Asphyxiating Thoracic Dystrophy (Jeune Syndrome)

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, a rare autosomal recessive disorder characterized by typical skeletal dysplasias, such as a narrow thorax and micromelia, with respiratory and renal manifestations.[1, 2] Respiratory symptoms widely vary from respiratory failure and infantile death to latent phenotype without respiratory symptoms. See the images below.

An infant with Jeune syndrome. Note the narrow chest and shortened upper extremities.

A child with Jeune syndrome. Note long narrow thorax with respiratory difficulty.

Note the shortened upper extremity with acromelic shortening.

JS has a wide variability of expression due to genetic heterogeneity. All patients have small chests, but the degree of the respiratory distress varies from negligible to rapidly fatal. In the more severe forms, patients present at birth with a narrow, immobile chest; short ribs and limbs; and characteristic radiographic changes. Lung hypoplasia, due to a restricted thoracic cage, is the major cause of death in infancy. Patients who survive the newborn period may later develop renal and pancreatic insufficiency.[3]

Frequency

United States

• Incidence is estimated at 1 case per 100,000-130,000 live births.[4]

Mortality/Morbidity

See the list below:

• Although JS may be associated with bilateral microcystic renal disease, which may gradually progress to tubular atrophy and renal failure, the most common and prominent clinical presentation is respiratory failure secondary to restrictive lung disease as a result of short horizontally placed ribs.

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

• Few patients reach adolescence or adulthood.

Race

JS has no race predilection.

Sex

The syndrome is not associated with any sex predilection.

Age

See the list below:

• JS may be detected at birth or during infancy because of typical clinical and radiographic signs.

The prognosis in JS depends on its expression.

Helpful links

These include the following:

US National Library of Medicine: https://ghr.nlm.nih.gov/condition/asphyxiating-thoracic-dystrophy

Genetic and Rare Diseases Information Center: https://rarediseases.info.nih.gov/diseases/3049/jeune-syndrome

Jeune Syndrome Foundation: http://www.jeunes.org.uk/

Clinical presentations of lethal, severe, and latent forms of JS vary.

• 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 upon inspiration. Severe dyspnea and extreme cyanosis may occur. However, some infants have only respiratory symptoms in conjunction with infection. Some individuals with JS have no respiratory symptoms in infancy or childhood.

• Chest deformity of varying degree

• Variable limb shortening

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

Thorax

Characteristics include the following:

• Narrowed thorax (bell shaped or long and narrow) with reduced thoracic cage capacity; lung hypoplasia - The bell-shaped thorax is usually associated with early respiratory failure, while patients with a long and narrow chest may have mild respiratory symptoms

• Shortened ribs with horizontal alignment

• Dysplastic costochondral junctions

• The small thorax usually improves with age for those who survive early childhood

Limbs

Characteristics include the following:

• Variable limb shortening
• Brachydactyly
• Occasional postaxial polydactyly of the hands and feet

Kidneys

Characteristics include the following

• 40% of patients with JS develop renal complications
• Renal failure due to nephron ciliary defect may develop during infancy, early adolescence, or the second decade of life
• An inability to concentrate urine is the earliest manifestation
• Polyuria, polydipsia, and hypertension may be present during the second or third year of life

Eyes

Characteristics include the following:

• Optic nerve hypoplasia

• Retinal dystrophy

• Abnormal retinal pigmentation

Hepatic and gastrointestinal

Characteristics include the following:

• Liver involvement (30% of cases) may lead to prolonged neonatal jaundice, polycystic liver disease, hyperplasia of the bile ducts, and congenital hepatic cirrhosis; signs may include vomiting, hyperbilirubinemia, elevated transaminases, hepatomegaly, and portal hypertension ^[5]
• Cystic changes of the pancreatic ducts and pancreatic exocrine insufficiency may be present in long-term survivors of JS
• Hirschsprung disease

Cardiovascular

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

Other

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

JS is known to be genetically heterogeneous and is the first chondrodysplasia to be linked to a defect in intraflagellar transport (IFT) or primary cilia function.

JS is a member of the family of skeletal ciliopathies, disorders associated with dysfunction of primary cilia, classified as 1 of the 6 short-rib polydactyly syndrome (SRPS) disorders.[6]  JS, along with Ellis–van Creveld syndrome, is an SRPS compatible with life, rather than 1 of the 4 lethal SRPS subtypes (SRPS I–IV).[7] In addition, JS is both phenotypically and genetically related to Sensenbrenner syndrome (cranioectodermal dysplasia; MIM 218330)[8] and Mainzer-Saldino syndrome (conorenal syndrome; MIM 266920).[9]

Genetic mutations have been mapped to several loci: 4p14, 2q24.3, 15q13,3q24-3q26, and 11q14.3-q23.1.

Currently identified gene mutations include the following:

• IFT80 ^[10]
• TTC21B/ IFT139 ^[11]
• TCTEX1D2 ^[12]
• IFT140 ^{[9, 13]}
• WDR19/ IFT144 8
• WDR35 ^[14]
• WDR60 ^{[15, 16]}
• DYNC2H1, ^[17] most common

All of these genes encode for proteins that participate in ciliary IFT, an evolutionarily conserved process that is essential for ciliogenesis and governs a variety of important cell-signaling events key to normal human development.[18, 19]

Schmidts et al detected 34 DYNC2H1 mutations in 29 (41%) of 71 patients from 19 (33%) of 57 families, showing it as a major cause of asphyxiating thoracic dystrophy, especially in Northern European patients.[13]  This included 13 early protein termination mutations (nonsense/frameshift, deletion, splice site), but no patients carried these in combination, suggesting the human phenotype is at least partly hypomorphic. DYNC2H1 patients largely lacked significant extraskeletal involvement, demonstrating an important genotype–phenotype correlation

Significant variability exists in the course and severity of the thoracic phenotype both between affected siblings with identical DYNC2H1 alleles and among individuals with different alleles. This suggests that the DYNC2H1 phenotype may be subject to modifier alleles, nongenetic factors, or epigenetic factors.

A study by Hu et al indicated that in WDR35 mutation—one cause of JS—skeletal dysplasia and fetal anomalies may result from copy number variation. Moreover, down-regulation of WDR35 may lead to cilia formation damage and, sequentially, indirect Gli signal regulation, with consequent negative regulation of osteogenic differentiation.[14]

The following studies are recommended in JS:

• Urinalysis

  • Hematuria

  • Proteinuria

  • Defective urine concentrating capacity

• Arterial blood gas (ABG) sampling: Hypoxia and hypercarbia in room air reflect severe restrictive lung disease

See the list below:

• 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-trimester 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

See the list below:

• Pulmonary function testing may reveal severe restrictive lung disease.

See the list below:

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

See the list below:

• 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 physial zone of hypertrophy and radiologically irregular metaphysial ends (asphyxiating thoracic dystrophy type I) and diffusely retarded and disorganized physes with smooth cartilage bone junctions and radiologically smooth metaphysial 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

The priority in managing patients with JS is supporting respiratory function.

Medical care in JS is supportive. Mechanical ventilation is urgently required in the most severe cases, in which 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 JS are obligatory carriers with a 25% recurrence risk.

Based on a case report of a pediatric JS patient with influenza pneumonia, as well as an analysis of 27 persons with a surrogate diagnosis of thoracic insufficiency (as listed in the Extracorporeal Life Support Organization [ELSO] registry), Hancock et al concluded that extracorporeal membrane oxygenation (ECMO) may offer supportive benefit in thoracic insufficiency cases. The rate of survival to discharge among the 27 patients did not significantly differ from that of previously healthy ECMO-supported individuals.[20]

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 are currently available on long-term follow-up care of patients who have been surgically treated.

Chest reconstruction

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 grafting can completely fill midsternal defect, 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.

Lateral thoracic expansion

A procedure of lateral thoracic expansion has been described in JS. 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 1 year.

A study by Muthialu et al indicated that thoracic expansion can be effectively performed bilaterally in one procedure rather than on one side of the chest wall at a time in separate procedures, reducing patients’ ventilator requirements. The study included seven children who underwent the bilateral procedure, with, at median 11-month follow-up, three children having been discharged home, two receiving significantly decreased respiratory support, one using noninvasive ventilation, and one remaining ventilated with a high oxygen requirement. (One patient died within 3 months postoperatively of pulmonary hypertension.)[21]

Other procedures

A vertical, expandable prosthetic titanium rib is a safe tool for the treatment of children with thoracic insufficiency syndrome. It may decrease carbon dioxide retention in some patients and may be most beneficial in younger children. A study by O’Brien et al indicated that use of a 70-mm–radius, vertical, expandable titanium rib can significantly increase the survival rate of individuals with JS. The prosthesis was implanted in the study’s patients at a mean age of 23 months, with follow-up averaging 8.4 years. The patient survival rate was 68%, and less ventilator dependence was noted.[22]

Distraction osteogenesis has been used successfully to distract both sternum and ribs in an infant with JS.[23]

Dialysis and renal transplantation are indicated for renal failure. Cadaver renal transplantation was successful in a 10-year-old boy with JS type 2.

See the list below:

• Clinical geneticist

• Radiologist

• Anesthesiologist

• Pediatric surgeon

See the list below:

• No special diet is required.

See the list below:

• No restriction of activities is required for survivors of this condition.

Drug therapy is not currently a component of the standard of care for asphyxiating thoracic dystrophy.

Recommendations for follow-up and monitoring are summarized below[2, 24] :

• Physical examination - Frequent until age 2 years, then yearly
• Liver function and urine osmolality - Every year
• Abdominal ultrasonogram - At ages 2, 5, 10, and 15 years or as indicated
• Spirometry assessments - After age 5 years
• Ophthalmologic examination - At ages 5 and 10 years

See the list below:

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

• Treat respiratory infections and cardiac insufficiency.

See the list below:

• 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.

See the list below:

• 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.

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

• The severity of thoracic constriction widely varies. 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.

Up-to-date information about the syndrome and resources is available to the families. The following websites and organizations can provide useful information:

• US National Library of Medicine: https://ghr.nlm.nih.gov/condition/asphyxiating-thoracic-dystrophy
• Genetic and Rare Diseases Information Center: https://rarediseases.info.nih.gov/diseases/3049/jeune-syndrome
• Jeune Syndrome Foundation: http://www.jeunes.org.uk/

Patients may also enroll in the UCLA International Skeletal Dysplasia Registry (ISDR).

Phone: 310-825-8998

E-mail: Salon@mednet.ucla.edu

Website: http://ortho.ucla.edu/isdr

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