Case report of twins with Bardet-Biedl syndrome exhibiting a rare mutation in the TTC8 gene

INTRODUCTION

Bardet-Biedl syndrome (BBS) is an autosomal recessive multisystem ciliopathy [1]. Cilia are cellular protrusions that arise from the base of the cell [2]. They can be categorised as primary cilia that act like sensors and have signalling functions, and motile – mechanic cilia which generate movement. Defects in primary cilia result in ciliopathies such as BBS [2, 3]. It can be caused by mutations in over 20 different genes that encode proteins of the basal body complex, from which cilia are formed. Bardet-Biedl syndrome is diagnosed clinically when either 4 major features or 3 major and 2 minor features are present [1]. The major features include retinal cone-rod dystrophy (present in 94% of cases). Initially, it manifests by night blindness, followed by progressive peripheral vision loss, a reduction in colour discrimination, and a subsequent loss of visual acuity. The second feature is central obesity, which develops in the first year of life [1]. The mean body mass index (BMI) was found to be 35.7 ±8.0 kg/m² in patients with a mean age of 33.2 ±1.0 years [1]. Nevertheless, the birth weight is typically within the normal range. The third symptom is postaxial polydactyly – the presence of additional digits on the ulnar side of the hand or the fibular side of the foot. The fourth symptom is cognitive impairment, characterised by impairments in verbal fluency, perceptual reasoning, attention capacity, and functional independence. It is notable that features associated with autism spectrum disorders are also frequent, with a prevalence of 77% [1]. Just a quarter of the individuals met the criteria for a diagnosis of intellectual disability. Furthermore, the intellectual functioning of all participants was 1.5 standard deviations below the mean. The fifth symptom is hypogonadism and genitourinary abnormalities. In males, the presence of micropenis, small-volume testes, and cryptorchidism may be observed. Female patients may present with anatomical anomalies of the uterus, fallopian tubes, vagina, and urinary tract. Infertility is a relatively common occurrence, although both sexes have been known to conceive children [1]. The sixth symptom is kidney disease, which is highly variable and can include structural anomalies, hydronephrosis, and vesicoureteral reflux. The initial diagnosis of renal disease was made within the first year of life in almost all cases diagnosed by the age of 5 years. The incidence of renal problems is approximately 52%; although it is not the most prevalent symptom, it remains a significant cause of mortality in patients with BBS [1].
Minor features include neurologic abnormalities (mainly developmental delay), anosmia and hyposmia with an abnormal magnetic resonance imaging appearance of the olfactory bulb, hearing loss, eye abnormalities, oral or dental abnormalities (crowding, hypodontia, high-arched palate), cardiovascular and thoracoabdominal abnormalities, gastrointestinal abnormalities, and endocrine or metabolic abnormalities, which are often accompanied by obesity [1]. Additionally, patients may present facial dysmorphia, short stature, and behavioural or psychiatric disorders [1, 2]. The typical symptoms of BBS are summarised in Table 2.
This study presents a description of twin sisters from Europe, specifically Poland, with abnormal variants present in the TTC8 gene, which is known to cause BBS. The prevalence of the TTC8 gene mutations in patients presenting with BBS symptoms is estimated to be approximately 2%. The 2 girls demonstrated some of the typical characteristics of BBS and underwent genetic testing [1]. According to our knowledge, this is the first report in the literature documenting BBS in twins.

CASE REPORT

We present a case of 2 female monozygotic twins, referred to as Patient 1 and Patient 2, both 7 years old. They were delivered at 37 weeks of gestation by caesarean section, during the mother’s third pregnancy and second labour. At birth, Patient 1 weighed 2070 g (< 3%) and was 48 cm in length (25%), compared to 3160 g (50–70%) and 53 cm (97%) for Patient 2. Both girls had Apgar scores of 10. Patient 1 exhibited postaxial polydactyly of the left foot, while Patient 2 had bilateral feet polydactyly.
Screening ultrasound of the abdomen shortly after birth revealed loss of corticomedullary differentiation, increased echogenicity, and small cysts in both kidneys of both patients. The kidney function was slightly reduced from the first year of life in both children. In Patient 1, the estimated glomerular filtration rate (eGFR) (calculated with Schwartz 3-markers equation and U25 equation) was 66 ml/min/1.73 m² at 5 months of age, 67 ml/min/1.73 m² at 6 years of age, and 82 ml/min/1.73 m² at 8 years of age. In Patient 2, eGFR was 76 ml/min/1.73 m² at 5 months of age, then 65 ml/min/1.73 m² at 6 years of age, and 82 ml/min1/.73 m2 at 8 years of age. At 5 months of age, the aforementioned results, in conjunction with the abnormalities observed in renal ultrasound, raised a suspicion of chronic kidney disease (CKD) in both patients. At 6 years of age the diagnosis of stage II CKD was certain. No other abnormalities in laboratory results concerning kidney function were noted. The most recent ultrasonography (2024) of the twins’ abdomens showed only a loss of corticomedullary differentiation, with no signs of cysts that were present in the neonatal period. Neither albuminuria nor hypertension was observed. In Patient 2, the urinary tract was examined only in infancy, and a voiding cystogram was performed with normal results. There was no family history of renal disease.
Neonatal echocardiography was normal in Patient 1. However, Patient 2 was found to have a patent foramen ovale (PFO) and mild stenosis of the left main pulmonary artery. Ophthalmologic examination revealed astigmatism in both Patient 1 (–1.5D in the right eye and –1.25D in the left eye) and Patient 2 (–1.5D in both eyes), as well as hyperopia in Patient 1 (+2.0D in both eyes) and Patient 2 (+2.0D in the right eye and +2.5D in the left eye).
Fundoscopy showed no abnormalities, but both patients were diagnosed with retinopathy due to night vision deterioration. From the second month of life, both girls showed rapid weight gain and visceral obesity. Physical examination revealed a broad facial shape, hypertelorism, narrow palpebral fissures, wide nasal root, retrognathia, and diastema. Some of these dysmorphisms are visible in Figure 1 and 2. Furthermore, they presented severe intellectual and physical disabilities, including aphasia and autism spectrum, as well as attention deficit, information processing difficulties, and delayed development of memory, compared to their peers. Gynaecological screenings were negative for both siblings. The patients’ clinical presentation was consistent with the BBS phenotype; therefore, during hospitalisation Patient 2 underwent genetic testing of the BBS10 gene, which revealed no pathogenic variants.
At the age of 18 months, the mother funded genome analysis of Patient 2. The BBS10 gene was analysed by Sanger sequencing of a blood sample and showed no mutations. Next-generation sequencing for less common genes associated with BBS revealed 2 potentially pathogenic heterozygous variants in the TTC8 gene, associated with BBS type 8: c.-104G>A [NM_001288783, rs119103286] and c.635T>C [NM_144596]. These findings were confirmed using Sanger sequencing. Subsequently, Patient 1 and the parents were screened for TTC8 mutations by Sanger sequencing. Patient 1 was found to have the same variants as her sister. The mother had the single heterozygous c.-104G>A variant, which was absent in the father, who had the single heterozygous c.635T>C mutation. Despite these mutations, the parents did not exhibit symptoms suggestive of BBS. The mother has a simple cyst in the right kidney, and the father has myopia, astigmatism (0.8D in the right eye), hyposmia and was recently diagnosed with colorectal adenocarcinoma. The patients’ 13-year-old brother did not undergo genetic testing. A boy shows sensory integration dysfunction, sensory hypersensitivity, and has been diagnosed with autism; however, he is developing appropriately and does not present a typical BBS clinical image.
Currently, at the age of 7.5 years, Patient 1 weighs 37 kg (97%) with a height of 138 cm (97%) and 19.4 kg/m² BMI, while Patient 2 has a body mass, height, and BMI of 46 kg (> 97%), 142 cm (> 97%), and 22.8 kg/m², respectively. They are under regular follow-up by a nephrologist, neurologist, ophthalmologist, and psychologist.

DISCUSSION

Bardet-Biedl syndrome is a rare pleiotropic ciliopathy characterised by the major typical features mentioned above. Both of the patients reported in our study presented some of the BBS symptoms: retinal dystrophy, excess body weight, postaxial polydactyly, cognitive impairment, developmental delay, astigmatism, hyperopia, hypertelorism, broad nose, mandibular retrusion, and diastema. Additionally, Patient 1 presented PFO and mild stenosis of the left branch of the pulmonary artery.
Some of the symptoms of BBS, like polydactyly in the feet and/or hands, visual problems, renal diseases, and cardiovascular abnormalities, may be present at birth. It is noteworthy that certain abnormalities, such as obesity, cone-rod dystrophy, dental abnormalities, developmental delay, or behavioural/psychiatric abnormalities, which are not present at birth, tend to manifest with age. The average age of onset of BBS is between 4 and 6 years [11]. The syndrome is rare, with a prevalence of 1/125,000 to 1/175,000 in Europe and North America. Consanguinity plays a remarkable role in the incidence of the syndrome, as shown by the Bedouin community in Kuwait, where the incidence of BBS is higher – 1/17,000. First-degree consanguineous marriages are common among families with BBS, ranging from 35 to 48% [11].
Bardet-Biedl syndrome is a genetically heterogeneous disorder. To date, 26 different genes have been identified as potential causes of BBS. The impact of each gene on the disease varies from patient to patient. The patients described in this study exhibited a mutation in the TTC8 gene, which has been designated as BBS type 8. This is one of the rarest mutations associated with this syndrome. In the literature, the prevalence of TTC8 gene mutations in this syndrome is described as 2%. Mutations in TTC8 gene are associated with non-syndromic retinitis pigmentosa and are also considered to be less syndromic with low penetrance of renal abnormalities [1]. However, renal diseases are a relatively prevalent symptom of BBS, present in 52% of patients [1]. In our case, both of the patients showed slightly improved kidney function based on eGFR values (from approximately 70 ml/min to approximately 82 ml/min in 8 years of life).
Substantial clinical variation among families with BBS is recognised, even among patients with the same mutation, suggesting the potential role of modifier genes. These might be other BBS genes or unrelated genes that do not cause BBS alone. Supporting this, 3 families have been reported where individuals with 3 mutations at 2 BBS loci show a more severe phenotype. This indicates that variations at one BBS locus can influence the phenotype of mutations at other loci. Extreme cases include disease non-penetrance, where individuals with the disease-causing genotype remain unaffected. An example includes siblings with BBS2 gene mutations where only one with an additional BBS6 mutation is affected. These findings suggest complex inheritance patterns, impacting recurrence risk assessments and our understanding of BBS biochemistry [2].
In patients with multiple abnormalities arising from different systems, accurate diagnosis is of critical importance. In the differential diagnosis of Bardet-Biedl syndrome, it is important to consider disorders such as Alström syndrome, McKusick-Kaufman syndrome, Meckel syndrome, Joubert syndrome, Senior-Løken syndrome, and Leber congenital amaurosis/early onset severe retinal dystrophy. These syndromes are caused by genetic mutations that can be confirmed by whole-exome sequencing which is the preferred first-line diagnostic test for patients with multiple congenital anomalies [1].
Stoetzel et al. described a cohort of 128 families with at least one member diagnosed with BBS. BBS8 (TTC8) mutations were found in 3 of the families (2%), 2 of them showing homozygous mutations and one showing a heterozygous mutation [12]. Another paper identified a BBS8 (TTC8) mutation in 1% of the examined families, which shows the rarity of this mutation [13]. The most prevalent mutation is BBS1, associated with 23.4% of BBS cases [1]. In northern European individuals, the most common alleles are BBS1 M390R and BBS10 C91LfsX5, while mutations in BBS4, BBS5, and TTC8 are primarily found in patients of Middle Eastern and North African descent [14].
In our report, 2 variants in the TTC8 gene were identified in both Patient 1 and Patient 2, namely: c.635C>T and c.-104g>A. Testing of the patients’ mother revealed only the c.-104g>A variant, and testing of the father showed only the c.635C>T variant.
There is no therapy to prevent multisystem and progressive organ involvement in BBS, necessitating coordinated multidisciplinary care. For cone-rod dystrophy, educational planning should assume future blindness, emphasising Braille, mobility training, adaptive skills, and the use of large-print materials. To manage obesity, a reduced-calorie diet and regular aerobic exercise, adapted for the blind, are recommended, with the support of a helper. Metabolic syndrome and other obesity-related complications should be managed as in the general population. Anosmia or hyposmia require alternative methods to detect dangerous substances. Renal, gastrointestinal, liver diseases, hypothyroidism, and hypogonadism should follow general treatment guidelines, and anatomical abnormalities may need surgical correction [1, 5]. For neurodevelopmental issues, approaches should be individualised. From birth to three years of age, early intervention programs offer therapies and support. From ages 3–5 years, developmental preschool programs are recommended, with evaluations to develop individualised education plans. For all ages, developmental paediatricians can ensure appropriate services and support. Education plans should be reviewed annually, with vision and hearing consultants included in the team. Children with BBS may benefit from interventions for autism spectrum disorder, such as applied behaviour analysis, tailored to individual needs. Concerns about depression and anxiety, especially in late teens, should be addressed by a paediatric psychiatrist [1].

CONCLUSIONS

Bardet-Biedl syndrome is a rare genetic disorder characterised by a wide range of clinical manifestations. This study documents the first description of BBS in twins. Due to the large number of mutations that can cause the disease, there are many variants that can be associated with different symptoms. We hope that this study, by focusing on the mutation in the TTC8 gene, will add to the current knowledge of this condition and provide clinicians with useful information.

DISCLOSURE

1. Institutional review board statement: Not applicable.
2. Written informed consent was obtained from the patients’ legal guardian for the publication of this case report (including all images).
3. Financial support and sponsorship: None.
4. Conflicts of interest: None.

REFERENCES