bluuebunny/crossref_metadata_2025_split huggingface dataset:
8151 The Genetic Etiology Is a Relevant Cause of Central Precocious Puberty
Authors: Machado Canton Ana Pinheiro , Seraphim Carlos Eduardo , Montenegro Luciana Ribeiro , Krepsichi Ana Cristina , Mendonca Berenice Bilharinho , Latronico Ana Claudia , Brito Vinicius Nahime 
Published: October 2024

Abstract
Disclosure: A.P. Canton: None. C.E. Seraphim: None. L.R. Montenegro: None. A. Krepsichi: None. B.B. Mendonca: None. A. Latronico: None. V.N. Brito: None.
Background: The etiology of central precocious puberty (CPP) has expanded with the identification of new genetic causes, including the monogenic deficiency of MKRN3 in familial cases. Objectives: To assess the prevalence of CPP causes and the predictors of genetic involvement in this phenotype. Methods: A single-center retrospective cohort study was performed for an etiological survey of patients with CPP. All patients had detailed medical history, deep phenotyping, and brain MRI. Patients with CPP and no pathological brain lesions, previously considered idiopathic forms, were submitted to genetic studies, mainly DNA sequencing studies, genomic microarray, and methylation analysis. Results: We assessed 270 patients (241 girls) with CPP; 50 (18.5%) patients had CPP-related brain lesions, whereas 220 (81.5%) patients had normal brain MRI. Of the latter, 174 (165 girls and 9 boys) were included for genetic studies. Genetic etiologies were identified in 22 patients (20 girls and 2 boys), indicating an overall frequency of genetic CPP of 12.6%, which was higher in boys (22.2%) than in girls (12.1%). The most common genetic defects were MKRN3, DLK1, and MECP2 loss-of-function mutations, followed by 14q32.2 imprinting defects (Temple syndrome). Univariate logistic regression identified positive family history (OR 3.3; 95%CI 1.3-8.3; p=0.01) and associated neurodevelopmental disorders (OR 4.1; 95%CI 1.3-13.5; p=0.02) as clinical predictors of genetic CPP. A novel algorithm for investigating the etiology of CPP was set up, including genetic studies guided by clinical parameters. Conclusion: Distinct genetic causes were identified in 12.6% of CPP patients previously classified as idiopathic, revealing the genetic etiology as a relevant cause of CPP in both sexes. Family history and neurodevelopmental disorders were identified as predictors of genetic CPP, recommending that both factors should be actively investigated in the CPP workup. A novel algorithm for investigating the etiology of CPP can be practice-changing for those who assist children with precocious puberty.
Presentation: 6/2/2024
8170 The Relationship Between SUOX Gene Mutation and Type 1 Diabetes
Authors: Green S , Ilaka-Chibuluzo S 
Published: October 2024

Abstract
Disclosure: S. Green: None. S. Ilaka-Chibuluzo: None.
Isolated Sulfite Oxidase Deficiency (ISOD) is a rare autosomal recessive inborn error of metabolism caused by a missense mutation in the SUOX gene (gene locus 12q13.2). The main sequalae of ISOD is neuro-cognitive developmental delay, microcephaly, muscle spasticity, chronic aspiration, severe scoliosis, and seizures. The sulfite oxidase enzyme catalyzes the final step of the breakdown of methionine and cysteine, sulfur-containing amino acids. Loss of function of SUOX gene causes increased production of reactive oxygen species, decreased activity of TCA cycle, and decreased ATP synthesis within the mitochondria. SUOX gene mutation has been found to be preliminarily linked to Type 1 Diabetes (T1D) through the loss of β cells through altered expression of macrophages and dendritic cells. However, there has not been in-depth analysis between this connection. OS is a seven-year-old male diagnosed with ISOD. He had an uncomplicated gestation and delivery and started having seizure activity of day of life one. The subsequent EEG showed abnormal background activity consistent with burst suppression, but no seizure activity. The MRI of his brain showed diffuse cerebral atrophy and basal ganglia ischemic injury. After numerous genetic screenings, he was found to have a SUOX mutation. During a recent hospitalization in 2023, he was found to have elevated pancreatic enzymes, hyperglycemia, and an elevated hemoglobin a1c, at which point he was diagnosed with T1D.
Presentation: 6/2/2024
6480 Variability in Breast Development in Response to Exogenous Estrogen in Girls
Authors: Kurman T M , Eugster E A 
Published: October 2024

Abstract
Disclosure: T.M. Kurman: None. E.A. Eugster: None.
Intro: Adolescents requiring treatment with exogenous estrogen (E2) include girls with primary and secondary hypogonadism and transfeminine youth. While 17B-estradiol is standard of care, the starting dose and escalation schedule are individualized. To what degree the response to E2 as assessed by breast Tanner stage is correlated with the dose is unknown. Similarly, whether the response to E2 varies depending on the underlying diagnosis has not been systematically analyzed. We aimed to investigate relationships between diagnosis, E2 dose, and breast Tanner staging in adolescent girls. Methods: We conducted a chart review of girls treated with E2 followed at our Pediatric Endocrine clinic between 2008-2022. Inclusion criteria included girls who were prepubertal at baseline and on a single increment of a 25 mcg E2 patch changed 2X/week from initiation of treatment to the first follow up visit. Only transgender girls being treated with a GnRH analog were included. Within each group of patients on the same starting dose, a Kruskal-Wallis test was conducted to evaluate differences in Tanner stage between diagnostic groups. Spearman’s correlation was used to evaluate the relationship between starting dose and Tanner stage. Finally, we evaluated differences within the Turner syndrome (TS) group for girls with monosomy X vs a mosaic karyotype. Results: Of 1,899 medical records, 70 eligible patients were identified. Of these, 33 (47.2%) had TS, 17 (24.3%) had primary ovarian insufficiency (POI), 15 (21.4%) had hypogonadotropic hypogonadism (HH), and 5 (7.1%) were transgender (TG). Twenty-three (32.9%) started on 1/4 patch (6.25 mcg), 29 (41.4%) on 1/2 patch (12.5 mcg) and 18 (25.7%) on a full patch (25 mcg). Girls on other regimens (e.g., 1/8 patch worn only at night) were excluded from analysis. The first f/u visit occurred at a median of 6 months (range 3-12 months). All TG girls were started on 25 mcg E2, which was significantly different compared to the other groups (p=0.002, p=0.005, and p=0.005 for TS, POI, and HH respectively). Breast Tanner stage at the first f/u visit ranged from 1-4 with no significant difference within each dose group based on diagnosis. However, a significant correlation between E2 dose and breast Tanner stage at f/u was seen in girls with HH (r=0.601, p=0.018). No effect of karyotype (monosomy X vs mosaic) on response to E2 in girls with TS was seen. Conclusion: There was striking variability in the starting dose of E2 in the vast majority of patients, highlighting the lack of standardization in clinical management. Interestingly, we found significant individual variability in terms of breast development in response to the initial dose of E2, regardless of diagnosis. Factors responsible for the unpredictable nature of the response to exogenous E2 are unexplored. Our findings provide important and novel prognostic information for patients and providers.
Presentation: 6/1/2024
7196 Variants in the Neurodevelopmental Gene BRINP2 are Associated with Severe Delayed Puberty
Authors: Al-Sayed Yasmin , Oleari Roberto , Cariboni Anna , He Wen , Chan Yee-ming , Howard Sasha R 
Published: October 2024

Abstract
Disclosure: Y. Al-Sayed: None. R. Oleari: None. A. Cariboni: None. W. He: None. Y. Chan: None. S.R. Howard: None.
Gonadotropin-releasing hormone (GnRH) is the master hormone regulating the reproductive axis and its pulsatile secretion is crucial for puberty onset and fertility. Disruption in GnRH neuron development or hypothalamic function can lead to absent or delayed puberty (DP) due to GnRH deficiency, with a phenotypic spectrum from severe delayed puberty to partial or complete Hypogonadotropic Hypogonadism (HH). HH can also be present as a shared trait with other neurodevelopmental disorders (NDDs). The aim of our study was to identify novel genetic etiology of severe DP by identifying variants in associated genes in our patient cohort; and ascertain the functional effects of identified variants of interest. Whole exome sequencing (WES) was performed on DNA samples from 180 probands with DP to identify potentially pathogenic rare coding variants in relevant gene pathways. Integrative analysis was performed on genomic data from human patients combined with transcriptomics analysis of rodent immortalized and primary GnRH neurons to determine novel regulators of GnRH neuronal development and function. Bone morphogenetic protein/retinoic acid inducible neural-specific 2 (BRINP2) was identified as a candidate gene of interest as it was found to be significantly upregulated during GnRH neuronal development in these single cell transcriptomics analyses. Mutations in this gene have been previously associated with NDDs such as autistic spectrum disorder (ASD). BRINP2 is localised to the olfactory bulb, a key site during GnRH neuron migration. Copy number variation in this gene is seen in multiple individuals from the Deciphering Developmental Disorders study with a phenotype including cryptorchidism and intellectual disability (https://www.deciphergenomics.org/gene/BRINP2/patient-overlap/cnvs). WES analysis identified four variants in BRINP2 (p.R726W, p.R649Q, p.I629V and p.D729N) in four unrelated probands with severely DP or partial HH, in combination with ASD or other NDD features. These four variants are all rare or ultra-rare and are predicted to be pathogenic by in silico tools including CADD, REVEL and SIFT. Protein expression of the four mutants was comparable to the reference protein. BRINP2 has been shown to inhibit neuronal cell proliferation by negative regulation of cell cycle transition and Brinp2 knockout mice show hyperactive behaviour representative of human attention-deficit hyperactivity disorder, but pubertal timing has not been assessed. Thus, BRINP2 is a novel candidate for GnRH deficiency with NDD and we have investigated the role of BRINP2 in GnRH biology via wildtype and mutant protein sub-cellular localization, as well as tissue expression in mouse hypothalamic tissue across development.
Presentation: 6/2/2024
7096 Variants in WASHC3, a component of the WASH complex, cause distinctive facial dysmorphism, short stature, and variable neurodevelopmental abnormalities
Authors: Jee Y , Lui J , Marafi D , Xia Z J , Bhatia R , Zhou E , Herman I , Temnycky A G , Whalen P , Elliot G , Leschek E , Wijngaard R , Beek R , Vreugd A , De Vries M , Karnebeek C , Oud M , Markello T , Barnes K , Alrohaif H , Freeze H H , Gahl W , Malicdan M , Posey J , Lupski J , Baron J 
Published: October 2024

Abstract
Disclosure: Y. Jee: None. J. Lui: None. D. Marafi: None. Z. Xia: None. R. Bhatia: None. E. Zhou: None. I. Herman: None. A.G. Temnycky: None. P. Whalen: None. G. Elliot: None. E. Leschek: None. R. Wijngaard: None. R. Beek: None. A. Vreugd: None. M. De Vries: None. C. Karnebeek: None. M. Oud: None. T. Markello: None. K. Barnes: None. H. Alrohaif: None. H.H. Freeze: None. W. Gahl: None. M. Malicdan: None. J. Posey: None. J. Lupski: None. J. Baron: None.
Genetic defects that impair growth plate chondrogenesis can result in a spectrum of phenotypes, ranging from skeletal dysplasia to mild short stature, sometimes accompanied by syndromic features. However, the genetic underpinnings of impaired skeletal growth often remain elusive. In our study, we investigated three unrelated families with short stature (height standard deviation score z &lt; -2), distinctive facies (down-slanting eyes, low set ears, high arched palate, and short neck), and various neurodevelopmental abnormalities (from leaning difficulties to low intelligence quotient). In these families, exome sequencing (ES) identified rare, predicted-pathogenic variant alleles in WASHC3 that segregated with the phenotype. WASHC3 is a component of the WASH complex, which is involved in endosome receptor recycling. In the first family, a de novo-dominant missense variant (p.L69F) impaired WASHC3 participation in the WASH complex. This variant led to altered PTH1R endosomal trafficking, resulting in diminished PTH1R signaling and impairing growth plate chondrocyte hypertrophic differentiation, providing a likely explanation for the short stature. Knockdown of other WASH complex components (WASH1, SWIP, Strumpellin) also diminished PTH1R signaling, confirming the importance of an intact WASH complex. In the second and third families, a homozygous variant in the start codon (p.M1?) markedly reduced WASHC3 protein expression by approximately 75%. In conclusion, our findings strongly suggest that the WASH complex is required for normal skeletal growth and that, consequently, genetic abnormalities impairing the function of the WASH complex (WASHopathy) cause short stature as well as distinctive facies and variable neurodevelopmental abnormalities. These effects are likely mediated through disruptions in endosomal receptor trafficking. This new pathological information sheds light on the molecular basis of impaired longitudinal bone growth.
Presentation: 6/3/2024
6369 Weiss-Kruszka Syndrome and Growth Hormone Deficiency, Adrenal Insufficiency, and Morbid Obesity
Authors: Falcon-Rodriguez Taimy , Solano Natalia , Diaz Alejandro 
Published: October 2024

Abstract
Disclosure: T. Falcon-Rodriguez: None. N. Solano: None. A. Diaz: None.
Background: Weiss-Kruszka syndrome (WKSA) is a rare autosomal dominant genetic disorder caused by heterozygous loss-of-function variants in the ZNF462 gene. Individuals affected by this condition exhibit distinctive craniofacial features, ptosis, dysgenesis of the corpus callosum, hearing loss, intellectual disability, and hypotonia. There is one other case report that described a boy with empty sella syndrome with growth hormone deficiency and delayed puberty. Case Presentation: We present the case of a 15-year-old boy who initially came under the care of endocrinology at age 9 due to severe obesity and short stature. Past medical history included ADHD (for which he was on stimulants since age 5), microcephaly, VUR, asthma, and developmental delay. He grew along the 2nd percentile for height from the ages of 6 and 13, after which his growth velocity notably decelerated. His initial bone age at 9 years old was advanced by 3 years. His BMI had exceeded the 99th percentile since age 3. His family history was relevant for maternal type 1 diabetes mellitus, paternal height of 165 cm, and maternal height of 160 cm. Upon physical examination, notable findings included short stature, severe obesity, a low anterior hairline, arched eyebrows, upslanted palpebral fissures, low-set ears, a tubular and short nasal bridge, and an exaggerated cupid's bow. At age 9, the patient was diagnosed with growth hormone (GH) deficiency following a clonidine and glucagon stimulation test, with a GH peak of 1.9 ng/mL (normal &gt;7 ng/mL). Additionally, he was diagnosed with adrenal insufficiency (cortisol peak of 5 ug/dL, after 250 mcg of cosyntropin). A brain/sella MRI revealed a hypoplastic pituitary gland. Subsequently, hydrocortisone replacement was initiated at a dose of 6 mg/m2/day, and GH treatment at a weekly dose of 0.3 mg/kg. Despite treatment with growth hormone and IGF-1 levels on the upper side of the normal range, his growth velocity did not improve significantly. He reached his peak adult height of 150 cm at age 15. His BMI had consistently been at the 99th percentile. According to his mother, he did not have issues with satiety, and his portion sizes were considered normal. He did not consume fast foods or sugary drinks, and his level of physical activity was suboptimal. Whole Exome Sequencing identified a heterozygous de novo pathogenic variant in the ZNF462 gene, specificallyc.2664 C&gt;A, p.(C888*) (NM_021224.4), consistent with the diagnosis of Weiss-Kruszka syndrome (OMIM # 618619). Conclusion: We present, to our knowledge, the first report of morbid obesity and central adrenal insufficiency in a child with WSKA. GH deficiency had been previously reported in 1 patient with WSKA. The finding of a hypoplastic pituitary gland supports the diagnosis of GH deficiency and central adrenal insufficiency.
Presentation: 6/3/2024
6987 Whole exome sequencing for permanent congenital hypothyroidism
Authors: Ahn J , Jeong H 
Published: October 2024

Abstract
Disclosure: J. Ahn: None. H. Jeong: None.
Background: Guidelines on congenital hypothyroidism (CH) recommend that genetic testing should aim to improve diagnosis, treatment or prognosis. Little information is available regarding the genetic heterogeneity of CH in Koreans. We aimed to investigate the genetic etiology of permanent CH to increase the genetic diagnosis rate and find associated diseases by whole exome sequencing (WES). Methods: A total of 32 patients with permanent CH were enrolled from Endocrinology Clinic at Jeju National University Hospital and Soonchunhyang University Cheonan Hospital. WES was performed on 3billion extracted through the patient's buccal swab. Variant classification is based on the guidelines presented by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP). Results: A total of 30 variants were identified in 20 patients. (62%). WES identified 22 variants in 6 genes (DUOX2, DUOXA2, TPO, PAX8, TG, TSHR). We detected 20 Pathogenic /Likely pathogenic of 5 genes in 15 patients (50%). The most frequently affected genes were DUOX2 (n = 10), TPO(n=4) DUOXA2 (n=3), TSHR(n=3)and PAX8 (n=2). 16 patients are monogenic and 4 patients have oligo-genic mutations. The test results of patients (n=6) with thyroid agenesis or ectopic thyroid gland were all negative. Conclusions: In patients with permanent congenital hypothyroidism, the mutation rate through the WES method is quite high. Genetic testing is useful for medication dose adjustment and genetic counseling through correlation of genotype and phenotype.
Presentation: 6/1/2024
6694 A Case of an Extraneous Organ: A Uterus Found in a Genotypic and Phenotypic Male
Authors: Zielinski Rachel A , Shteyman Sara , Samat Aashish G 
Published: October 2024

Abstract
Disclosure: R.A. Zielinski: None. S. Shteyman: None. A.G. Samat: None.
Background: Persistent Mullerian Duct Syndrome (PMDS) is a rare entity that occurs when a phenotypic male is found to have female reproductive organs. In our case we describe an XY male who was found to have an abdominal mass consistent with a uterus on pathology. Clinical Case: Our patient is a 58-year-old male with hypertension, obesity, and obstructive sleep apnea who presented to the ED with 3 weeks of left upper quadrant pain. Abdominal CT showed two homogeneous enhancing oval lesions in the pelvis superior to the urinary bladder; 8.3 x 4.6 cm on the right and 3.6 x 3 cm on the left. Exploratory laparotomy was performed, and intraoperatively the mass was firm with a left satellite lesion and two fibrous bands that appeared similar in structure to round ligaments. Microscopically the tissue contained mullerian-type epithelium and smooth muscle with cystic degeneration. It was CK7 positive, estrogen receptor variable positive, and CK20 negative. Genetic testing confirmed the patient’s karyotype to be XY without genetic mosaicism. Our patient had two children spontaneously, regular spontaneous erections, and occasional hot flashes. Physical exam revealed an obese male (BMI 51) with bilateral gynecomastia and normal testicular size. He had no history of intra-abdominal or undescended testes requiring surgery. Labs showed increased total estrogen (283.7 pg/mL, n 60-190 pg/mL) and estradiol (39 pg/mL, n &lt;= 29 pg/mL), decreased total testosterone (86 ng/dL, n 250-1,100 ng/dL), and normal free testosterone when corrected for SHBG (140 ng/dL, n 110-574 ng/dL). Testicular ultrasound was unrevealing. 3 years postoperatively his estradiol level normalized (34 pg/mL) and his total testosterone improved from 86 ng/dL to 223 ng/dL after losing 40 pounds on semaglutide. Discussion and Conclusion: Although the exact incidence of PMDS is unknown, it is a rare phenomenon. Only 200 cases between 1964 and 2000 and 34 cases between 2013 and 2017 have been reported. Mullerian ducts are embryologic structures present in both XY and XX fetuses until week 8 of life, when XY fetuses produce anti-mullerian hormone (AMH). In PMDS, the XY fetus either fails to produce AMH, or there is a defect in the AMH receptors, leading to the persistence of mullerian ducts. These ducts can then differentiate into a uterus, fallopian tubes, and/or the upper vagina. Our patient is a genotypical and phenotypical male with a uterus-like organ. The mild elevation in his estrogen level is likely secondary to his obesity. The estrogen could have increased the size of the uterus, causing the patient’s initial symptoms of abdominal pain which prompted his presentation to the hospital. References: Picard, Jean-Yves, et al. “The Persistent Müllerian Duct Syndrome: An Update Based UponPersonal Experience of 157 Cases.” Sexual Development, vol. 11, no. 3, 2017, pp. 109-125, https://doi.org/10.1159/000475516.
Presentation: 6/3/2024
8661 A case of post-menopausal female with virilization due to Sertoli-Leydig cell ovarian tumor recurring in contralateral ovary 8 years later
Authors: Maharaul M S , Miller J L 
Published: October 2024

Abstract
Disclosure: M.S. Maharaul: None. J.L. Miller: None.
Introduction: Sertoli-Leydig cell tumors (SLCTs) are rare androgen-secreting tumors of the ovaries, accounting for less than 0.5% of all ovarian tumors. Their incidence peaks in the second to third decade of life. New onset of severe hyperandrogenism with virilization in postmenopausal women is exceedingly rare, and the three most frequent causes are ovarian tumors, ovarian hyperthecosis and adrenal androgen producing tumors. We report one such case of ovarian androgen producing tumor which was further complicated by recurrence in the contralateral ovary. Case: A 66-year-old woman presented for evaluation of hyperandrogenism. Physical examination revealed evidence of virilization and clitoromegaly. Laboratory workup was remarkable for total serum testosterone level of 367 ng/dL with normal dehydroepiandrosterone sulfate and cortisol levels. A computerized scan of abdomen did not show any adrenal masses. Transvaginal ultrasound revealed uterine myomas but did not show any ovarian pathology. She underwent selective vein catheterization of her adrenal glands as well as ovaries and was noted to have right ovary secreting 3,982 ng/dL of testosterone whereas all other samples had total testosterone levels &lt; 200 ng/dL. She underwent right salpingo-oophorectomy. Histopathologic examination revealed a 2.2 cm well differentiated Sertoli-Leydig cell tumor confined to the ovary; the fallopian tube was negative for tumor. Six weeks later, her serum total testosterone level was 18 ng/dL. 8 years later, she returns with recurrent symptoms of hyperandrogenism. Repeat workup revealed a total testosterone level of 662 ng/dL. A computerized scan of abdomen and transvaginal ultrasound revealed an unremarkable uterus and left ovary. Magnetic resonance imaging of the pelvis was done that showed a 1.2 cm enhancing mass in the left ovary. She then underwent left salpingo-oophorectomy and supracervical hysterectomy. Histopathologic examination revealed a 1.5 cm Sertoli-Leydig-cell tumor of the left ovary, the fallopian tube was negative for tumor. Six weeks later, her serum total testosterone level was 24 ng/dL and she felt significant improvement in her symptoms. Conclusion: We present an interesting case of virilization in a post-menopausal female due to Sertoli-Leydig cell tumor that resolved after unilateral oophorectomy but recurred 8 years later in the contralateral ovary with resolution after completion oophorectomy.
Presentation: 6/2/2024