Miami Children's Hospital

ABSTRACT Objective Trofinetide is the first approved treatment for Rett syndrome (RTT) in the United States and Canada. Trofinetide improved the core symptoms of RTT in clinical trials, and real‐world evidence supports the findings of clinical trials. As RTT experts in the United States have now gained nearly 3 years of real‐world experience with trofinetide, a modified Delphi process was conducted in the United States to establish consensus recommendations for the practical use of trofinetide in the treatment of RTT. Methods A multidisciplinary steering group of five trofinetide‐experienced RTT experts practicing at an International Rett Syndrome Foundation (IRSF)‐designated center of excellence convened and developed 72 consensus statements across six domains: first‐line use, pre‐treatment assessment, initiation, benefit evaluation, tolerability management, and discontinuation strategies. The statements were then assigned a 4‐point Likert scale for testing via email by the Delphi panel identified by the steering group. Consensus was reached for individual statements if they met the pre‐specified consensus threshold of ≥ 75% agreement. Results Two rounds of assessments were completed by 25 respondents in each round, resulting in agreement ≥ 75% being reached across the final statement set. The consensus supports trofinetide as the standard of care for eligible patients with early initiation and an individualized approach to titration to maximize efficacy and tolerability. The panel reflected the steering group's view that trofinetide is efficacious. While side effects can emerge with trofinetide, they are manageable in most cases. Conclusions Recommendations highlight a flexible, patient‐centered approach to trofinetide use to optimize efficacy while addressing tolerability challenges and supporting adherence.

Abstract Disclosure: E. Silverstein: None. C. Eliazo: None. A. Diaz: None. Introduction: Classic congenital adrenal hyperplasia (CAH) is a rare condition affecting 1:16,000 newborns and is characterized by elevated testosterone levels from abnormal production of cortisol. Mutations of the CYP21A2 gene are the most common cause of CAH and can present as mild cases: non-classic/late onset CAH, or severe forms, as in classic CAH. Classic CAH can be simple virilizing or salt-wasting types, the latter, a life-threatening condition if not diagnosed soon after birth. In the U.S., screening for CAH is included on newborn screening; however, this evaluation is not often done in developing countries. Lack of early diagnosis and, in some cases surgical intervention, can be life threatening. Case report: We present the case of a 16-year-old girl born in rural Honduras and assigned as male at birth based on her male-appearing genitalia: a normal-sized and formed phallus with bilateral cryptorchidism. During infancy, this child had recurrent hospitalizations due to severe dehydration, hyponatremia, and hypotension. At 4-months of life, she was transferred to Tegucigalpa, the country's capital, and diagnosed with salt-wasting CAH. At that time, the family was asked to change her name and her gender to female, and she was started on hydrocortisone and fludrocortisone. The family moved to the U.S. when the child was 7 months old; and at that time, she was evaluated by endocrinology. A karyotype was reported as 46, XX and molecular analysis confirmed the diagnosis of CAH (Intron-2 deletions: homozygous in CYP21A2). Although legally the child appears as a male with a masculine name, the family raised her as a girl and socially changed her name. Due to non-typical gender behavior, a gender role evaluation was done by psychology at 8 years of age. However, due to learning difficulties, this evaluation was inconclusive; she identified as a girl, which matches her gender expression. Upon physical examination she has a Tanner V phallus with the urethral opening at the tip (Prader V) and bilateral cryptorchidism. She reached menarche at age 11 and has monthly bleeding through the urethra. She has been evaluated by urology and underwent cystourethroscopy and vaginogram, which showed bladder diverticula. She has had multiple urinary tract infections, some with septic shock, requiring PICU admissions. Due to lack of insurance, surgical repair is not possible. She receives prophylactic antibiotics with suboptimal compliance. Conclusion: Early CAH diagnosis is critical to prevent severe medical and social complications. While the timing of genital surgery in children with differences in sex development remains controversial, multidisciplinary evaluation is critical, especially for CAH patients, to minimize severe complications. Many adult patients report preferring genital surgery in early childhood. Unfortunately, lack of insurance coverage and surgical costs hinder access to care in the U.S. Presentation: Monday, July 14, 2025

Bone age (BA) assessment is an essential tool in pediatric endocrinology, used to assess growth and perturbations in pubertal onset. BA advancement is common in children with premature adrenarche (PA), potentially leading to additional evaluation or intervention. The extent to which BA advancement reflects variation in metabolic and demographic factors, including body mass index (BMI), sex, race, and ethnicity, remains insufficiently characterized. We conducted a retrospective chart review of 296 children (72% female, mean age 7.3 ± 1.6 years) with isolated PA seen at a tertiary pediatric endocrinology clinic. Absolute and standardized BA advancement were analyzed in relation to BMI, sex, race, and ethnicity. Multivariate linear regression adjusted for age and covariates. BA advancement was greater in children with obesity (19.2 ± 15.1 months) versus those below the 95th% (11.4 ± 13.5), and in males (19.9 ± 14.3) versus females (12.4 ± 14.3). White race was associated with lower advancement (p = 0.02). BMI (p < 0.0001), male sex (p < 0.0001), and Hispanic vs. White ethnicity (p = 0.023) significantly affected standardized BA advancement. BMI, sex, and race/ethnicity influence BA advancement in PA, supporting individualized interpretation and further study of clinical implications. Bone age (BA) advancement is an important consideration in the diagnostic workup of children with premature adrenarche. In this diverse cohort, BMI status, sex, race, and ethnicity were significantly associated with BA advancement, suggesting that both metabolic and demographic factors influence skeletal maturation. While BA advancement in obesity and premature adrenarche is recognized, this study underscores their combined effects and the variability across populations. These findings point to limitations in current BA standards and support the need for individualized interpretation. Further research should explore how BA advancement in obesity and across ethnic groups affects adult height and long-term outcomes.

Abstract Disclosure: M.F. Henriquez Abramuk: None. A. Diaz: None. A. Carrillo-Iregui: None. A. Vargas-Espana: None. G. Rivera Rodriguez: None. A. Granados: None. Background: Although the most common cause of virilization in the female fetus is congenital adrenal hyperplasia (CAH), which affects approximately 1 in 15,000 to 1 in 17,000 newborns (both males and females), other causes of virilization in the female fetus need to be evaluated. If maternal virilization during pregnancy is also documented, conditions such as pregnancy luteomas, aromatase deficiency, and Krukenberg tumors should be suspected. Case Report: A full-term female was unexpectedly found to have ambiguous genitalia, as prenatal testing reported a 46,XX fetus. Upon physical examination, she was noted to have clitoromegaly (phallus of 2.5 cm), fused labial folds, a urogenital opening at the base of the phallus, and no palpable gonads. A pelvic ultrasound reported a uterus. Karyotype analysis revealed 46,XX, and 17-Hydroxyprogesterone was 87 ng/dL. Genetic testing for Disorders of Sex Development (DSD) (Invitae: 53 genes) was negative including CYP19A1 and CYP11B1. Family history was significant for maternal virilization during pregnancy, including acne, facial hair, deepening of voice, and clitoromegaly, beginning in the first trimester. Ovarian masses were identified during pregnancy and were resected at the time of delivery. Pathology reported Signet Ring Cell Carcinoma (Krukenberg tumor), an ovarian metastasis of a primary gastrointestinal tumor. Conclusion: This case underscores the importance of a complete clinical history in any virilized girl. When maternal virilization during pregnancy is identified, conditions such as Krukenberg tumors should be included in the differential diagnosis. This is particularly important since approximately 20% of newborns with congenital adrenal hyperplasia may be missed by newborn screening. Presentation: Monday, July 14, 2025

Abstract Disclosure: J. Limonta: None. G. Rivera Rodriguez: None. A. Diaz: None. C. Bustamante Escobar: None. A. Carrillo: None. A. Granados: None. This case highlights a rare presentation of a newborn with two genetic mutations affecting bone/calcium metabolism: CASR and KIF22, leading to complex metabolic and skeletal anomalies. The CASR mutation, associated with hyperparathyroidism and the KIF22 mutation associated with skeletal dysplasia and fractures. A newborn female was admitted to the NICU for respiratory distress, mild hypercalcemia and skeletal abnormalities. She was full term and developed respiratory distress requiring CPAP. She received feedings via an oro-gastric tube. Initial labs revealed a ionized calcium of 1.36 mmol/L, total calcium 11.8 mg/dL, phosphorus 4.3 mg/dl, iPTH 727 pg/mL, alkaline phosphatase (AP) 828 IU/L, 25 OH vitamin D of 41 ng/mL, and urinary Ca/Cr ratio 0.3 (neonate ref range 0.9-2.2). Imaging revealed diffuse osteopenia with skeletal abnormalities, including a bell-shaped thorax, gracile ribs, irregular costochondral junctions, periosteal reactions, and dysplastic versus healing non-displaced fractures. Brain CT showed wide cranial sutures without fractures. Patient was started on low calcium formula (Calcilo). Genetic testing reported a mutation in the gene CASR with the variant c.652 T&amp;gt;C p. (Y218H), heterozygous, classified as likely a pathogenic variant and KIF22 with the variant c.707 C&amp;gt;T p. (A236V), heterozygous, classified as a variant of unknown significance. Calcium improved to 9.6 mg/dl but iPTH and ALP continued to rise (1180 pg/ml and 1345 IU/L respectively). The patient was started on cinacalcet with the purpose of decreasing the iPTH, considering the severity of the bone findings. Despite treatment, she continued with persistent hyperparathyroidism (iPTH 1,546 pg/mL) and markedly elevated ALP (1,562 IU/L). Vi) and improved calcium of 8.9mg/dl. Upon follow up, her levels of 25 OH vitamin D were borderline low (/mL) and she was started on vitamin D3 400 IU daily. Patient required phosphorus replacement for a short period of time due to mild hypophosphatemia and high iPTH (phosphorus of 3.2 mg/dl). She was weaned from the oxygen and a gastric tube was placed due to feeding difficulties. Laboratory evaluations done prior to discharge showed a normal total calcium of 9.6 mg/dL, elevated iCal 1.36 mmol/L, iPTH 21.2, and phosphorus 4.4 mg/dl. The infant was discharged home on a low calcium formula, cinacalcet 4 mg PO BID, and vitamin D3 400 IU daily. The skeletal abnormalities observed, including fractures and osteopenia, was a consequence of the KIF22 mutation. Hypocalciuric hypercalcemia was secondary by the CASR mutations. The significant elevation of iPTH and ALP are likely secondary to the influence of these two mutations, since in isolation, no one is expected to produce these findings. This case illustrates how these two mutations resulted in a specific and unique clinical scenario. A deep understanding of the pathophysiology was essential to navigate this case. Presentation: Saturday, July 12, 2025

Pediatric finger fractures are among the most common injuries of the hand. Although most can be treated nonsurgically with good results, a small subset benefits from intervention. The purpose of this review was to provide an update on potentially problematic pediatric phalanx fractures. We will review common finger fractures unique to pediatric patients, classifications, surgical indications, and treatment options for chronic presentations.