Smith-Magenis syndrome affects roughly one in 15,000 to 25,000 births and is caused in most cases by a heterozygous deletion of chromosome band 17p11.2 that includes RAI1, a gene whose dosage is critical for normal brain development. A smaller fraction of patients instead carry a point mutation within RAI1 itself. The classic phenotype, which includes self-hugging, sleep disruption driven by an inverted melatonin rhythm, self-injurious behavior, and intellectual disability, typically crystallizes only after the first year or two of life. In an infant, before the behavioral fingerprint emerges, the diagnosis is notoriously easy to miss, and the syndrome can hide behind a scatter of unconnected problems.

That is precisely what happened here. The boy had been born by cesarean section at 35 weeks and five days, weighed 2,700 grams, and scored a perfect 10 on his Apgar assessments, giving no clue of what was coming. Yet his newborn heel-prick screen came back suspicious: thyroid-stimulating hormone was elevated at 8.58 micro-international units per milliliter while free thyroxine was low at 5.71 picomoles per liter, a biochemical signature of congenital hypothyroidism. Levothyroxine was started promptly, a decision that would later prove critical, because untreated thyroid deficiency in infancy compounds the neurodevelopmental damage caused by an underlying genetic disorder.

In February 2025, at around seven months of age, the boy was hospitalized elsewhere with a urinary tract infection complicated by sepsis. The numbers were alarming: a white blood cell count of 21.46 billion per liter, C-reactive protein of 120.6 milligrams per liter, procalcitonin of 10.2 nanograms per milliliter, and elevated lactate. Imaging revealed bilateral hydronephrosis with dilated ureters, meaning both kidneys were swollen with backed-up urine. He recovered after treatment with meropenem and piperacillin/tazobactam, but the family interrupted his levothyroxine in early April, setting the stage for the thyroid dysfunction to resurface at his next admission.

When he returned to Wuxi in May 2025 with fever, chills, and pyuria, the clinical team assembled a comprehensive picture. Physical examination showed a square face, a mildly depressed nasal bridge, left strabismus, eversion of the upper lip, abnormally short fingers on both hands, generalized low muscle tone, early closure of the anterior fontanel, a short penis, and phimosis. He could not yet sit steadily or crawl, and his language and fine motor skills lagged behind. Urinary injury markers were striking: alpha1-microglobulin at 96.80 milligrams per liter against a reference ceiling of 12.5, microalbumin at 70.70 milligrams per liter, and immunoglobulin G at 24.40 milligrams per liter, all pointing to kidney tubular and glomerular stress.

The urologic workup delivered the headline finding. Voiding cystourethrography, in which contrast dye is instilled into the bladder and tracked under X-ray while the child voids, demonstrated bilateral grade IV vesicoureteral reflux, the second-highest severity on a five-point scale, meaning urine was surging backwards from the bladder up dilated ureters into the renal pelvis on both sides. Static DMSA scintigraphy revealed focal cortical defects in the upper and lower poles of the right kidney, a sign of scarring or impaired perfusion. Dynamic DTPA scintigraphy quantified the damage: effective renal plasma flow measured 180.33 milliliters per minute in the left kidney and 133.77 milliliters per minute in the right, a split function of 57.4 percent versus 42.6 percent that documented early, asymmetric right renal compromise.

To explain the syndromic pattern, the team turned to trio whole-exome sequencing with copy-number-variant analysis, comparing the child’s genome against both parents’. The test found the smoking gun: a heterozygous deletion spanning positions 16,692,403 to 20,321,263 on chromosome 17, roughly 3.63 megabases, encompassing RAI1 and the Smith-Magenis critical region, present in the child but in neither parent. Under ACMG/AMP and ACMG/ClinGen classification standards the deletion was deemed pathogenic, formally establishing the diagnosis. The sequencing also surfaced a maternally inherited heterozygous DUOX2 variant, c.2635G>A (p.Glu879Lys), classified as likely pathogenic. DUOX2 encodes an enzyme essential for thyroid hormone synthesis, so the variant is an intriguing candidate for the boy’s hypothyroidism, but the authors are careful: without functional validation, and with no evidence of overt thyroid disease in the mother, its contribution remains unproven, and a clinically silent carrier state cannot be excluded. Two additional heterozygous variants in CCBE1 and RAG2 were flagged as uncertain significance and do not explain the phenotype.

The genetics here carries a broader lesson about genotype-phenotype architecture. Genitourinary anomalies have been reported in approximately 15 to 35 percent of individuals with 17p11.2 deletions, including collecting-system duplication, renal agenesis or ectopia, and ureterovesical obstruction, yet they are essentially absent from comparable cohorts of patients with intragenic RAI1 point variants. A 2006 genotype-phenotype study of 31 patients found renal or urinary abnormalities in 15 percent of deletion carriers and in none of the 11 individuals carrying RAI1 mutations. The implication is that genes elsewhere in the deleted interval, not RAI1 alone, shape the structural anomalies, meaning Smith-Magenis syndrome caused by a large deletion is best understood as a contiguous-gene disorder with a wider clinical footprint. The closest prior comparator in the literature was an eight-year-old boy with bilateral grade IV reflux who ultimately required ureteroplasty on both sides; the present case extends that picture into infancy with quantitative renal scintigraphy.

Management proceeded along multiple tracks simultaneously. The acute infection responded to cefoperazone/sulbactam, followed by oral amoxicillin/clavulanate, and continuous antibiotic prophylaxis at 76 milligrams once daily at bedtime was initiated, a strategy supported by randomized trial evidence for infants with grade III to V reflux, including the 2014 RIVUR trial and a 2023 European study in infants. Levothyroxine was resumed, and thyroid function returned to normal. A planned phimosis surgery had to be postponed after the boy suffered an afebrile seizure during sleep, which was treated with oxygen, monitoring, and phenobarbital; video-electroencephalography later showed no definite abnormality. Mouse models have shown that loss of Rai1 enhances hippocampal excitability and epileptogenesis, providing biological context for seizure susceptibility, but the authors decline to diagnose epilepsy, instead describing brief ocular convergence episodes observed during follow-up as possible seizure-like events under continued evaluation.

By late August 2025, the trajectory was cautiously encouraging. Creatinine had fallen to 25.0 micromoles per liter, cystatin C to 1.39 milligrams per liter, and the estimated glomerular filtration rate stood at 103.66 milliliters per minute per 1.73 square meters, with a urine protein-to-creatinine ratio of 0.12 grams per gram and no recurrent infections. Thyroid indices normalized, and growth in height and weight was satisfactory, though gross-motor, fine-motor, and language delays persisted, with a Gesell developmental quotient of 72 recorded at 9.2 months. The case’s principal message extends beyond one child: when an infant presents with developmental delay and hypotonia alongside dysmorphic features, skeletal findings, genitourinary anomalies, and endocrine dysfunction, clinicians should think syndromically and order genomic testing capable of detecting copy-number variants, because microdeletions can slip past both routine karyotyping and exome workflows restricted to single-nucleotide changes. Catching Smith-Magenis syndrome early does not change the deletion, but it transforms care, replacing episodic firefighting with coordinated renal protection, thyroid replacement, neurologic surveillance, developmental rehabilitation, and informed genetic counseling for the family.

Subject of Research: Early infantile presentation of Smith-Magenis syndrome with bilateral high-grade vesicoureteral reflux, hypothyroidism, and seizure

Article Title: Case Report: Smith-Magenis syndrome with bilateral high-grade vesicoureteral reflux, hypothyroidism, and seizure in infancy

Article References: Cheng, Y., Liu, X., Yang, L., & Xu, J. (2026). Case Report: Smith-Magenis syndrome with bilateral high-grade vesicoureteral reflux, hypothyroidism, and seizure in infancy. Frontiers in Pediatrics, 14, Article 1906694. https://doi.org/10.3389/fped.2026.1906694

Image Credits: AI Generated

DOI: 10.3389/fped.2026.1906694

Keywords: Smith-Magenis syndrome, RAI1, 17p11.2 deletion, vesicoureteral reflux, congenital hypothyroidism, DUOX2, whole-exome sequencing, copy-number variant, pediatric nephrology, seizure, developmental delay, case report