The baby’s physical examination revealed distinctive craniofacial features, including a depressed nasal bridge, bilateral infraorbital creases, a thin vermilion border, microretrognathia, and hirsutism. Her skeletal findings were even more telling: rhizomelic shortening of both the upper and lower limbs, syndactyly fusing the fourth and fifth digits of her right hand, and mesoaxial polydactyly on the left, meaning an extra finger had grown in the middle of her hand rather than along its edges. Additional congenital anomalies included a high-arched palate, isolated right choanal atresia, a blockage of the nasal passage that required nasopharyngoscopy to detect, and an imperforate anus with a rectovaginal fistula that necessitated a loop colostomy on day 5 of life.

Imaging studies deepened the clinical mystery. Echocardiography revealed an ostium secundum atrial septal defect, a hole in the wall separating the heart’s two upper chambers. Abdominal ultrasonography demonstrated a solitary left kidney, with complete agenesis of the right kidney and no adrenal tissue visualized in the right renal fossa. But the most consequential finding came from brain magnetic resonance imaging, which identified a large, non-enhancing exophytic lesion arising from the tuber cinereum, a region at the base of the hypothalamus. Measuring 5.0 by 3.4 by 3.2 centimeters, the mass extended into the prepontine, interpeduncular, and suprasellar cisterns, exerting mass effect on the brainstem, displacing the optic chiasm superiorly, and compressing the pituitary stalk. This was a hypothalamic hamartoma, a benign but strategically located growth of disorganized neural tissue.

The combination of a hypothalamic hamartoma and mesoaxial polydactyly is the defining signature of Pallister-Hall syndrome, a rare autosomal dominant disorder caused by variants in the GLI3 gene. First linked to GLI3 frameshift mutations in 1997, the syndrome takes its name from the gene’s role as a zinc-finger transcription factor in the Sonic Hedgehog signaling pathway, a master regulator of embryonic limb and central nervous system development. The gene occupies a peculiar position in medical genetics: truncating variants in the middle third of its coding sequence, roughly open reading frame nucleotides 1998 through 3481, most often produce Pallister-Hall syndrome, while variants that simply reduce the amount of functional protein, a mechanism called haploinsufficiency, more commonly cause a different condition entirely, Greig cephalopolysyndactyly syndrome. The relationship is strong but not absolute, and exceptions on both sides have been documented.

Whole-exome sequencing was performed at an external clinical laboratory using the xGen Exome Research Panel v2.0 combined with the xGen Human mtDNA Research Panel v1.0 from Integrated DNA Technologies, followed by sequencing on an Illumina NovaSeq X instrument. Secondary analysis used DRAGEN against the hg38 human reference genome, with tertiary analysis on the Geneyx Analysis platform. The assay achieved a mean target coverage of 195.8-fold, with 95.35 percent of targeted bases covered at least 20-fold, well above the thresholds typically required for confident variant calling. The analysis identified a heterozygous GLI3 variant, NM_000168.6:c.2410del, which produces a frameshift beginning at amino acid 804 and predicted to truncate the protein five residues downstream as p.Val804SerfsTer5. The variant was absent from gnomAD v4.1, the largest public database of human genetic variation, and from ClinVar, the clinical variant archive, at the time of analysis in December 2025.

Sanger sequencing, a targeted confirmation method, verified the variant in the proband and demonstrated its absence in both parents and in her 4-year-old brother, supporting a presumed de novo origin, meaning the mutation arose spontaneously in the child rather than being inherited. The frameshift begins downstream of the zinc-finger domain, squarely within the middle-third PHS-associated region. The variant was provisionally classified as likely pathogenic using American College of Medical Genetics and Genomics criteria, specifically PM1, PM6, PM2_supporting, and PP4. Notably, the strongest criterion for loss-of-function variants, PVS1, was deliberately not applied, because Pallister-Hall syndrome is associated with a location-specific truncated-repressor mechanism rather than conventional loss of function. In other words, the disease mechanism depends not simply on losing GLI3 function but on where along the gene the truncation occurs, a subtlety that separates sophisticated variant interpretation from rote application of guidelines.

The differential diagnosis had initially pointed elsewhere. The combination of anorectal, cardiac, renal, and limb anomalies raised consideration of VACTERL association, a non-random clustering of vertebral, anal, cardiac, tracheoesophageal, renal, and limb defects. But VACTERL does not typically include hypothalamic hamartoma or mesoaxial polydactyly, and the co-occurrence of these two cardinal findings strongly favored Pallister-Hall syndrome. Greig cephalopolysyndactyly syndrome was considered and set aside because it typically features macrocephaly, hypertelorism, and preaxial polydactyly, with hypothalamic hamartoma not being characteristic. Other GLI3-related disorders, oral-facial-digital syndromes, and ciliopathies were similarly weighed and excluded based on the specific constellation of findings and the position of the truncating variant.

One element of the family history demanded careful interpretation. The proband’s 4-year-old brother had been diagnosed with a choroid plexus papilloma, a rare tumor of the brain’s cerebrospinal fluid-producing tissue, and treated with ventriculoperitoneal shunting. Sanger sequencing confirmed that he did not carry the GLI3 variant identified in his sister. In the absence of a shared variant or an established association between GLI3-related Pallister-Hall syndrome and choroid plexus papilloma, the sibling’s tumor is considered most likely incidental, a conclusion that spares the family unnecessary anxiety about inherited cancer risk.

Comparing this case with regional and molecularly relevant reports reveals both patterns and puzzles. A Saudi Arabian patient carrying a nearby variant, NM_000168.5:c.2396dup predicted as p.Lys800Ter, also had hypothalamic hamartoma and polydactyly, but developed gelastic seizures, the characteristic laughing fits of hypothalamic hamartomas, at 13 months, along with central precocious puberty during infancy and subsequent central hypothyroidism. A Lebanese clinical case combined hypothalamic hamartoma and polydactyly with orofacial narrowing and tethered cord, though no patient-specific molecular variant was reported. In an Iranian family, a homozygous c.1927C>T variant producing p.Arg643Ter was associated with a broad, severe PHS-like phenotype in a fetus, while heterozygous relatives had only polydactyly, suggesting an effect of allelic dosage. Larger molecular series reinforce the location-dependent association: the variant c.2385del, producing p.Ile796fsTer13, was reported in Pallister-Hall syndrome near the position affected in the present patient, while c.2374C>T, producing p.Arg792Ter, represents a documented Greig cephalopolysyndactyly exception within the PHS-associated region. In the Démurger cohort of 76 individuals from 55 families, renal anomalies occurred in 41 percent of evaluable PHS cases, ranging from hypoplasia to agenesis, indicating that the present patient’s right renal agenesis falls within recognized syndrome variability rather than establishing a novel association.

At the last documented assessment, the patient was 89 days old, clinically stable, and had shown no seizures and no biochemical evidence of pituitary dysfunction. Baseline endocrine evaluation, including free thyroxine, thyroid-stimulating hormone, growth hormone, and gonadotropins, had yielded values within age-appropriate reference ranges. Yet the authors are careful to note that the absence of seizures or endocrine dysfunction at this early age cannot predict later outcome, because these manifestations may emerge with time. Ongoing surveillance includes neurological and developmental assessment, monitoring of growth and pubertal development, age-appropriate pituitary testing, and neuroimaging as directed by the treating team. The case adds variant-level evidence to the global GLI3 literature and demonstrates a principle that extends far beyond a single patient: molecular position, clinical phenotype, and the age at which a patient is assessed must all be interpreted together before drawing conclusions about genotype-phenotype relationships in rare disease.

Subject of Research: A de novo GLI3 frameshift variant causing Pallister-Hall syndrome in a Palestinian infant

Article Title: Case Report: Pallister-Hall syndrome associated with a previously unreported de novo GLI3 frameshift variant and diagnostic insights from the Middle East

Article References: Khalil, G., Hemieid, I. K., & Malki, E. G. (2026). Case Report: Pallister-Hall syndrome associated with a previously unreported de novo GLI3 frameshift variant and diagnostic insights from the Middle East. Frontiers in Pediatrics, 14, Article 1818628. https://doi.org/10.3389/fped.2026.1818628

Image Credits: AI Generated

DOI: 10.3389/fped.2026.1818628

Keywords: Pallister-Hall syndrome, GLI3, hypothalamic hamartoma, polydactyly, whole-exome sequencing, de novo variant, genetics, rare disease, Middle East, pediatrics, Sonic Hedgehog pathway, genotype-phenotype correlation

The acute crisis, physicians concluded, was an episode of acute kidney injury superimposed on advanced, previously unrecognized chronic kidney disease, precipitated by the dehydration of her gastrointestinal illness. She had never undergone renal ultrasound, biochemical kidney function testing, or assessment of her estimated glomerular filtration rate, because she had never before sought medical care for her underlying condition. The case, published as a case report in Clinical Case Reports, documents how a rare multisystem genetic disorder called Bardet–Biedl syndrome went entirely undiagnosed into adulthood, allowing progressive kidney damage to accumulate unchecked until a routine infection brought the hidden disease to the surface.

Bardet–Biedl syndrome is a rare autosomal recessive ciliopathy, meaning it arises from defects in the primary cilium, a tiny antenna-like organelle that projects from nearly every cell in the body and coordinates crucial developmental and signaling pathways. The syndrome is defined by a constellation of features: rod–cone dystrophy of the retina that typically begins as night blindness and progresses to blindness, central obesity, extra fingers or toes known as polydactyly, intellectual disability, hypogonadism or genitourinary anomalies, and kidney involvement. Because the condition shows variable penetrance, its presentation can differ dramatically even among siblings in the same family, complicating recognition. In European outbred populations, prevalence is estimated at roughly one in 125,000 to one in 160,000 people, but isolated communities with founder mutations can carry far heavier burdens, most famously the Faroe Islands, where a single BBS1 splice-site mutation produces a prevalence of one in 3,700.

The patient in Lahore carried nearly the full textbook picture. Blind since age 19 after night blindness first appeared at age 8, she had a body mass index of 29, primary amenorrhea, childhood intellectual disability, bilateral polydactyly of both hands and feet, widely spaced eyes, strabismus, and a history of cystostomy for urethral stricture. Two of her siblings were affected by a similar constellation of problems, and she was born to first-cousin parents, a consanguinity pattern that dramatically raises the probability of homozygosity for recessive disease alleles. Laboratory workup added further findings: severe macrocytic anemia with hemoglobin of 6.8 g/dL, elevated alkaline phosphatase at 480 U/L, and an HbA1c of 8.2 percent with random glucose of 250 mg/dL, indicating poorly controlled diabetes mellitus that had also escaped prior diagnosis.

Imaging sealed the clinical picture. Abdominal ultrasound showed coarse liver echotexture, mild splenomegaly, and kidneys with increased echogenicity and reduced corticomedullary differentiation, hallmarks of chronic parenchymal damage. Computed tomography of the kidneys, ureters, and bladder then demonstrated bilaterally small kidneys, the right measuring 83 by 27 millimeters and the left 83 by 33 millimeters, with lobulated, irregular cortices consistent with longstanding scarring. In a young adult, kidneys of this size and texture represent years of accumulated nephron loss. The combination of retinal dystrophy, kidney disease, polydactyly, obesity, intellectual disability, primary amenorrhea, and affected siblings pointed decisively toward a hereditary ciliopathy, and the principal differential, Alström syndrome, was excluded because it does not typically involve polydactyly or intellectual disability. A clinical diagnosis of Bardet–Biedl syndrome was made, though genetic confirmation was not pursued because of resource limitations.

At the molecular level, BBS is strikingly heterogeneous: at least 26 genes have been identified, most encoding proteins essential for ciliary assembly and intracellular trafficking. Disruption of ciliary signaling, including the non-canonical Wnt pathway, is implicated in the cystogenesis and progressive nephron loss that characterize BBS-related kidney disease. Genotype–phenotype studies suggest that patients with variants in chaperonin-like genes such as BBS6, BBS10, and BBS12 tend to develop more severe chronic kidney disease than those with BBS1 variants, a finding that could eventually guide how intensively clinicians surveil renal function once sequencing becomes accessible in settings like Pakistan. Diagnostic criteria originally proposed by Beales and colleagues require either four primary features or three primary features plus two secondary ones, and a recent European Reference Networks consensus has updated the framework to incorporate molecular diagnosis alongside clinical findings. This patient fulfilled the primary criteria of rod–cone dystrophy, postaxial polydactyly, obesity, intellectual disability, genitourinary anomalies, and renal dysfunction.

What makes the case exceptional is timing. The mean age of clinical BBS diagnosis is around nine years, yet this patient reached her third decade without a formal syndromic diagnosis of any kind. Renal involvement affects more than half of BBS patients and is the leading driver of premature mortality in the syndrome, ranging from structural anomalies such as fetal lobulation and increased parenchymal echogenicity to cystic dysplasia and progressive loss of glomerular filtration. In the largest reported cohort, kidney failure requiring renal replacement therapy occurred in roughly 6 percent of adult and 5 percent of pediatric patients, and affected children tend to follow one of two trajectories, either developing severe chronic kidney disease early or remaining comparatively spared through childhood. An early warning sign, reduced urinary concentrating capacity producing polyuria and polydipsia, reflects tubular dysfunction tied to disrupted ciliary signaling and can flag declining renal function years before crisis.

Treatment of the acute episode followed standard nephrology practice. The patient received three sessions of hemodialysis, broad-spectrum antibiotics, intravenous fluids, and antipyretics, and improved over subsequent days with a notable recovery of urine output before discharge with strict follow-up advice. Her echocardiogram was normal, reassuring given that cardiovascular abnormalities have been documented in a subset of BBS patients. Longer-term management of the syndrome demands a genuinely multidisciplinary approach spanning nephrology, ophthalmology, endocrinology, genetics, and cardiology, with regular blood pressure monitoring, annual ophthalmologic evaluation, and periodic assessment of renal and metabolic parameters. Should her kidneys progress to outright failure, renal transplantation remains viable with outcomes comparable to the general population, although coexisting obesity can complicate both pre-transplant workup and post-transplant metabolic management. No disease-modifying therapy yet exists for the renal or retinal manifestations, making surveillance the principal tool for delaying irreversible complications.

The Pakistani context adds a public-health dimension. Roughly half to two-thirds of marriages in the country are consanguineous, most commonly between first cousins, a pattern that should, in principle, elevate the prevalence of autosomal recessive disorders like BBS. Yet reported Pakistani cases remain scarce, a paradox the report’s authors attribute to underdiagnosis rather than genuinely low prevalence, driven by limited access to ophthalmologic, nephrologic, and genetic testing. A recent case series from Multan described four affected individuals from two sibling pairs, illustrating both marked intrafamilial variability and diagnostic delay, and the literature now includes scattered reports from Dera Ismail Khan, Peshawar, Karachi, and Islamabad. Most patients present in childhood or adolescence with retinal and developmental features and are diagnosed clinically rather than genetically, and the present case appears to be among the few from Pakistan in which unrecognized chronic kidney disease progressed to acute kidney injury in adulthood before the underlying syndrome was ever identified.

The broader lesson reaches beyond one hospital ward. Bardet–Biedl syndrome’s features can appear so scattered across specialties, an eye problem here, extra digits there, obesity and developmental delay elsewhere, that no single clinician assembles the full picture until something acute forces the issue. Greater awareness among pediatricians, ophthalmologists, and family physicians, combined with systematic renal surveillance of children showing the syndrome’s cardinal features, could allow earlier diagnosis and potentially forestall exactly the kind of delayed, dramatic presentation seen in Lahore. Genetic counseling remains central to comprehensive care, informing families about recurrence risk and the value of screening apparently healthy relatives for subclinical complications. For this 27-year-old woman, the gastroenteritis that nearly overwhelmed her kidneys also finally gave her disease a name, and with it, at last, the possibility of coordinated care.

Subject of Research: Bardet–Biedl syndrome presenting as acute kidney injury on undiagnosed chronic kidney disease in a young adult

Article Title: Bardet–Biedl Syndrome Presenting With Acute Kidney Injury Revealing Previously Undiagnosed Advanced Chronic Kidney Disease in a Young Adult: A Case Report

Article References: Abbas, A., Amjad, N., Mufti, A. F., Waqas, M., Iqbal, M., Ali, H., Habib, A., Samadi, Y., & Haider, M. U. (2026). Bardet–Biedl Syndrome Presenting With Acute Kidney Injury Revealing Previously Undiagnosed Advanced Chronic Kidney Disease in a Young Adult: A Case Report. Clinical Case Reports, 14(10), Article e73672. https://doi.org/10.1002/ccr3.73672

Image Credits: AI Generated

DOI: 10.1002/ccr3.73672

Keywords: Bardet-Biedl syndrome, ciliopathy, acute kidney injury, chronic kidney disease, polydactyly, rod-cone dystrophy, consanguinity, Pakistan, hemodialysis, genetic diagnosis, primary cilium, rare disease