scholarly journals SAT-227 Long-Term Outcomes of Two Siblings with X-Linked Congenital Adrenal Hypoplasia Due to a Mutation in NR0B1 (DAX1) Gene: Reproductive and Neuropsychiatric Aspects

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Hugo Valente do Couto Pereira ◽  
Carlos Eduardo Seraphim ◽  
Sorahia Domenice ◽  
Klevia Nunes Feitosa ◽  
Flávia Rezende Tinano ◽  
...  
Keyword(s):  
Cyproterone Acetate ◽  
Pubertal Development ◽  
Genetic Defect ◽  
Snp Array ◽  
Bone Age ◽  
Autism Spectrum ◽  
Testosterone Levels ◽  
Congenital Adrenal Hypoplasia ◽  
Adrenal Hypoplasia

Abstract Background: X-linked congenital adrenal hypoplasia (CAH) is a rare disease caused by mutations in the NR0B1 (DAX-1) gene. Non-classical manifestations have been described, including late-onset adrenal insufficiency (AI) and gonadotropin-independent precocious puberty (GIPP). We report long-term endocrine and neuropsychiatric outcomes of two siblings with CAH due to mutation in NR0B1.Case report: A 2-yr-old boy was referred due to progressive clinical signs of puberty since 6 months of age. At the age of 3 yr, AI was diagnosed, and the molecular analysis revealed a mutation in the NR0B1 (p.Cys65Leufs*6). Glucocorticoid replacement resulted in reduced testicular volume and decreased testosterone levels. At 11 yr, cyproterone acetate was indicated due to pubertal progression and bone age advancement. At 17 yr the patient had incomplete sexual development and no pubarche. Testosterone levels declined, despite pubertal levels of basal and GnRH-stimulated gonadotropin levels, indicating partial hypogonadotropic hypogonadism. Adult height was 156 cm (SDS: -2.7) within his target height of 161 cm (SDS: -2.1). This patient also presented a psychiatric diagnosis of mood disorder and attention-deficit/hyperactivity disorder (ADHD), and was under methylphenidate, topiramate and sertraline. Both the patient and his mother had SNP array performed, which excluded contiguous gene syndrome. His younger brother also harbored the same mutation in the NR0B1, confirmed shortly after birth. AI was diagnosed with 1 month of age. Cortisone acetate and fludrocortisone were initiated. At 11 months of age, he presented signs of pubertal development with an elevated ACTH and testosterone levels with suppressed gonadotropins, confirming the diagnosis of GIPP. He was treated with cyproterone acetate. At 8 yr, a pubertal response to the GnRH test was detected, and leuprorelin was added. At 9 yr, due to the low growth velocity and advanced bone age, rhGH was started. However, this patient presented a poor compliance and severe obesity (BMI 33 kg/m2). Treatment for GIPP and secondary CPP was stopped at 10 yr, with bone age of 13.5 yr and height of 151 cm (SDS: - 2.3). The diagnosis of ADHD and autism spectrum disorder was made after neuropsychiatric assessment and the patient received treatment with methylphenidate and sertraline. Conclusion: Pubertal development of patients with CAH due to NR0B1 mutations can be heterogeneous. However, the intriguing neuropsychiatric features in two siblings may suggest a role of NR0B1 in neuropsychological development or other still unknown underlying genetic defect.

scholarly journals Serum Insulin-Like Factor 3 Levels during Puberty in Healthy Boys and Boys with Klinefelter Syndrome

2006 ◽  
Vol 91 (11) ◽  
pp. 4705-4708 ◽  
Author(s):  
Anne M. Wikström ◽  
Katrine Bay ◽  
Matti Hero ◽  
Anna-Maria Andersson ◽  
Leo Dunkel
Keyword(s):  
Aromatase Inhibitor ◽  
Leydig Cell ◽  
Klinefelter Syndrome ◽  
Pubertal Development ◽  
Bone Age ◽  
University Hospital ◽  
Initial Increase ◽  
Prospective Clinical Study ◽  
Testosterone Levels ◽  
Cell Dysfunction

Abstract Context: Levels of the Leydig cell-specific hormone insulin-like factor 3 (INSL3) are incompletely characterized in boys during pubertal development. Objective: The objective of the study was to characterize changes in INSL3 levels during spontaneous puberty in healthy boys, boys with aromatase inhibitor-induced hypergonadotropic hyperandrogenism, and boys with Leydig cell dysfunction. Design: This was a prospective clinical study. Setting: The study was conducted at a university hospital pediatric endocrinology outpatient clinic. Patients: Patients included 30 healthy boys with idiopathic short stature (ISS) aged 9.0–14.5 yr and 14 boys with Klinefelter syndrome (KS) aged 10–13.9 yr. Intervention: In ISS boys, intervention included aromatase inhibitor letrozole or placebo for 24 months. Main Outcome Measures: Serum INSL3 levels in relation to bone age, Tanner pubertal stages, and LH and testosterone levels were measured. Results: Onset of puberty was associated with a significant increase in INSL3 levels from 0.06 ± 0.01 ng/ml at Tanner G1 to 0.32 ± 0.16 ng/ml at G2 (P < 0.0001). Adult INSL3 levels (≥0.55 ng/ml) were attained at bone age 13–14 yr. ISS boys with letrozole-induced hypergonadotropic hyperandrogenism had, after 12 months of therapy, higher INSL3 levels than did placebo treated (0.85 ± 0.54 vs. 0.26 ± 0.17 ng/ml, P < 0.01). In KS boys during spontaneous puberty, after an initial increase similar to that in healthy boys, INSL3 concentrations leveled off despite hyperstimulation by LH. Positive correlations occurred between serum INSL3 and LH and between INSL3 and testosterone levels in all three groups (P < 0.0001). Conclusions: In boys, the Leydig cell-specific hormone INSL3 may serve as a new marker for onset and progression of puberty. Pubertal increase in INSL3 levels seems to depend on LH. In KS subjects, INSL3 concentrations indicate Leydig cell dysfunction from midpuberty onward.

scholarly journals A novel severe N-terminal splice site KISS1R gene mutation causes hypogonadotropic hypogonadism but enables a normal development of neonatal external genitalia

2012 ◽  
Vol 167 (2) ◽  
pp. 209-216 ◽  
Author(s):  
Oded Breuer ◽  
Maha Abdulhadi-Atwan ◽  
Sharon Zeligson ◽  
Hila Fridman ◽  
Paul Renbaum ◽  
...  
Keyword(s):  
Splice Site ◽  
Pubertal Development ◽  
Hypogonadotropic Hypogonadism ◽  
Genetic Defect ◽  
Snp Array ◽  
Premature Stop Codon ◽  
External Genitalia ◽  
Response To Therapy ◽  
Human Menopausal Gonadotropin ◽  
Exon 2

BackgroundKisspeptin 1 receptor (KISS1R) gene mutations are rare but have recently become an important etiology of normosmic isolated hypogonadotropic hypogonadism (IHH).ObjectivesTo characterize the genetic defect, the phenotype, and response to therapy of three IHH siblings with a novel severe KISS1R mutation.Patients and methodsThree siblings (16- and 22-year-old sisters and their 20-year-old brother) born to consanguineous parents with normal neonatal external genitalia presented with no pubertal development, normosmia, and a low response to GNRH stimulation. Homozygosity mapping, KISS1R gene sequencing, and RNA expression were performed.ResultsThe females' basal low estradiol level (50 pmol/l) failed to rise in response to human chorionic gonadotropin (hCG). The brother's low testosterone (1.87 nmol/l) responded to combined hCG and human menopausal gonadotropin (hCG) and HMG therapies, but the testes remained small (1–2 ml). Secondary sexual characteristics were attained by exogenous sex steroid replacement. SNP array studies revealed shared homozygosity for a chromosome 19 region encompassing KISS1R. Sequencing revealed a novel homozygous KISS1R mutation at the nt-1 canonical acceptor splice site of intron 1 in affected siblings. The mother (menarche at 14 years) was heterozygous. cDNA sequencing showed that the G>A mutation results in skipping of exon 2 and a premature stop codon at residue 151.ConclusionsThe novel severe N-terminal KISS1R splice site (c.245−1G>A) mutation results in IHH. Heterozygous female carriers may manifest a subtle fertile phenotype. The subnormal gonadal response to hCG in patients may implicate a direct role of KISS1R in gonadal function. The normal neonatal virilization in a male homozygous to this severe mutation challenges the hypothesis that KISS1R is required for fetal development of male external genitalia.

Gonadotropin- and Adrenocorticotropic Hormone-Independent Precocious Puberty of Gonadal Origin in a Patient with Adrenal Hypoplasia Congenita Due to DAX1 Gene Mutation – A Case Report and Review of the Literature: Implications for the Pathomechanism

2018 ◽  
Vol 91 (5) ◽  
pp. 336-345 ◽  
Author(s):  
Stella A. Nagel ◽  
Michaela F. Hartmann ◽  
Felix G. Riepe ◽  
Stefan A. Wudy ◽  
Martin Wabitsch
Keyword(s):  
Gene Mutation ◽  
Precocious Puberty ◽  
Adrenocorticotropic Hormone ◽  
Pubertal Development ◽  
Hypogonadotropic Hypogonadism ◽  
Bone Age ◽  
Pubic Hair ◽  
Adrenal Hypoplasia Congenita ◽  
Body Odour ◽  
Adrenal Hypoplasia

Background/Aims: Mutations in the DAX1 gene cause X-linked adrenal hypoplasia congenita (AHC) classically associated with hypogonadotropic hypogonadism. Unexpectedly, precocious puberty (PP) has been reported in some cases, its mechanism remaining unclear. Methods: We longitudinally studied a boy with AHC due to DAX1 gene mutation who developed peripheral PP at age 4.5 years. Initially he presented pubic hair, penile enlargement, advanced bone age and elevated testosterone levels. PP progressed with acne, body odour and ejaculations. In addition, we summarized reported findings of patients with DAX1 mutations and PP in the literature in a structured manner providing a basis to discuss possible pathomechanisms of PP in DAX1 patients. Results: In our patient, hydrocortisone treatment was increased to 20 mg/m2/day as suggested in similar published cases. However, despite the suppression of adrenocorticotropic hormone (ACTH), this remained without clinical effect or change in laboratory results. The progression of symptoms of pubertal development was well suppressed under cyproterone acetate treatment. Twenty-four-hour steroid urine excretion rate measurements excluded an effect of adrenal androgens and showed a prepubertal rise of excreted testosterone. Testes size remained small. GnRH testing showed peripheral PP. Conclusion: We hypothesize that an intrinsic, gonadotropin- and ACTH-independent activation of steroidogenesis in the DAX1 deficient testes leads to PP in AHC patients with DAX1 mutations.

Comparing the Genetic Detox Ability and Heavy Metal Burden in a Cohort of Samples of Egyptian Children and those with Autistic Spectrum Disorder

2019 ◽  
Author(s):  
Blaurock-Busch E
Keyword(s):  
Heavy Metal ◽  
Autism Spectrum ◽  
Control Group ◽  
Potentially Toxic Metals ◽  
Gstt1 Null Genotype ◽  
Egyptian Children ◽  
Glutathione S Transferases ◽  
Metal Burden ◽  
Detoxification Pathway

The heavy metal burden of patients with Autism spectrum disorders (ASD) has been widely discussed [1-5]. Present knowledge suggests that ASD patients, compared to ‘normal’s’ show a greater metal burden, which may be a cause of the ASD pathogenesis, possibly due to a limited detoxification potential. We thus aimed to evaluate if the metal burden of ASD children is due to comprised detoxification ability, and if missing of enzymes such as the glutathione-S-transferases provide an explanation, or if additional factors play a role. Genetically, we noticed a slight difference in the detoxification ability of the ASD group compared to the Control group. In the ASD group, carrier of the genotype GSTT1 null genotype (i.e. the homozygous loss) are 1.7 times more common as in the Control group and the GSTT1 allele is more frequent in the ASD patient collective. These findings are not statistically significant but indicate a trend. In addition, our data indicates that levels of potentially toxic metals in blood and hair of both groups demonstrate a similar immediate and long-term exposure. However, 36% of the ASD group showed signs of zinc deficiency compared to 11% of the Control group and this points towards inefficiency of the Phase I detoxification pathway. More research is needed to explore the role of other elements in the detoxification pathway.

Emotion Dysregulation in Autism Spectrum Disorder

2018 ◽  
pp. 282-298
Author(s):  
Emily Neuhaus
Keyword(s):  
Autism Spectrum Disorder ◽  
Social Communication ◽  
Educational Outcomes ◽  
Emotion Dysregulation ◽  
Research Priorities ◽  
Theoretical Models ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Spectrum Disorder

Autism spectrum disorder (ASD) is defined by deficits in social communication and interaction, and restricted and repetitive behaviors and interests. Although current diagnostic conceptualizations of ASD do not include emotional difficulties as core deficits, the disorder is associated with emotion dysregulation across the lifespan, with considerable implications for long-term psychological, social, and educational outcomes. The overarching goal of this chapter is to integrate existing knowledge of emotion dysregulation in ASD and identify areas for further investigation. The chapter reviews the prevalence and expressions of emotion dysregulation in ASD, discusses emerging theoretical models that frame emotion dysregulation as an inherent (rather than associated) feature of ASD, presents neurobiological findings and mechanisms related to emotion dysregulation in ASD, and identifies continuing controversies and resulting research priorities.

scholarly journals X-linked congenital adrenal hypoplasia: a case presentation

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Hong Ouyang ◽  
Bo Chen ◽  
Na Wu ◽  
Ling Li ◽  
Runyu Du ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Hormone Replacement ◽  
Slipped Capital Femoral Epiphysis ◽  
Clinical Manifestations ◽  
Addison’S Disease ◽  
Addison's Disease ◽  
Case Presentation ◽  
Early Symptoms ◽  
Congenital Adrenal Hypoplasia ◽  
Adrenal Hypoplasia

Abstract Background Most patients with congenital adrenal hypoplasia (AHC) develop symptoms during infantile and juvenile periods, with varying clinical manifestations. AHC is a disease that is easily misdiagnosed as Addison’s disease or congenital adrenal hyperplasia (CAH). There was also a significant time difference between the age at which patients developed symptoms and the age at which they were diagnosed with AHC. Most patients showed early symptoms during infantile and juvenile periods, but were diagnosed with AHC many years later. Case presentation We are currently reporting a male patient who developed systemic pigmentation at age 2 and was initially diagnosed with Addison’s disease. At 22 years of age, he experienced a slipped capital femoral epiphysis (SCFE), a disease mostly seen in adolescents aged 8–15 years, an important cause of which is endocrine disorder. Testes evaluated using color Doppler Ultrasonography suggested microcalcifications. Further genetic testing and auxiliary examinations revealed that the patient had hypogonadotropic hypogonadism (HH) and DAX-1 gene disorders, at which time he was diagnosed with AHC complicated by HH. He was given hormone replacement therapy, followed by regular outpatient review to adjust the medication. Conclusions The typical early symptoms of AHC are hyperpigmentation and ion disturbance during infantile and juvenile periods, while few patients with AHC develop puberty disorders as early symptoms. AHC is prone to being misdiagnosed as Addison’s disease, and then gradually develops the symptoms of HH in adolescence. The definitive diagnosis of AHC ultimately is based on the patient’s clinical presentation, laboratory results and genetic testing results.

025 Sleep Disruption on an Orbital Shaker alters Glutamate in Prairie Vole Prefrontal Cortex

SLEEP ◽  
2021 ◽  
Vol 44 (Supplement_2) ◽  
pp. A11-A12
Author(s):  
Carolyn Jones ◽  
Randall Olson ◽  
Alex Chau ◽  
Peyton Wickham ◽  
Ryan Leriche ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Prefrontal Cortex ◽  
Early Life ◽  
Autism Spectrum ◽  
Prairie Vole ◽  
Sleep Disruption ◽  
Glutamatergic Synapses ◽  
The Brain ◽  
Orbital Shaker

Abstract Introduction Glutamate concentrations in the cortex fluctuate with the sleep wake cycle in both rodents and humans. Altered glutamatergic signaling, as well as the early life onset of sleep disturbances have been implicated in neurodevelopmental disorders such as autism spectrum disorder. In order to study how sleep modulates glutamate activity in brain regions relevant to social behavior and development, we disrupted sleep in the socially monogamous prairie vole (Microtus ochrogaster) rodent species and quantified markers of glutamate neurotransmission within the prefrontal cortex, an area of the brain responsible for advanced cognition and complex social behaviors. Methods Male and female prairie voles were sleep disrupted using an orbital shaker to deliver automated gentle cage agitation at continuous intervals. Sleep was measured using EEG/EMG signals and paired with real time glutamate concentrations in the prefrontal cortex using an amperometric glutamate biosensor. This same method of sleep disruption was applied early in development (postnatal days 14–21) and the long term effects on brain development were quantified by examining glutamatergic synapses in adulthood. Results Consistent with previous research in rats, glutamate concentration in the prefrontal cortex increased during periods of wake in the prairie vole. Sleep disruption using the orbital shaker method resulted in brief cortical arousals and reduced time in REM sleep. When applied during development, early life sleep disruption resulted in long-term changes in both pre- and post-synaptic components of glutamatergic synapses in the prairie vole prefrontal cortex including increased density of immature spines. Conclusion In the prairie vole rodent model, sleep disruption on an orbital shaker produces a sleep, behavioral, and neurological phenotype that mirrors aspects of autism spectrum disorder including altered features of excitatory neurotransmission within the prefrontal cortex. Studies using this method of sleep disruption combined with real time biosensors for excitatory neurotransmitters will enhance our understanding of modifiable risk factors, such as sleep, that contribute to the altered development of glutamatergic synapses in the brain and their relationship to social behavior. Support (if any) NSF #1926818, VA CDA #IK2 BX002712, Portland VA Research Foundation, NIH NHLBI 5T32HL083808-10, VA Merit Review #I01BX001643

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