Urologic manifestations of hypotonia, ataxia, and delayed development syndrome (HADDS), a rare neurodevelopmental disorder.

INTRODUCTION: Early B-cell factor 3 (EBF3) is a transcription factor involved in neuronal differentiation and maturation. Pathogenic variants are associated with hypotonia, ataxia, and delayed development syndrome (HADDS) (MIM#617330). Urologic manifestations are common and may have implications regarding long term renal function. OBJECTIVE: To review all known patients with pathogenic variants of the EBF3 gene resulting in HADDS with urologic manifestations. We hypothesize a high rate of bladder dysfunction secondary to the EBF3 variant's impact on relaxation of the urinary sphincter leading to detrusor sphincter dyssynergia (DSD). METHODS: The PubMed database was queried for publications of the EBF3 mutation between January 2017 and January 2023. Search terms were "EBF3 mutation OR HADDS AND urology OR phenotype". Retrospective analysis of HADDS patients cared for in our institution was performed. Demographic and clinical information was collected. RESULTS: We identified 52 patients (33F:19M) through literature (28F:18M) and retrospective review (5F:1M). There was a high prevalence of genitourinary physical exam abnormalities, history of urinary tract infection, vesicoureteral reflux (VUR), and diagnosis of neurogenic bladder. Within the literature review cohort, 67% had a urologic diagnosis. Females were disproportionately affected with urologic manifestations. In our cohort, four of six children were diagnosed with VUR and severe voiding dysfunction consistent with neurogenic bladder (67%). These children were managed with a vesicostomy. Five children had bowel dysfunction requiring therapy. Urodynamics suggested a high prevalence of external sphincter dyssynergia. Less severe forms of DSD were felt to be implicated in the abnormal voiding parameters in children who presented later in life based on non-invasive flow studies. DISCUSSION: There is significant variability in the phenotypic presentation of patients with HADDS. While EBF3 plays a clear role in neurodevelopment, it also impacts muscle development and may impact muscle relaxation. The location of the genetic variant may impact the degree of DSD, with more severe forms leading to earlier presentations. Initial work-up should include a renal ultrasound (RUS) and post void residual (PVR). Consideration can be given to obtaining a VCUG, DMSA scan or urodynamic studies. Yearly screening should be pursued with an RUS and PVR in those with an initial unremarkable work-up given the variable timing and severity of presentation. CONCLUSION: Urologic manifestations of HADDS include high rates of bladder dysfunction secondary to DSD, vesicoureteral reflux, urinary tract infection, and cryptorchidism. These patients are at risk of renal deterioration if urinary abnormalities are not properly diagnosed and managed.

Pathologic fracture in metastatic kidney cancer: Identifying widening disparities and opportunity for quality improvement.

BACKGROUND: Management and palliation of pathologic fracture (PFx) secondary to metastatic prostate (mCaP) and renal cancer (mRCa) is hospital resource intensive. Using a national all-payer database, we assessed the burden of PFx secondary to mCaP and mRCa nationwide. Admission rates, mortality, surgical fixation rates, and risk factors for high-cost admissions for pathologic fractures were assessed METHODS: National Inpatient Sample was queried from 2013 to 2015 for mCaP and mRCa admissions. Hospitalization costs of PFx was assessed over time by cancer type. Hospitalization outcomes were stratified by cancer type. Multivariable logistic regression models were constructed to examine predictors of high-cost admission for PFx (>75th percentile). RESULTS: From 2013 to 2015, there were 21,466 and 6,334 admissions for mCaP and mRCa with bone metastasis, respectively. Proportion of admissions for PFx was greater in mRCa than mCaP (15.9% vs. 7.2%, P < 0.01). PFx secondary to mRCa was associated with longer length of stay, hospitalization cost, and greater rate of surgical fixation. Costs of admission for PFx increased by $4,005 dollars from 2013 to 2015 for mRCa (P = 0.03), but did not increase for mCaP (P = 0.5). On multivariable analysis, mRCa was associated with greater odds of PFx (OR:2.12, P < 0.01), and high-cost hospitalization for mRCa associated PFx (OR:1.37, P = 0.02). CONCLUSIONS: PFx secondary to mRCa represents a significant health care burden. mRCa was associated with greater odds of PFx compared to mCaP, as well as greater inpatient morbidity and cost. Formalized guidelines on screening and management of bone lesions in mRCa may be needed to mitigate this under-recognized health care burden.