AUTHOR INFORMATION

Section 1 of 12

Authored by Harold Chen, MD, MS, FAAP, FACMG, Chief, Professor, Department of Pediatrics, Section of Perinatal Genetics, Louisiana State University Medical Center

Harold Chen, MD, MS, FAAP, FACMG, is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, American Medical Association, American Society of Human Genetics, and Teratology Society

Edited by James Bowman, MD, Senior Scholar of Maclean Center for Clinical Medical Ethics, Professor Emeritus, Department of Pathology, University of Chicago; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Hagop Youssoufian, MSc, MD, Medical Director, Adjunct Associate Professor, Clinical Discovery Department, Bristol-Myers Squibb; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Harold Chen, MD, MS, FAAP, FACMG
Editor's Email:	James Bowman, MD

eMedicine Journal, November 30 2005, VOLUME 6, Number 11

INTRODUCTION

Section 2 of 12

Background: In 1955, Jeune et al described familial asphyxiating thoracic dystrophy in a pair of siblings with severely narrow thoraxes. This condition is also known as Jeune syndrome. 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 manifestations vary widely from respiratory failure and infantile death to latent phenotype without respiratory symptoms.

Pathophysiology: Classic manifestations in infancy include dwarfism with short ribs, short limbs, and characteristic radiographic changes in the ribs and pelvis. Severity of clinical and radiographic features is variable. All patients have small chests, but the degree of the respiratory distress varies from negligible to rapidly fatal. Lung hypoplasia, presumably due to a restricted thoracic cage, is the major cause of death in infancy. Renal lesions lead to progressive renal failure later in life. Variability in clinical, radiographic, and pathological manifestations may be related to genetic heterogeneity.

Frequency:

• In the US: Incidence is estimated at 1 per 100,000-130,000 live births.

Mortality/Morbidity:

• Although Jeune syndrome may be associated with bilateral microcystic renal disease, which gradually may progress to tubular atrophy and renal failure, the most common and prominent clinical presentation is alveolar hypoventilation. Alveolar hypoventilation is caused by impaired chest expansion as a result of short horizontally placed ribs.

• Furthermore, most patients with Jeune syndrome (approximately 60-70%) die from respiratory failure in early infancy and early childhood. Chronic renal failure may ensue in survivors.

• Few patients reach adolescence or adulthood.

Race: No race predilection exists.

Sex: No sex predilection exists.

Age: Jeune syndrome may be detected at birth or during infancy because of typical clinical and radiographic signs.

CLINICAL

Section 3 of 12

History: Recognized variability exists among clinical presentations of lethal, severe, and latent forms of Jeune syndrome.

• Respiratory distress


• • Respiratory distress may occur secondary to a small thorax. The thorax remains motionless, and respiration is entirely abdominal. Considerable supraclavicular and suprasternal retraction of the intercostal space may be present on inspiration.
  
  
  
  • Severe dyspnea and extreme cyanosis may occur. However, some infants have only respiratory symptoms in conjunction with infection.
  
  
  
  • Some individuals with Jeune syndrome have no respiratory symptoms in infancy or childhood.
  
  
  
• Chest deformity of varying degree



• Short-limbed dwarfism



• Other symptoms: History also may reveal failure to thrive, gastroenteritis, recurrent rectal prolapse, diarrhea, congestive cardiac failure, puffy face, and ankle swelling.

Physical:

• Dwarfism is noted.



• Thoracic findings are as follows:


• • A long, narrow, and abnormally small thorax with reduced thoracic cage capacity; lung hypoplasia; and respiratory distress usually lead to early death.
  
  
  
  • The small thorax usually improves with age for those who survive early childhood.
  
  
  
• Limbs exhibit variable micromelia and short digits with bulbous terminal phalanges and occasional postaxial polydactyly of the hands and feet.



• Eyes exhibit occasional retinal degeneration.



• Patients may have occasional intestinal malabsorption.



• Renal failure may develop during infancy, early adolescence, or second decade of life.



• Polyuria, polydipsia, and hypertension may be present during the second or third year of life.



• Occasional involvement of the liver may include prolonged neonatal jaundice, polycystic liver disease, hyperplasia of the bile ducts, and congenital hepatic cirrhosis.



• Occasional involvement of the heart may include cardiac failure secondary to increased pulmonary vascular resistance, thoracic constriction, alveolar hypoplasia, and possible intrinsic myocardial disease.



• Cystic changes of pancreatic ducts and pancreatic exocrine insufficiency may be present in long-term survivors of Jeune syndrome.



• Occasional involvement of the teeth, nails, and other organs may occur.

Causes:

• Jeune syndrome is autosomal recessive.



• The gene has not been mapped, but the locus may be on chromosome arm 12p.

DIFFERENTIALS

Section 4 of 12

Achondrogenesis
Achondroplasia
Cartilage-Hair Hypoplasia
Ellis-van Creveld Syndrome
Hypophosphatasia
Thanatophoric Dysplasia

Other Problems to be Considered:

Diastrophic dysplasia

Barnes syndrome (thoracolaryngopelvic dysplasia) (OMIM 187760): This is an autosomal dominant disorder characterized by a small bell-shaped thorax, laryngeal stenosis, and small iliac wing and pelvis.

Short rib polydactyly syndrome type I (Saldino-Noonan syndrome) (OMIM 263530): This is a lethal condition of newborns characterized by hydropic appearance, postaxial polydactyly, severely shortened and flipperlike limbs, and striking metaphyseal dysplasia of tubular bones. The pelvis resembles that of Ellis-van Creveld syndrome and asphyxiating thoracic dystrophy, with small ilia and osseous spurs projecting medially and laterally from the acetabular roofs. As in type II, polycystic kidneys, transposition of great vessels, and atretic lesions of the gastrointestinal and genitourinary systems occur.

Short rib polydactyly syndrome type II (Majewski syndrome) (OMIM 263520): This is a lethal entity characterized by median cleft lip, preaxial and postaxial polysyndactyly, short ribs and limbs, genital abnormalities, and anomalies of epiglottis and viscera.

Short rib polydactyly syndrome type III (Verma-Naumoff syndrome) (OMIM 26351): This is a lethal entity characterized by a short cranial base, bulging forehead, depressed nasal bridge, and flat occiput. Another difference is the radiologic appearance of the long tubular bones, which have a distinct corticomedullary demarcation, somewhat widened metaphyses, and marked longitudinal spurs.

Short rib syndrome (Beemer-Langer syndrome) (OMIM 269860): This is a lethal entity characterized by hydrops, ascites, median cleft of the upper lip, narrow chest, and short bowed limbs.

WORKUP

Section 5 of 12

Lab Studies:

• Urinalysis


• • Hematuria
  
  
  
  • Proteinuria
  
  
  
  • Defective urine concentrating capacity
  
  
  
• Arterial blood gas (ABG): Hypoxia and hypercarbia in room air reflect severe restrictive lung disease.

Imaging Studies:

• Newborn and infant radiography


• • Small and bell-shaped thorax with reduced transverse and anterior-posterior diameter
  
  
  
  • Short and horizontally oriented ribs with irregular costochondral junctions and bulbous and irregular anterior ends
  
  
  
  • Short squared iliac wings
  
  
  
  • Trident appearance of acetabular margin
  
  
  
  • Short limbs relative to trunk
  
  
  
  • Variable limb-shortening
  
  
  
  • Short phalanges, metacarpals, or metatarsals with or without polydactyly
  
  
  
  • Premature ossification of the capital femoral epiphyses
  
  
  
• Childhood radiology


• • Relatively large thorax with growth of ribs
  
  
  
  • Short ilium with normal flaring of iliac wings
  
  
  
  • Striking cone-shaped epiphyses and early fusion between the epiphyses and metaphyses of the distal and middle phalanges
  
  
  
  • Short distal and middle phalanges
  
  
  
  • Varying shortening of extremities relative to trunk
  
  
  
• Prenatal ultrasonography


• • Detection of affected second- and third-trimester fetuses of at-risk families has been reported.
  
  
  
  • Characteristic findings include a narrow thorax, short hypoplastic ribs, and short tubular bones.
  
  
  
  • Other ultrasonographic findings include polyhydramnios and absent or feeble fetal respiratory movements.
  
  
  

Other Tests:

• Pulmonary function testing may reveal severe restrictive lung disease.

Procedures:

• Renal biopsy may reveal cystic tubular dysplasia with or without glomerular sclerosis.

Lungs - Hypoplastic lungs due to a marked reduction in the number of alveolar ducts and alveoli (hypoplasia of alveoli)

Cartilages - Irregular endochondral ossification with patchy distribution of physeal zone of hypertrophy and radiologically irregular metaphyseal ends (asphyxiating thoracic dystrophy type I) and diffusely retarded and disorganized physes with smooth cartilage bone junctions and radiologically smooth metaphyseal ends (asphyxiating thoracic dystrophy type II)

Kidneys - Cystic renal dysplasia and hypoplasia, nephronophthisis or interstitial nephritis (diffuse interstitial and periglomerular fibrosis, round cell lymphocytic infiltration, hyalinized glomeruli, pericapsular thickening, thickened basement membrane, dilated or atrophic tubules), pyelonephritis with scarring, and distortion of renal parenchyma

Liver - Periportal hepatic fibrosis, bile duct proliferation, and early cirrhosis

TREATMENT

Section 6 of 12

Medical Care:

• Medical care is supportive.

• Mechanical ventilation is urgently required in the most severe cases, those when respiratory distress develops immediately after birth. Less-severe cases gradually progress to respiratory failure as a result of multiple recurrent pulmonary infections.



• Treat respiratory infections vigorously with antibiotics, endotracheal suctioning, and postural drainage.



• Nasogastric or gastrostomy feedings may be required.



• Genetic counseling is indicated. The parents of a child affected with Jeune syndrome are obligatory carriers with a 25% recurrence risk.

Surgical Care:

• Surgery is indicated only in the most severe cases in which failure to intervene will result in progressive pulmonary damage and eventual death. No data is currently available on long-term follow-up care of patients who have been surgically treated.



• Chest reconstruction and enlargement of the thoracic cage by sternotomy and fixation with bone grafts or a methylmethacrylate prosthesis plate provides patients with the time needed for thoracic cage growth. Bone graft can fill midsternal defect completely, thus preventing lung herniation, and supplies equal support along the sternal wound edges avoiding localized high-pressure areas; no ribs or iliac crest grafts have to be harvested from the patient. A methylmethacrylate prosthesis can be made before surgery, thus saving considerable anesthesia time. The prosthesis supplies support along the entire length of the sternal edges to prevent herniation of the heart and lungs. The material is inert and the prosthesis can be replaced later if a larger strut is needed.



• A second-stage procedure is needed to provide a better and more natural environment for further continuous expansion of the chest.



• A procedure of lateral thoracic expansion was recently described in Jeune asphyxiating thoracic dystrophy. The chest wall is enlarged by dividing the ribs and underlying tissue in a staggered fashion so that either rib or periosteum covers the lung. New bone formation has been demonstrated, and viable enlargement has been obtained. This procedure has been found to be safe and effective in selected patients older than one year.



• Dialysis and renal transplantation are indicated for renal failure. Recently, cadaver renal transplantation was successful in a 10-year-old boy with Jeune syndrome type 2.

Consultations:

• Clinical geneticist



• Radiologist



• Anesthesiologist



• Pediatric surgeon

Diet: No special diet is required.

Activity: No restriction of activities is required for survivors of this condition.

MEDICATION

Section 7 of 12

Drug therapy is currently not a component of the standard of care for this condition.

FOLLOW-UP

Section 8 of 12

Further Inpatient Care:

• Treat postoperative ventilatory problems, and minimize secondary damage to lungs caused by prolonged ventilatory support.



• Treat respiratory infections and cardiac insufficiency.

Complications:

• Pneumothorax



• Mucous plugging of a bronchus



• Repeated infections



• Progressive herniation of lung through sternal defect



• Cardiac insufficiency



• Development of significant respiratory compromise after pectus excavatum repair


• • Respiratory compromise generally develops years after the original pectus operation.
  
  
  
  • Most patients exhibit severe growth retardation of the upper chest wall resulting in restrictive pulmonary function test results.
  
  
  

Prognosis:

• Prognosis is 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.



• Jeune syndrome is compatible with life, though respiratory failure and infections are often fatal during infancy.



• Considerable variation in the severity of thoracic constriction exists. For those patients who survive infancy, the thorax tends to revert to normal with improving respiratory function. This suggests that the lungs have a normal growth potential and the respiratory problems are secondary to restricted rib cage deformity.



• Renal failure may ensue later. Renal involvement is the major prognostic factor in those patients who survive the respiratory insufficiency during infancy.



• Survivors are short in stature.

Patient Education:

• Up-to-date information about the syndrome and resources should be available to the families:


• • Jeune’s Syndrome Support Network
    c/o Kurt Hernon
    1400 S Lakeview Boulevard
    Lorain, OH 44052
    Phone: 440-246-1578
    Email: kurage@centuryinter.net
  
  
  
  • Jeune Family Support Group
    Asphyxiating Thoracic Dystrophy
    3710 W Temperance
    Lambertville, MI 48144
    Phone: 313-854-8132
  
  
  
  • Little People of America (LPA), Inc.
    PO Box 745
    Lubbock, TX 79408
    Phone: 888-LPA-2001
    Email: LPADataBase@juno.com
  
  
  
  • International Skeletal Dysplasia Registry
    Cedars-Sinai Medical Center
    444 S San Vicente Boulevard, Suite 1001
    Los Angeles, CA 90048
    Phone: 310-855-7488
    E-mail: mpriore@mailgate.csmc.edu
  
  
  
  • International Center for Skeletal Dysplasia
    St Joseph Hospital
    7620 York Road
    Towson, MD 21204
    Phone: 410-337-1250
  
  
  

MISCELLANEOUS

Section 9 of 12

Medical/Legal Pitfalls:

• Failure to give genetic counseling after confirmation of the diagnosis


• • Recurrence risk is 25%.
  
  
  
  • Prenatal diagnosis by ultrasonography is possible in the second trimester.
  
  
  

TEST QUESTIONS

Section 10 of 12

CME Question 1: Which of the following is not a characteristic feature of Jeune syndrome?

A: Uniformly fatal
B: Autosomal recessive inheritance
C: A narrow thorax
D: Respiratory distress
E: Renal failure

The correct answer is A: Jeune syndrome is not uniformly fatal, though respiratory failure and infections are often fatal during infancy. Most patients with Jeune syndrome (approximately 60-70%) die from respiratory failure in early infancy and early childhood. Chronic renal failure may ensue in survivors.

CME Question 2: Which of the following statements regarding Jeune syndrome is not true?

A: Frequency is about 1 per 100,000-130,000 live births.
B: Approximately 60-70% of patients die from respiratory failure in early infancy or early childhood.
C: Chronic renal failure may be present in survivors.
D: Polydactyly is common.
E: Patients are of normal intelligence.

The correct answer is D: Postaxial polydactyly of the hands and feet occurs only occasionally in patients with Jeune syndrome.

Pearl Question 1 (T/F): Jeune syndrome is a rare autosomal recessive disorder characterized by typical skeletal dysplasias.

The correct answer is True: 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 manifestations vary widely.

Pearl Question 2 (T/F): During the second and third trimesters of pregnancy, prenatal ultrasonography can detect fetuses affected with Jeune syndrome.

The correct answer is True: Characteristic findings include a narrow thorax, short hypoplastic ribs, and short tubular bones. Other ultrasonographic findings include polyhydramnios and absent or feeble fetal respiratory movements.

Pearl Question 3 (T/F): Cystic tubular dysplasia with or without glomerular sclerosis is a characteristic finding of renal biopsy in those with Jeune syndrome.

The correct answer is True: Renal biopsy in those with Jeune syndrome reveals cystic tubular dysplasia with or without glomerular sclerosis. Nephronophthisis (diffuse interstitial fibrosis), round cell lymphocytic infiltration, pericapsular thickening, thickened basement membrane, dilated tubules, progressive interstitial nephritis, pyelonephritis with scarring, and distortion of renal parenchyma are other histological findings.

Pearl Question 4 (T/F): The recurrence risk for parents who had a previous child with Jeune syndrome is 25%.

The correct answer is True: The recurrence risk for parents who had a previous child with Jeune syndrome is 25%. Prenatal ultrasound may detect a narrow thorax and short tubular bones.

PICTURES

Section 11 of 12

Caption: Picture 1. An infant with Jeune syndrome. Note the narrow chest and shortened upper extremities.
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Caption: Picture 2. A child with Jeune syndrome. Note long narrow thorax with respiratory difficulty.
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Caption: Picture 3. Asphyxiating thoracic dystrophy (Jeune syndrome). Note cystic renal dysplasia on the left kidney and renal hypoplasia on the right kidney.
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Caption: Picture 4. Asphyxiating thoracic dystrophy (Jeune syndrome). Note the narrow chest and shortened ribs.
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Caption: Picture 5. Asphyxiating thoracic dystrophy (Jeune syndrome). Note the shortened upper extremity with acromelic shortening.
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BIBLIOGRAPHY

Section 12 of 12

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• Aronson DS, van Nierop JC, Taminiau A, Vos A: Homologous bone graft for expansion thoracoplasty in Jeune's asphyxiating thoracic dystrophy. J Pediatr Surg 1999; 34: 500-503[Medline].
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• Sharoni E, Erez E, Chorev G, et al: Chest reconstruction in asphyxiating thoracic dystrophy. J Pediatr Surg 1998 Oct; 33(10): 1578-81[Medline].
• Todd DW, Tinguely SJ, Norberg WJ: A thoracic expansion technique for Jeune's asphyxiating thoracic dystrophy. J Pediatr Surg 1986 Feb; 21(2): 161-3[Medline].
• Turkel SB, Diehl EJ, Richmond JA: Necropsy findings in neonatal asphyxiating thoracic dystrophy. J Med Genet 1985 Apr; 22(2): 112-8[Medline].
• Weber TR, Kurkchubasche AG: Operative management of asphyxiating thoracic dystrophy after pectus repair. J Pediatr Surg 1998 Feb; 33(2): 262-5[Medline].
• Weber TR: Further experience with the operative management of asphyxiating thoracic dystrophy after pectus repair. J Pediatr Surg 2005 Jan; 40(1): 170-3; discussion 173[Medline].
• Yang SS, Heidelberger KP, Brough AJ, et al: Lethal short-limbed chondrodysplasia in early infancy. Perspect Pediatr Pathol 3: 1-40[Medline].
• Yang SS, Langer LO Jr, Cacciarelli A, et al: Three conditions in neonatal asphyxiating thoracic dysplasia (Jeune) and short rib-polydactyly syndrome spectrum: a clinicopathologic study. Am J Med Genet Suppl 1987; 3: 191-207[Medline].

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