Abstract
Bardet-Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy characterised by rod-cone dystrophy, obesity, postaxial polydactyly, cognitive impairment, hypogonadism, renal abnormalities, and rarely, laryngeal webs or bifid epiglottis. Most patients present with obesity. Multiple genes are involved in causation of BBS and there is also evidence of triallelic inheritance. We herein report an Asian boy who had weak cry and stridor since birth, and on evaluation was found to have both laryngeal web and bifid epiglottis. Mutation analysis revealed a homozygous variant in BBS10 gene.
Keywords: genetics, ear, nose and throat/otolaryngology, paediatrics
Background
The Bardet-Biedl syndrome (BBS) phenotype consists of obesity (72%), postaxial polydactyly (69%) and rod-cone dystrophy mostly seen after 8 years, hypogonadism, cognitive impairment and renal abnormalities. Other associated features can be hepatic fibrosis, diabetes mellitus, reproductive abnormalities, endocrinological disturbances, short stature, developmental delay and speech deficits.1 BBS is an autosomal recessive disorder caused by mutations in BBS genes whose function is related to the primary cilium. Until mutations in 24 BBS genes have been reported however mutations in BBS1, BBS2 and BBS10 account for 50% of BBS cases.2 The disease-causing gene is identified in 80% of cases.3 The prevalence of upper airway abnormalities in BBS remains unknown, but laryngeal webs and bifid epiglottis (BE) have been reported.4 Congenital laryngeal web is an upper airway malformation resulting from incomplete recanalisation of the primitive larynx, which represents less than 5% of larynx congenital anomalies.5 We report a child with BBS having laryngeal web and BE. This case is interesting because of the peculiarity of presentation with upper airway malformation thereby highlighting the importance of ruling out upper airway malformations in case of BBS.
Case presentation
An 11-month-old male child, resident of Jammu region, initially presented with voracious appetite, noisy breathing and snoring. Parents also reported excessive weight gain and weak cry noted from 4 months of age. The child had mild developmental delay. He was born of third degree consanguineous marriage, by caesarean section in view of previous caesarean section, with birth weight of 3500 g and a smooth perinatal transition. There was no significant family history. On examination vitals were stable, weight was 15 kg corresponding to +4.4 z-score, length was 77 cm (+0.56 z-score), body mass index being 24.8 (+5.03 z-score) and head circumference of 48 cm (+1.52 z-score). The child had craniofacial dysmorphism in the form of brachycephaly, wide and deep set eyes, long smooth philtrum, depressed nasal bridge micrognathia, retrognathia (figure 1), stubby built, bilateral epicanthic folds, polydactyly in both hands, syndactyly of third and fourth fingers in right hand (figure 2), hepatomegaly, short systolic murmer, short penis with testicular volume of 2 cc. Since the child had dysphonia, bronchoscopy was done and it showed BE, laryngeal web and membrane between vocal cords and small glottis chink (figure 3). Ultrasonography of abdomen revealed enlarged kidneys. In view of the findings of high birth weight, obesity, polysyndactyly, nephromegaly, cardiac involvement, hypogonadism and upper airway findings possibility of BBS and Simpson-Golabi-Behmel syndrome (SGBS) were kept, and targeted exome sequencing was done.
Figure 1.
Facial profile showing brachycephaly, prominent forehead, deep and wide set eyes, long smooth philtrum, depressed nasal bridge, retrognathia and micrognathia.
Figure 2.
Postaxial polysyndactyly in child with Bardet-Biedl syndrome.
Figure 3.
Bronchoscopy showing laryngeal web and membrane between vocal cords.
Investigations
The routine investigations including blood counts, lipid profile, renal function tests, liver function test (table 1), eye and hearing examination were within normal limits. The thyroid stimulating hormone level was elevated hence the child was started on eltroxin. Skeletal survey was grossly normal. Echo was suggestive of 2 mm atrial septal defect, abdominal ultrasound showed bilateral nephromegaly. Clinical exome sequencing was done which showed homozygous single-base pair duplication in exon 2 of BBS10 gene on chromosome 12. This frameshift mutation led to premature truncation of protein downstream of codon 91.
Table 1.
Haematological and biochemical findings in the child with Bardet-Biedl syndrome
| Haemoglobin | 0.9 g/dL |
| White cell count | 16×109/L |
| Platelets | 401×109/L |
| DLC (NLME), % | 46/40/8/4.1 |
| AST/ALT/ALP | 28/13/250 IU |
| T3 | 0.989 (0.6–1.8) IU |
| T4 | 4.68 (4.5–12.7) IU |
| TSH | 4.13 (0.3–5.5) IU |
| HbA1c | 5.8% |
| Triglyceride | 134 mg/dL |
| HDL | 32.2 IU |
| LDL | 123.9 IU |
ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; DLC, differential leucocyte count; HbA1c, glycated haemoglobin; HDL, high-density lipoprotein; LDL, low-density lipoprotein; NLME, Neutrophils, lymphocytes, monocytes, eosinophils; TSH, thyroid stimulating hormone.
Differentials
The association of obesity with syndactyly and subtle dysmorphism led to possibility of BBS and SGBS for which genetic evaluation was done and mutation responsible for BBS was identified. Also recurrent respiratory papillomatosis due to human papillomavirus type 6 (HPV6) and HPV type 11 (HPV11), leading to voice change and life-threatening airway obstruction, should be kept in mind especially in children of less than 5 years.6
Treatment
Laser excision of glottic web was done under general anaesthesia for laryngeal web. For hypothyroidism, thyroxine treatment was started. For obesity, dietary modifications were advised.
Outcome
The child is on regular follow-up, with no complications post-laryngeal web excision and has no further excessive weight gain. The obesity-related complications like hyperlipidaemia and abnormal glucose homeostasis have been ruled out. Plan is to monitor for retinal changes with ophthalmological evaluation in long term.
Discussion
BBS is a rare autosomal recessive genetic disorder characterised by rod-cone dystrophy, obesity, postaxial polydactyly, cognitive impairment, hypogonadism and renal abnormalities.7 Patients with mutations in BBS1 gene present with milder phenotype compared with those with mutation in BBS2 or BBS10 genes. Also BBS2 and BBS10 were seen to have higher penetrance of renal anomalies and polydactyly than patients with mutations in BBS1. Our patient had mutation in BBS10 gene and severe phenotype with obesity, renal anomalies, polydactyly, cardiac anomalies, hypogonadism, developmental delay and the airway anomaly in the form of laryngeal web and BE.2 The otolaryngological features most commonly found are speech and language disorders, sensorineural hearing loss and orodental abnormalities.4 Among the laryngeal anomalies, acquired lesions secondary to infections are more commonly reported than congenital laryngeal anomalies in which laryngomalacia has been reported as the most common lesion, occurring in 60%–70% of cases; whereas laryngeal webs (5% of cases), and specifically BE, have been found rarely.8 Out of the 30 cases of BE reported in literature, only 4 of them were associated with BBS.7 9 We found one earlier report of a 5-year-old female child with an anterior laryngeal web associated with BBS.10 But only one study described these two abnormalities in the same patient: a 9-month-old boy with recurrent respiratory tract infections and hoarseness of voice was diagnosed with BBS, and on laryngoscopy had BE and anterior laryngeal web and had homozygous deletion on BBS10 gene.11 Whereas the patients with causative mutations in BBS1, BBS4 or BBS8/TTC8 collectively suffer from renal anomalies only in 60% cases. Clinical presentation can range from stridor, hoarseness or dysphonia to acute respiratory distress requiring immediate intubation at birth. Diagnosis is by bronchoscopy. In the present case, the child had dysphonia and stridor. However, there were no recurrent respiratory tract infections, and bronchoscopy revealed BE, laryngeal web and membrane between vocal cords with small glottic chink. We also confirmed the diagnosis by molecular testing. Nowadays, next generation sequencing can easily diagnose patients with disorders having genetic heterogeneity. There are at least 19 genes implicated in BBS. Triallelic inheritance for some patients of BBS has also been seen. Conservative treatment is frequently preferred for asymptomatic patients or those with minor aspiration symptoms.5 If surgical management is required, endoscopic or open surgery may be performed. In present case, surgical treatment in the form of laser excision of laryngeal web was done successfully. Severe obesity as such is also associated with night snoring and sleep apnoeas. Thus, this case highlights the unusual upper airway findings in BBS due to homozygous BBS10 gene variant.
Learning points.
Postaxial polydactyly is clue to Bardet-Biedl syndrome.
It is a cause of childhood obesity.
Upper airway assessment for webs and bifid epiglottis is important since these can lead to life-threatening complications.
Footnotes
Contributors: PK: writing of the manuscript. CC and HN: patient care and management. IP: inpatient diagnosis and care and motivation for writing the manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Parental/guardian consent obtained.
Provenance and peer review: Not commissioned; externally peer reviewed.
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