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Table of Contents
CLINICOPATHOLOGICAL PEARLS
Year : 2019  |  Volume : 2  |  Issue : 3  |  Page : 176-178

Extensive unilateral bronchiectasis in a child with 6q22.31 duplication syndrome


1 Faculty of Medicine, Umm Al-Qura University, Mecca, Kingdom of Saudi Arabia
2 Department of Pediatrics, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia

Date of Web Publication1-Jul-2019

Correspondence Address:
Ahlam Abdulbari Mazi
Department of Pediatrics, King Abdulaziz University, PO Box: 80215, Jeddah 21589
Kingdom of Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JNSM.JNSM_76_18

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How to cite this article:
Bannani HH, Mazi AA. Extensive unilateral bronchiectasis in a child with 6q22.31 duplication syndrome. J Nat Sci Med 2019;2:176-8

How to cite this URL:
Bannani HH, Mazi AA. Extensive unilateral bronchiectasis in a child with 6q22.31 duplication syndrome. J Nat Sci Med [serial online] 2019 [cited 2019 Sep 15];2:176-8. Available from: http://www.jnsmonline.org/text.asp?2019/2/3/176/254485




  Case Report Top


A 10-year-old boy with developmental delay, facial dysmorphism, growth restriction, and left retinal detachment was transferred for the evaluation of chronic suppurative lung disease.

He was diagnosed with asthma at the age of 18 months, with a significant response to asthma medications. He had one episode of choking with a meal at the age of 7 years; however, symptoms resolved spontaneously. His parents denied any correlation between this event and worsening respiratory symptoms. Further history was not suggestive of aspiration, serious infections, or systemic disease.

His developmental assessment is consistent with the age of 18–24 months. He has a frequent temper tantrum and impaired social communication.

He was born at 38 weeks with birth weight (1820 g), length (47 cm), and head circumference (29 cm), all below the 3rd centile. He had symmetrical intrauterine growth restriction, hypotonia, and facial dysmorphism. He had an atrial septal defect, which closed spontaneously.

His parents are first-degree cousins from the southern region of Saudi Arabia (Jizan) [Figure 1]a. His mother was healthy 24 years and his father was 34 years at the time of birth. Neither of the parents has similar facial features; however, one sibling had similar features with moderate developmental and intellectual disability.
Figure 1: (a) Family pedigree demonstrates the affected proband. The father has chromosome Y inversion. A male sibling with chromosome Y inversion and moderate features, however, was not tested. (b) Chest X-ray showed persistent right tracheal and mediastinal deviation associated with extensive dilatation of the right bronchial tree and right lung parenchymal cystic changes. (c) Computed tomography scan showed a progressive saccular and cystic bronchiectatic disease involving the right bronchial tree with right lung consolidative process and collapse

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The patient's height (114.5 cm) and weight (13.6 kg) were below the 3rd centile. He had microcephaly, triangular face, frontal bossing, hypertelorism, downward slanting palpebral fissure, depressed nasal bridge, S-shaped nasal septal deviation, high-arched palate, low-set ears, and micrognathia. Clubbing of the nail beds was noted on both the hands. Breath sounds were decreased over the right side associated with crackles and bronchial breathing. Heart sounds were normal but displaced over the right side. The remainder of the examination was unremarkable.

The initial chest X-ray (CXR) showed white out of the right hemithorax with placement of the cardiac shadow over the right hemithorax. The primary physician thought that it was dextrocardia with right side pneumonia. Therefore, he was initially treated with intravenous (IV) antibiotics. An echocardiogram to assess cardiac position and anomaly was within normal. Immunodeficiency and cystic fibrosis workup were unremarkable.

The patient's clinical status had not changed despite medical treatment. Therefore, a follow-up CXR showed a dilatation of the right bronchial tree that was suggestive of bronchiectasis and/or congenital malformation [Figure 1]b. Moreover, a computed tomography scan showed saccular and cystic bronchiectatic disease involving the right bronchial tree [Figure 1]c. There was no foreign body or excessive mucus plugs during flexible bronchoscopy.

Furthermore, an array comparative genomic hybridization (aCGH) showed 82.58 kb duplication of the cytoband 6q22.31 with genomic coordinates of (120974310-121056893); (arr [hg19] 6q22.31 (120974310-121056893) × 3). The aCGH used 180k oligonucleotides distributed throughout the genome to detect genetic alterations (manufactured by Agilent Technologies), with an analysis resolution of 40 kb. He also has a small pericentric inversion of the Y chromosome involving Yp11.2 and Yq11.2. This small 6q-duplication and its genomic coordinates have not been reported previously to cause pathological phenotype. Unfortunately, neither parents nor the sibling was tested due to socioeconomic reasons.


  What Is the Diagnosis? Top


Discussion

Partial 6q-duplication is a rare, well-defined syndrome characterized by distinctive facial dysmorphism (prominent forehead, flat nasal bridge, low-set ears, downward slanting palpebral fissure, hypertelorism, and micrognathia); growth restriction; hypotonia; joint contracture; intellectual disability; and behavioral disorder and multiorgan malformation involving the brain, heart, and urogenital system.[1] Most reports correlated the severity and disparity of phenotypic features to the location, size of duplication, genes involved, and/or the presence of additional chromosomal monosomy.[2] Moreover, previously reported 6q-duplication segments and size are quite variable, which mostly involved the distal portion of the long arm of chromosome 6 with a duplication size of ≥5–10 Mb.[3] Although the proband had a severe phenotype, the duplication size was small (82.58 kb) and the genomic position did not overlap with what previously reported.[2] The ocular manifestations reported included cloudy cornea,[4] congenital glaucoma,[5] and bilateral retinal detachment.[6] However, each had different 6q-duplication segment and size compared to the proband. Furthermore, cases with similar duplication segment of 6q22.31 affecting TRDN and NKAIN2 genes had extreme heterogeneity in their clinical features.[7],[8] Newbury et al. described a pervasive developmental disorder, speech apraxia, and some facial dysmorphism in a child with a de novo 16p11.2 deletion and 6q22.3 duplication.[7] However, Sheth et al. described severe phenotype feature in a toddler with a small 6q22.31 duplication size (~0.62 Mb).[8] In spite of this, the proband phenotype correlates to a new genomic location, which does not comprise recognized genes. Moreover, two additional cases suggested genotype–phenotype heterogeneity that described family members with an identical 6q-duplication band with extreme variability in phenotypic features.[9],[10] Likewise, our findings are in favor of genotype heterogeneity because the described 6q-duplication phenotype is attributed to microduplication (82.58 kb) on a new genomic location that was not previously reported. Although primary immunodeficiency has been reported,[3] it was not associated with pulmonary manifestation. Nevertheless, the proband had 6q-phenotype with extensive unilateral bronchiectasis; this finding could be incidental and not indeed attributed to 6q-duplication. However, such finding has not been described with any medical or genetic disorder. Unilateral bronchiectasis usually involves a single lobe caused by localized congenital abnormality, intraluminal obstruction/foreign body, or extraluminal compression, unlike our case. Whereas, the majority of syndromes (Young, Yellow Nail, Marfan, Usher, Mounier–Khun, and William Campbell), genetic diseases (cystic fibrosis and primary ciliary dyskinesia), aspiration syndromes, autoimmune, and immunodeficiency diseases would cause bilateral progressive bronchiectasis. None of these conditions or the choking event could explain the extensive bronchiectasis in the proband.[11]

6q-duplication syndrome has genomic heterogeneity on which duplication size, genomic coordinates, and genes affected may not be the major determinants of phenotype severity as previously suggested. The proband's severe phenotype had 6q microduplication on a diverse genomic location that does not comprise a recognized gene. Nonetheless, the presence of chromosome Y inversion and the high-degree consanguinity may contribute to the proband phenotype.

Final diagnosis and management

Extensive unilateral bronchiectasis, could be the part of multiorgan involvement of 6q-duplication syndrome. Our therapeutic goal was to ensure adequate mucus clearance and prevent further progression and involvement of the left lung. Therefore, the proband received 2 weeks of IV antibiotics inhospital with long-term airway clearance therapy (Ventolin, hypertonic saline nebulization, and chest physiotherapy) and prophylactic antibiotics (azithromycin). In addition, pulmonary toilet one to two time a year, or if the patient develops pulmonary exacerbations. Although the prognosis of 6q-duplication syndrome is variable, the proband was clinically well after initiation of the treatment. He had a few respiratory exacerbations; however, there was no further progression or left lung involvement over 12 months of follow-up.


  Clinicopathological Pearls Top


  1. Chromosome 6q-duplication is a well-defined syndrome with distinctive clinical feature
  2. Duplication size, genomic coordinates, and genes affected may not be the major determinants of phenotype severity as previously suggested
  3. The presence of other chromosome abnormality and the high-degree consanguinity may contribute to the severity of the phenotype
  4. Suppurative lung disease and bronchiectasis could be an incidental finding or part of 6q-duplication multiorgan involvement phenotype.


Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Wentzel C, Annerén G, Thuresson AC. A maternal de novo non-reciprocal translocation results in a 6q13-q16 deletion in one offspring and a 6q13-q16 duplication in another. Eur J Med Genet 2014;57:259-63.  Back to cited text no. 1
    
2.
Conrad BA, Higgins RR, Pierpont ME. Duplication 6q22⟶qter: Definition of the phenotype. Am J Med Genet 1998;78:123-6.  Back to cited text no. 2
    
3.
Sanmann JN, Casas KA, Bevilacqua J, Bishay DL, Clark T, Van Dyke AZ, et al. The first patient with tandem duplication of 6q14q16: Molecular and phenotypic characterization. Am J Med Genet A 2016;170:2416-20.  Back to cited text no. 3
    
4.
Chase TR, Jalal SM, Martsolf JT, Wasdahl WA, Opitz JM. Duplication 6q24 → 6qter in an infant from a balanced paternal translocation. Am J Med Genet 1983;14:347-51.  Back to cited text no. 4
    
5.
Brøndum-Nielsen K, Bajalica S, Wulff K, Mikkelsen M. Chromosome painting using FISH (fluorescence in situ hybridization) with chromosome-6-specific library demonstrates the origin of a de novo 6q+marker chromosome. Clin Genet 1993;43:235-9.  Back to cited text no. 5
    
6.
Pierpont ME, MacCarthy KG, Knobloch WH. Partial trisomy 6q and bilateral retinal detachment. Ophthalmic Paediatr Genet 1986;7:175-80.  Back to cited text no. 6
    
7.
Newbury DF, Mari F, Sadighi Akha E, Macdermot KD, Canitano R, Monaco AP, et al. Dual copy number variants involving 16p11 and 6q22 in a case of childhood apraxia of speech and pervasive developmental disorder. Eur J Hum Genet 2013;21:361-5.  Back to cited text no. 7
    
8.
Sheth F, Trivedi S, Andrieux J, Blouin JL, Sheth J. Pure interstitial dup(6)(q22.31q22.31) – A case report. Ital J Pediatr 2015;41:5.  Back to cited text no. 8
    
9.
Srebniak MI, van Zutven LJ, Petit F, Bouquillon S, van Heel IP, Knapen MF, et al. Interstitial 6q21q23 duplication – Variant of variable phenotype and incomplete penetrance or benign duplication? Mol Cytogenet 2016;9:43.  Back to cited text no. 9
    
10.
Pazooki M, Lebbar A, Roubergues A, Baverel F, Letessier D, Dupont JM, et al. Pure familial 6q21q22.1 duplication in two generations. Eur J Med Genet 2007;50:60-5.  Back to cited text no. 10
    
11.
Gould CM, Freeman AF, Olivier KN. Genetic causes of bronchiectasis. Clin Chest Med 2012;33:249-63.  Back to cited text no. 11
    


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