BBS is genetically heterogeneous, with mutations identified in over 20 genes, including BBS1, BBS2, ARL6, BBS4, BBS5, and others [14] [15] . While a direct correlation between specific mutations and disease severity remains elusive, some trends have been observed. For instance, certain mutations in the BBS1 gene appear to be associated with milder ophthalmologic involvement [16] . Conversely, mutations in BBS10 may predispose individuals to obesity and insulin resistance [17] .

The clinical spectrum of BBS is broad, encompassing both major and minor features. Major features are those that occur with higher frequency and are often considered cardinal manifestations of the syndrome. Minor features, while less prevalent, contribute to the overall clinical picture and can significantly impact patient management. See Table 1 to see the diverse clinical features and their approximate frequencies.

Bardet-Biedl syndrome (BBS) presents unique challenges for affected children and their families. Given the rarity and complexity of this multisystem disorder, parents often feel unprepared to navigate the associated medical, developmental, and psychosocial issues [18] . Therefore, healthcare professionals play a crucial role in providing comprehensive support and guidance.

Note: The frequencies presented in this table are approximate and may vary across different studies and populations.

Effective care for children with BBS requires a multidisciplinary approach, involving collaboration amongst various specialists, including geneticists, ophthalmologists, endocrinologists, nephrologists, and developmental pediatricians [23] . Early diagnosis and intervention are essential to optimize outcomes and improve quality of life.

Hirschsprung’s disease (HSCR) and Bardet-Biedl syndrome (BBS) are seemingly distinct genetic disorders. HSCR affects the development of the enteric nervous system, leading to intestinal obstruction, while BBS is a multisystem ciliopathy with a wide range of clinical manifestations, including obesity, retinopathy, polydactyly, and renal dysfunction. However, a growing body of evidence suggests a potential link between these two conditions.

Studies have identified mutations in BBS genes among patients diagnosed with both BBS and HSCR, suggesting a possible genetic interaction. Zhang et al. [30] investigated two families with both conditions. In one family of Caucasian origin (F1), three siblings affected by a short-segment HSCR harbored two heterozygous missense mutations in a BBS gene. In another family of Moroccan origin (F2), two out of five siblings with BBS also had confirmed HSCR, with all five siblings exhibiting a homozygous 1-bp deletion in the BBS4 gene. Additionally, a sporadic case (SB25) was identified with an infant born to healthy parents of Caucasian origin presenting with both HSCR and BBS, who inherited a heterozygous missense BBS4 mutation from their father [31] .

Further analysis revealed that patients with BBS and HSCR are often carriers of the RET allele, a gene known to be associated with HSCR. Kuil [32] suggests sequencing patients for RET mutations to identify potential BBS and HSCR links. In the F1 family, all three affected siblings were homozygous for the intronic hypomorphic T allele of RET, while in the F2 family, only the two siblings with both BBS and HSCR were homozygous for this allele. This suggests that epistasis, or gene-gene interaction, between RET and BBS mutations, may contribute to the development of HSCR.

BBS is a genetically heterogeneous disorder with at least 12 loci and 10 genes identified [24] . It is characterized by defects in primary cilia, which play critical roles in various cellular processes, including signal transduction and development. Interestingly, recent research has implicated cilia dysfunction in the pathogenesis of HSCR. This raises the possibility that shared molecular pathways involving cilia dysfunction may underlie the link between BBS and HSCR.

Both HSCR and BBS can significantly impact a child’s quality of life. HSCR can lead to complications such as intestinal obstruction, constipation, enterocolitis, and potentially life-threatening infections. BBS, with its multisystem involvement, can result in vision loss, obesity, renal dysfunction, developmental delays, and behavioral issues.

The prevalence of BBS varies geographically, ranging from 1 in 140,000 to 1 in 160,000 newborns in North America and Europe [34] . HSCR is more common in males and can present with symptoms such as abdominal distention, constipation, and vomiting. Children with BBS may exhibit a range of behavioral issues, including internalizing problems like anxiety and depression [35] . Table 2 summarizes the key features and overlapping manifestations found in both HSCR and BBS.

While the link between HSCR and BBS is becoming increasingly evident, further research is needed to fully elucidate the underlying mechanisms. Investigating the role of cilia dysfunction in both conditions, identifying additional genetic interactions, and exploring potential shared signaling pathways may provide valuable insights for diagnosis, treatment, and genetic counseling.

In interrelationship marriages, individuals should be counseled on the features, impacts, and effects of their situation, including the genetic implications. HSCR is a congenital malformation with a 4% overall recurrence risk in the proband’s siblings (relative risk = 200). In isolated HSCR, the sex and aganglionic segment of the proband, as well as the gender of the sibling, provide adequate relative risk estimates. Many instances of HSCR are linked to other genetic abnormalities, and the severity of these associated malformations impacts the long-term prognosis. This highlights the significance of a genetic counselor’s comprehensive examination of all infants with HSCR [37] .

Hirschsprung disease (HSCR) can be treated surgically by removing the colon segment lacking nerve cells. In contrast, Bardet-Biedl syndrome (BBS) has no definitive treatment and focuses on managing specific signs and symptoms. According to Bergmann [38] , BBS is associated with various classical features, and some patients may not receive a precise diagnosis for several years. Ogundele [39] noted that diagnosis difficulties often arise when a child has learning disabilities and weight management issues but no congenital abnormalities, making the diagnosis uncertain.

Retinal disease diagnosis may require consultation with ophthalmologists and a definitive examination, such as an electroretinogram (ERG). Esposito [40] suggested that genetic testing could aid in diagnosing patients with BBS1 and BBS10 gene mutations, although Caudle et al. [41] pointed out that such tests may not be available in all laboratories. Primary treatment for BBS involves addressing specific symptoms, and kidney transplantation may be necessary for severe kidney disease [38] .

Recent progress in HSCR stem cell-based medicinal research has been significant, though many essential questions remain unanswered. This review provides a brief background on HSCR, outlines future approaches to stem cell-based treatment, reviews key recent articles, and discusses ethical and technical challenges before clinical translation [42] .

In HSCR, surgical treatment aims to restore normal bowel function and remove the tonic contraction of the internal anal sphincter [43] . Various surgical procedures, including the Soave and Duhamel procedures, are used. One-stage procedures are applicable for short-segment diseases, while long-segment diseases may require total colonic ganglions and temporary enterostomy before definitive surgery. Ghorbanpour et al. [44] proposed laparoscopic and transanal pull-through techniques for HSCR diagnosis. Table 3 covers the complications and outcomes of HSCR Surgery.

In the United States, approximately 90% of initial HSCR diagnoses occur within the first year of life, with 10% during childhood and less than 1% during adolescence or adulthood [45] . Postoperative treatment should include measures to minimize complications, such as regular physical examinations, kidney and urinary bladder function evaluations, and monitoring of vital signs. If all signs are normal, patients can be sent home with instructions for bowel irrigation three times a day at the operation site. Children with a history of HSCR are at higher risk of developing enterocolitis, characterized by explosive diarrhea, lethargy, and abdominal distension [46] .