Hello everyone. I would like to thank the organization committee for giving me the opportunity to speak at such a beautiful event. It's an honor for me to make this presentation here. I would like to disclose that I have no conflict of interest related to this presentation. In my presentation plan, firstly, we will see the types and approach of congenital adrenal hypoplegia with cases. Then we will talk about treatment and screening if time permits. Congenital adrenal hypoplegia is a very important and comprehensive subject. I will touch on the important points of this. Corticotropin-releasing hormone is released from the hypothalamus, which stimulates the release of ACTH from the pituitary leading to the release of cortisol from the adrenal glands. This hypothalamic-pituitary-adrenal axis is regulated by feedback mechanisms. Congenital adrenal hypoplegia is an inherited autosomal recessive inability to synthesize cortisol. Approximately more than 90% of cases of congenital adrenal hypoplegia are caused by 21-hydroxylase deficiency caused by mutations in the C21A2 gene. The classic form is defined by several reduced or absence enzyme activity with impaired cortisol production manifesting clinically in the neonatal period. Due to the high rate of consanguinity marriage in Turkey, congenital adrenal hypoplegia, like other autosomal recessive diseases, is more common. Its prevalence is approximately 1 in 15,000 neonates. This prevalence especially depends on consanguinity marriage and ethnicity and geographic area. The first case is a 5-year-old male infant referred by the absence of palpable gonads. He was born full-term, had an adequate birth weight, and was the first pregnancy of a mother who had a first delivery. There is no family history. On physical examination, atypical genitalia characterized by a 2-centimeter follus, non-palpable gonads in the labiosacral folds, hyperpigmentation, and perinatal hypospadias characterized as pre-stage 3. In laboratory, normal serum levels with mildly elevated potassium and slightly low serum bicarbonate levels. Low cortisol suggested of adrenal insufficiency with elevated ACTH levels indicating an acquired cortisol production. Significantly elevated renin activity and low aldosterone consists with minor alcoholic deficiency. And elevated 70-hydroxyprogesterone with elevated testosterone and androstedone levels indicating excessive androgen production. In pelvic, ultrasonography reveals malignant structures and karyotype confirms 46XX genotype. This patient, 46XX DST, low cortisol with elevated ACTH and elevated 70-hydroxyprogesterone levels. Clinical findings and laboratory results, the diagnosis of classic southwestern congenital adrenal hyperplasia and cortisol therapy was initiated to replace cortisol and suppresses for ACTH secretion. Genetic analysis confirmed this C21A2 gene homozygous mutation. On day of life, 10 days, hyponatremia, hyperkalemia, and decreased serum bicarbonate levels with elevated ACTH and renin activity. What we forget, what we should start together with hydrocortisone, actually fructocortisone. Fructocortisone is given to all newborns with classical congenital adrenal hyperplasia detected in neonatal screening programs even before hyponatremia develops. Minerocorticoid resistance and anti-minerocorticoid effects of elevated 17-hydroxyprogesterone neonates require higher fructocortisone doses than older children. 21-hydroxylase deficiency is the most common type I mentioned. This blocks the 21-hydroxylase progressing enough, and then adrenal insufficiency occurs when the adrenal glands cannot produce enough cortisol, leading to the loss of negative feedback to the hypothalamic pituitary gland system, counter-regulatory overproduction of adrenocorticotropic hormone, which turns to excessive adrenal androgen production and adrenal hyperplasia. 21-hydroxylase deficiency is clinically divided into two types, classic and non-classic form. The classic form groups are also divided into two types, salt wasting and simple virilizing. The determining factor here is the residual enzyme activity levels. There is no enzyme activity in salt wasting type while there is 1-2% enzyme activity in simple virilizing type. In non-classical form, retiring up to 20-50% of enzyme activity, they must not have adrenal insufficiency but might have partial glucocorticoid deficiency. These patients in females have normal genitalia. Individuals might present with symptoms of hyperandrogenism. Male individuals frequently go undergoing in school age present by early pubertal, puberty, and sexual preecoccy. In genotype-phenotype correlation, there are four general groups in CYP21A2 mutations. Deletions, large gene conversions, missense mutations, comparison mutations, group null, and other one is group B and C. We have 40XX DCD, congenital adrenal hyperplasia. As we think the early surgery, genital surgery, both parenteral treatment of prevention and realization and postnatal surgical correction of genitalia are highly commercial. The most difficult aspect of managing a patient with DST diagnosis who has amygdala genitalia is the assignment of an appropriate gender. This is very complex and ethical situation, so I don't want to go to further detail. The vast majority of individuals in 46XX karyotype congenital adrenal hyperplasia who are assigned female at birth identify as girl and woman. We prefer to perform early genital surgery on these patients in surgical clinics with extensive clinical experience in this field. Gender assignment should be determined by evaluation of the patient's chromosomal structure, specific diagnosis, fertility, pubertal stage, phallus length, psychosocial orientation, family wish, and the consensus opinion of experienced specialist physicians. Now we move on to another case. 11-year-old boy diagnosed with SW congenital adrenal hyperplasia due to 21-hydroxylase deficiency. He is under hydrocortisone and fructocortisone treatment, but he has poor adherence to treatment. He has significant advanced bone age and elevated ACTH and 70-hydroxyprogesterone levels. What approach should we have this patient? We can increase doses of hydrocortisone for better suppress ACTH levels and normalize androgen levels. We should educate family and patients on the importance of consistent medication. We must closely monitor this patient's growth rate and bone age progression. We increase the patient's hydrocortisone dose from 10 to 15 and the daily intake frequency from 2 to 3 doses, not change the full hydrocortisone dose. At 6 months post-intervention, signs of relation mild, no significant progression, and significant reduction of 70-hydroxyprogesterone, ACTH, and androgen levels. Plasma reining activity is under the control. There is no progress in bone age. Now we continue with case 2. He is now 15 years old. On physical examination, palpable mass in bilateral testicular noted enduring routine examination and progressive signs of androgen excess. Patient reports intermittent adherence to medication over the past 4 years. Bone age significantly advanced. 70 years old. On sclerotal ultrasonography, it consists with testicular adrenal rest Tamar's tart. What approach should we have? There is an increased risk of hypogonadism and infertility in congenital adrenal hyperplasia, cause of adrenal excessive androgen production and testicular adrenal rest Tamar's. Actually, Tamar's tart is mostly bilateral and seen 1 in 3 men with classical congenital adrenal hyperplasia. This tart abhorrent adrenocortical cells that migrate with the gonads from the urogenital reached during fatal development. Presence of tart often associated with poor adrenal androgen control and excess of ACTH. The prevalence is tart is increased with age and related the severity of genotype. In a case with congenital adrenal hyperplasia with tart, what would you be approach? Suppress ACTH levels by optimizing glucocorticoid therapy to reduce ACTH stimulation. To ensure proper management of adrenal function and control of hyperandrogenism with base of hydrocortisone dosage. To monitor the size and characteristic of tart annual ultrasonography width. And particularly if tart is affecting fertility, spam cryoprevalentization should be considered. Another one is tart became symptomatic or there is a significant increase in the size or impact on infertility. Maybe you can think the surgical invention. In this case, hydrocortisone increased to 20 mg per m2 day and three divided doses. When final adult has been reached, some patients may benefit from switching to long-action synthetic glucocorticoids. Prednisone or prednisolone for improved adherence. Because of long half-life of this substance, all of the reduction of the dosing frequency in once and twice a day. Case 3, a 50 years old patient is being followed up with hydrocortisone and filtrocortisone treatment. Due to 21 hydroxylase deficiency, congenital adrenal hyperplasia. There is non-compliance with treatment. She has menstrual irregularity and obesity. Here you see the laboratory values and hormone profile. What should we think these patients? Firstly, we want to look pelvic ultrasonography and consensus with this polycystic ovary syndrome. There is an increased 70 hydroxyprogesterone and androgen levels. Also, elevated LH value. Pelvic ultrasonography compatible with polycystic ovary syndrome. What will be the approach in this patient? Increased hydrocortisone dosing frequency. Separatorine acetate, spironolactone, fultamate and finacetarate for the treatment. Hyperandrogenic symptoms. Oral contraceptives for LH suppression. Reduce conodal and adrenal androgen synthesis. Increased and modulation testosterone, dihydrotestosterone rations. Switching to prednisone or prednisolone to improve adherence. Here you can see the medication that you can use to treat hyperandrogenism in congenital adrenal hyperplasia patients. After 6 months with lifestyle changes, diets, exercise and oral contraceptive treatment, there is a decrease in weight and body mass. Improvement in hormone values was also detected. Another case, 5 years old girl, present with pubic hair growth in last 6 months. Parents reported that rapid growth recently. No menstrual bleeding, no consanguinity. On physical examination, tenors stage 2 pubic hair development. And little clitoral megalith stage 2. In laboratory, normal serum-elevated tanks and advanced bone age with normal pervertal pelvic ultrasonography. There is no central precoccus puberty. But elevated 70-hydroxyprogesterone levels we detected. 5 years old girl with premature puberty. Prepubertal breast tenors stage 1. Elevated 70-hydroxyprogesterone with normal cortisol levels. Advanced bone age. No central puberty precoccus. We think about the non-classical 21-hydroxylase deficiency. And genetic analysis is homozygote, whereas some is suspected. Disease spectrum in congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Clinical phenotype is seen according to the remaining enzyme activity levels associated with the mutation. Here the types of clinical according to genetic mutations are seen. This is the most common type. This is the most common type. This is the most common type in both classic form, salt-vesting and simple virulizing. In investigations, 70-hydroxyprogesterone samples should be taken in the morning because of the urinal routine. Congenital adrenal hyperplasia types can be evaluated according to the response in 70-hydroxy levels in ACTH test. In classic forms, treatment based on two pillars, glucocorticoid and myocorticoid replacement and androgen control. Patients with non-classical congenital adrenal hyperplasia, not every patient may need treatment. They might need treatment for symptoms or hyperandrogenism such as precoxal pseudopuberty, growth, acceleration, acne, hirsutism, menstrual dyspareunce, and supferability. The aim of the mimicked circadian rhythm of cortisol secretion often requires supraphysiological doses in suppressed androgen excess. Recommended glucocorticoid in children is hydrocortisone, cause of the minimized negative effect on the bone for treatment and growth. Glucocorticoid dose often has been increased in adolescent cause of the clearance increasing in adolescent. Fortunately, we should be avoided the higher than 70 milligram meters required per day doses to optimize growth. The suggested target 70 hydroxyprogesterone range is three to 36 nanomole per liter. For myocorticoid replacement, fructalocortisone is the sensitive myocorticoid administered of patients with the salt wasting form. In infants with classical 21-hydroxylase deficiency, they need relatively high dose of fructalocortisone in the first year of life cause of physiological myocorticoid resistance. This needs decrease as the patient gets older. FMODE, this is the new form of hydrocortisone was introduced in 2017. Modified realized formulation of hydrocortisone. The drug has a delayed realized coiting layer, the pharmacodynamics replace the natural urinal cortisol cycle and improve hormonal control. An additional treatment apart from these basic treatments, we provide sometimes we need the additional treatments as aromatase inhibitors and combinator with growth hormone and monotropine releasing hormone analogs. The aim is here, reach the patients to a higher final height. This is the clinical study, which has significantly higher final adult height than their initial predicted height in both male and female congenital adrenal hyperplasia patients treated with growth hormone therapy. In other study, additional of aromatase inhibitor to growth hormone releasing analogs and growth hormone recombinant therapy then significantly delays bone maturation and may increase the final height. Retrozole is aromatase inhibitors. This is the can delay bone maturation and improve predicted adult height. Case five, 18 day old neonate. Referred to clinical due to ambiguous genitalia and parents are first degree cousins. On physical examination, we detected the high blood pressure. He has ambiguous genitalia consists with predile stage three no palpable gonads in the labiosacral folds but hyperpigmentation presents. In laboratory elevated 70-hydroxyprogesterone and ACTH level with low cortisol, aldosterone and renin levels. On pelvic ultrasonography, malarian structure present. Karyotypes relays 46XX. In this case suspected 11-beta-hydroxysteroid dehydrogenase deficiency measurement basal and ACTH simulated 11-deoxycortisone and deoxycortisone elevates are measured. 11-beta-hydroxysteroid deficiency is the second most common congenital adrenal hyperplasia. Depending on the severity of the enzyme deficiency, it can lead to cortisol deficiency and adrenal axis, androgen axis and hypertension due to increased mineral corticoid precursors levels. Impaired 11-hydroxylation results to decrease corticosterone and cortisol synthesis with increased ACTH levels and excess androgens. Elevated concentrations of deoxycorticoid strains suppress the renin-angiostensin system and this lead to hypertension, low plasma renin activity and low aldosterone concentrations. A non-classic form of this enzyme caused by type 11B1 mutations exist, but is very rare. It depends on the severity of enzyme deficiency. Clinically, patients with 11-beta-hydroxylase deficiency presence similar to patients with 21-hydroxylase deficiency patients with signs of androgen axis, but patients with 11-beta-hydroxyprogesterone deficiency also have hypertension rather than saltwast. Let's look at the next patient, six-year-old female patient under follow-up for permyoadrenal insufficiency with hydrocortisone and fructocortisone treatment. Adrenal insufficiency cause not determinate. On physical examination, bilateral inguinal mast palpable. In laboratory, elevated ACTH levels and low androgen levels. On pelvic ultrasonography, there is no mylar structure present and abdominal MRI imaging bilateral adrenal hyperplasia is remained. Karyotype analyzing is 46XY patient. And when we examine the retrospective analysis, we see that the overall steroid profile is low with elevated ACTH concentration. Monocular analysis revealed the homozygous mutation in star gene. Then we continue the hydrocortisone and fructocortisone therapy, but surgical consultation for gonadectomy due to malignancy risk of gonads. Other case, a 20-day patient was hospitalized and adrenal crisis with hypoglycemia, hyponatremia and hyperkalemia. Parents were first degree cousins. On physical examination, patient has pigmentation throughout of his body and genital examination was consistent with the girl appearance pre-stage one. The gonads were in the bilateral inguinal lesion palpated. In laboratory, elevated ACTH levels with low cortisol and elevated high renin activity. On pelvic ultrasonography, show no echogenic malarial structure, but there is a presence testis in bilateral in the inguinal canal. Glicocorticoid and minocorticoid treatment was started for adrenal insufficiency. And molecular analysis revealed the novel homozygous mutation we detected in star gene. In patient with adrenal insufficiency, hyperpigmentation, girl genital appearance, but 46XY patient, lipoid congenital adrenal hyperplasia star should always be considered. Lipoid congenital adrenal hyperplasia characterized by the old street hormones deficiency. This is the rarest form of congenital adrenal hyperplasia types. These patients with neonatal crisis, female external genitalia in both 46XX or XY infants. Patients with star mutations characterized by lipoid accumulation in the adrenal glands, adrenal insufficiency, and female external genitalia. These patients typically present in the first year of life with adrenal crisis. Salt-wasting, very low sodium steroids, high ACTH levels with plasma renin activity, and large adrenal fluid loaded with cholesterol and cholesterol esters. In non-classic form of these star mutations, clinical phenotypes are highly variable. These patients onset late age glucocorticoid deficiency and mild minocorticoid deficiency with high ICTH levels concentrations. Present the clinical preliminary 16 years patient. She has never had a menstrual period and lack of secondary sexual characterist. Blood pressure is high with Prader-Stage 2 ambigus in Italia with no palpable gonads. The absence of enzyme causes decreased cortisol and sex stress levels leads to high production ACTH further drives to overproduction 11-deoxycorticosterone and deoxycortisone. And she has hypokalemia. On pelvic ultrasonography bilateral adrenal hyperplasia no ovarian tissue identified. Karyotype is 46XY. Patient with female permyorammonia, 46XY chromosome analyzed, absence of secondary sexual characterized, hypertension with hypokalemia. Consists with diagnosis 70-alpha-hydroxylase deficiency. 70-alpha-hydroxylase deficiency CYP17A1 gene caused at enzyme that express both 70-alpha-hydroxylase and 70-20-liase. Elevated deoxycorticosterone and corticosterone, high concentration of deoxycorticosterone cause of sodium retention, hypertension and hypokalemia with suppressant of aldosterone production. The presence of corticosterone which has glucocorticoid activity, patients prevents from having adrenal crisis even though cortisol production is low or absence. Adolescent female with absence secondary sexual characterized, hypertension with lowering hypokalemia. And elevated deoxycorticosterone and progesterone levels, low cortisol aldosterone, 70-hydroxypregnolone and 70-hydroxyprogesterone, renin, dihydroepiandrostenedione and androstenedione levels. Another one, 15-day-old neonates referred to the Pediatric Endocrinology Clinic the MB just in Italia. Hypospadias, cryptosutism and micropenis. Patients have not elevated 70-hydroxyprogesterone and low dihydroepiandrostenedione levels with high plasma renin activity and elevated ACTH levels. Patients pelvic ultrasonography consists with the bilateral enlarged adrenal glands and both testes are undescending. Karyotype is 46XY. Low 70-hydroxyprogesterone, androstenedione, cortisol, aldosterone. This diagnosis, 3-beta-hydroxysteroid dehydrogenase deficiency. This is the rare type of congenital adrenal hyperplasia. This patient's treatment replaced both adrenal gonadal steroid deficiency. Elevated ratio of pregnenolone to progesterone and 70-hydroxypregnenolone to 70-hydroxyprogesterone is very important. The other one, the poor deficiency. Poor deficiency patients with typically normal electrodes and myocorticoid functions, nearly normal cortical levels that response poorly ACTH stimulation. Increased levels of 70-hydroxyprogesterone that responds to variability of ACTH levels. In 46XX females, virilization for causes two points. Poor deficiency diverts into the backdoor pathway of dihydrotestosterone biosynthesis and placental aromatase requires poor. Pregnant women carrying fetus with the poor mutations may experience virilism during pregnancy. Generally, patients with poor deficiency do not have myocorticoid deficiency as the impaired 70-alpha-hydroxylase increase production of myocorticoid intermediate. Most patients require either permanent or stress-dosed glucocorticoid coverage. An antelope big cell syndrome can occur to these patients with craniosynostosis, radio-ulnar or radio-humeral synostosis, mid-phase hypoplasia, and other skeletal manifestations. Diagnosis, the primary biomarker of congenital adrenal hypoplasia, 21-hydroxylase deficiency is the only 70-alpha-hydroxyprogesterone levels. Increased concentrations in 70-hydroxyprogesterone in random sample take any time to diagnosis as 21-hydroxylase deficiency. In neonatal screening, congenital adrenal hyperplasia with 21-hydroxylase deficiency now done more than 40 countries. The main goal is to prevent adrenal crisis and deaths in the neonatal period. The congenital adrenal hyperplasia newborn screening program first started as a pilot study in Turkey in 2017. Later an expanded study was started. Now congenital adrenal hyperplasia is included in the national newborn screening program in our country. In order to reduce the recall rate of congenital adrenal reduced recall rate screening caused without missing classical 21-hydroxylase cases, the second stage cut-off volley in the screening strategy was changed to upper than the expanded treatment. We can take questions. Yes, I will, sorry. Thank you. Novel therapeutics other approach to reduce androgen production without chronic supraphysiological glucocorticoid exposure include GER1 antagonist, ACTH antibodies, MC2R antagonist, adrenocortical agents, adrenolectomy. Approach to reduce androgen production without chronic supraphysiological glucocorticoid exposure. And thank home message. Presence, ambiguous genitalia or non-palpable test is considered 46 XX realized 21-hydroxylase deficiency. Poor hormonal control increased the risk of the advanced bone age. Persistence, ACTH elevation in poor controlled congenital adrenal hyperplasia suggested that the testicular adrenal rest tumors. Hypertension with hypokalemia consists consider 70-alpha-hydroxylase deficiency as a possible cause. In patients with permyoid adrenal infection constitute causes such as star mutations, completely female appearance in 46 XY individuals. Aim for 70-hydroxyprogesterone range of 100 to 1,019 degrees. Avoid corticosteroid dose existence 70 milligram per meter squared a day to present growth potential. Thank you.

congenital adrenal hyperplasia

21-hydroxylase deficiency

C21A2 gene mutations

hypothalamic-pituitary-adrenal axis

glucocorticoid therapy

newborn screening

hyperandrogenism