Laryngotracheomalacia in a Patient with Mosaic Trisomy 8

Abstract

Mosaic trisomy 8 is a condition characterized by a great phenotypic and cytogenetic variability whose incidence ranges around 1 in 25,000 to 50,000 live births. Here, we report a mosaic trisomy 8 patient presenting laryngotracheomalacia, an uncommon finding, analyzing its possible role over morbidity, and mortality. The patient was a boy who, after birth, had tachypnea and paleness. He presented periods of respiratory dysfunction with need of ventilatory support. Respiratory syncytial virus test was positive. Naso fibrobronchoscopy showed moderate laryngotracheomalacia. He also had recurrent episodes of pneumonia and difficulty in withdrawing continuous positive airway pressure. The patient also presented leucoma, abnormal and low-set ears, pectus excavatum, clenched fists with overlapping fingers, cryptorchidism, clubfeet, and deep longitudinal plantar creases. G-bands by Trypsin using giemsa (GTG-banding) karyotype from a peripheral blood sample revealed a mosaic trisomy 8: mos 47,XY, + 8[15]/46,XY[7]. At 4 months, the patient developed respiratory failure, and a chest computed tomography scan showed areas of atelectasis and gross fibroatelectatic striae. He ended up presenting clinical worsening and died at 4 months and 8 days. In our literature review, we found some reports describing patients with mosaic trisomy 8 and laryngotracheomalacia. However, we cannot rule out the possibility that this association could be casual, since laryngotracheomalacia is a relatively common finding in children. Therefore, more studies are still necessary to understand the possible relation between both conditions and the role of laryngotracheomalacia over morbidity and prognosis of mosaic trisomy 8 patients.

Introduction

Mosaic trisomy 8 is considered as a chromosomal anomaly compatible with postnatal survival. ¹ Its incidence ranges around 1 in 25,000 to 50,000 live births. ² It is believed that mosaic trisomy 8 could be originated from a zygote with trisomy 8 that has a postzygotic loss of one copy of the same chromosome or from a postzygotic nondisjunction of a normal cell that originates a trisomy 8 lineage. ³

Background

Trisomy 8 is considered a lethal chromosomal anomaly. However, it can have a mosaic-shaped constitution which may be compatible with postnatal survival. This mainly occurs when the percentage of unaffected cells is higher. ¹ Despite its rarity, mosaic trisomy 8 is only less frequent than trisomies 21, 18, and 13. ² Male and Afro descendant individuals have been described as most commonly affected (sex ratio of 5:1). ^{3 4 5} It is believed that mosaic trisomy 8 could be possibly originated from two different events: (1) the first, a meiotic nondisjunction during gametogenesis, resulting in a zygote with trisomy 8 that has a postzygotic loss of the same extranumerary chromosome; and (2) from a postzygotic nondisjunction of a normal cell that originates a cell lineage with a extranumerary chromosome 8 (trisomy 8). ³

Genetic counseling for mosaic trisomy 8, especially in prenatal care, remains difficult due to the marked phenotypic and cytogenetic variability. The percentage of cells with trisomy 8, both in the peripheral blood and in the skin, does not correlate with the severity of clinical manifestations, frequency of malformations, and degree of mental retardation. In addition, the percentage of cells with trisomy 8 may decrease with age. ³ Moreover, patients with mosaic trisomy 8 should be investigated for the possible presence of an associated chromosome 8 uniparental disomy (UPD) to provide more information for the proper genetic counseling. The UPD can occur as a result of the loss of the extra chromosome 8, from a cell with trisomy 8, leading to the formation of a lineage with only two chromosomes 8 originated from the same parent. ⁶

Clinical Manifestation

Mosaic trisomy 8 is characterized by a wide phenotypic and cytogenetic variability which ranges from asymptomatic patients to others with multisystemic involvement. Phenotypic abnormalities have been described in approximately 40% of cases ^{3 7} and they may have an influence over the diagnosis. ⁸

Diagnosis

Mosaic trisomy 8 diagnosis is based on evidence of a cell lineage with an additional chromosome 8 associated with a normal one. It is unfrequently made during the prenatal period. The additional chromosome 8 usually is detected through karyotype or even by fluorescence in situ hybridization (FISH). It is noteworthy that, such as fluorescent quantification by polymerase chain reaction (FQ-PCR) and array comparative genomic hybridization (aCGH), have limited detection in cases of low-grade mosaicism (less than 15–20%). ^{6 9 10 11} However, recently, a microarray test with 50-P single nucleotide polymorphisms (SNP; microarray Affymetrix 50K Xba SNP) was able to identify mosaicisms of up to 10%. ¹² Mosaic 8 trisomy may not be detected through amniocentesis, due to the disappearance of amniocytes with trisomy 8 probably caused by a growth disadvantage of the abnormal cell line during culture. Therefore, when mosaic trisomy 8 is found in chorionic villus samples, there is a preference for performing cordocentesis over amniocentesis to confirm the diagnosis. ⁷

However, the cell distribution with an extra chromosome 8 ranges from one patient to another and even between tissues of the same individual. ⁷ In some cases, the chromosomal alteration is found only in fibroblasts, while in other patients it may predominate in lymphocytes, not manifesting in other tissues.

Management

The management of patients with mosaic trisomy 8 is closely related to the findings presented by them which can range from minor to major anomalies with necessity of surgical treatment, such as congenital heart defects and gastrointestinal malformations. ^{8 13} In addition, eye and skeletal abnormalities are common and often require intervention. ^{1 2 3 14 15} Some patients may present epilepsy, requiring therapy with anticonvulsants. ¹⁶

Prognosis

Survival of mosaic trisomy 8 patients has been variable, ranging from almost normal to a poor survival. ⁸ The presence of some underlying major malformations, such as heart defects, seems to influence the prognosis, making the clinical picture more severe and thus reducing the life span. ¹⁷

Case Presentation

Our aim was to report a child with mosaic trisomy 8 presenting laryngotracheomalacia, an uncommon finding and to analyze its role over morbidity and mortality. The patient was the first son of a young couple without similar family cases. During his pregnancy, the mother presented two episodes of urinary tract infection. The child was born by vaginal delivery at 36 weeks, weighing 2,240 g, measuring 43.5 cm, with a cephalic perimeter of 29.5 cm and Apgar's scores of 10, both at first and fifth minutes.

After birth, the child remained in hospital due to tachypnea and paleness. During hospitalization, he developed bronchopneumonia and anemia for which he received blood transfusion.

An 8-day-old ophthalmological evaluation revealed a whitish area in the right crystalline. However, this finding was no longer observed later. The patient evolved with several periods of respiratory dysfunction, with need of ventilatory support (including mechanical ventilation) during the first weeks of life. Later, at 1 month and 20 days, the respiratory syncytial virus test was positive. Naso fibrobronchoscopy also showed moderate laryngotracheomalacia, with a proximal tracheal deviation to the right. He also had recurrent episodes of pneumonia and difficulty in withdrawing continuous positive airway pressure (CPAP).

In the meantime, he had an episode of seizure which was treated with phenytoin and phenobarbital. Brain magnetic resonance imaging (MRI) only disclosed a pellucid septum and vergae cavum persistence.

On physical examination, the patient had abnormal and low-set ears with the left showing a shell form, hypoplastic helix, and anomalous folds; inverted nipples; pectus excavatum; clenched fists with overlapping fingers; cryptorchidism on the right; and clubfeet and two longitudinal plantar creases on the right foot ( Fig. 1 ).

Fig. 1.

Findings observed on the physical examination of the patient at 10 days of life. Note, especially abnormal and low-set ears ( A ), clenched fist with overlapping fingers ( B ), and two longitudinal and deep plantar creases on the right foot ( C ).

The new ophthalmological examination revealed a corneal opacity in the left eye, without compromising the visual axis but with a scar aspect, compatible with leucoma. Echocardiography only showed a small ductus arteriosus persistence, without hemodynamic repercussions. Abdominal ultrasound was normal. G-bands by Trypsin using Giemsa (GTG-banding) karyotype from a peripheral blood sample revealed a mosaic trisomy 8: mos 47,XY, + 8[15]/46,XY[7] ( Fig. 2 ).

Fig. 2.

GTG-banding karyotype evidencing an extra chromosome 8, compatible with full trisomy 8.

At 4 months, the patient developed respiratory failure, and chest computed tomography scan showed atelectasis containing permeate bronchiectasis, especially in basilar segments of lower lobes and upper segment of the right posterior lobe, as well as gross fibroatelectatic striae in the lingula, anterior segment of upper lobe, and left middle lobe. He ended up presenting clinical worsening and died at 4 months.

Discussion

As previously stated, the clinical picture of patients with mosaic trisomy 8 can be variable. ¹ Some authors suggest that this variability could be related to the proportion of trisomy 8 cells detected in the blood or skin ^{1 16} ; however, others have not found such association. ³

Craniofacial dysmorphia is considered common among patients with mosaic trisomy 8. Among them, stand out macrocephaly, prominent forehead, hypertelorism, ptosis, strabismus, deep set eyes, wide nasal root, thick lips with everted lower lip, facial clefts, highly arched palate, micrognathia, and short winged neck. ¹⁸ Corneal opacity is also a frequent finding, ¹⁵ and it was also present in our patient. The corneal lesion described in mosaic trisomy 8 affects more superficial layers, which differentiate it from Peters' anomaly, and which involve the anterior segment of the eye. ¹⁴ In our case, the corneal opacity had a scar aspect, compatible with leucoma.

As for the ears, the most common finding, as observed in our patient, is low-set ears. Other anomalies described include posteriorly rotated ears and helix abnormalities. ¹⁸ Our patient also presented a left ear with a shell form hypoplastic helix and anomalous folds. Congenital velopharyngeal insufficiency can also be observed among patients with mosaic trisomy 8. ^{2 3}

Neurological abnormalities are rarer and consist of corpus callosum agenesis and epilepsy (especially childhood spasms). ¹⁶ Datta et al ¹⁶ tried to link the occurrence of seizures with the 8q24 region. Our patient presented a seizure episode, requiring treatment with phenytoin and phenobarbital. His evaluation through head MRI revealed pellucid septum and vergae cavum persistence which are considered anatomical variations of normality. In spite of the prematurity, it could be observed that his birth conditions were good. However, he developed respiratory problems at time of the seizure and was also diagnosed with a moderate laryngotracheomalacia which could lead to hypoxia and justify the episode of seizure.

Deep hand and feet creases are highly characteristic of mosaic trisomy 8, ¹⁸ and they were present in our patient. In addition, skeletal anomalies, mainly of the spine, ribs, and joints, are also frequent. Sternal anomalies, congenital elbows dislocation, and pelvis and patella abnormalities have also been described. ^{1 2 3} It is noteworthy in our case the presence of clubfeet, a finding that seems unusual among patients with mosaic trisomy 8.

Gastrointestinal malformations are less common and they generally involve the anal region. ¹³ In addition, skin alterations, such as hypochromic linear patches following Blaschko's lines, may be present. This skin finding has an association with the presence of mosaicism. ¹⁹

Survival of mosaic trisomy 8 patients has been variable and seems to be influenced by the presence of some underlying major malformations. ^{8 17} In our patient, it is noteworthy that the presence of a moderate laryngotracheomalacia.

Airway malacia can affect from the larynx to the bronchi. In the case of the larynx (laryngomalacia), there is an abnormality in its structure that leads to an internal collapse of the supraglottic airway during inspiration. It is the most common congenital anomaly of the pediatric airways. ²⁰ Laryngomalacia can vary from mild to severe. Infants with the moderate form may present association with other airway anomalies, in special tracheomalacia (62%) ²¹ as seen in our patient. Tracheomalacia in turn results from an abnormal development of the tracheal cartilage and it is the most common congenital tracheal abnormality. ²⁰

Children with moderate laryngotracheomalacia, as seen in our patient, have impaired ability to clear secretions from the airways and an excessive dynamic collapse. As a result, they may present inspiratory stridor, cyanosis episodes, apnea, difficulty in weaning from ventilatory support, recurrent bacterial bronchitis or pneumonia, feeding problems, growth impairment, and weight gain difficulty. ^{20 22} The need for surgical intervention correlates directly both with these symptoms and their respective severity as the presence of comorbidities, such as genetic syndromes. ²²

In our literature review, we found the report of only two patients with mosaic trisomy 8 presenting laryngotracheomalacia. The first had mos 46,XX/46,XX-8, + dic(8) and an associated pulmonary stenosis. ²³ The other was a boy who presented full trisomy 8 in mosaic and cerebral palsy. The diagnosis of laryngotracheomalacia was made at 8 months and he had an important stridor associated with suprasternal, intercostal, and subcostal retractions. ²⁴ Despite the descriptions, there is no mention of the evolution presented by the patients in both reports. ^{23 24} In our case, laryngotracheomalacia seemed to be an important finding which appeared to influence the prognosis, because the patient had frequent need for respiratory care during the first months of life, until his death at 4 months, in absence of other major malformations that could justify his symptoms. However, we cannot rule out the possibility that the respiratory syncytial virus infection presented by him may have contributed for a more important worsening of the respiratory function and, consequently, a more severe clinical evolution.

Conclusion

In our literature review, we found some reports describing patients with mosaic trisomy 8 and laryngotracheomalacia. Based on these findings, we believe that laryngotracheomalacia should be considered, especially in individuals with feeding difficulties, respiratory dysfunction, and episodes of pneumonia, as observed in our case. However, we cannot rule out the possibility that this association could be casual, since laryngotracheomalacia is a relatively common finding in children. Therefore, more studies are still necessary to understand the possible relation between both conditions and the role of laryngotracheomalacia over morbidity and prognosis of mosaic trisomy 8 patients.