FOXP1 syndrome is a neurodevelopmental disorder caused by mutations or deletions that disrupt the forkhead box protein 1 (FOXP1) gene, which encodes a transcription factor important for the early development of many organ systems, including the brain. Numerous clinical studies have elucidated the role of FOXP1 in neurodevelopment and have characterized a phenotype. FOXP1 syndrome is associated with intellectual disability, language deficits, autism spectrum disorder, hypotonia, and congenital anomalies, including mild dysmorphic features, and brain, cardiac, and urogenital abnormalities. Here, we present a review of human studies summarizing the clinical features of individuals with FOXP1 syndrome and enlist a multidisciplinary group of clinicians (pediatrics, genetics, psychiatry, neurology, cardiology, endocrinology, nephrology, and psychology) to provide recommendations for the assessment of FOXP1 syndrome.
Objectives. To evaluate the effect of pneumococcal conjugate vaccine (PCV13) on the burden of acute otitis media (AOM) and to evaluate the characteristics of AOM versus otitis media with effusion (OME) in the 2 PCV periods. Methods. A cohort of fully vaccinated children aged 18 to 60 months diagnosed with AOM from 2006 to 2015 was identified. Patients with otorrhea/bulging tympanic membrane were considered as true AOM, while those without bulging/otorrhea were considered to have OME. Burden of true AOM in the PCV7 and PCV13 periods and clinical features of true AOM versus OME were compared. Results. Of 393 episodes in our cohort, 50.8% occurred in PCV7 period. Burden of true AOM in the 2 PCV groups was similar: 26% in PCV7 versus 26.4% in PCV13 (odds ratio [OR] = 1.02, 95% confidence interval [CI] = 0.65-1.60). Factors significantly associated with OME were cold season (OR = 1.54, 95% CI = 1.04-2.4), fever (OR = 2.05, 95% CI = 1.29-3.3), and recurrence (OR = 2.24, 95% CI = 1.22-4.09). No complications of AOM were identified. Majority episodes were treated with antibiotics. Conclusion. Unlike the role of PCV13 in reducing invasive pneumococcal disease, its effect on reducing the burden of AOM is minimal as compared with PCV7. With regard to characteristics of AOM versus OME, findings of tympanic membrane should be used to suggest a diagnosis of AOM, instead of occurrence of fever or recurrence of AOM episodes. Using this approach would help in guiding the use of antibiotics appropriately.
Purpose of reviewThe present review summarizes recent advances in the diagnosis and management of patients with X-linked adrenoleukodystrophy (ALD).Recent findingsAlthough ALD screening has been on the list of Recommended Uniform Screening Panel since 2016, only 30 states in the United States are currently testing their newborns for this disease. Hematopoietic stem cell transplant (HSCT) remains the only successful treatment option available for early cerebral ALD but does not reverse neurological changes or affect the course of adrenal insufficiency. There remains a significant knowledge gap in our understanding and treatment of this disease. Novel therapies such as gene therapy and gene editing have shown promising results in animal models and are exciting potential treatment options for the future.Recently, the American Academy of Neurologists released their consensus guidelines on the diagnosis, surveillance, and management of ALD.SummaryEarly diagnosis and HSCT are key to improving the morbidity and mortality associated with ALD. The implementation of universal newborn screening for ALD and rigorous investigations of novel diagnostic and therapeutic agents is the need of the hour.
Background Phelan–McDermid syndrome (PMS) is caused by 22q13 deletions including SHANK3 or pathogenic sequence variants in SHANK3 and is among the more common rare genetic findings in autism spectrum disorder (ASD). SHANK3 is critical for synaptic function, and preclinical and clinical studies suggest that insulin-like growth factor-1 (IGF-1) can reverse a range of deficits in PMS. IGF-1 release is stimulated by growth hormone secretion from the anterior pituitary gland, and this study sought to assess the feasibility of increasing IGF-1 levels through recombinant human growth hormone (rhGH) treatment, in addition to establishing safety and exploring efficacy of rhGH in children with PMS. Methods rhGH was administered once daily for 12 weeks to six children with PMS using an open-label design. IGF-1 levels, safety, and efficacy assessments were measured every 4 weeks throughout the study. Results rhGH administration increased levels of IGF-1 by at least 2 standard deviations and was well tolerated without serious adverse events. rhGH treatment was also associated with clinical improvement in social withdrawal, hyperactivity, and sensory symptoms. Limitations Results should be interpreted with caution given the small sample size and lack of a placebo control. Conclusions Overall, findings are promising and indicate the need for larger studies with rhGH in PMS. Trial registration NCT04003207. Registered July 1, 2019, https://clinicaltrials.gov/ct2/show/NCT04003207.
Background The spectrum of disorders associated with hyperinsulinemic hypoglycemia (HHI) has vastly increased over the past 20 years with identification of molecular, metabolic and cellular pathways involved in the regulation of insulin secretion and its actions. Hereditary tyrosinemia (HT1) is a rare metabolic disorder associated with accumulation of toxic metabolites of the tyrosine pathway due to a genetically mediated enzyme defect of fumarylacetoacetate hydrolase. Transient tyrosinemia of the newborn (TTN) is a benign condition with a maturational defect of the enzymes associated with tyrosine metabolism without any genetic abnormalities. Results We describe two rare cases of HHI, one in a patient with HT1 and for the first time, in a patient with TTN. Each of our patients presented in the neonatal period with persistent hypoglycemia that on biochemical evaluation was consistent with HHI. Each patient received diazoxide therapy for 3.5 months and 17 months of life, respectively and HHI resolved thereafter. Conclusion Despite the fact that HHI has been described in HT1 for several decades, no specific mechanism has been delineated. Although we considered the common embryonal origin of the liver and pancreas with the hepatotoxic effect in HT1 also impacting the latter, this was not a possible explanation for TTN. The commonality between our two patients is the accumulation of certain amino acids which are known to be insulinotropic. We therefore hypothesize that the excess of amino acids such as leucine, lysine, valine and isoleucine in our patients resulted in HHI, which was transient. Both patients responded to diazoxide. This novel presentation in TTN and the reassuring response in both HT1 and TTN to diazoxide will be useful to inform physicians about managing HHI in these patients. Further studies are required to delineate the mechanism of HHI in these infants.
Context Males with adrenoleukodystrophy (ALD) have an 80% lifetime risk of developing adrenal insufficiency (AI), which can be life-threatening when undetected. Newborn screening (NBS) for ALD has been implemented in 29 states, yet the impact of NBS upon clinical management has not been reported. Objective To investigate whether the implementation of NBS has altered the time to diagnosis of AI in children with ALD. Design We conducted a retrospective medical chart review of pediatric patients with ALD. Setting All patients were seen in a leukodystrophy clinic in an academic medical center. Patients We included all pediatric patients with ALD who were seen between May 2006 and January 2022. We identified 116 patients (94% boys). Main Outcome Measures We extracted information about ALD diagnosis in all patients and AI surveillance, diagnosis, and treatment in boys with ALD. Results Thirty-one (27%) patients were diagnosed with ALD by NBS and 85 (73%) were diagnosed outside the newborn period. The prevalence of AI among boys in our patient population was 74%. AI diagnosis was made significantly earlier in boys diagnosed with ALD by NBS than in boys diagnosed outside the newborn period (median [IQR] age of diagnosis = 6.7 [3.9,12.12] months vs 6.05 [3.74,8.35] years) (p<0.001). When maintenance dose of glucocorticoids were initiated, there were significant differences in ACTH and peak cortisol levels in patients diagnosed by NBS and outside the newborn period. Conclusions Our results suggest that implementing NBS for ALD leads to significantly earlier detection of AI and earlier initiation of glucocorticoid supplementation in boys affected by ALD.
Background Antifungals act on fungal sterols structurally similar to human cholesterol. Ketoconazole reversibly suppresses steroidogenesis by inhibiting cytochrome P450 enzymes and interferes with dihydrotestosterone (DHT) activity by binding to the androgen receptor. Hypospadias was reported in infants exposed to nystatin in utero. Case presentation A male infant exposed to antepartum nystatin presented with severe under-undervirilization and transient adrenal corticosteroid abnormalities. He was born in USA at 31 weeks gestation to a mother treated with vaginal Polygynax capsules (nystatin-100,000 international units, neomycin sulphate-35,000 international units and polymyxin B-35,000 international units) for vaginal discharge in the Ivory Coast. She used approximately 60 capsules between the first trimester until delivery. The infant was born with micropenis, chordee, perineo-scrotal hypospadias and bifid scrotum with bilaterally palpable gonads. The karyotype was 46,XY. No Mullerian structures were seen on ultrasound. Serum 17-hydroxyprogesterone (17 OHP) on newborn screening was high (304 ng/ml, normal < 35). Cortisol response to cosyntropin on the 3rd day of life (DOL) was 10 mcg/ml; the subnormal cortisol response may have resulted from prematurity and the predelivery treatment with betamethasone. The elevation of several adrenal corticosteroids was not consistent with any specific enzymatic defect. Hydrocortisone and fludrocortisone were initiated at another hospital for suspected mild glucocorticoid and mineralocorticoid deficiencies. Genetic screening for adrenal and gonadal developmental defects performed when transferred to our care were normal. All medications were gradually discontinued over 5–8 months. Adrenal and testicular responses to cosyntropin and human chorionic gonadotropin (hCG) were normal at 8 months. Conclusions We report severe undervirilization in a 46,XY infant born to a mother treated with prolonged and high dose nystatin during pregnancy. This presentation suggests that prolonged antepartum use of high dose nystatin could lead to severe but transient defects in androgen synthesis and/or action possibly by acting as an endocrine disruptor. Further studies are warranted to confirm this finding. Thus, endocrine disruptors should be considered in male newborns with atypical genitalia not explained by common pathologies.
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