophy: a new approach. Ann Thorac Surg 60:694–696, 1995.
den Hollander NS, Robben SG, Hoogeboom AJ, et al.: Early prenatal sono- graphic diagnosis and follow-up of Jeune syndrome. Ultrasound Obstet Gynecol 18:378–383, 2001.
Elçioglu NH, Hall CM: Diagnostic dilemmas in the short rib-polydactyly syn- drome group. Am J Med Genet 111:392–400, 2002.
Elejalde BR, de Elejalde MM, Pansch D: Prenatal diagnosis of Jeune syn- drome. Am J Med Genet 21:433–438, 1985.
Finegold MJ, Katzew H, Genieser NB: Lung structure in thoracic dystrophy.
Am J Dis Child 122:153–159, 1971.
Friedman JM, Kaplan HG, Hall JG: The Jeune syndrome (asphyxiating tho- racic dystrophy) in an adult. Am J Med 59:857–862, 1975.
Giorgi PL, Gabrielli O, Bonifazi V, et al.: Mild form of Jeune syndrome in two sisters. Am J Med Genet 35:280–282, 1990.
Herdman RC, Langer LO: The thoracic asphyxiant dystrophy and renal dis- ease. Am J Dis Child 116:192–201, 1968.
Hsieh YY, Hsu TY, Lee CC, et al.: Prenatal diagnosis of thoracopelvic dyspla- sia. A case report. J Reprod Med 44:737–740, 1999.
Jeune M, Beraud C, Carron R: Dystrophic thoracique asphxiante de caractere familial. Arch Fr Pediatr 12:886–891, 1955.
Kaddoura IL, Obeid MY, Mroueh SM, et al.: Dynamic thoracoplasty for asphyxiating thoracic dystrophy. Ann Thorac Surg 72:1755–1758, 2001.
Kozlowski K, Masel J: Asphyxiating thoracic dystrophy without respiratory disease: report of two cases of the latent form. Pediatr Radiol 5:30–33, 1976.
Labrune P, Fabre M, Trioche P, et al.: Jeune syndrome and liver disease: report of three cases treated with ursodeoxycholic acid. Am J Med Genet 87:324–328, 1999.
Langer LO Jr: Thoracic-pelvic-phalangeal dystrophy: asphyxiating thoracic dystrophy of the newborn, infantile thoracic dystrophy. Radiology 91:447–456, 1968.
Morgan NV, Bacchelli C, Gissen P, et al.: A locus for asphyxiating thoracic dystrophy, ATD, maps to chromosome 15q13. J Med Genet 40:431–435, 2003.
Oberklaid F, Danks DM, Mayne V, et al.: Asphyxiating thoracic dysplasia.
Clinical, radiological, and pathological information on 10 patients. Arch Dis Child 52:758–765, 1977.
Özçay F, Derbent M, Demirhan B, et al.: A family with Jeune syndrome.
Pediatr Nephrol 16:623–626, 2001.
Phillips CI, Stokoe NL, Bartholomew RS: Asphyxiating thoracic dystrophy (Jeune’s disease) with retinal aplasia: a sibship of two. J Pediatr Ophthalmol Strabismus 16:279–283, 1979.
Pirnar T, Neuhauser EB: Asphyxiating thoracic dystrophy of the newborn. Am J Roentgenol Radium Ther Nucl Med 98:358–364, 1966.
Sarimurat N, Elcioglu N, Tekant GT, et al.: Jeune’s asphyxiating thoracic dys- trophy of the newborn. Eur J Pediatr Surg 8:100,101, 1998.
Schinzel A, Savoldelli G, Briner J, et al.: Prenatal sonographic diagnosis of Jeune syndrome. Radiology 154:777–778, 1985.
Shah KJ: Renal lesion in Jeune’s syndrome. Br J Radiol 53:432–436, 1980.
Sharoni E, Erez E, Chorev G, et al.: Chest reconstruction in asphyxiating tho- racic dystrophy. J Pediatr Surg 33:1578–1581, 1998.
Skiptunas SM, Weiner S: Early prenatal diagnosis of asphyxiating thoracic dys- trophy (Jeune’s syndrome). Value of fetal thoracic measurement. J Ultrasound Med 6:41–43, 1987.
Tahernia AC, Stamps P: “Jeune syndrome” (asphyxiating thoracic dystrophy).
Report of a case, a review of the literature, and an editor’s commentary.
Clin Pediatr (Phila) 16:903–908, 1977.
Todd DW, Tinguely SJ, Norberg WJ: A thoracic expansion technique for Jeune’s asphyxiating thoracic dystrophy. J Pediatr Surg 21:161–163, 1986.
Tongsong T, Chanprapaph P, Thongpadungroj T: Prenatal sonographic findings associated with asphyxiating thoracic dystrophy (Jeune syndrome). J Ultrasound Med 18:573–576, 1999.
Turkel SB, Diehl EJ, Richmond JA: Necropsy findings in neonatal asphyxiat- ing thoracic dystrophy. J Med Genet 22:112–118, 1985.
Weber TR, Kurkchubasche AG: Operative management of asphyxiating tho- racic dystrophy after pectus repair. J Pediatr Surg 33:262–265, 1998.
Wiebicke W, Pasterkamp H: Long-term continuous positive airway pressure in a child with asphyxiating thoracic dystrophy. Pediatr Pulmonol 4:54–58, 1988.
Yang SS, Heidelberger KP, Brough AJ, et al.: Lethal short-limbed chondrodys- plasia in early infancy. Perspect Pediatr Pathol 3:1–40, 1976.
Yang SS, Langer LO Jr, Cacciarelli A, et al.: Three conditions in neonatal asphyxiating thoracic dysplasia (Jeune) and short rib-polydactyly syn- drome spectrum: a clinicopathologic study. Am J Med Genet Suppl 3:191–207, 1987.
Yerian LM, Brady L, Hart J: Hepatic manifestations of jeune syndrome (asphyxiating thoracic dystrophy). Semin Liver Dis 23:195–200, 2003.
Fig. 1. A neonate died of respiratory insufficiency. The chest is severely narrow and limbs are mildly shortened (Perspect Pediatr Pathol 3:1–40, 1976). The longitudinal section of the humerus shows irregular cartilage-bone junctions. There is a premature ossification center in the proximal epiphysis. The photomicrograph of the physeal growth zone shows scattered areas (left 2/3rd of the picture) of severe retardation and disorganization. Consequently, the cartilage-bone junction is irregular.
Fig. 2. Radiographs of the skeletal system of a neonate with type II asphyxiating thoracic dystrophy. The ribs are short. The ilia are verti- cally shortened. The findings are similar in both types I and II.
However, the metaphyseal ends of tubular bones do not show irregu- larity or spurs as in type I. Photomicrograph of the proximal femur shows generalized retardation and disorganization of the physeal growth zone. The cartilage columns in the metaphysis form a lattice- like meshworks.
Fig. 3. An infant with type II asphyxiating thoracic dystrophy showing a narrow thorax and short upper extremities. The radiographs showed the handlebar clavicles, short horizontal ribs with widened/cupped anterior rib ends, and square-shaped iliac bones with the medial spurs of both acetabular roofs. The necropsy showed lung hypoplasia and renal cystic dysplasia and hypoplasia.
Fig. 4. A 7-year-old boy with asphyxiating thoracic dystrophy show- ing a narrow thorax and short limbs. He had dwarfism, postaxial poly- dactyly, and respiratory distress since birth. Radiographs showed a handlebar clavicles, short horizontal ribs, oblique superior acetabular margins, shortened tubular bones, shortened phalanges especially the middle and distal phalanges, and cone-shaped epiphyses. CT of the chest showed a narrow thorax, shortened ribs, and lung hypoplasia.
Histology of the ribs showed that resting chondrocytes were widely separated by abundant cartilaginous matrix. Histology of a rib physeal growth zone shows greatly reduced number of chondrocytes. In some areas, they are completely nonexistent.
Fig. 5. A boy with type II asphyxiating thoracic dystrophy at 7 month and 15 month.
