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A Novel Presentation of Diffuse Lung Disease Caused by Congenital Hypothyroidism

A Novel Presentation of Diffuse Lung Disease Caused by Congenital Hypothyroidism
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   A Novel Presentation of Diffuse Lung Disease Caused by CongenitalHypothyroidism  Ambika Shenoy, MD, Americo E. Esquibies, MD, Nancy Dunbar, MD, MPH, Megan K. Dishop, MD, Miguel Reyes-Mugica, MD,Claire Langston, MD, Johnny Deladoe¨y, MD, PhD, Rasha Abu-Khudir, MSc, Thomas Carpenter, MD, and Alia Bazzy-Asaad, MD  A term infant was born with respiratory distress, and subsequent imaging, histopathologic, and hormonal stud-ies confirmed congenital hypothyroidism. This report is intended to alert pediatricians to the possibility of con-genital hypothyroidism as a cause of respiratory symptoms of unknown cause in neonates with respiratorydistress.  (J Pediatr 2009;155:593-5) T hyroidhormone(TH)playsanimportantroleinthede-veloping brain and bone. However, the effect on thestructureandfunctionofthedevelopinglungisunclear.Interstitial lung disease (ILD) is a group of disorders char-acterized by impaired gas exchange and diffuse infiltrates onradiographic imaging. 1 Here, we describe the clinical, imag-ing, and histopathologic study findings that demonstratean association between ILD and undiagnosed congenitalhypothyroidism. Case Report AtermboywasbornwithnormalApgarscores.Thenext day,respiratory distress developed, and the patient required pos-itive pressureventilationforaweek followed by100% oxygen0.2 L/min via nasal cannula. Prenatal history was normal ex-ceptformaternalhypothyroidism caused by postpartumthy-roiditis that was treated with levothyroxine; the motherremained euthyroid throughout this pregnancy. At age4 weeks the infant was transferred to our institution for fur-ther evaluation. Chest radiography ( Figure 1 ) and computedtomography demonstrated bilateral ‘‘ground glass’’ opacities.The result of echocardiography was normal. Because the pa-tient had adequate oral intake and had gained weight appro-priately with a normal chest examination, he was dischargedhome after 1 week on 100% oxygen 0.1 L/min.Over 4 weeks our patient’s oxygen requirement increased,and he had mild hypotonia. Mutational analysis of surfactantprotein (SP) B, C, and ABCA3 genes and a sweat chloride testresult were normal. A lung biopsy specimen was obtained atage 2.5 months because of continued hypoxemia and un-changed radiography results.At age 3 months respiratory failure developed requiringmechanical ventilation. In the interim the lung histologicfindings ( Figure 2 ,  A  to  C  ) showed interstitial edema, lack of prominent inflammatory cells, and impaired alveolardevelopment and growth. The interstitial compartment waswidened and hadamyxoidcharacter.Byelectronmicroscopy ( Figure 2 ,  D ) this material corresponded to extracellularground matrix, without increased glycogen or other storagematerial. These features did not support any known causesof ILD 2 but resembled those observed in a previously exam-ined infant with hypothyroidism (C. Langston, unpublishedobservation relayed by oral and written communication onDecember 4, 2007.). The infant’s newborn screening samplehad been reportedly obtained at the birth hospital; however,on later investigation receipt of the sample in the screeninglaboratory was not documented. Because only abnormal Figure1. A,  Chest radiograph obtained at age 1 monthdem-onstrates patchy bilateral airspace opacities and groundglass appearance, without significant volume loss.  B,  Chestradiographobtainedatage9monthsshowscompleteresolu-tion of patchy opacities. From the Department of Pediatrics (A.S., A.E., N.D., T.C., A.B.), the Sections of Respiratory Medicine (A.S., A.E., A.B.) and Endocrinology (N.D., T.C.), and theDepartmentofPathology(M.R.),YaleUniversitySchoolofMedicine,NewHaven,CT,the Department of Pathology (M.D., C.L.), Texas Children’s Hospital, Houston, TX,and the Endocrinology Service and Research Center (J.D., R.A.), Sainte-JustineHospital and Department of Pediatrics, University of Montreal, Montreal, Quebec,CanadaThe authors declare no real or perceived conflict of interest. 0022-3476/$ - see front matter. Copyright ª 2009 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2009.02.049 ILD Interstitial lung diseasePNEC Pulmonary neuroendocrine cellsSP Surfactant proteinTH Thyroid hormone 593  results are reported in the program, the absent report hadbeen interpreted as consistent with euthyroid status.Nevertheless, because of the histologic study findings,thyroid function testing was performed and revealed elevatedthyroid-stimulating hormone (561 uIU/mL, normal 0.3-4.2uIU/mL) and low thyroxine (<1.0  m g/dL, normal 5-11  m g/dL). A technetium 99–pertechnetate thyroid scan suggestedathyreosis. TH replacement therapy was initiated and as thy-roxine levels increased to the normal range,the infant’s respi-ratory status improved significantly.The TITF1 gene, a transcription factor that is involved indifferentiation of lung buds and thyroid tissue, of the infantand his parents was sequenced with previously describedmethods. 3 Neither point mutations nor deletions were foundby direct sequencing (exons and large intron junctions of TITF1 on chromosome 14q13.3) or by high-definition com-parative genomic hybridization arrays for chromosome 14.At present, the infant is breathing room air, and theground glass opacities have resolved ( Figure 1 ,  B ). He isreaching developmental milestones and thriving adequately. Discussion We describe an infant in whom histologic evidence of myx-edematous pulmonary interstitium confirmed neonatal ILDcaused by congenital hypothyroidism (CH). ILD in childrencomprises a large and heterogeneous group of disorders. 2 Be-cause ILD usually involves the distal airspaces in addition tothe parenchyma, the term  diffuse infiltrative lung disease  hasbeen suggested. Figure2. A  to  C, Microscopic examination oflungtissue sections demonstrates altered alveolar architecture withmildlydilatedandbranchingairspacewithgenerallydeficientseptationforstatedgestationalage.Theinterstitiumshowsdiffusemildwideningwith rarefaction suggesting edema or possibly mucoid material. There is no evidence of diffuse alveolar epithelial hyperplasia.The airways and pulmonary vasculature are normal.  D,  Electron microscopy reveals normal type II pneumocytes with lamellarbodies in appropriate numbers and normal whorled architecture. The interstitium is expanded by increased finely granularground substance and probable edema, but there are no abnormal intracellular deposits or accumulation of storage material.Occasional interstitial fibroblast-like cells are seen, without increased glycogen. Collagen fibers are splayed by the edemaand ground substance.  AL,  Alveolar space;  IN,  interstitial space;  PnII,  type II pneumocyte. T HE  J OURNAL OF  P EDIATRICS    Vol. 155, No. 4 594  Shenoy et al  The initial clinical and radiographic findings in this infantled us to consider a surfactant protein (SP-B, SP-C andABCA3)deficiency. 1 InfantswithSP-Bdeficiencyusuallypres-ent with a severe neonatal course, and SP-C or ABCA3 defi-ciencies have a variable clinical presentation ranging fromsevere respiratory distress in early infancy to developing ILDin adulthood or remaining symptom free. 1 A full sequenceanalysis of these 3 genes did not reveal any mutations.Other causes of ILD in neonates are neuroendocrine cellhyperplasia of infancy and pulmonary interstitial glycogeno-sis. Neuroendocrine cell hyperplasia of infancy is character-ized by the presence of pulmonary neuroendocrine cells(PNEC) on lung biopsy specimens. PNECs are responsiblefor producing bombesin-like peptide, serotonin, and calcito-nin, mediators that can affect airway and vascular tone. 4 PNECs are abundant at birth and decrease markedly throughthe first year. In our case, there was no observed abnormality inPNEC. Pulmonary interstitial glycogenosis ischaracterizedby accrual of mesenchymal cells within the alveolar intersti-tium 2 and is usually associated with a benign clinical course. 5 Interstitial alveolar mesenchymal cells were not present inour patient.The description of CH associated with respiratory prob-lems in infants is rare but has been described in animals. Hy-pothyroid lambs had poor alveolar differentiation andabnormal surfactant production. 6 In rats, hypothyroidismwas associated with abnormal intrauterine pulmonary devel-opment, including hypoplasia. 7 TH has also been shown toinfluence epithelial cell differentiation during murine fetallung development. 8 In a case report a term infant with hypo-thyroidism was described as having respiratory distress andhypoxia with hyaline membrane formation and decreased al-veolar numbers. 9 These findings differ from those found inour patient, where a prominent feature was widening of theinterstitium with mucoid material. This material is likely myxedema (a waxy interstitial ground substance), which isgenerally limited to severe, chronic hypothyroidism, al-though many patients with hypothyroidism do not presentwith overt myxedema. 10 This case emphasizes that clinicalsuspicion of disease must not be preempted by the assump-tion that screening tests have excluded disease. Reasons forscreening failures include inadequate sample collection, sam-ple loss in transport, misidentification, and technical errorsin assay performance. Ideally, screening programs shouldbe able to identify mechanisms to avoid these potential fail-ures. Implementing procedures such as notification by thescreening laboratory of both normal and abnormal results,and identification of new births in the catchment area fromwhom no samples are received, would be helpful.In summary, CH should be considered when unexplainedILD occurs in infants with respiratory distress. In addition,clinical suspicion should always supersede presumed normalnewborn screening results.  n Submitted for publication Sep 30, 2008; last revision received Dec 22, 2008;accepted Feb 26, 2009.Reprintrequests:AliaBazzy-Asaad,MD,DepartmentofPediatrics, Sectionof RespiratoryMedicine,333CedarSt,Fitkin510,NewHaven, References 1.  Fan LL, Deterding RR, Langston C. Pediatric interstitial lung diseaserevisited. Pediatr Pulmonol 2004;38:369-78. 2.  Deutsch GH, Young LR, Deterding RR, Fan LL, Dell SD, Bean JA, et al.Diffuse lung disease in young children: application of a novel classifica-tion scheme. Am J Respir Crit Care Med 2007;176:1120-8. 3.  Maquet E, Costagliola S, Parma J, Christophe-Hobertus C, Oligny LL,Fournet JC, et al. Lethal respiratory failure and mild primary hypothy-roidism in a term girl with a de novo heterozygous mutation in theTITF1/NKX2.1 gene. J Clin Endocrinol Metab 2008 [Epub ahead of print]. 4.  Deterding RR, Pye C, Fan LL, Langston C. Persistent tachypnea of in-fancy is associated with neuroendocrine cell hyperplasia. Pediatr Pulmo-nol 2005;40:157-65. 5.  Fan LL, Langston C. Pediatric interstitial lung disease: children are notsmall adults. Am J Respir Crit Care Med 2002;165:1466-7. 6.  Cunningham MD, Hollingsworth DR, Belin RP. Impaired surfactantproduction in cretin lambs. Obstet Gynecol 1980;55:439-43. 7.  Krude H, Schutz B, Biebermann H, von Moers A, Schnabel D, Neitzel H,et al. Choreoathetosis, hypothyroidism, and pulmonary alterations dueto human NKX2-1 haploinsufficiency. J Clin Invest 2002;109:475-80. 8.  Archavachotikul K, Ciccone TJ, Chinoy MR, Nielsen HC, Volpe MV.Thyroidhormoneaffectsembryonicmouselungbranchingmorphogen-esis and cellular differentiation. Am J Physiol Lung Cell Mol Physiol2002;282:L359-69. 9.  Gatrad AR. Cretinism as a cause of respiratory distress in a neonate. Br JClin Pract 1982;36:164-5. 10.  Setian NS. Hypothyroidism in children: diagnosis and treatment. JPediatr (Rio J) 2007;83(Suppl):S209-16. October 2009  CLINICAL AND LABORATORY OBSERVATIONS  A Novel Presentation of Diffuse Lung Disease Caused by Congenital Hypothyroidism  595
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