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Principal Investigator: Deborah Merke
Organization: CLINICAL CENTER
Fiscal Year: 2024
Funding agency: NIH Clinical Center
Our recruitment of patients continues to be excellent and represents the largest cohort of CAH and FMPP patients ever seen at one center. To date, we have enrolled over 500 patients with CAH, and 19 patients with FMPP. This Natural History study allows for longitudinal characterization and timely referral to clinical trials of novel treatments.
Comprehensive clinical phenotyping of patients with CAH due to 21-hydroxylase deficiency has been performed. Detailed clinical evaluations reveal great variation in treatment approaches of referred patients, especially among adults, with only 30% of patients in acceptable disease control based on adrenal hormones. Adult short stature, abnormal growth and development of children, cardiovascular risk factors, reduced bone mineral density and adrenal and testicular tumor formation are common. Longitudinal assessment of risk factors for cardiovascular disease revealed higher prevalence of metabolic morbidity in patients with CAH compared to the general population (NHANES) across the lifespan. Associations with treatment- and disease-related factors differed during childhood and adulthood, with onset of metabolic risk prior to age 10 years.
Children with CAH are at risk for early puberty. In a retrospective study of data from our Natural History study, we evaluated the effect of gonadotropin releasing hormone analogue (GnRHa) therapy on bone health in the CAH population. Childhood GnRHa therapy to delay central puberty for an average of 4.5 years in patients with CAH did not affect bone mineral density (BMD) at attainment of adult height or during early adulthood when peak BMD occurs in healthy individuals and is expected. However, an overall decrease in BMD occurred during the second and third decades of life, regardless of GnRHa therapy, a possible effect of chronic supraphysiologic glucocorticoids. Children with CAH who experience early puberty benefit from GnRHa treatment as evidenced by a positive effect on adult height. The height gain for treated patients was 0.8 SD (approximately 2 ½ inches) from predicted height at the start of puberty, which is clinically meaningful.
Patients with CAH and other forms of adrenal insufficiency have been reported to have poor quality-of-life. Cognition, emotional processing, memory and quality-of-life is being evaluated. In 2024, we developed the first validated patient reported outcome (PRO) instrument to capture disease-specific health-related quality of life outcomes in CAH, named CAHQL. The instrument will be valuable in the clinical management of adults with CAH and could be used to assess the efficacy of novel treatments in development.
We evaluated mental health in our population of CAH patients in response to the COVID-19 pandemic. Lower levels of anxiety/distress were observed in the first year of the COVID-19 pandemic in women with CAH compared to men with CAH, and controls of both sexes suggesting that early androgen exposure may enhance resilience to chronic stress. The expected sex differences of women disproportionally displaying high rates of anxiety/distress relative to men in response to the COVID-19 pandemic was present in our controls, but absent in the CAH cohort and women with CAH are exposed to high levels of androgens in utero. Our study strongly suggests that sex hormones during the early critical period of development may underly a determining epigenetic regulatory mechanism of internalizing disorders. This study provides a proof of concept for the potential role of androgen as a protective factor in the psychological impact of chronic stress.
Genotyping and genetic counseling are important in the management of CAH, and genotyping has been suggested as a potential second tier screen to hormonal measurements in neonatal screening programs. The gene encoding 21-hydroxylase, CYP21A2, is mapped to the short arm of chromosome 6 (6p21.3) within the HLA complex. The high rate of genetic variability at this locus, the presence of CYP21A2 gene duplications, and the presence of the CYP21A1P pseudogene complicate the determination of disease and carrier status. This year we identified rare disease causing CYP21A1P/CYP21A2 chimeras including a novel attenuated chimera that retains partial 21-hydroxylase activity.
An important concurrent project is the evaluation of neighboring genes, including TNXB and C4, in relation to phenotype. We described a novel CAH-Tenascin X Contiguous Gene Deletion Syndrome, termed CAH-X Syndrome. Tenascin-X deficiency, in recessive or dominant form, is a cause of hypermobility type Ehlers-Danlos Syndrome (EDS). In the first ever systematic study tenascin deficiency in CAH patients, we found that 14 (7 percent) of 193 consecutive unrelated CAH patients have the novel CAH-X Syndrome. We have subsequently identified novel chimeric genes as a cause of CAH-X, broadening the spectrum of this syndrome. Approximately 10 to 15 percent of CAH patients are now estimated to be affected by CAH-X. Studies are underway to better define the clinical, molecular and biochemical aspects of CAH.
Terms: <0-11 years old><10 year old><10 years of age><21+ years old><21-Hydroxylase><21-hydroxylase deficiency><6p21.3><Acceleration><Adrenal Gland Insufficiency><Adrenal Gland Neoplasms><Adrenal Gland Tumor><Adrenal Hormone><Adrenal Insufficiency><Adrenal Tumor><Adrenal gland hypofunction><Adrenal hormone preparation><Adult><Adult Human><Affect><Androgenic Agents><Androgenic Compounds><Androgens><Anxiety><Attenuated><Biochemical><Bone Density><Bone Mineral Density><CA21H><CAH1><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 years><CPS1><CYP1ALPHA><CYP21><CYP21A2><CYP21A2 gene><CYP21B><Cardiovascular Diseases><Causality><Child><Child Development><Child Youth><Childhood><Children (0-21)><Chimera><Chimera organism><Chromosome 6><Chromosome Arm><Chronic><Chronic stress><Clinical><Clinical Evaluation><Clinical Management><Clinical Testing><Clinical Trials><Cognition><Complex><Congenital adrenal hyperplasia><Country><Cutis Elastica><Cytochrome P450 Family 21 Subfamily A Polypeptide 2><Cytochrome P450 Subfamily XXIA (Steroid 21-Hydroxylase) Polypeptide 2><Cytochrome P450 XXIB><Cytosteroid 21-Monooxygenase><Cytotacin><Cytotactin><Data><Development><Differences between sexes><Differs between sexes><Disease><Disorder><Distress><Ehlers-Danlos Disease><Ehlers-Danlos Syndrome><Emotional><Enrollment><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Etiology><Evaluation><Exposure to><Female infertility><Future><Gene Deletion><Gene Duplication><General Population><General Public><Generalized Growth><Genes><Genetic><Genetic Counseling><Genetic study><Genotype><Glucocorticoids><Gonadal Steroid Hormones><Gonadotropin-Releasing Hormone Analog><Growth><Growth and Development><Growth and Development function><Height><Hexabrachion><High Prevalence><Hormonal><Hyperandrogenism><Hypoadrenalism><Individual><Infant and Child Development><Investigators><Knowledge><LH-RH Analogs><Life><Luteinizing Hormone-Releasing Hormone analogs><Maps><Measurement><Mediating><Memory><Mental Health><Mental Hygiene><Metabolic><Molecular><Morbidity><Morbidity - disease rate><NHANES><Names><National Health and Nutrition Examination Survey><Natural History><Neonatal Screening><Newborn Infant Screening><Orphan Disease><Outcome><P450-C21B><P450c21B><Patient Outcomes Assessments><Patient Recruitments><Patient Reported Measures><Patient Reported Outcomes><Patients><Phenotype><Population><Precocious Puberty><Pseudogenes><Psychological Health><Psychological Impact><Puberty><QOL><Quality of life><Rare Diseases><Rare Disorder><Reporting><Research Personnel><Researchers><Retrospective Studies><Risk><Risk Assessment><Role><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Sex Differences><Sex Hormones><Sex Steroid Hormones><Sexual differences><Steroid 21-Hydroxylase><Steroid 21-Monooxygenase><Syndrome><Tenascin><Tenascin-C><Testicular Neoplasms><Testicular Tumor><Testis Neoplasms><Testis Tumor><Therapeutic Androgen><Therapeutic Intervention><Tissue Growth><US State><Variant><Variation><Woman><adrenal neoplasm><adulthood><age 10 years><androgen excess><attenuate><attenuates><bone health><build resilience><build resiliency><cardiovascular disorder><cardiovascular risk><cardiovascular risk factor><carrier status><causation><chimeras><chimeric gene><clinical phenotype><clinical test><cohort><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><critical period><cutis hyperelastica><design><designing><determine efficacy><develop resilience><develop resiliency><developmental><disease causation><disease control><disorder control><early adulthood><early experience><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><elastic skin><emerging adult><enhance resilience><enhance resiliency><enroll><epigenetically><evaluate efficacy><examine efficacy><gene deletion mutation><gonadal steroids><health related quality of life><improve resilience><improve resiliency><in utero><increase resilience><increase resiliency><infertility in women><instrument><intervention therapy><kids><life span><lifespan><male><men><name><named><naming><newborn screening><novel><ontogeny><orphan disorder><participant recruitment><patient profile><pediatric><premature><prematurity><profiles in patients><promote resilience><promote resiliency><protective factors><psychologic><psychological><research clinical testing><resilience development><response><screening program><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><sex><sex based differences><sex steroid><sex-dependent differences><sex-related differences><sex-specific differences><social role><ten year old><ten years of age><tenascin X><unable to bear children><youngster>