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Journal of
Pediatrics and Congenital Disorders
Case report
Open Access
Congenital Lung Anomalies in Kabuki Syndrome
Lai KV*, Nussbaum E, Do P, Chen J, Randhawa IS, Chin T
Department of Pediatric Pulmonology, Miller Children’s Hospital, University of California, Irvine School
of Medicine, 2801 Atlantic Ave, Long Beach, CA 90806
*Corresponding author: Lai KV, Department of Pediatric Pulmonology, Miller Children’s Hospital, University of
California, Irvine School of Medicine, 2801 Atlantic Ave, Long Beach, CA 90806; E-mail: [email protected]
Received Date: August 20, 2014 Accepted Date: December 20, 2014 Published Date: December 23, 2014
Citation: Lai KV, et al. (2014) Congenital Lung Anomalies in Kabuki Syndrome. J Pedia Cong Disord 1: 1-5
Abstract
Tracheobronchial tree abnormalities and Kabuki syndrome are rare in isolation, but may have an association. We report a
case of tracheal bronchus in a child with Kabuki syndrome, recurrent pneumonia and asthma. This communication aims to
alert the clinician to the possible association between recurrent pulmonary exacerbations in Kabuki syndrome and tracheobronchial abnormalities in order to prompt targeted investigation and treatment in refractory cases unresponsive to conventional medical management.
Introduction
type 2 von Willebrand disease, arthritis, developmental delay
and autism.
Tracheobronchial tree abnormalities and Kabuki Syndrome (KS) are two rare disorders, and when they occur together suggest an association. We report a case of tracheal
bronchus in a child with KS, and review the literature on pulmonary manifestations and tracheobronchial anomalies seen
in patients with KS.
On physical exam the patient exhibited facial features
suggestive of KS including arched eyebrows, long eye lashes,
long palpebral fissures and a flat, broadened tip of the nose.
His head and neck examination was also significant for nasal
turbinate and palatine tonsillar hypertrophy. There was no evidence of any cleft palate. His cardiac examination was benign
with normal heart sounds, precordial activity and pulses. The
pulmonary exam at the time of initial evaluation did not reveal any wheeze, rale or diminished breath sound, and did not
exhibit any obvious chest wall deformity or scoliosis. He did
not have any digital clubbing. His neurologic evaluation did
not reveal any abnormal reflexes although he did have mildly
decreased muscular tone.
Case Report
A 6 year old boy with KS and asthma was admitted
to the hospital following three days of fever, abdominal pain,
vomiting, diarrhea, and increased work of breathing. Since
birth, he has had eight episodes of pneumonia including two
hospitalizations within the past four months. During the first
hospitalization, he was diagnosed with a right middle lobe
pneumonia and respiratory syncytial virus infection. Right
lower lobe pneumonia was diagnosed during the second hospitalization. His parents report that his previous pneumonias
were typically in the right lung. His asthma history was notable for approximately 15 hospitalizations for asthma exacerbations, none requiring intensive care. In the past 4 months,
he had required 3 courses of oral corticosteroids. Prior to his
most recent hospitalizations, he had not been on any daily inhaled corticosteroids, and rather had taken inhaled albuterol 1
to 2 times a week. His triggers were “colds” and possible allergies. He had a nocturnal cough once per week, and a history of
snoring. He recently moved to our area 6 months ago, and had
been followed by various subspecialists previously for comorbidities that included seizure disorder, chronic otitis media,
tonsillar and adenoidal hypertrophy, gastroesophageal reflux,
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A chest roentgenogram (CXR) upon admission showed
the presence of a right pericardial infiltrate. The review of serial films demonstrated a right basilar infiltrate during the first
hospitalization, and a right middle and lower lobe infiltrate in
the second hospitalization (Figure 1). A computed tomography
angiogram (CTA) of the chest revealed an accessory right upper lobe bronchus supplying the top portion of the right upper
lobe, with a normal right upper lobe bronchus supplying the
more inferior portion of the right upper lobe. The pulmonary
arterial supply and venous drainage of the right upper lobe appeared normal (Figure 2). Flexible fiberoptic bronchoscopy
confirmed the right tracheal bronchus with 3 subsegmental
sections. The rest of the tracheobronchial tree, including the
right upper lobe, appeared normal without significant inflammation or mucus plugging (Figure 3). These findings were
consistent with a supernumerary tracheal bronchus.
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Figure 1: Right middle and lower lobe infiltrates seen on CXR during patient’s second hospitalization.
Figure 2: Appearance of an accessory right upper lobe bronchus exiting from the trachea seen on CTA of chest.
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Figure 3: Accessory tracheal bronchus (arrow 1) arising from the distal trachea seen during flexible fiberoptic
bronchoscopy. Entrance of the right upper lobe (arrow 2) can been seen from view of right mainstem bronchus
(arrow 3). The carina (arrow 4) and entrance to left mainstem bronchus (arrow 5) is on the left upper view.
Further evaluation included a normal pneumogram
and nocturnal desaturation study, normal spirometry without
significant improvement after bronchodilators, and normal
impulse oscillometry study without evidence of reversibility
with bronchodilators. A ventilation/perfusion scan showed no
evidence of any ventilation or perfusion abnormalities. Workup for immunodeficiency revealed normal quantitative immunoglobulins and IgG subclasses, normal CH50, however diphtheria and tetanus titers were low initially at 0.0 IU/mL and
0.1 IU/mL, respectively. Pneumococcal titers were normal. T
cell enumeration panel was normal except for decreased CD56
positive natural killer cell at 2% (normal range is 4% to 27%)
and count of 47 cells/mL. Two months after booster vaccination, tetanus titers normalized to 1.41 IU/mL. Sweat chloride
was normal. Allergy testing revealed an elevated IgE of 45 IU/
mL, and radioallergosorbent test was positive for allergies to
dog dander and bermuda grass.
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He was found to have enterovirus/rhinovirus by polymerase chain reaction, and received intravenous fluids and
ceftriaxone for a right sided pneumonia. An upper GI series
showed normal anatomy and a modified barium swallow did
not show aspiration despite findings of decreased oral motor
strength and the recommendation for dysphagia diet by occupational therapy. He was discharged home on oral antibiotics, daily inhaled corticosteroids, a leukotriene inhibitor, as
well as amoxicillin antibiotic prophylaxis. He continues to be
followed in our pediatric pulmonology clinic and has normal
spirometric variables with forced vital capacity of 1.95 L which
is 119% of predicted, forced expiratory volume in 1 second of
1.64 L which is 112% of predicted, and forced expiratory flow
25-75% of 1.61 L/sec which is 86% of predicted. Despite normal lung function, he continues to have frequent respiratory
symptoms, and recently has been hospitalized for asthma exacerbation due to enterovirus/rhinovirus infection.
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Discussion
Tracheal bronchus is defined as a right upper lobe
bronchus originating from the trachea. More specifically, it is
a collection of bronchial variations originating from either the
trachea or a main bronchus that is directed to the upper lobe of
the lung[1-3]. It has a prevalence of 0.1-2% [4], and is classified
by its morphologic pattern: displaced, rudimentary, supernumery, or anomalous right upper lobe [5]. While most tracheobronchial variations are asymptomatic, symptoms can develop
when there is impaired drainage of the anomalous bronchus
or if there are coexisting abnormalities [1,2,6]. Clinical manifestations include recurrent local infections, persistent cough,
stridor, hemoptysis, pneumonia, abscess, bronchiectasis, and
acute respiratory distress [1,2,7]. Tracheal bronchus may also
occur in association with other congenital abnormalities of the
tracheobronchial tree such as tracheoesophageal fistula, tracheal stenosis, and bronchostenosis [1]. It is also seen more
commonly in children with congenital heart disease [8]. Our
patient presented with repeated episodes of pneumonia and
difficult to control asthma.
Kabuki syndrome, first described in 1981 by two independent groups of Japanese scientists Niikawa and Kuroki,
is a congenital syndrome with an estimated prevalence of 1
in 32,000 [9]. Identified mainly by the presence of distinctive
craniofacial anomalies (eversion of the lower lateral eyelid,
arched eyebrows, depressed nasal tip, prominent ears [10]), it
is characterized by a peculiar, characteristic face reminiscent
of Japanese Kabuki actors, skeletal abnormalities, dermatoglyphic abnormality, short stature, and a variable intellectual
disability [11]. Since then, many other features have been
noted, including microcephaly, renal and cardiac malformations, recurrent infections, hearing loss, and persistent fetal
fingertip pads [12]. The main cause of KS arises from de novo
dominant mutations in KMT2D (MLL2), which was found in
56% to 75% of screened KS cohorts [12-14]. For approximately
30% of patients however, the underlying genetic cause remains
unidentified.
Few reports exist regarding the pulmonary manifestations of patients with KS. Although respiratory abnormalities
are uncommon, airway problems were seen in 58% of KS patients who have presented to a multidisciplinary craniofacial
clinic [15]. Recurrent pneumonia was the most common problem, but it is unknown whether this was secondary to underlying immune dysregulation or airway abnormalities. Obstructive sleep apnea requiring tonsillectomy and adenoidectomy
was found in several patients. Case reports have described
lymphoid interstitial pneumonia [16] and granulomatous
lymphocytic interstitial lung disease [17] in KS patients. Pulmonary hemorrhage has also been described in one patient,
following an episode of Henoch–Schönlein purpura, and was
partially attributed to development of pulmonary hypertension secondary to congenital heart disease [18].
There are no previously reported cases of tracheal
bronchus in patients with KS and only two published reports
of tracheobronchial abnormalities of any kind. The first report
involved two patients with central airway stenosis [19]. The
first patient had respiratory distress at birth, and at 3 months
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of age, was found by bronchography to have local stenosis of
the right upper lobe bronchus, necessitating lobectomy. The
second patient also had respiratory distress at birth and was
diagnosed with a congenital diaphragmatic hernia (CDH)
with a retrosternal defect of the diaphragm (Morgagni type),
and herniation of the liver in the right hemithorax. At 3 years
of age, lung function was severely compromised, and bronchoscopy showed severe bronchomalacia and an abnormal
right bronchial tree. The patient later died of respiratory failure
due to a combination of lung hypoplasia associated with CDH,
bronchopulmonary dysplasia, and recurrent aspiration pneumonia caused by gastroesophageal reflux. The second report
documented the presence of left-sided bronchial isomerism in
a patient with KS and a novel MLL2 mutation [20].
The paucity of data regarding KS and tracheobronchial
disease requires the physician to use clinical judgment regarding the overall management. For our patient, the question of
surgical removal had been pondered, however many factors
argue against this option. Previous reports of resection of a
tracheal bronchus mainly occurred in patients with recurrent
right upper lobe pneumonias [21-23] or malignancy [24,25].
However our patient had findings of pneumonia in the right
lower and middle lobes suggesting other causes for his pneumonias, which included primary or secondary aspiration. He
also presented with difficult to treat asthma which is likely related to his comorbid conditions such as upper airway disease,
gastroesophageal reflux, and chronic infections all of which
are known to negatively influence asthma management [26].
There is also the possibility of tracheobronchomalacia given
the normal pulmonary function tests and recurrent asthma
symptoms and therefore reevaluation with bronchoscopy with
light sedation should be considered. There is a previous report
of a tracheal bronchus causing asthma [27] and this needs to
be taken into consideration for our patient. Ventilation and
perfusion abnormalities have been documented with tracheal
bronchus [28], however our patient had a normal ventilation/
perfusion scan. Given the lack of recurrent right upper lobe
pneumonias, normal ventilation and perfusion parameters,
and comorbid conditions, the patient’s tracheal bronchus does
not appear to be the focal reason for his chronic respiratory
disease and resection is unlikely to be curative in this particular case.
In summary, while pulmonary abnormalities are rare in
KS patients, and its association to KS may be random, the persistence of recurrent respiratory tract infections or persistent
infiltrate on CXR should prompt more extensive evaluation of
the pulmonary system in order to deploy focused respiratory
treatments. In KS patients, the presence of tracheal bronchus
or other anatomical abnormalities may contribute to increased
frequency of respiratory tract infections, particularly if there
may be immune dysregulation present as well. However, as
our patient has demonstrated, increased infections can occur
in the absence of any underlying immune deficiency. In every
patient with KS with recurrent respiratory symptoms, we recommend screening for anatomic abnormalities of the tracheobronchial tree in concert with a full immunologic evaluation.
Surgical correction may be necessary to prevent development
of respiratory compromise as a result of frequent or persistent
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pulmonary infections. In our patient, despite normal pulmonary function variables, he necessitates close follow-up secondary to his pulmonary exacerbations.
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