interstitial lung disease ( ild ) is defined as a specific form of chronic fibrosing interstitial pneumonitis limited to the lung .
it is a rare , chronic , progressive , usually fatal interstitial lung disorder ( 1 - 3 ) . in children , interstitial pneumonitis ( ip )
presents with a wide spectrum of histologic abnormalities that usually do not fit the classification for ip used in the adult population ( 4 ) .
the familial form can be described , as ip occurred in at least two members of a family ( 2 , 3 , 6 ) .
the proportion of familial ild is unknown , and a genetic basis of it is estimated to be 0.5 - 2.2% of cases ( 6 ) . in approximately half of the clinically unaffected family members , it is transmitted as an autosomal dominant trait with reduced penetrance but autosomal recessive pattern is not excluded ( 3 , 6 - 8 ) . although the etiology of the majority of ilds is still unknown ,
there is increasing understanding of the cellular and cytokine interactions associated with inflammation and fibrosis .
host susceptibility , genetic factors and environmental cofactors may influence clinical expression of each disease ( 9 ) .
the inflammatory process of ild begins with an initial injury to the alveolar and interstitial structures ( alveolitis ) , which is followed by a stage of tissue repair and variable degrees of fibrosis , and an alveolar infiltrate with variable amounts of proteinaceous material ( 4 , 10 ) .
the accumulation of proteinaceous material in the alveolar space is a characteristic finding in lung diseases associated with surfactant system abnormalities ( 4 ) .
there are reports that mutations in surfactant protein b ( sp - b ) and surfactant protein c ( sp - c ) are associated with familial usual interstitial pneumonitis in adults and with cellular nonspecific interstitial pneumonitis ( nsip ) in children ( 6 ) .
recently , a mutation in the gene encoding the hydrophobic , lung - specific sp - c was discovered in association with a decrease in the level of sp - c in familial ilds ( 4 , 10 , 11 ) . here
we report a very young korean girl with symptoms and radiological findings of ild similar to those of her older sister who died from this disease .
chest computed tomography ( ct ) scans of both sisters were compared and the findings , etiology and treatment of this disease are discussed .
a 21 month - old girl was brought to asan medical center suffering fever , cough and tachypnea for 4 months .
abnormal lung findings were first noted by a chest radiography taken due to fever when she was 8 months old .
the symptoms of the patient at 21 months of age were the same as those that her sister had shown at age 4 yr .
physical examination of the patient revealed tachypnea at rest ( beyond 60/min ) and chest retraction without rales or wheezing , but no digital clubbing .
on arrival at the hospital , the denver symptom score ( 12 ) of ild gave a value of 2 points meaning the patient showed respiratory symptoms but oxygen saturation was normal in room air under all conditions .
blood , urine , sputum and stool studies revealed no evidence of acute viral or bacterial infection .
neither virus ( adenovirus , influenza virus , parainfluenza virus , respiratory syncytial virus , cytomegalovirus ) nor bacteria was found in bronchoalveolar lavage fluid .
the chest radiography showed a dense hazy area at the central region of both lungs and blunting on the left costophrenic angle .
1a ) demonstrated diffuse fibrosis on the medial portion of both lung fields and subpleural consolidation along both lateral pleura .
1b ) , the sister of the patient had been diagnosed with uncharacterized ild , and died 5 months after diagnosis . surgical open lung biopsy ( fig .
a diagnosis of nsip was made based on the findings of diffuse , uniform thickening of the interstitium with lymphoplasmacytic infiltration and collagen fibrosis .
some alveoli contain accumulation of intra - alveolar macrophages , while some alveoli had hyperplastic type ii alveolar pneumocytes .
examination of peripheral blood cells from the patient 's parents also showed no evidence of mutations in these genes .
the patient was treated with high - dose intravenous methylprednisolone ( 30 mg / kg / day , 3 doses every other day , monthly ) and oral hydroxychloroquine ( daily ) . during treatment , tachypnea and dyspnea on exertion
were still evident and the denver symptom score was 2 points at follow - up .
follow - up high resolution ct ( hrct ) showed that there was no further disease progression after 21 months .
there have been previous reports of familial ild , and infants with this disease can become symptomatic in the first 6 weeks of life ( 1 ) .
such patients have tachypnea and respiratory distress with grunting , intercostal and subcostal retraction , and cyanosis .
the mortality rate is high , especially in children younger than 1 yr ( 1 ) .
the ild of unknown origin which was developed in the present patient 's sister progressed quickly and she died at 4 yr of age , 5 months after she had been diagnosed .
risk factors for ild are virus ( adenovirus , epstein - barr virus , influenza virus , cytomegalovirus ) , mycoplasma or other infectious agents , drugs , chronic aspiration , environmental factors like metal dust and wood dust , and genetic predisposition ( 5 , 13 ) . given that investigations on the etiology of the present patient ruled out any environmental or infectious causes , we examined genetic factors .
there were analyses of candidate loci near the human leukocyte antigen ( hla ) region of chromosome 6 to suggest a genetic basis for ild in familial cases ( 6 ) .
in addition , an association has been established between interstitial pulmonary fibrosis and 1-antitrypsin inhibition alleles present on chromosome 14 ( 2 ) .
recently , several investigators reported that multiple heterozygous mutations in the surfactant protein c gene were associated with ild ( 10 ) .
triggers such as infection or toxins may contribute to the wide diversity in clinical presentation of surfactant protein c gene - associated pulmonary fibrosis ( 6 ) . in our case ,
the pathological findings were compatible with nsip but we did not find a surfactant protein gene mutation in lung biopsy samples or peripheral blood cells from the patient , or in peripheral blood cells from her parents . there was a report of fatal respiratory diseases in full - term infants with symptoms of surfactant deficiency in whom a deficiency of surfactant protein b was excluded .
it suggested that the mutation of the genes for atp - binding cassette transporter a3 ( abca3 ) that were involved in the transport of phospholipids and sterols could be associated with unexplained surfactant deficiency in full - term infants ( 14 ) .
hrct allows early diagnosis of ild and commonly shows patchy , predominantly peripheral , subpleural , bibasilar reticular abnormalities ( 15 ) .
the extent of pulmonary infiltration on ct is an important predictor of survival ( 2 ) .
we had two similar hrct images , one from the patient and the other from her sister whose disease had progressed further .
the chronic pneumonitis in infancy is characterized by interstitial thickening with mesenchymal cells rather than inflammatory cells and by an alveolar infiltration with variable amounts of proteinaceous material ( 10 , 15 ) .
the findings of the lung biopsy specimen from the present patient also showed mild , diffuse , and uniform thickening of the interstitium with mild fibrosis , consistent with the diagnosis of nsip .
corticosteroid administration ( 1 , 16 , 17 ) has been the mainstay of therapy for ild , and chloroquine and hydroxychloroquine ( 1 , 17 ) have also been used successfully in the treatment of childhood ip .
for the present patient , treatment with methylprednisolone and hydroxychloroquine was initiated soon after ild diagnosis due to her family history .
the denver symptom score was used to evaluate the symptoms , and continued use of this system indicated that patient 's disease was not progressing during 21 months of follow - up . in summary , we have described an infant with nsip whose sibling died from a similar disease .
the need of early diagnosis and treatment with corticosteroids in combination with hydroxychloroquine for the familial ild could be considered . trying to determine the etiology of the familial form of this disease is likely to result in better treatment for these patients .
 most of the interstitial lung diseases are rare , chronic , progressive and fatal disorders , especially in familial form . 
 the etiology of the majority of interstitial lung disease is still unknown . 
 host susceptibility , genetic and environmental factors may influence clinical expression of each disease . with familial interstitial lung diseases , mutations of surfactant protein b and surfactant protein c or other additional genetic mechanisms ( e.g. mutation of the gene for atp - binding cassette transporter a3 ) could be associated . 
 we found a 21 month - old girl with respiratory symptoms , abnormal radiographic findings and abnormal open lung biopsy findings compatible with nonspecific interstitial pneumonitis that is similar to those of her older sister died from this disease . 
 we performed genetic studies of the patient and her parents , but we could not find any mutation in our case . 
 high - dose intravenous methylprednisolone and oral hydroxychloroquine were administered and she is still alive without progression during 21 months of follow - up . 
INTRODUCTION
CASE REPORT
DISCUSSION