Tachypnea of Infancy as the First Sign of SanfilippoSyndrome

abstractThis report describes the first known case of Mucopolysaccharidosistype IIIA presenting with respiratory symptoms and characteristic lungpathology. This case highlights under-recognized areas of systemic in-volvement and earlier modes of presentation in lysosomal storage dis-orders as well as the importance of investigating infants who havepersistent tachypnea. Pediatrics 2014;134:e884–e888

AUTHORS: Jackie Chiang, MA, MD, FRCPC,a,b JulianRaiman, MBBS, MSc, MRCP,b,c Ernest Cutz, MD, FRCPC,d,e

Melinda Solomon, MD, FRCPC,a,b and Sharon Dell, BEng,MD, FRCPCa,b

Divisions of aRespiratory Medicine, cGenetics and Metabolics,and dPathology, The Hospital for Sick Children, Toronto, Ontario;and bDepartment of Pediatrics and eDepartment of Laboratorymedicine and Pathobiology, University of Toronto, Toronto,Ontario

KEY WORDStachypnea, infant, Mucopolysaccharidosis III, pathology

ABBREVIATIONSABCA3—adenosine triphosphate-binding cassette protein member A3CT—computed tomographyMPS—mucopolysaccharidosis

Dr Chiang reviewed the existing literature and drafted the initialmanuscript; Dr Raiman was a co-principal author, providingcritical mechanistic insights; Dr Cutz reviewed the lung biopsy,provided the pathology figures, and critically reviewed themanuscript; Dr Solomon critically reviewed the manuscript;Dr Dell critically reviewed and revised the manuscript; and allauthors approved the final manuscript as submitted.

www.pediatrics.org/cgi/doi/10.1542/peds.2013-2765

doi:10.1542/peds.2013-2765

Accepted for publication Feb 19, 2014

Address correspondence to Sharon Dell, BEng, MD, FRCPC,Division of Respiratory Medicine, The Hospital for Sick Children,555 University Ave, Toronto, ON, M5G 1X8. E-mail: sharon.dell@sickkids.ca

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2014 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they haveno financial relationships relevant to this article to disclose.

FUNDING: No external funding.

POTENTIAL CONFLICT OF INTEREST: The authors have indicatedthey have no potential conflicts of interest to disclose.

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Primary lung involvement is a well-recognized feature of several lysosomalstorage diseases including NeimannPickdisease typeBandGaucherdisease.In the other mucopolysaccharidosis(MPS) disorders, a variety of respiratorymanifestations occur, with both upperand lower airway obstruction beingprominent late features of MPS I and II.Restrictive lungdiseasepredominates inthose who have significant skeletal in-volvement, suchasMPS IVandVI.1 To ourknowledge, this case is the first reportof respiratory symptoms and subse-quent lung pathology leading to a di-agnosis of MPS III, otherwise known asSanfilippo syndrome.

CASE PRESENTATION

A 37-week-gestation boy was born toconsanguineous parents by inducedvaginal delivery after an uncomplicatedpregnancy. The indication for inductionwas a previous term stillbirth of un-known etiology. Birth weight was 3160 gandApgar scoreswere 7 and 9 at 1 and5minutes, respectively. At 10 minutes oflife, he started grunting and his oxygensaturation was 80% in room air. Con-tinuous positive airway pressure with40% oxygen was initiated. Arterial bloodgas revealed a pH of 7.45, PCO2 of 42, andbicarbonate of 23. A chest radiographshowed a bilateral, diffuse ground-glassappearance. At 36 hours of life he wasintubated and ventilated owing toworsening respiratory distress. On day5 of life, he was transferred to a tertiarylevel NICU for further management. Hereceived 3 doses of surfactant withminimal improvement. Infectious workupwas negative. An echocardiogram per-formed on the seventh day of life revealedgood biventricular function, no rightventricular dilatation, mild septal flat-tening in diastole, and a patent foramenovale that showed blood flow shuntingfrom left to right. He failed extubationonce before being successfully extubatedto nasal continuous positive airway

pressure on day 13 of life. A chest com-puted tomography (CT) scan revealeddiffuse bilateral ground-glass opacifi-cations (Fig 1A). The unexplained termneonatal respiratory distress promptedgenetic testing for surfactant deficiency.Gene sequence analysis of AdenosineTriphosphate-Binding Cassette proteinmember A3 (ABCA3) revealed 2 sequencevariants of unknown significance inp.T385A and c.4165-8G.A. His asymp-tomatic father was later shown to carrythe same variants. No mutations werefound with gene sequence analysis ofsurfactant protein B or C.

Over the course of several weeks, theinfant was successfully weaned off sup-plemental oxygen. However, persistenttachypnea (respiratory rate of 60 to 70per minute) and increased work ofbreathing (intercostal in-drawing) withfeeding difficulty remained. He was dis-charged from the hospital at 2 months ofage.

At 4 months of age, the infant was read-mitted to hospital for feeding difficulties

and failure to thrive (weight and heightbelow third percentiles). He remainedtachypneic (respiratory rate over 60breaths per minute) but was able tomaintain normal oxygen saturations. Ametabolicscreen, includingserumaminoacids, urine amino acids, and urine or-ganic acids, did not detect any abnor-malities. A sweat chloride test wasnegative and serum immunoglobulinswerewithin normal limits. A repeat chestCT revealed patchy ground-glass opaci-fication in both lungs centrally and focalemphysematous changes in the medialaspect of both lower lobes (Fig 1B).

A lungbiopsywasperformedat 5monthsof age. Light microscopy showed no evi-dence of an inflammatory process andnormal septal wall thickness but didreveal diffuse over-expansion of alveo-lar spaces owing to deficient alve-olarization, similar to cases of postsurfactantbronchopulmonarydysplasia(Fig 2A).2 Electron microscopy identifiedinterstitial cellswith vacuolated cytoplasmand flocculent substrate suggestive ofamucopolysaccharide substance (Fig 2 BandC). Type II pneumocyteswere found tohave normal ultrastructure with no evi-dence of abnormal lamellar bodies.

A metabolic assessment for storagedisease was then performed; thin-layerchromatography for urine mucopoly-saccharides showed an increased ex-cretionofheparansulfate, suggestiveofMPS III. Enzymatic testing was consis-tent with a diagnosis of MPS IIIA withdeficient heparan sulfamidase activityat 0 nmoles/mg protein/17 h (NR 25–75). Genetic testing confirmed the di-agnosis with homozygous mutations inthe SGSH gene (p.R74H).

At 2 years of age, the boy is well, withresolution of his feeding issues andtachypnea, adequategrowth (weight andheight at the 50th to 75th percentiles),appropriate verbal, motor, and socialdevelopmental milestones, and normalneurologic examination. The only stig-mata of his devastating diagnosis are

FIGURE 1A, Chest CT scan on day 5 of life showed diffusebilateral ground-glass opacifications. B, Repeatchest CT scan on day 20 of life revealed bilateralpatchy ground-glass opacifications centrally andfocal emphysematous changes in the lower lobes.

CASE REPORT

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subtle coarse facial features, includ-ing prominent eyebrows and supra-orbital ridge, and an umbilical hernia.

A recent chest radiograph shows per-sistent increased interstitial lung mark-ings, which are less pronounced thanprevious imaging, in keeping with mildinterstitial lung disease (Fig 3).

DISCUSSION

MPSIII,alsoknownasSanfilipposyndrome,is an autosomal recessive lysosomalstorage disease resulting in mucopoly-sacchariduria and accumulation of gly-cosaminoglycan heparan sulfate in thetissues.3 Compared with other muco-polysaccharidoses, the central nervoussystem appears to be the major organaffected in MPS III.4 MPS III has 4 var-iants, based on the respective defi-ciency of the catalytic enzymes, whichall lead to the same phenotype: MPSIIIA (heparin N-sulphatase), MPS IIIB(a-N-acetylglucosaminidase), MPS IIIC(acetyl-coenzyme A: a-glucosaminideacetyltransferase), and MPS IIID(N-acetylglucosamine 6-sulfatase).

In themajorityofpatientswhohaveMPSIIIA, the first signs and symptoms ofdisease appear at 2 to 3 years of age,with a median age of diagnosis of 4.5years.5 Initial symptoms consist of de-velopmental delay (primarily speech)and/or behavioral problems (hyperac-tivity, aggression, or destructive behav-ior). Progressive mental deterioration

eventually culminates in severe de-mentia and death by a median age of 18years.3,4 Other medical problems includehearing and vision abnormalities, sei-zures, diarrhea, and sleep disturbances.3

Respiratory disease is not reported inassociation with MPS III.6

The typical clinicalphenotypeofMPS IIIAwas not displayed in this case, likelyowing to his unusually young age atdiagnosis. His initial symptoms wereprimarily respiratory. The simplified,over-expanded alveoli evident on lungbiopsy could potentially be attributed toMPS and its deleterious effects on lungdevelopment, and may have influencedthe clinical presentation. It is alsopossible that the compound heterozy-gous ABCA3 mutations found in ourpatient may have contributed to hisrespiratory symptoms. ABCA3 plays arole in surfactant lipid transport intolamellar bodies, and mutations in thisgene have been shown to cause inter-stitial lung disease owing to surfactantdeficiency.7 The classic lung pathologyfindings include desquamative inter-stitial pneumonia-like picture with orwithout alveolar proteinosis and abnor-mal lamellar bodies with dense inclu-sion bodies observed on electronmicroscopy, which were not evident inour case.8 Lung disease caused by ABCA3mutations requires mutations in bothalleles as it is inherited as an autosomalrecessive disorder.9 The ABCA3 se-quence variants in our patient werelikely not disease-causing, as his un-affected father was shown to carry thesame variants. However, previous stud-ies have shown that heterozygous ABCA3mutations can modify the severity oflung disease associated with surfactantprotein C mutations.10 Single ABCA3mutations have also been found to in-crease the risk for neonatal respiratorydistress syndrome in infants 34 weeks’gestation and older.11 It is therefore plau-sible that heterozygous ABCA3 mutationsmay sufficiently exacerbate lung disease

FIGURE 2A, Light microscopy view of open lung biopsyshowed diffuse over-expansion and simplificationof alveolar spaces (asterisk) with well-preservedlung parenchyma including small bronchioles(Br)andpulmonaryarteries (PA)withnoevidenceof septal wall thickening. B, Lowmagnification EMview of lung biopsy showed interalveolar septumdelineated by alveolar spaces (Alv), some withalveolar type 2 cells (white arrow) containingseveral vacuolated interstitial storage cells (as-terisk) characteristic of MPS. C, Higher magnifi-cation of interstitial storage cells, some withnucleus (n) and cytoplasm filled with mucopoly-saccharide appearing as empty spaces owing toextraction (asterisk). Interstitial collagen (Col).

FIGURE 3Chest radiograph at 2 years of age with persis-tent increased interstitial lung markings.

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associated with mucopolysaccharidedeposition to produce clinically appar-ent respiratory symptoms.

Currently all the MPS disorders remainincurable, but a variety of therapies havebecome available in the last decade.These include exogenous enzyme re-placement therapy, with phase II trialscompleted for MPS IIIA,12 and otherspecific therapies under development.13

Maximal therapeutic benefit will likelyrequire early diagnosis and treatmentinitiation. This case demonstrates thatrespiratory symptoms may herald thediagnosis of MPS III before neurologicdeterioration.

It is imperative that any infant who haschronic tachypnea and diffuse paren-chymal abnormalities on lung imaginghave prompt and appropriate inves-tigations to help elucidate an etiology(Table 1). In this case, flexible bron-choscopy with bronchoalveolar lavagewas not performed but is usually rec-ommended to exclude infection or air-way abnormalities as possible causes ofdiffuse lung disease.14 Lung biopsy, al-though invasive, should be consideredfor those in whom the diagnosis is un-certain. In particular, electron micros-copy should be part of routine handlingfor all pediatric lung biopsies, as ul-trastructural studies play a significantrole in the diagnosis of respiratory

disorders in young children.15 Further-more, all metabolic storage diseases,including MPS IIIA, should be includedin the differential diagnosis of diffuselung disease.14 Infants should be care-fully examined for features of metabolic

storage diseases (including coarse facialfeatures and hepatosplenomegaly) and,if present, consultation with a metabolicspecialist should be requested to guidefurther investigations, such as urine formucopolysaccharidoses.

REFERENCES

1. Muhlebach MS, Wooten W, Muenzer J. Respira-tory manifestations in mucopolysaccharidoses.Paediatr Respir Rev. 2011;12(2):133–138

2. Cutz E, Chaisson D. Chronic lung diseaseafter premature birth [Letter to the Editor].N Engl J Med. 2008(7);358:743–745

3. Valstar MJ, Neijs S, Bruggenwirth HT, et al.Mucopolysaccharidosis type IIIA: clinicalspectrum and genotype-phenotype corre-lations. Ann Neurol. 2010;68(6):876–887

4. Valstar MJ, Ruijter GJ, van Diggelen OP,Poorthuis BJ, Wijburg FA. Sanfilippo syndrome:

a mini-review. J Inherit Metab Dis. 2008;31(2):240–252

5. Meyer A, Kossow K, Gal A, et al. Scoringevaluation of the natural course of muco-polysaccharidosis type IIIA (Sanfilippo syn-drome type A). Pediatrics. 2007;120(5).Available at: www.pediatrics.org/cgi/con-tent/full/120/5/e1255

6. Semenza GL, Pyeritz RE. Respiratory com-plications of mucopolysaccharide storagedisorders. Medicine (Baltimore). 1988;67(4):209–219

7. Bullard JE, Wert SE, Whitsett JA, Dean M,Nogee LM. ABCA3 mutations associated withpediatric interstitial lung disease. Am JRespir Crit Care Med. 2005;172(8):1026–1031

8. Nogee LM. Genetics of pediatric interstitiallung disease. Curr Opin Pediatr. 2006;18(3):287–292

9. Wert SE, Whitsett JA, Nogee LM. Geneticdisorders of surfactant dysfunction.Pediatr Dev Pathol. 2009;12(4):253–274

10. Bullard JE, Nogee LM. Heterozygosity forABCA3 mutations modifies the severity of

TABLE 1 Causes of Chronic Tachypnea of Infancy With Diffuse Parenchymal Abnormalities on LungImaging

Etiology Potential Informative Investigations

Infection and post-infectious processes Microbiological samples: nasopharyngeal swab, serology andbronchoalveolar lavage; maternal cervical swab forChlamydia

Chlamydia trachomatis (,6 mo)AdenovirusOther

Congenital heart disease EchocardiogramAspiration syndromes Swallowing and esophageal studies, neurologic examinationCystic fibrosis Sweat chloride test, genetic testingPrimary ciliary dyskinesia Ciliary biopsy, genetic testingImmunodeficiency disease Complete blood count and differential, immunoglobulins,

antibody titers to previously administered vaccines,lymphocyte subset analysis

Interstitial lung disease Chest CT, infant pulmonary function testing, bronchoalveolarlavage fluid for cytology and pathology, lung biopsy, geneticsfor surfactant metabolism defects

Lung growth abnormalities (includingchronic lung disease of prematurity)

Neuroendocrine hyperplasia of infancyPulmonary interstitial glycogenosisSurfactant dysfunction disordersHypersensitivity pneumonitisEosinophilic pneumonia

Langerhans cell histiocytosis Bone scan, bronchoalveolar lavage fluid for cytology, lung biopsyPulmonary vascular diseases Echocardiogram, chest CT, cardiac catheterization, lung biopsyPulmonary lymphatic disorders Chest CT, lung biopsyMetabolic storage diseases:

Gaucher diseaseNiemann Pick disease type B

Complete blood count, creatinine, paired plasma/urine aminoacids, urine glycosaminoglycans (MPS), disease-specificlysosomal enzymology, abdominal ultrasound, skin biopsy(electron microscopy/fibroblast culture)

MucopolysaccharidosesLysinuric protein intolerance

CASE REPORT

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lung disease associated with a surfactantprotein C gene (SFTPC) mutation. PediatrRes. 2007;62(2):176–179

11. Wambach JA, Wegner DJ, Depass K, et al.Single ABCA3 mutations increase risk forneonatal respiratory distress syndrome.Pediatrics. 2012;130(6). Available at: www.pediatrics.org/cgi/content/full/130/6/e1575

12. Safety, tolerability, ascending dose anddose frequency study of rhHNS via an IDDD

in MPS IIIA patients. ClinicalTrials.gov.Available at: http://clinicaltrials.gov/ct2/show/NCT01155778?term=MPS+IIIA&rank=1.Accessed May 28, 2013

13. de Ruijter J, Valstar MJ, Wijburg FA.Mucopolysaccharidosis type III (SanfilippoSyndrome): emerging treatment strategies.Curr Pharm Biotechnol. 2011;12(6):923–930

14. Kurland G, Deterding RR, Hagood JS, et al.An Official American Thoracic Society Clin-

ical Practice Guideline: classification, eval-uation, and management of childhoodinterstitial lung disease in infancy. Am JRespir Crit Care Med. 2013;188(3):375–394

15. Langston C, Patterson K, Dishop MK, et alchILD Pathology Co-operative Group. Aprotocol for the handling of tissue obtainedby operative lung biopsy: recommendationsof the chILD Pathology Co-operative Group.Pediatr Dev Pathol. 2006;9(3):173–180

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DOI: 10.1542/peds.2013-2765 originally published online August 11, 2014; 2014;134;e884Pediatrics 

Jackie Chiang, Julian Raiman, Ernest Cutz, Melinda Solomon and Sharon DellTachypnea of Infancy as the First Sign of Sanfilippo Syndrome

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DOI: 10.1542/peds.2013-2765 originally published online August 11, 2014; 2014;134;e884Pediatrics 

Jackie Chiang, Julian Raiman, Ernest Cutz, Melinda Solomon and Sharon DellTachypnea of Infancy as the First Sign of Sanfilippo Syndrome

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