Pediatric Pulmonology 44:198–201 (2009)

Case Report

Ciliopathy Spectrum Expanded? Jeune SyndromeAssociated With Foregut Dysmotility and Malrotation

Tim Hall, MRCS,1* Andrew Bush, MD,2 John Fell, MD,3 Amaka Offiah, PhD,4

Virpi Smith, PhD,5 and Robin Abel, PhD6

Summary. We report the association and surgical management of gastrointestinal dysmotility

and malrotation with Jeune asphyxiating thoracic dystrophy (JATD), an autosomal recessive

condition that often results in respiratory failure due to a small rib cage. A 4-month-old male with

JATD presented with vomiting and aspiration pneumonitis compounding already severe

respiratory morbidity. A contrast study revealed esophageal and gastric dysmotility with associated

malrotation. This was treated surgically with good results. Some cases of JATD are caused by

missense mutations in the gene IFT80, which encodes a protein implicated in the process of

intraflagellar transport of primary cilia. We speculate that these abdominal complications might

also be part of the extending spectrum of ciliopathy. Pediatr Pulmonol. 2009; 44:198–201.

� 2009 Wiley-Liss, Inc.

Key words: Jeune asphyxiating thoracic dystrophy; foregut dysmotility; malrotation;

ciliopathy; IFT80.

INTRODUCTION

Jeune syndrome or asphyxiating thoracic dystrophy(JATD) is a congenital disorder with a point prevalence inone study of 2.6:100,0001 and defined as ‘‘a multi-systemautosomal recessive disorder associated with character-istic skeletal dysplasia and variable renal, hepatic,pancreatic, and retinal abnormalities.’’2,3 In 2006, theNosology Group of the International Skeletal DysplasiaSociety included JATD in the short rib dysplasia (with orwithout polydactyly) group.4 JATD is clearly geneticallyheterogeneous. One study of four JATD families founda common locus at chromosome 15q13,3 but in anotherfamily, JATD was related to the IFT80 gene on chromo-some 3.5 IFT80 encodes a conserved intraflagellar trans-port (IFT) protein, which is important in ciliary function,leading to the conclusion that JATD may be part of theexpanding spectrum of pleiotropic ciliopathies.5

Congenital abnormalities of motile ciliary functionwere already implicated in airway disease but primaryciliary defects are now known to play a causative role in adiverse set of rare syndromes with specific manifestations,particularly hepatic, renal, and retinal.6 Nodal cilia areimportant in determining situs. Disorders of situs havealso featured in reports of short rib/polydactyly syndromesand JATD.7 The expanding spectrum of ciliopathy hasrecently been reviewed.8

We report a case of foregut dysmotility and malrotationin a 4-month-old male infant with known JATD. Wespeculate that some or all of these abdominal manifes-tations may be ciliopathy related.

1Department of Paediatrics, Hammersmith Hospital, London, UK.

2Department of Paediatrics, The Royal Brompton Hospital, London, UK.

3Department of Paediatrics, Chelsea and Westminster Hospital, London,

UK.

4Department of Radiology, Great Ormond Street Hospital, London, UK.

5Department of Histopathology, Great Ormond Street Hospital, London,

UK.

6Department of Paediatric Surgery, Hammersmith Hospital, London, UK.

*Correspondence to: Tim Hall, MRCS, Bristol Royal Hospital for Children,

Upper Maudlin St, Bristol BS2 8BJ, UK. E-mail: timhall@doctors.org.uk

Received 30 July 2008; Revised 2 October 2008; Accepted 9 October 2008.

DOI 10.1002/ppul.20960

Published online 9 January 2009 in Wiley InterScience

(www.interscience.wiley.com).

� 2009 Wiley-Liss, Inc.

CASE REPORT

The patient has non-consanguineous parents of NorthAfrican origin who had two previous healthy children. Anultrasound scan at 25 weeks gestation identified pulmo-nary hypoplasia. The parents were offered a terminationof the pregnancy but declined. The baby was born at42 weeks gestation (birth-weight 3.48 kg) in a moderatecondition (Apgar scores were 6, 8, and 9 at 1, 5, and10 min, respectively). He was spontaneously ventilatingin air until day 6 of life but thereafter required nasalcontinuous positive airway pressure (CPAP). An echo-cardiogram revealed severe pulmonary hypertension,subsequently treated with sildenafil, and moderatetricuspid regurgitation in a structurally normal heart. Askeletal survey (Figs. 1–3) confirmed the diagnosis ofJATD. He was transferred to the Royal Brompton HospitalHigh Dependency Unit in London at 2 months of agefor respiratory management in the light of worseningpulmonary hypertension diagnosed on echocardiographicmeasurement of tricuspid regurgitation, and failure towean from respiratory support. A tracheostomy was sited,and a nasojejunal tube was placed to improve nutritionalsupport. Subsequently, he was transferred to the PediatricIntensive Care with septic shock and aspiration pneumo-nitis with persistent, non-bile-stained vomiting. This wasthought to be gastro-esophageal reflux disease although adiagnosis of pyloric stenosis was entertained based onultrasound measurements. A subsequent upper gastro-intestinal contrast series showed a distended esophaguswith extremely slow emptying of the distal esophagus butno gastro-esophageal reflux or anatomical gastric outletobstruction. There was little gastric peristalsis, very slow

gastric emptying, and delayed emptying of the duodenumwith malrotation. After discussion between the parentsand respiratory, gastroenterology, and surgical teams, hewas transferred to the operating room. Initial esophago-gastroduodenoscopy showed normal epithelium. Thegastroscope light could be seen externally in the rightlower quadrant, and laparotomy confirmed a grosslydistended stomach. Next, a Ladd’s procedure withappendicectomy, Nissen fundoplication, and insertion ofdouble lumen gastrostomy and feeding jejunostomy wasperformed. Additionally, a central line was placed in hisright internal jugular vein. Ongoing heparin treatmentfor a previous femoral vein thrombosis was carefullymanaged peri-operatively, and there was no excessivebleeding. Seromuscular biopsies from the proximal anddistal jejunum and terminal ileum subsequently showed

Fig. 1. AP chest (performed at birth). Long narrow thorax.

Short horizontal ribs with broad anterior ends. Note ‘‘handlebar’’

appearance of clavicles.

Fig. 2. AP pelvis (performed at birth). Note the relatively broad

iliac wings and horizontal, trident acetabulae.

Fig. 3. Right upper limb (performed at birth). Mild shortening

of all long bones. Poor hand view but sufficient to exclude

polydactyly (seen in 90% of Ellis van Creveld but only 10% of

JATD) but not cone-shaped epiphyses (seen in both).

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JATD and Foregut Anomaly 199

no histological diagnostic features. The biopsies wereganglionic. There was no ganglionitis, myositis, fibrosis,or vacuolation of leiomyocytes noted. Immunostaining fordesmin and alpha smooth muscle actin was unremarkable.Immunostaining for CD56 did show CD56-positivesmooth muscle cells in the innermost layer of the circularmuscle coat. Sections from the appendix were histo-logically unremarkable. He returned to the PaediatricIntensive Care Unit and required ongoing ventilatorysupport. Following the procedure, there have been nofurther episodes of vomiting and aspiration pneumonitis.He remains in high dependency care on continuous BiPAPsupport via the tracheostomy and is being considered for athoracic enlargement procedure.

DISCUSSION

We report on an infant with radiologically confirmedJATD, who also had abdominal complications, includinggastric dysmotility and malrotation. Pathological changesin JATD are known to occur to varying degrees in thechest, kidneys, liver, and retina but usually the main issueis respiratory failure secondary to a dysplastic rib cage.Short, horizontal ribs limit lateral expansion of the smallchest cavity; ventilation is almost exclusively diaphrag-matic. Ultrasound has been used to diagnose JATD inthe pre-natal period as early as 14 weeks gestation bymeasurement of limb length or disparity of fetal thoracicand abdominal circumferences.9,10 The prognosis variesbut most patients die in early infancy of respiratory failureor progressive renal failure in childhood. Managementis primarily ventilatory support, but renal function mustbe monitored.11 The progression of hepatic dysfunctionappears to be controlled with ursodeoxycholic acid.12

In the case described here, the infant deteriorated withevidence of gastric distension, vomiting, and aspirationpneumonitis. An association of JATD with upper gastro-intestinal dysmotility has never been reported in theEnglish literature. Two cases of Hirschsprung’s diseaseassociated with JATD have been reported,13 which isalso rarely associated with malrotation (up to 1.7%).14

Foregut dysmotility is not a documented feature of theother ciliopathies. It is most common in infants withneuro-developmental diagnoses such as cerebral palsy andoccurs in some metabolic disorders and in syndromes suchas Noonan’s. Manifestations include vomiting, bloating,gastro-esophageal reflux, and feeding difficulties. Surgi-cal management is commonly required. In our case, thesymptoms and dilated stomach were thought to be relatedto chronic obstruction, either due to malrotation, intrinsicdysmotility, or both. The aim of surgery was to provideimmediate relief for the patient from vomiting whilstoptimizing respiratory function to enable considerationof further interventions, including thoracic wall surgery.Subsequently, he has gradually improved.

The biopsies taken during laparotomy showed nodiagnostic histological features of enteric neuromusculardisease. The only unusual observation was that theleiomyocytes of the innermost circular muscle layerstained for CD56. We speculate that the malrotation andgastric dysmotility may be part of the expanding spectrumof ciliopathy although, without an affected sibling or someother inheritance pattern establishing definitive proof of anew form of JATD, the association could be incidental.Cilia were until recently regarded as part of the airwaypulmonary defense mechanisms, and congenital disordersof motility (primary ciliary dyskinesia, or Kartagener’ssyndrome) were known to be associated with upper andlower airway disease. Nodal cilia are important indetermining situs; situs inversus occurs in around 50%of patients with primary ciliary dyskinesia.15 Recently,the spectrum of ciliopathy has been extended anddefective primary cilia are implicated in polycystichepatic and renal disease, hydrocephalus, biliary atresia,retinal degeneration, rare syndromes such as Bardet–Biedl, Alstrom and Meckel–Gruber and oro-facial-digitalsyndromes in addition to nephronophthisis.6,8 JATD isanother of these pleiotropic ciliopathies. Some cases havehad missense mutations demonstrated in the IFT80 gene,so-called as it codes for a protein with a putative rolein IFT, a process essential for the formation of normalcilia.5 One study has also demonstrated a long isoform,IFT80-L, highly expressed in proliferating cells butnot differentiated ones, suggesting its role in proliferatingand differentiating stages.16 Malrotation is an occasionalfeature of ciliopathies, particularly Meckel–Grubersyndrome.17 Situs anomalies are a feature of ciliopathiessuch as nephrophthitis type 2.18 They also feature in casereports of short rib polydactyly syndromes and JATD.7

Although important not to assume that malrotation isnecessarily a forme fruste of situs inversus, malrotation isa feature of the heterotaxy syndromes19 and it is notimprobable that the abdominal complications of our childmight also be part of the extending spectrum of ciliopathy.

In summary, we report on a case of JATD withabdominal complications for two reasons. The first is todraw attention to a hitherto undescribed problem in JATDto increase awareness and to facilitate early diagnosisin future cases; and secondly, to propose the hypothesisthat abdominal malrotation and possibly gut dysmotilitymay be part of the expanding spectrum of ciliopathy.We speculate that screening of infants with apparentlyisolated malrotation for some of the many genes impli-cated in ciliary structure should be considered.

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