Bi-allelic variants in CELSR3 are implicated in central nervous system and urinary tract anomalies.

CELSR3 codes for a planar cell polarity protein. We describe twelve affected individuals from eleven independent families with bi-allelic variants in CELSR3. Affected individuals presented with an overlapping phenotypic spectrum comprising central nervous system (CNS) anomalies (7/12), combined CNS anomalies and congenital anomalies of the kidneys and urinary tract (CAKUT) (3/12) and CAKUT only (2/12). Computational simulation of the 3D protein structure suggests the position of the identified variants to be implicated in penetrance and phenotype expression. CELSR3 immunolocalization in human embryonic urinary tract and transient suppression and rescue experiments of Celsr3 in fluorescent zebrafish reporter lines further support an embryonic role of CELSR3 in CNS and urinary tract formation.

Intrauterine enzyme replacement therapies for lysosomal storage disorders: Current developments and promising future prospects.

Lysosomal storage disorders (LSDs) are a group of monogenic condition, with many characterized by an enzyme deficiency leading to the accumulation of an undegraded substrate within the lysosomes. For those LSDs, postnatal enzyme replacement therapy (ERT) represents the standard of care, but this treatment has limitations when administered only postnatally because, at that point, prenatal disease sequelae may be irreversible. Furthermore, most forms of ERT, specifically those administered systemically, are currently unable to access certain tissues, such as the central nervous system (CNS), and furthermore, may initiate an immune response. In utero enzyme replacement therapy (IUERT) is a novel approach to address these challenges evaluated in a first-in-human clinical trial for IUERT in LSDs (NCT04532047). IUERT has numerous advantages: in-utero intervention may prevent early pathology; the CNS can be accessed before the blood-brain barrier forms; and the unique fetal immune system enables exposure to new proteins with the potential to prevent an immune response and may induce sustained tolerance. However, there are challenges and limitations for any fetal procedure that involves two patients. This article reviews the current state of IUERT for LSDs, including its advantages, limitations, and potential future directions for definitive therapies.

Novel association of Dandy-Walker malformation with CAPN15 variants expands the phenotype of oculogastrointestinal neurodevelopmental syndrome.

Oculogastrointestinal neurodevelopmental syndrome has been described in seven previously published individuals who harbor biallelic pathogenic variants in the CAPN15 gene. Biallelic missense variants have been reported to demonstrate a phenotype of eye abnormalities and developmental delay, while biallelic loss of function variants exhibit phenotypes including microcephaly and craniofacial abnormalities, cardiac and genitourinary malformations, and abnormal neurologic activity. We report six individuals from three unrelated families harboring biallelic deleterious variants in CAPN15 with phenotypes overlapping those previously described for this disorder. Of the individuals affected, four demonstrate radiographic evidence of the classical triad of Dandy-Walker malformation including hypoplastic vermis, fourth ventricle enlargement, and torcular elevation. Cerebellar anomalies have not been previously reported in association with CAPN15-related disease. Here, we present three unrelated families with findings consistent with oculogastrointestinal neurodevelopmental syndrome and cerebellar pathology including Dandy-Walker malformation. To corroborate these novel clinical findings, we present supporting data from the mouse model suggesting an important role for this protein in normal cerebellar development. Our findings add six molecularly confirmed cases to the literature and additionally establish a new association of Dandy-Walker malformation with biallelic CAPN15 variants, thereby expanding the neurologic spectrum among patients affected by CAPN15-related disease.

PRDM16 Deletion Is Associated With Sex-dependent Cardiomyopathy and Cardiac Mortality: A Translational, Multi-Institutional Cohort Study.

BACKGROUND: 1p36 deletion syndrome can predispose to pediatric-onset cardiomyopathy. Deletion breakpoints are variable and may delete the transcription factor PRDM16. Early studies suggest that deletion of PRDM16 may underlie cardiomyopathy in patients with 1p36 deletion; however, the prognostic impact of PRDM16 loss is unknown. METHODS: This retrospective cohort included subjects with 1p36 deletion syndrome from 4 hospitals. Prevalence of cardiomyopathy and freedom from death, cardiac transplantation, or ventricular assist device were analyzed. A systematic review cohort was derived for further analysis. A cardiac-specific Prdm16 knockout mouse (Prdm16 conditional knockout) was generated. Echocardiography was performed at 4 and 6 to 7 months. Histology staining and qPCR were performed at 7 months to assess fibrosis. RESULTS: The retrospective cohort included 71 patients. Among individuals with PRDM16 deleted, 34.5% developed cardiomyopathy versus 7.7% of individuals with PRDM16 not deleted (P=0.1). In the combined retrospective and systematic review cohort (n=134), PRDM16 deletion-associated cardiomyopathy risk was recapitulated and significant (29.1% versus 10.8%, P=0.03). PRDM16 deletion was associated with increased risk of death, cardiac transplant, or ventricular assist device (P=0.04). Among those PRDM16 deleted, 34.5% of females developed cardiomyopathy versus 16.7% of their male counterparts (P=0.2). We find sex-specific differences in the incidence and the severity of contractile dysfunction and fibrosis in female Prdm16 conditional knockout mice. Further, female Prdm16 conditional knockout mice demonstrate significantly elevated risk of mortality (P=0.0003). CONCLUSIONS: PRDM16 deletion is associated with a significantly increased risk of cardiomyopathy and cardiac mortality. Prdm16 conditional knockout mice develop cardiomyopathy in a sex-biased way. Patients with PRDM16 deletion should be assessed for cardiac disease.

When is the best time to screen and evaluate for treatable genetic disorders?: A lifespan perspective.

This paper focuses on the question of, "When is the best time to identify an individual at risk for a treatable genetic condition?" In this review, we describe a framework for considering the optimal timing for pursuing genetic and genomic screening for treatable genetic conditions incorporating a lifespan approach. Utilizing the concept of a carousel that represents the four broad time periods when critical decisions might be made around genetic diagnoses during a person's lifetime, we describe genetic testing during the prenatal period, the newborn period, childhood, and adulthood. For each of these periods, we describe the objectives of genetic testing, the current status of screening or testing, the near-term vision for the future of genomic testing, the advantages and disadvantages of each approach, and the feasibility and ethical considerations of testing and treating. The notion of a "Genomics Passbook" is one where an early genomic screening evaluation could be performed on each individual through a public health program, with that data ultimately serving as a "living document" that could be queried and/or reanalyzed at prescribed times during the lifetime of that person, or in response to concerns about symptoms of a genetic disorder in that individual.

Complex Repair of Anomalous Left Coronary Artery From the Pulmonary Artery in a 55-Year-Old Patient.

Anomalous left coronary artery from the pulmonary artery (ALCAPA) is a congenital malformation that classically presents within the first year of life. Few patients survive into adulthood, and initial presentation after the fourth decade of life is rare. We describe a 55-year-old woman who presented after cardiac arrest. She initially refused surgery and underwent automated implantable cardioverter defibrillator placement, followed later by surgical repair involving reimplantation of the left coronary artery to the aorta and pulmonary artery reconstruction using interposition grafts. We report this late presentation of ALCAPA and successful surgical management.

Phase I study of liver depot gene therapy in late-onset Pompe disease.

Gene therapy with an adeno-associated virus serotype 8 (AAV8) vector (AAV8-LSPhGAA) could eliminate the need for enzyme replacement therapy (ERT) by creating a liver depot for acid α-glucosidase (GAA) production. We report initial safety and bioactivity of the first dose (1.6 × 1012 vector genomes/kg) cohort (n = 3) in a 52-week open-label, single-dose, dose-escalation study (NCT03533673) in patients with late-onset Pompe disease (LOPD). Subjects discontinued biweekly ERT after week 26 based on the detection of elevated serum GAA activity and the absence of clinically significant declines per protocol. Prednisone (60 mg/day) was administered as immunoprophylaxis through week 4, followed by an 11-week taper. All subjects demonstrated sustained serum GAA activities from 101% to 235% of baseline trough activity 2 weeks following the preceding ERT dose. There were no treatment-related serious adverse events. No subject had anti-capsid T cell responses that decreased transgene expression. Muscle biopsy at week 24 revealed unchanged muscle glycogen content in two of three subjects. At week 52, muscle GAA activity for the cohort was significantly increased (p < 0.05). Overall, these initial data support the safety and bioactivity of AAV8-LSPhGAA, the safety of withdrawing ERT, successful immunoprophylaxis, and justify continued clinical development of AAV8-LSPhGAA therapy in Pompe disease.

Whole-genome sequencing holds the key to the success of gene-targeted therapies.

Rare genetic disorders affect as many as 3%-5% of all babies born. Approximately 10,000 such disorders have been identified or hypothesized to exist. Treatment is supportive except in a limited number of instances where specific therapies exist. Development of new therapies has been hampered by at least two major factors: difficulty in diagnosing diseases early enough to enable treatment before irreversible damage occurs, and the high cost of developing new drugs and getting them approved by regulatory agencies. Whole-genome sequencing (WGS) techniques have become exponentially less expensive and more rapid since the beginning of the human genome project, such that return of clinical data can now be achieved in days rather than years and at a cost that is comparable to other less expansive genetic testing. Thus, it is likely that WGS will ultimately become a mainstream, first-tier NBS technique at least for those disorders without appropriate high-throughput functional tests. However, there are likely to be several steps in the evolution to this end. The clinical implications of these advances are profound but highlight the bottlenecks in drug development that still limit transition to treatments. This article summarizes discussions arising from a recent National Institute of Health conference on nucleic acid therapy, with a focus on the impact of WGS in the identification of diagnosis and treatment of rare genetic disorders.

Assisted reproductive technology and association with childhood cancer subtypes.

OBJECTIVES: To investigate the association between assisted reproductive technology (ART) use and childhood cancer subtype. STUDY DESIGN: We deployed a cross-sectional survey of 1701 parents of children with cancer about their ART use, demographics, and gestational and perinatal factors. Multivariable logistic regression modeled the association between ART use, birthweight and multiple gestation status with childhood cancer, by subtype. RESULTS: ART use was highest among children with osteosarcoma relative to children with other cancer types, and this association was statistically significant in multivariable models (OR = 4.4; 95% CI = 1.7-11.3; p = 0.0020). ART use was also elevated among children with hepatoblastoma, but this relationship appeared to be due to the strong associations between ART use and lower birthweight in our sample. No specific ART modality appeared to drive these associations. In univariate models, multiple gestation was associated with a 2.7-fold increased odds of hepatoblastoma (OR = 2.71; 95% CI = 1.14-6.42; p = 0.02) and a 1.6-fold increased odds of neuroblastoma (OR = 1.62; 95% CI = 1.03-2.54; p = 0.03), but these associations were not retained in multivariable models. CONCLUSIONS: Associations between ART use and hepatoblastoma risk may be attributable to birthweight, a known hepatoblastoma risk factor. ART use may also be associated with osteosarcoma, independent of birthweight, an association not previously observed in studies limited to cancers diagnosed before adolescence. Evaluating long-term health outcomes in children conceived by ART, throughout adolescence and potentially into adulthood, appears warranted.

Rapid Whole Genome Sequencing in Critically Ill Neonates Enables Precision Medicine Pipeline.

Rapid genome sequencing in critically ill infants is increasingly identified as a crucial test for providing targeted and informed patient care. We report the outcomes of a pilot study wherein eight critically ill neonates received rapid whole genome sequencing with parental samples in an effort to establish a prompt diagnosis. Our pilot study resulted in a 37.5% diagnostic rate by whole genome sequencing alone and an overall 50% diagnostic rate for the cohort. We describe how the diagnoses led to identification of additional affected relatives and a change in management, the limitations of rapid genome sequencing, and some of the challenges with sample collection. Alongside this pilot study, our site simultaneously established a research protocol pipeline that will allow us to conduct research-based genomic testing in the cases for which a diagnosis was not reached by rapid genome sequencing or other available clinical testing. Here we describe the benefits, limitations, challenges, and potential for rapid whole genome sequencing to be incorporated into routine clinical evaluation in the neonatal period.

In Utero Enzyme-Replacement Therapy for Infantile-Onset Pompe's Disease.

Patients with early-onset lysosomal storage diseases are ideal candidates for prenatal therapy because organ damage starts in utero. We report the safety and efficacy results of in utero enzyme-replacement therapy (ERT) in a fetus with CRIM (cross-reactive immunologic material)-negative infantile-onset Pompe's disease. The family history was positive for infantile-onset Pompe's disease with cardiomyopathy in two previously affected deceased siblings. After receiving in utero ERT and standard postnatal therapy, the current patient had normal cardiac and age-appropriate motor function postnatally, was meeting developmental milestones, had normal biomarker levels, and was feeding and growing well at 13 months of age.

Development of a clinically validated in vitro functional assay to assess pathogenicity of novel GAA variants in patients with Pompe disease identified via newborn screening.

Purpose: The addition of Pompe disease (Glycogen Storage Disease Type II) to the Recommended Uniform Screening Panel in the United States has led to an increase in the number of variants of uncertain significance (VUS) and novel variants identified in the GAA gene. This presents a diagnostic challenge, especially in the setting of late-onset Pompe disease when symptoms are rarely apparent at birth. There is an unmet need for validated functional studies to aid in classification of GAA variants. Methods: We developed an in vitro mammalian cell expression and functional analysis system based on guidelines established by the Clinical Genome Resource (ClinGen) Sequence Variant Interpretation Working Group for PS3/BS3. We validated the assay with 12 control variants and subsequently analyzed eight VUS or novel variants in GAA identified in patients with a positive newborn screen for Pompe disease without phenotypic evidence of infantile-onset disease. Results: The control variants were analyzed in our expression system and an activity range was established. The pathogenic controls had GAA activity between 0% and 11% of normal. The benign or likely benign controls had an activity range of 54%-100%. The pseudodeficiency variant had activity of 17%. These ranges were then applied to the variants selected for functional studies. Using the threshold of <11%, we were able to apply PS3_ supporting to classify two variants as likely pathogenic (c.316C > T and c.1103G > A) and provide further evidence to support the classification of likely pathogenic for two variants (c.1721T > C and c.1048G > A). One variant (c.1123C > T) was able to be reclassified based on other supporting evidence. We were unable to reclassify three variants (c.664G > A, c.2450A > G, and c.1378G > A) due to insufficient or conflicting evidence. Conclusion: We investigated eight GAA variants as proof of concept using our validated and reproducible in vitro expression and functional analysis system. While additional work is needed to further refine our system with additional controls and different variant types in order to apply the PS3/BS3 criteria at a higher level, this tool can be utilized for variant classification to meet the growing need for novel GAA variant classification in the era of newborn screening for Pompe disease.

Novel PAX6 variant in a family with ophthalmologic, pancreatic, and olfactory features.

Variants in the PAX6 gene have been associated with ophthalmologic, neurologic, and pancreatic differences. We report on a proband, mother, and affected brother who presented with congenital cataracts and glaucoma at a young age. Nonocular findings are also reported among these family members. After a congenital cataracts next-generation sequencing (NGS) gene panel was found to be nondiagnostic in 2016, a more expanded panel in 2020 revealed a novel variant: c.178T > A; p.Tyr60Asn in exon 6 of the PAX6 gene in the proband. The variant is also present in the affected mother and affected brother; it is absent in an unaffected brother. The clinical findings of these three relatives, in conjunction with their genetic testing and the associated PAX6 features reported in the literature, suggest that this novel familial variant may be an underlying etiology for these individuals' ophthalmologic, pancreatic, and olfactory symptoms.

Hydrops fetalis-trends in associated diagnoses and mortality from 1997-2018.

OBJECTIVES: To describe and evaluate trends in the etiology and mortality risk in neonates admitted for neonatal intensive care with hydrops fetalis. STUDY DESIGN: A retrospective review of de-identified patient data in the Pediatrix Clinical Data Warehouse from 1997 to 2018. RESULTS: We identified 2144 infants diagnosed with hydrops fetalis. The most common diagnoses were congenital heart disease (n = 325, 15.2%), genetic diagnoses (n = 269, 12.5%) and cardiac arrhythmia (n = 176, 8.2%). Of 2144 neonates, 988 (46%) survived to hospital discharge and 775 (36%) died prior to discharge. Mortality rate was highly variable across diagnoses, ranging from 90% in infants with congenital diaphragmatic hernia to 0% in infants with atrial flutter. Over the study period, more infants were diagnosed with trisomies and fewer with twin-to-twin transfusion. Mortality decreased by 5% from 1997-2007 to 2008-2018. CONCLUSIONS: The risk of death among neonates with hydrops fetalis is highly dependent on the underlying cause, with increasing risk of mortality at lower gestational ages.

Nonlethal presentations of CYP26B1-related skeletal anomalies and multiple synostoses syndrome.

Retinoic acid exposures as well as defects in the retinoic acid-degrading enzyme CYP26B1 have teratogenic effects on both limb and craniofacial skeleton. An initial report of four individuals described a syndrome of fetal and infantile lethality with craniosynostosis and skeletal anomalies caused by homozygous pathogenic missense variants in CYP26B1. In contrast, a 22-year-old female was reported with a homozygous missense pathogenic variant in CYP26B1 with complex multisuture craniosynostosis and intellectual disability, suggesting that in some cases, biallelic pathogenic variants of CYP26B1 may be compatible with life. Here we describe four additional living individuals from two families with compound heterozygous pathogenic missense variants in CYP26B1. Structural assessment of these additional missense variants places them further from the catalytic site and supports a model consistent with milder nonlethal disease. In addition to previously reported findings of multisuture craniosynostosis, conductive hearing loss, joint contractures, long slender fingers, camptodactly, broad fingertips, and developmental delay/intellectual disability, skeletal imaging in our cases also revealed gracile long bones, gracile ribs, radioulnar synostosis, and carpal and/or tarsal fusions. These individuals broaden the phenotypic range of biallelic pathogenic variants in CYPB26B1 and most significantly clarify that mortality can range from perinatal lethality to survival into adulthood.

EP300-related Rubinstein-Taybi syndrome: Highlighted rare phenotypic findings and a genotype-phenotype meta-analysis of 74 patients.

Pathogenic variants in the homologous and highly conserved genes-CREBBP and EP300-are causal for Rubinstein-Taybi syndrome (RSTS). CREBBP and EP300 encode histone acetyltransferases (HAT) that act as transcriptional co-activators, and their haploinsufficiency causes the pathology characteristic of RSTS by interfering with global transcriptional regulation. Though generally a well-characterized syndrome, there is a clear phenotypic spectrum; rare associations have emerged with increasing diagnosis that is critical for comprehensive understanding of this rare syndrome. We present 12 unreported patients with RSTS found to have EP300 variants discovered through gene sequencing and chromosomal microarray. Our cohort highlights rare phenotypic features associated with EP300 variants, including imperforate anus, retained fetal finger pads, and spina bifida occulta. Our findings support the previously noted prevalence of pregnancy-related hypertension/preeclampsia seen with this disease. We additionally performed a meta-analysis on our newly reported 12 patients and 62 of the 90 previously reported patients. We demonstrated no statistically significant correlation between phenotype severity (within the domains of intellectual disability and major organ involvement, as defined in our Methods section) and variant location and type; this is in contrast to the conclusions of some smaller studies and highlights the importance of large patient cohorts in characterization of this rare disease.

Genetic variation associated with childhood and adult stature and risk of MYCN-amplified neuroblastoma.

BACKGROUND: Neuroblastoma is the most common pediatric solid tumor. MYCN-amplification is an important negative prognostic indicator and inherited genetic contributions to risk are incompletely understood. Genetic determinants of stature increase risk of several adult and childhood cancers, but have not been studied in neuroblastoma despite elevated neuroblastoma incidence in children with congenital overgrowth syndromes. METHODS: We investigated the association between genetic determinants of height and neuroblastoma risk in 1538 neuroblastoma cases, stratified by MYCN-amplification status, and compared to 3390 European-ancestry controls using polygenic scores for birth length (five variants), childhood height (six variants), and adult height (413 variants). We further examined the UK Biobank to evaluate the association of known neuroblastoma risk loci and stature. RESULTS: An increase in the polygenic score for childhood stature, corresponding to a ~0.5 cm increase in pre-pubertal height, was associated with greater risk of MYCN-amplified neuroblastoma (OR = 1.14, P = .047). An increase in the polygenic score for adult stature, corresponding to a ~1.7 cm increase in adult height attainment, was associated with decreased risk of MYCN-amplified neuroblastoma (OR = 0.87, P = .047). These associations persisted in case-case analyses comparing MYCN-amplified to MYCN-unamplified neuroblastoma. No polygenic height scores were associated with MYCN-unamplified neuroblastoma risk. Previously identified genome-wide association study hits for neuroblastoma (N = 10) were significantly enriched for association with both childhood (P = 4.0 × 10-3 ) and adult height (P = 8.9 × 10-3 ) in >250 000 UK Biobank study participants. CONCLUSIONS: Genetic propensity to taller childhood height and shorter adult height were associated with MYCN-amplified neuroblastoma risk, suggesting that biological pathways affecting growth trajectories and pubertal timing may contribute to MYCN-amplified neuroblastoma etiology.

Targeted Therapy for Pulmonary Hypertension in Premature Infants.

Pulmonary hypertension (PH) is common in premature infants with bronchopulmonary dysplasia (BPD) and is associated with significant mortality. Despite expert consensus suggesting the use of targeted therapies such as phosphodiesterase inhibitors, endothelin receptor antagonists, and prostanoids, there is little data on safety and outcomes in infants with BPD-associated PH (BPD-PH) treated with these medications. We sought to describe the pharmacologic management of BPD-PH and to report outcomes at our institution. Premature infants with BPD-PH born between 2005 and 2016 were included. Follow-up data were obtained through January 2020. A total of 101 patients (61 male, 40 female) were included. Of these, 99 (98.0%) patients were treated with sildenafil, 13 (12.9%) with bosentan, 35 (34.7%) with inhaled iloprost, 12 (11.9%) with intravenous epoprostenol, and nine (8.9%) with subcutaneous treprostinil. A total of 33 (32.7%) patients died during the study period and 10 (9.9%) were secondary to severe to pulmonary hypertension. Of the surviving patients, 57 (83.8%) had follow-up data at a median of 5.1 (range 0.38-12.65) years and 44 (77.2%) were weaned off PH medications at a median 2.0 (range 0-8) years. Mortality for BPD-PH remains high mostly due to co-morbid conditions. However, for those patients that survive to discharge, PH therapies can frequently be discontinued in the first few years of life.

Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities.

Nucleoporins (NUPs) are an essential component of the nuclear-pore complex, which regulates nucleocytoplasmic transport of macromolecules. Pathogenic variants in NUP genes have been linked to several inherited human diseases, including a number with progressive neurological degeneration. We present six affected individuals with bi-allelic truncating variants in NUP188 and strikingly similar phenotypes and clinical courses, representing a recognizable genetic syndrome; the individuals are from four unrelated families. Key clinical features include congenital cataracts, hypotonia, prenatal-onset ventriculomegaly, white-matter abnormalities, hypoplastic corpus callosum, congenital heart defects, and central hypoventilation. Characteristic dysmorphic features include small palpebral fissures, a wide nasal bridge and nose, micrognathia, and digital anomalies. All affected individuals died as a result of respiratory failure, and five of them died within the first year of life. Nuclear import of proteins was decreased in affected individuals' fibroblasts, supporting a possible disease mechanism. CRISPR-mediated knockout of NUP188 in Drosophila revealed motor deficits and seizure susceptibility, partially recapitulating the neurological phenotype seen in affected individuals. Removal of NUP188 also resulted in aberrant dendrite tiling, suggesting a potential role of NUP188 in dendritic development. Two of the NUP188 pathogenic variants are enriched in the Ashkenazi Jewish population in gnomAD, a finding we confirmed with a separate targeted population screen of an international sampling of 3,225 healthy Ashkenazi Jewish individuals. Taken together, our results implicate bi-allelic loss-of-function NUP188 variants in a recessive syndrome characterized by a distinct neurologic, ophthalmologic, and facial phenotype.

The Utility of Early Tongue Reduction Surgery for Macroglossia in Beckwith-Wiedemann Syndrome.

BACKGROUND: Macroglossia, a cardinal feature of the (epi)genetic disorder Beckwith-Wiedemann syndrome, is associated with obstructive sleep apnea, speech and/or feeding difficulties, and dental or jaw malalignment. These sequelae may be treated and/or prevented with tongue reduction surgery; the authors sought to determine whether certain Beckwith-Wiedemann syndrome patients may benefit from early surgical intervention before age 12 months. METHODS: The authors conducted a retrospective review of patients with Beckwith-Wiedemann syndrome who underwent tongue reduction from 2014 to 2019. The authors assessed primary outcomes of change in obstructive sleep apnea by polysomnography, respiratory support required, and feeding route before and after tongue reduction, and reviewed postoperative complications and the need for repeated tongue reduction. RESULTS: Of the 36 patients included, the median age at tongue reduction was 9.5 months (interquartile range, 3.8 to 22.8 months). For those with severe obstructive sleep apnea, there was a significant reduction in the obstructive apnea hypopnea index from 30.9 ± 21.8 per hour to 10.0 ± 18.3 per hour (p =0.019) and improvement in nadir oxyhemoglobin saturation from 72 ± 10 percent to 83 ± 6 percent (p =0.008). Although there was no significant change in overall supplemental feeding tube or respiratory support, there were specific patients who experienced clinically meaningful improvement. Of note, these positive outcomes applied equally to those who underwent surgery at a younger age (<12 months). To date, only one patient required a repeated tongue reduction. CONCLUSION: Based on improved polysomnographic findings and rarity of surgical complications or repeated surgery, the authors' data support the safety and efficacy of this early intervention when clinical indications are present and an experienced multidisciplinary team is available for consultation. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.