osteogenesis imperfecta is a rare connective tissue disorder characterized by bone fragility and low bone density . most cases are caused by an autosomal dominant mutation in either col1a1 or col1a2 gene encoding type i collagen we present a patient with severe respiratory distress due to osteogenesis imperfecta simulating type ii , born to a non - consanguineous couple with mixed african - american and african - hispanic ethnicity . cultured skin fibroblasts demonstrated compound heterozygosity for mutations in the lepre1 gene encoding prolyl 3-hydroxylase 1 confirming the diagnosis of autosomal recessive osteogenesis imperfecta type viii , perinatal lethal type . osteogenesis imperfecta is a rare group of heritable bone diseases characterized by propensity to spontaneous fractures , growth deficiency and in some subtypes , blue sclerae . osteogenesis imperfecta is more commonly caused by an autosomal dominant ( ad ) mutation in the col1a1 or col1a2 gene , which encodes type i collagen ( 1 ) . however , emerging research has demonstrated autosomal recessive ( ar ) mutations leading to osteogenesis imperfecta ( 2 ) . these genes encode the cartilage - associated protein ( crtap ) , prolyl 3 hydroxylase 1 ( p3h1/lepre1 ) or cyclophilin b ( encoded by ppib ) . together , these proteins help form the collagen prolyl 3-hydroxylation complex that facilitates modification of the  chains of type i collagen . according to the ncbi database , lepre1 is leucine proline - enriched proteoglycan ( leprecan ) 1 [ homo sapiens ] ( gene i d : 64175 ) . lepre1 has been found to be a founder mutation in 1.5% of asymptomatic individuals from west africa and in 0.310.5% of asymptomatic african - americans . we present the clinical , radiological and autopsy findings in a patient who was diagnosed in utero with short femora and bone fractures . cultured fibroblasts from a skin biopsy disclosed two causative mutations in the lepre1 gene resulting in the lethal ar perinatal form of osteogenesis imperfecta . the patient is the result of a first pregnancy to a non - consanguineous couple . the mother is of african - colombian descent and the father is of african - american descent . there was good prenatal care and routine laboratory screens were all negative ; however , the antenatal screening ultrasound study at 18 weeks gestation revealed short femora . detailed ultrasound studies at 25 and 35 weeks gestation showed short extremities with bowing of the long bones including the radii , ulnae and femora as well as fractures of the femora . the parents had declined an amniocentesis . at 35 weeks gestation , the mother presented with preterm labor . due to breech positioning and previous noted abnormalities , the female infant was delivered by emergency cesarean section . apgar ( activity , pulse , grimace , appearance & respiration ) scores were 2 , 6 and 7 at 1 , 5 and 10  min of life , respectively . respiratory distress was evident soon after delivery and was managed by nasal continuous positive airway pressure ( ncpap ) ventilation in the neonatal intensive care unit . examination revealed a generally hypotonic and edematous infant with respiratory distress and short limbs in varus deformity . the birth weight was between 3rd and 10th percentile , head circumference just above 10th percentile and length grossly below 3rd percentile for gestational age . initial radiographs ( figure 1 ) showed diffuse osteopenia with multiple bilateral healing fractures of the seventh and eighth ribs ( arrows ) . there was symmetrical shortening of the humeri , radii , ulnae , femora , tibiae and fibulae and widening of the metaphyseal segments of all long bones . healing fractures of the right proximal humerus and both femora were noted along with lateral bowing of the tibiae and fibulae . ( a ) chest radiograph on day 1 of life demonstrating demineralization of the bones and multiple healing rib fractures , including two each in the right and left seventh and eighth ribs ( arrows ) . ( b ) frontal view of the upper part of the body depicting shortening and demineralization of long bones , more recent fractures of both proximal humeri . ( c ) frontal view of the lower limbs demonstrating demineralization with shortening and bowing of all of the long bones . there are healing fractures of the mid - shafts of both femora and both proximal tibiae . ( d ) lateral view of the right femur at 10  days of age showing more fractures as evidenced by increasing areas of callus formation . early consultation with genetics , endocrinology and orthopedic specialties were pursued and the consensus was made for gentle handling , no casting and provision of adequate analgesia , chromosomal analysis and collagen mutation testing . by day 7 of life , the infant was weaned off ncpap and oxygen supplementation and was tolerating enteral feeds administered via an orogastric tube . she required minimal morphine dosing . in the succeeding weeks , the infant experienced progressive respiratory deterioration . she was first noted to be desaturating frequently when handled despite preadministration and increased dosing of morphine . she then had to be re - placed on supplemental oxygen via nasal cannula on day 14 of life . chest radiographs did not show any significant parenchymal abnormalities although lung expansion seemed consistently poor . there was gradually increasing inspiratory oxygen fraction ( fio2 ) requirement over the following week requiring re - placement on ncpap ventilation . on day 29 of life , she went into severe respiratory failure requiring mechanical ventilation using a high - frequency oscillatory ventilator ( hfov ) . a c - reactive protein was elevated at 2.8  mg / dl with a relative neutropenia ( wbc 4900/mm ) and increased bands of 23% . enterococcus faecalis was isolated in the blood culture and klebsiella pneumoniae was isolated from the endotracheal tube culture . antibiotic therapy was adjusted and continued for 21  days to cover for the possibility of meningitis . in the meantime , karyotype studies were reported as normal . by day 36 of life , a week after being on mechanical ventilation , there was no clinical improvement . the infant continued with co2 retention and borderline oxygen saturations despite maximal settings on the hfov and an fio2 of 1.0 . a multidisciplinary meeting was held , including the palliative care team , social worker , neonatology and the patient 's family . it was determined that if needed , chest compressions may be ineffective , detrimental and painful for the infant given her propensity for fractures . respiratory support would continue but the patient would not receive escalation of care with vasopressors and cardiopulmonary resuscitation ( cpr ) if needed . on day 48 of life , the infant was replaced on a conventional ventilator at high settings and switched to continuous fentanyl infusion for pain management . the results of dna sequencing for col1a1 and col1a2 mutations in the patient 's peripheral blood were reported as negative and a skin biopsy for further analysis was performed . she continued with frequent and deep desaturations and as per previous discussion with the family , in the event of bradycardia , resuscitation was to be limited to one dose of intravenous epinephrine . on day 54 of life , the patient developed bradycardia , which did not respond to intravenous epinephrine , and expired . the parents were informed of the events , counseled by the staff and gave consent for an autopsy . the autopsy demonstrated the body of a female child with multiple skeletal dysplastic features , measuring 31.5  cm from crown to rump , 12.5  cm from rump to heel and weighing 3826  g. there was shortening and bowing of the upper and lower extremities ( figure 2 ) , with both lower extremities having a varus deformity . the chest circumference was 38.5  cm and that of the abdomen was 33.5  cm . the soft tissues of the scalp were edematous resulting in a cephalic circumference of 36  cm ( normal : 31.5  cm ) . the patient 's posterior view at autopsy demonstrating short and bowed upper and lower extremities . notice redundant skin that seems excessive for the bone length . internal examination revealed pleural petechiae bilaterally . there was a 2.2  1.7  1.7  cm cystic mass with serous fluid located on one ovary and a similar cyst located on the other ovary , measuring 1.2  0.8  0.8  cm . microscopic examination of the ribs ( figure 3 ) demonstrated an irregular costochondral junction , thinning bony trabeculae and callous formation at the site of a healing fracture . the vertebral column disclosed a compressed vertebral body with expansion of the intervertebral disc as well as callous formation and thinning bony trabeculae . the lungs had collapsed parenchyma with congestion , numerous desquamated pneumocytes with intra - alveolar hemosiderin - laden macrophages , and patchy hyaline membranes . there was mucus and neutrophils located in the bronchi and bronchioli indicative of acute bronchopneumonia . ( a ) age - matched control of costochondral junction demonstrating a well - demarcated straight line between the cartilage to the right and the bone to the left . ( b ) our patient 's costochondral junction depicting an irregular demarcation between bone and cartilage . the vertebral body occupies almost the entire field of view , leaving a minimal portion of cartilage ( intervertebral disc ) to the left . ( d ) compressed vertebral body from our patient ( all the photographs were taken with the 4 lens ) . fibroblast culture from a skin biopsy was sent to the collagen diagnostic laboratory at the university of washington , seattle . their report indicated heterozygosity for two causative mutations in the lepre1 gene , the gene that encodes p3h1 , confirming the diagnosis of perinatal lethal osteogenesis imperfecta . no abnormalities were found in the gene sequencing analysis of col1a1 and col1a2 , crtap or ppib genes . osteogenesis imperfecta is a rare group of connective tissue disorders that increase the patient 's susceptibility to multiple bone fractures . as a group , it has a prevalence of approximately 1 in every 20  000 births ( 3 ) . there are currently 11 well - defined subtypes of osteogenesis imperfecta , mainly being separated by their genetic mutation and clinical presentation . types i  iv are the classical sillence types and are all ad with defects in either the col1a1 or col1a2 genes . type v , which has a distinctive histology but unknown etiology , is also ad . type vi is ar and is phenotypically characterized by a mineralization defect and distinctive histology . types vii  ix are ar and are due to 3-hydroxylation defects , while types x and xi are also ar , but are secondary to chaperone defects ( 4 ) . under the new classification , this is the perinatal severe to lethal form due to an ar mutation in the lepre1 gene , which encodes p3h1 . the p3h1 , along with crtap and cyclophilin b ( cypb ) , form the prolyl 3-hydroxylase complex in the endoplasmic reticulum . this complex is a part of the post - translational modification system of type i collagen ( 5 ) . there are currently 17 known mutations of the lepre1 allele , occurring throughout the gene ( 6 ) . a very small proportion of mid - atlantic african - americans ( 0.4% ) are estimated to be carriers of the lepre1 mutation , resulting in recessive osteogenesis imperfecta in an estimated 1/260,000 births in that population . it is believed that the carriers were brought to the united states during the slave trade , as an estimated 1.5% of ghanians and nigerians are carriers ( 7 ) . the parent 's of our patient are both of african descent , with the mother being of african - hispanic descent and the father of african - american descent . this patient 's phenotype differs from the classical severe ad perinatal form of osteogenesis imperfecta ( type ii ) because even though our patient had intrauterine fractures , bone deformities and slight macrocephaly ( spuriously increased because of scalp edema ) , she did not have blue sclerae , and she survived for 7 weeks in the neonatal intensive care unit . a phenotype similar to our patient has been previously described in type viii osteogenesis imperfecta . the majority of the patients present with rhizomelia and fractures in the long bones and rib cage . the head circumference is usually normal , but the skull is poorly mineralized with enlarged fontanelle . the mode of inheritance needs to be addressed for proper genetic counseling , as the perinatal severe forms tend to be de novo mutations without risk of recurrence ; however , in severe ar inheritance the parents must be informed about the 25% risk of recurrence in every subsequent pregnancy . while bisphosphonates , physical therapy and orthopedic surgery are mainstays in the treatment of the other types of osteogenesis , there is currently no effective treatment in patients with the perinatal lethal type . however , there are trials , mainly in animal models , that use pharmacologic targeting of stem cells to induce osteoblastic differentiation ( 8) and there is hope that the future generations of affected infants may benefit from pharmacogenomics . the authors report no conflicts of interest . the authors alone are responsible for the content and writing of the article .
col1a1osteogenesis imperfecta is a rare connective tissue disorder characterized by bone fragility and low bone density . 
 most cases are caused by an autosomal dominant mutation in either col1a1 or col1a2 gene encoding type i collagen 
 . however , autosomal recessive forms have been identified . 
 we present a patient with severe respiratory distress due to osteogenesis imperfecta simulating type ii , born to a non - consanguineous couple with mixed african - american and african - hispanic ethnicity . 
 cultured skin fibroblasts demonstrated compound heterozygosity for mutations in the lepre1 gene encoding prolyl 3-hydroxylase 1 confirming the diagnosis of autosomal recessive osteogenesis imperfecta type viii , perinatal lethal type .