Images: Atypical presentation of congenital central hypoventilation syndrome in an infant with central and obstructive sleep apnea.

Congenital central hypoventilation syndrome (CCHS), a rare disease caused by paired-like homeobox 2B variants, affects control of breathing. We report on a 21-month-old boy with CCHS caused by a novel nonpolyalanine repeat mutation, neuroblastoma, severe obstructive and central sleep apnea, and sleep-related hypoxemia without hypoventilation. At 10 months, due to persistent central sleep apnea during serial polysomnography, bilevel positive airway pressure therapy was initiated despite the absence of hypoventilation. Nonpolyalanine repeat mutations are associated with severe phenotypes requiring continuous assisted ventilation, Hirschsprung's disease, and neural crest tumors; however, our patient had a relatively milder respiratory phenotype requiring sleep-only assisted ventilation without tracheostomy. Although alveolar hypoventilation is the hallmark of CCHS, our patient lacked hypoventilation. Bilevel positive airway pressure could be considered in some infants with CCHS requiring sleep-only assisted ventilation for tracheostomy avoidance. Our case demonstrates the expanding phenotypic spectrum in CCHS and the importance of formulating an individualized care plan. CITATION: Fain ME, Raghunandan S, Pencheva B, Leu RM, Kasi AS. Images: atypical presentation of congenital central hypoventilation syndrome in an infant with central and obstructive sleep apnea. J Clin Sleep Med. 2024;20(3):478-481.

Congenital Central Hypoventilation Syndrome: Diagnosis and Long-Term Ventilatory Outcomes.

Background: Congenital central hypoventilation syndrome (CCHS), a rare disease caused by variants in the paired-like homeobox 2B (PHOX2B) gene, affects regulation of respiration necessitating lifelong assisted ventilation (AV). Most patients require full-time AV during infancy and some patients may sustain adequate spontaneous ventilation during wakefulness and change AV modalities at a later age. The aims of this study were to assess the changes in duration and modalities of AV, long-term respiratory outcomes, and to correlate them with PHOX2B genotypes. Methods: We conducted a retrospective study of patients with CCHS treated at our institution between January 1997 and May 2022. Results analyzed included: clinical presentation, PHOX2B genotype, modality and duration of AV at diagnosis and follow-up, survival, and transition to adult care. Results: We identified 30 patients with CCHS-8 with PHOX2B nonpolyalanine repeat mutations (NPARMs), 21 with polyalanine repeat mutations (PARMs), and 1 with unknown PHOX2B genotype. The median age at presentation was 0.25 months (IQR 0.1-0.7 months). At diagnosis of CCHS, 24 (80%) patients required continuous AV and 28 (93%) received AV via tracheostomy. Twenty-six patients required sleep-only AV at a median age of 9 months (IQR 6-14 months). Nine patients requiring sleep-only AV underwent tracheostomy decannulation at a median age of 11.2 years (IQR 5.9-15.7 years) and used noninvasive positive pressure ventilation or diaphragm pacing. There was insufficient evidence to conclude that patients with PARMs and NPARMs differed by age at presentation (P = .39), tracheostomy (P = .06), and transition to sleep-only AV (P = .9). Six patients transitioned to adult care, 23 continued receiving pediatric care, and 1 patient died due to complications from Hirschsprung's disease. Conclusion: Our study demonstrates prolonged survival and good long-term respiratory outcomes possibly related to the early diagnosis of CCHS, optimizing AV strategies, and multidisciplinary care. The increasing number of patients attaining adulthood highlights the necessity for multidisciplinary care for adults with CCHS.

Inactive Matrix Gla Protein, Arterial Stiffness, and Endothelial Function in African American Hemodialysis Patients.

BACKGROUND: Matrix Gla protein (MGP) is a vascular calcification inhibitor dependent upon vitamin K for activation. Evidence suggests that elevated plasma inactive MGP levels (desphospho-uncarboxylated MGP, dp-ucMGP; indicating poorer vascular vitamin K status) are associated with greater cardiovascular disease (CVD) risk. Despite African Americans experiencing highest rates of kidney failure and CVD events, relationships between dp-ucMGP and CVD risk markers have not been examined in this population. We investigated vascular vitamin K status (via plasma dp-ucMGP) between African American hemodialysis (HD) patients and healthy controls, and the associations of dp-ucMGP with arterial stiffness and endothelial function in HD patients only. METHODS: In 37 African American HD patients and 37 age- and race-matched controls, plasma dp-ucMGP was measured by enzyme immunoassay as a marker of vascular vitamin K status. Carotid-femoral pulse wave velocity (PWV; arterial stiffness measurement) and brachial artery flow-mediated dilation (FMD; endothelial function measurement) were assessed by applanation tonometry and ultrasound, respectively, in HD patients only. RESULTS: Mean dp-ucMGP levels were 5.6 times higher in HD patients vs. controls (2,139 ± 1,102 vs. 382 ± 181 pmol/l, P < 0.01). Multiple linear regression, adjusting for age, sex, dialysis vintage, diabetes mellitus, CVD history, body mass index, and blood pressure, revealed that dp-ucMGP was independently related to PWV (standardized ß = 0.49) and FMD (standardized ß = -0.53) (both P < 0.01). CONCLUSIONS: Our data suggest that the higher plasma dp-ucMGP concentrations found in African American HD patients may be associated with greater arterial stiffness and endothelial dysfunction.

Phylloquinone Intake Is Associated with Cardiac Structure and Function in Adolescents.

BACKGROUND: Associations between childhood vitamin K consumption and cardiac structure and function have not been investigated. OBJECTIVE: We determined associations between phylloquinone (vitamin K-1) intake and left ventricular (LV) structure and function in adolescents. METHODS: We assessed diet with three to seven 24-h recalls and physical activity (PA) by accelerometry in 766 adolescents (aged 14-18 y, 50% female, 49% black). Fat-free soft tissue (FFST) mass and fat mass were measured by dual-energy X-ray absorptiometry. LV structure [LV mass (g)/height (m)2.7 (LV mass index) and relative wall thickness] and function [midwall fractional shortening (MFS) and ejection fraction] were assessed by echocardiography. Associations were evaluated by comparing the LV structure and function variables across tertiles of phylloquinone intake. Prevalence and OR of LV hypertrophy (LV mass index >95th percentile for age and sex) were also assessed by phylloquinone tertiles. RESULTS: The prevalence of LV hypertrophy progressively decreased across tertiles of phylloquinone intake (P-trend < 0.01). Multinomial logistic regression-adjusting for age, sex, race, Tanner stage, systolic blood pressure, FFST mass, fat mass, socioeconomic status, PA, and intakes of energy, fiber, calcium, vitamin C, vitamin D, and sodium-revealed that compared with the highest phylloquinone intake tertile (reference group), the adjusted OR for LV hypertrophy was 3.3 (95% CI: 1.2, 7.4) for those in the lowest phylloquinone intake tertile. When LV structure variables were compared across phylloquinone intake tertiles adjusting for the same covariates, there were significant linear downward trends for LV mass index (6.5% difference, tertile 1 compared with tertile 3) and relative wall thickness (9.2% difference, tertile 1 compared with tertile 3; both P-trend ≤ 0.02). Conversely, significant linear upward trends across phylloquinone intake tertiles were observed for MFS (3.4% difference, tertile 1 compared with tertile 3) and ejection fraction (2.6% difference, tertile 1 compared with tertile 3; both P-trend < 0.04). CONCLUSION: Our adolescent data suggest that subclinical cardiac structure and function variables are most favorable at higher phylloquinone intakes.

Nonlinear Relationship between Birth Weight and Visceral Fat in Adolescents.

OBJECTIVE: To determine the association of birth weight with abdominal fat distribution and markers known to increase risk for cardiovascular disease and type 2 diabetes in adolescents. STUDY DESIGN: In 575 adolescents aged 14-18 years (52% female, 46% black), birth weight was obtained by parental recall. Fasting blood samples were measured for glucose, insulin, lipids, adiponectin, leptin, and C-reactive protein. Subcutaneous abdominal adipose tissue and visceral adipose tissue were assessed by magnetic resonance imaging. RESULTS: When we compared markers of cardiometabolic risk across tertiles of birth weight, adjusting for age, sex, race, Tanner stage, physical activity, socioeconomic status, and body mass index, there were significant U-shaped trends for homeostasis model assessment of insulin resistance, leptin, and visceral adipose tissue (all Pquadratic < .05). A significant linear downward trend across tertiles of birth weight was observed for triglycerides (Plinear = .03). There were no differences in fasting glucose, blood pressure, total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, adiponectin, C-reactive protein, or subcutaneous abdominal adipose tissue across tertiles of birth weight. CONCLUSIONS: Our data suggest that both low and high birth weights are associated with greater visceral adiposity and biomarkers implicated in insulin resistance and inflammation in adolescents.