Bardet-Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy with multisystem involvement, including retinal dystrophy, obesity, polydactyly, renal anomalies, hypogonadism, and cognitive impairment. Early diagnosis is often delayed due to gradual symptom onset. The revised diagnostic criteria for BBS, considering molecular diagnosis, ensures diagnostic certainty. We report a case of a 15-year-old girl born out of a nonconsanguineous marriage with delayed puberty, progressive vision loss, and obesity. Family history revealed similar symptoms in her 3 younger siblings. All four fulfilled diagnostic criteria for BBS. Whole exome sequencing in the index case and Sanger sequencing in the other 3 siblings identified a pathogenic homozygous 1 base pair deletion in exon 3 of the MKKS gene (p.Ser236Ter), confirming BBS type 6. BBS is a clinically and genetically heterogeneous disorder. Genetic confirmation aids early diagnosis, enabling timely intervention and multidisciplinary management to alleviate the burdensome complications. This case highlights the importance of early recognition and genetic confirmation in BBS, even in the background of nonconsanguinity. Early diagnosis can improve quality of life and long-term outcomes.

Incomplete cloaca is a rare cloacal variant that refers to a persistent urogenital sinus in girls with the bowel opening anteriorly in the perineum or the vestibule (summary figure). Most of these girls present primarily to pediatric surgeons/urologists as neonatal hydrocolpos. This study outlines the diagnosis and management of this condition while highlighting its association with Bardet-Biedl syndrome (BBS). The latter is a genetically heterogenous group of autosomal recessive disorders characterised by multisystem affection: pigmentary retinopathy, obesity, mental defect, polydactyly, genitourinary abnormalities, and parenchymatous kidney disease. A prospectively maintained database (2007 through 2024) of Anorectal anomalies and allied conditions was queried for cases of incomplete cloaca. We identified 5 girls all presenting primarily with neonatal hydrocolpos and postaxial polydactyly. Comprehensive clinical, radiological, and surgical data were gathered. Although BBS was not initially recognized, follow-up evaluations revealed features indicative of BBS, prompting further ophthalmological, renal, and cognitive assessment. Pelvic imaging and lower panendoscopy confirmed the anatomical findings consistent with the diagnosis. Surgical management involved a staged approach, with initial urogenital decompression (3/5), followed by definitive reconstruction using a combined abdominoperineal (2/3) or pure perineal approach (1/3). In the remaining two, a one-stage correction was possible after successful clean intermittent catheterisation of the vagina with urogenital mobilization in one and laparoscopic-assisted vaginal pull-through in the other. Limited sagittal anorectoplasty was performed in 3/5 cases to correct the symptomatic anterior anorectal displacement. Four girls were available for follow up (median 6 years). During the initial evaluation, the association with BBS was not recognized, as polydactyly was attributed to the known limb anomalies accompanying anorectal malformations. With the evolving clinical update, the clinical diagnosis of BBS was established in 3 cases. The remaining patients, one had polydactyly and obesity but was lost to follow-up while the other did not exhibit further cardinal features of BBS and assumed to have McKusick-Kaufman syndrome. This case series illustrates the significant association between incomplete cloaca and BBS. Postaxial polydactyly and obesity are important clues for the possible syndromic association. Pediatric surgeons/urologists need to be aware of this association and promptly refer these girls to the appropriate multidisciplinary specialties to assure an expedient management and support for these girls and their families as they navigate the challenges associated with this syndrome. This is a case series. Level IV evidence.

This case report highlights the clinical complexity of Bardet-Biedl syndrome, a rare autosomal recessive disorder, emphasizing reproductive anomalies to aid in diagnosis and management. It underscores the importance of thorough assessment and advocates for genetic testing to optimize care, despite current financial, and laboratory constraints.

Persistent urogenital sinus (PUGS) presents as a solitary abnormality or is in association with syndromes, such as congenital adrenal hyperplasia (CAH), VACTERL association (common abbreviation for vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities), Bardet-Beidl syndrome, McKusick-Kaufman syndrome (MKS), and Townes-Brocks syndrome, to name a few. Those affected usually have overlapping phenotypic features of two or more syndromes. Because such children may grow up to be intellectually challenged with multiple other anomalies including gonadal hyperplasia, congenital heart defects, and sensorineural hearing loss, antenatal diagnosis becomes important. Moreover, those who survive into childhood may need a holistic approach to improve their quality of life. This is a rare case of an eight-year-old female child who is a postnatally diagnosed case of congenital heart disease, urogenital sinus with polydactyly, and bilateral hydroureteronephrosis at birth and who is now showing features of multiple overlapping syndromes.

Primary cilia are crucial for neurogenesis, and cilium-related genes are involved in the closure of neural tubes. Inositol polyphosphate-5-phosphatase (Inpp5e) was enriched in primary cilia and closely related to the occurrence of neural tube defects (NTDs). However, the role of Inpp5e in the development of NTDs is not well-known. To investigate whether Inpp5e gene is associated with the neural tube closure, we established a mouse model of NTDs by 5-fluorouracil (5-FU) exposure at gestational day 7.5 (GD7.5). The Inpp5e knockdown (Inpp5e-/-) mouse embryonic stem cells (mESCs) were produced by CRISPR/Cas9 system. The expressions of Inpp5e and other cilium-related genes including intraflagellar transport 80 (Ift80), McKusick-Kaufman syndrome (Mkks), and Kirsten rat sarcoma viral oncogene homolog (Kras) were determined, utilizing quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), western blot, PCR array, and immunofluorescence staining. The result showed that the incidence of NTDs was 37.10% (23 NTDs/62 total embryos) and significantly higher than that in the control group (P < 0.001). The neuroepithelial cells of neural tubes were obviously disarranged in NTD embryos. The mRNA and protein levels of Inpp5e, Ift80, Mkks, and Kras were significantly decreased in NTD embryonic brain tissues, compared to the control (P < 0.05). Knockdown of the Inpp5e (Inpp5e-/-) reduced the expressions of Ift80, Mkks, and Kras in mESCs. Furthermore, the levels of α-tubulin were significantly reduced in NTD embryonic neural tissue and Inpp5e-/- mESCs. These results suggested that maternal 5-FU exposure inhibited the expression of Inpp5e, which resulted in the downregulation of cilium-related genes (Ift80, Mkks, and Kras), leading to the impairment of primary cilium development, and ultimately disrupted the neural tube closure.