pancreatic fibrosis

Asphyxiating Thoracic Dysplasia 1

Clinical Characteristics
Ocular Features: 

This is a genetically and clinically heterogeneous condition for which the nosology remains to be worked out.  Not all patients have ocular disease but those who survive infancy may have a pigmentary retinopathy resembling retinitis pigmentosa.  In fact, a 5 year old presented with symptoms of visual loss and night blindness only.  The severeity of the systemic malformations has so far precluded a full description of the ocular phenotype.

Systemic Features: 

The most life-threatening and characteristic systemic feature of ATD is short-ribbed thoracic constriction with respiratory insufficiency.  The chest is small and narrow and sometimes described as bell-shaped.  This deformity can lead to death by asphyxiation, and is a serious risk during infancy.  Other individuals live to adulthood and may have only minimal respiratory difficulties.  Patients who survive childhood can develop cystic renal and hepatic disease.  Pancreatic fibrosis has also been reported.  Brachydactyly and postaxial polydactyly are sometimes present and involve the feet more commonly than the hands.  Short stature secondary to short limbs is frequently noted.

Genetics

Jeune syndrome, or at least some forms of it, is an autosomal recessive condition.  Consanguinity is often present.  A locus (15q13) containing homozygous mutations in ATD has been proposed as one candidate site.  There is considerable genetic heterogeneity with at least 5 types described, all with mutations in different genes.

Another disorder with some similar features causing respiratory distress is Majewski syndrome (263520).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Assisted ventilation can be lifesaving in milder cases.  Thoracic reconstruction has also been helpful in a few individuals.  However, careful patient selection is necessary since some patients have severe pulmonary hypoplasia with underdeveloped alveoli. Ursodeoxycholic acid may slow the progression of the liver disease.

References
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Pearson Marrow-Pancreas Syndrome

Clinical Characteristics
Ocular Features: 

Although systemic disease is usually evident during infancy, ocular symptoms such as ptosis and ophthalmoplegia may not be apparent until adulthood in those that survive.  The ocular myopathy in adults can resemble Kearns-Sayre syndrome (530000) as the result of a phenotypic shift from a predominantly hematopoietic disorder to a mitochondrial myopathy.  Bilateral zonular cataracts and strabismus have been reported in a 3 year old male.  A midperiphery pigmentary retinopathy has been observed.  Endothelial cell failure leads to corneal edema. 

Systemic Features: 

Low birth weight, failure to thrive, hypoplastic anemia and exocrine pancreatic dysfunction are often seen in infancy.  Precursor cells in the marrow show typical vacuolization. Malabsorption and insulin-dependent diabetes often develop.  The pancreas and bone marrow may become fibrotic.  Patients with the classic syndrome as a child can develop features of the Kearns-Sayre syndrome if they survive childhood.  Progressive muscle weakness in pharyngeal, facial, neck, and limb muscles is sometimes seen in older individuals and muscle biopsy reveals ragged-red fibers characteristic of mitochondrial disease.  Some patients have an organic aciduria and others develop hepatic failure with elevated transaminase, bilirubin and lipid levels.  Kidney damage results in Fanconi syndrome.  Young children may recover from the refractory anemia eventually but metabolic acidosis with life-threatening lactic acidosis is a constant threat and responsible for many childhood deaths.

Genetics

Deletions in mtDNA involving numerous genes are responsible for this condition.  As a result, it is maternally transmitted but somewhat inconsistently due to mitochondrial heteroplasmy.  Both sexes are affected.  The irregular size of the mtDNA deletions and the tissue distribution of affected mitochondria results in considerable variation in clinical expression.  Defective oxidative phosphorylation seems to be the underlying cause of many of the signs and symptoms.

Treatment
Treatment Options: 

This multisystem disease requires careful monitoring throughout life.  Blood transfusions may be required and careful attention needs to be given to nutrition and metabolic dysfunction.  A few patients have required insulin.  In spite of vigorous treatment of electrolyte imbalances, correction of acidosis, and hormonal supplements, many patients do not survive beyond childhood.  Organ failure requires individualized treatment.

References
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