1. Congenital adrenal hyperplasia
Presenter: PGY: David Hung 洪上祐

2. Basic information Name： 沈x君之子 Sex： Boy Age： 12 days
Chart Number： 1786OOOO
Date of Birth ：2016/10/02
Date of Admission：2016/10/14
Ethnicity： Taiwan
Data Provider： Family

3. Chief complaint
Abnormal new born screen, susp. Congenital adrenal hyperplasia

4. Present illness Term baby, 38+5weeks Born at 大林慈濟H via NSD
Prenatal exman  normal
But no amniocentesis or Level II sonography
Newborn screen (2016/10/05)elevation of 17-OH Progesterone: 24.9嘉基H
Rechecked 17-OH Progesterone58
Referred to Dr.蔡孟哲's OPD
ACTH 0-46 TT
17OH

5. Birth history Term, 38+5 weeks, G4P2AA2, NSD Apgar score: 9 --> 10
Birth body weight: 3185gm (25-50th percentile), Birth body length: 49.2cm (50-75th percentile)
Now
BW: 3.304kg (50th percentage)
BL: 51cm (50~75th percentage)
Vaccine: HBV(1st)

6. Physical examination T/P/R: 37.2°C/146/44, BP: 77/54mmHg(10/14 14:40)
Hyperpigmentation of penis and scrotums
No ambiguous genitalia 、his testis was both palpable at scrotum

7. Admission course 檢驗名稱 (單位) 血液 2016-10-15 12:22 WBC(10^3/μL) 14.1
RBC(10^6/μL)
3.50(L)
Hb(g/dL)
11.7(L)
Hct(%)
34.8(L)
MCV(fl)
99.5
MCH(pg)
33.4
MCHC(g/dL)
33.5(L)
RDW(%)
15.3
Plt(10^3/μL)
539(H)
MPV(fL)
7.6
Blast(%)
Pro(%)
Myelo(%)
Meta(%) 2
Band(%)
Seg(%)
58(H)
Eos(%)
6(H)
Baso(%)
0(L)
Mono(%) 12
Lymph(%)
20(L)
Aty-lym(%)
NRBC(/Count WBCs)
檢驗名稱
(單位) 血液
15:31 pH
7.492(H)
PO2(mmHg)
54.5(L)
PCO2(mmHg)
30.2(L)
BEb(mmol/L)
0.4
BEecf(mmol/L)
-0.7
HCO3-(mmol/L)
22.6
%sO2c(%)
90.8
NA(mmol/L)
137.3
micro K(mmol/L)
5.80(H)
micro Ca(mmol/L)
1.273
CL(mmol/L)
102.4
檢驗名稱
(單位) 血液
11:43
GLU.A.C.(mg/dL)
Na(mmol/L)
133(L)
K(mmol/L)
5.4(H)

8. Clinical Course No weakness, anorexia, vomiting, dehydration, Low BP
Hyponatremia and hyperkalemia

9. Discharge planning Cortisone 25mg/tab (Cortisone)] 0.1 tab BID
OPD follow up Testosterone, 17p, corticosteroid, Aldosterone, ACTH
Cortisol
3.97
ug/dl
Testosterone(T.T)
2.34
ng/ml
17-OH Progesterone
64.5
Aldo
849
pg/ml
ACTH
230.0
pg/ml

10. Congenital adrenal hyperplasia (CAH) due to 21-Hydroxylase Deficiency
Discussion
Congenital adrenal hyperplasia (CAH) due to 21-Hydroxylase Deficiency

11. 6 types:
teroidogenic acute regulatory protein (StAR)、20,22-hydroxylase、3b-hydroxysteroid-dehydrogenase、17-hydroxylase、21-hydroxylase (Most common)、11b-hydroxylase

12. Pathophysiology Nelson Textbook of Pediatrics 19th edition
aldosterone ok but have ↑ androgens simple virilizing disease
classic 21-hydroxylase deficiency
nonclassic disease have relatively mildly elevated levels of androgens.
Cortisol deficiency->↑ACTH->adrenocortical hyperplasia ↑ intermediate metabolites.
Nelson Textbook of Pediatrics 19th edition

13. Clinical Presentation
Autosomal recessive disorders
Clinical severity depends on degree of 21-hydroxylase deficiency
Good genotype phenotype correlations
Classical CAH(1/ )
Simple Virilizing(25%): Ambiguous genitalia in females
Salt Wasting(75%): Dehydration, vomiting and diarrhoea. If untreated can prove fatal
Non-classical CAH (1/1000)
Milder than classical CAH
Androgen excess can cause precocious puberty in either sex
Males are often undiagnosed/asymptomatic
The severity of congenital adrenal hyperplasia depends on the residual enzyme activity of the least affected allele
Simple Virilsing: Prenatal excess androgen production causes virilisation of female foetuses, resulting in ambiguous genitalia.
Salt Wasting: Severe aldosterone deficiency causes sodium to be lost from the kidney, colon and sweat glands. Symptoms include dehydration, vomiting and diarrhoea. If untreated can prove fatal Simple virilising; Partial/greatly reduced 21-hydroxylase activity In males, excess androgen production leads to early/precocious virlisation
Salt wasting: In around three quarters of individuals, 21-hydroxylase activity is completely abolished which leads to salt wasting.
Carrier rate 1 in 50. Other symptoms include short stature due to premature epiphyseal fusion etc
分類(型)：由於CYP21基因缺陷的嚴重度不一，可分成三種類型鹽份喪失型  (salt-losing) 缺少2個CYP21基因，因此腎上腺皮質素和留鹽激素的製造不足，患者因留鹽激素缺乏可能在出生後不久(4~15天內)就會出現嘔吐、嗜睡、腹瀉、脫水等症狀。如果沒有適當的治療，即會因電解質和水份的流失，休克而致死。女嬰因受大量雄性素的刺激，所以外生殖器官的特徵有男性化現象，如陰蒂肥大看起來像陰莖，左右陰唇互相連結癒合在一起，像似中空的陰囊。單純男性化型 (simple virilizing)  缺少1個CYP21基因，還有1個CYP21基因，能製造少量的21-羥酵素，但腎上腺皮質素的分泌仍不足，有適量的留鹽激素，所以患孩沒有鈉流失和脫水的現象，不過雄性素的濃度還是很高，所以女嬰的外生殖器官會有程度不一的男性化表徵，例如陰蒂肥大，左右陰唇互相連結等情形。晚發作型 (late onset)CYP21基因缺陷最輕微，腎上腺皮質素和留鹽激素的分泌正常，但雄性素的濃度仍較高，患者出現症狀的期間不一定。 又區分為典型即非典型:鹽分喪失及單純男化形為典型，晚發作型即為非典型。

14. The 21-Hydroxylase Gene
C4A
CYP21P
C4B
CYP21
The 21-hydroxylase (CYP21) gene and its pseudogene (CYP21P) are located at 6p21.3
Analysis of CYP21 is complicated due to the high sequence homology between CYP21 and CYP21P
5% mutant alleles not generated by recombination (97%) deletions; unequal crossing over, point mutations gene conversion where one or more deleterious mutations in CYP21P are transferred to CYP21

15. Clinical Manifestations
Glucocorticoid
Weight loss
Weakness
Glucose↓
Minerocorticoid
(aldosterone)
-Anorexia
-Vomiting
-Dehydration
-BP ↓
-Na ↓
-K↑
Nelson Textbook of Pediatrics 19th edition

16. Clinical Manifestations
Prenatal androgen excess
Clitoromegaly
Ambiguous genitalia
Urogenital sinus
precursors 17-hydroxyprogesterone(androstenedione -> testosterone GA 8-10 wk )
labial fusion
Nelson Textbook of Pediatrics 19th edition

17. Clinical Manifestations
Postnatal androgen excess
Rapid somatic growth
Precocious puberty
rapid somatic growth and accelerated skeletal maturation. tall in childhood but premature closure of the epiphyses Muscular development may be excessive. Pubic and axillary hair may appear; and acne and a deep voice may develop. The penis, scrotum, and prostate may become enlarged in affected boys; however, the testes are usually prepubertal in size so that they appear relatively small in contrast to the enlarged penis.
Nelson Textbook of Pediatrics 19th edition

18. Clinical manifestations- Age of onset
boys with SW-type 21-OHD detected by the par-ents was significantly younger than those with SV-type (8 days vs. 4.5 years; p < 0.01). The situationwas similar for girls. However, boys were detectedat a later age than girls for both SW- and SV-type21-OHD.
J Formos Med Assoc. 2010 Feb;109(2):

19. Clinical manifestations-Common symptoms in pre-screening era
SW-type 21-OHD 
Dehydration
Poor feeding
Failure to thrive
Clitoromegaly
Ambiguous genitalia
Boys with SV-type 21-OHD 
Rapid growth
Tall stature
Advanced bone age
Girls with SV-type 21-OHD 
Clitoromegaly
SW-type 21-OHD were dehydration, poor feeding, and failure to thrive, and the most frequent initial clinical manifestations in girls with SW-type were clitoromegaly, dehydra-tion, and ambiguous genitalia. Conversely, the most frequent clinical manifestations of boys with
SV-type 21-OHD were rapid growth, tall stature, and advanced bone age, whereas the most frequent initial clinical manifestations in girls with SV- type were clitoromegaly and advanced bone age.
J Formos Med Assoc. 2010 Feb;109(2):

20. Laboratory Findings lab Salt lossing Virilizing Na ↓ N K ↑ pH Glucose
Cortisol
androstenedione and testosterone
ACTH
17-OHP
Corticotropin (ACTH) levels are elevated but have no diagnostic utility over 17-hydroxyprogesterone levels.
↑ 17-hydroxyprogesterone (But high during the first 2-3 days)
Cortisol ↓ salt-losing type. Normal simple virilizing type but inappropriately low in relation to the ACTH and 17-hydroxyprogesterone levels.
salt-losing disease ↓ Na , ↑ K, ↓ pH, ↓ glucose (1-2 wk)
androstenedione and testosterone ↑ females; normal infant males >childhood.
17-OHP before and 30 or 60 min after an IV bolus of mg of cosyntropin (ACTH 1-24).
100ng/ml
Nelson Textbook of Pediatrics 19th edition

21. Prenatal Diagnosis and Treatment
late 1st trimester or 2nd trimester with an affected child (chorionic villi sampling or aminocentesis)
Dexamethasone(DEX) since GA 6 wks
determine the sex and genotype of the fetus
affected females  keep till birth
affected males  no need of treatment
dexamethasone (20 μg/kg prepregnancy maternal weight BID TID) 6 wk
Nelson Textbook of Pediatrics 19th edition

22. Newborn Screening 17-hydroxyprogesterone
Positive->additional testing (electrolytes and repeat 17-hydroxyprogesterone) at 2 wk.
國內自89年(2000)7月開始於新生兒篩檢中增列先天性腎上腺增生症
Nonclassic form not reliably detected by newborn screening, but of little clinical significance
Nelson Textbook of Pediatrics 19th edition

25. Treatment
Glucocorticoid replacement classic mg/m2/24 hr of hydrocortisone TID nonclassic not necessary
Mineralocorticoid replacement Infants fludrocortisone mg BID + sodium supplementation (1-3 g) -> children mg daily
Surgical management of ambiguous genitalia
Stress dose(illness, surgery or trauma): normal dose x2 or 3
In general, desirable 17-hydroxyprogesterone levels are in the high normal range or several times normal; low-normal levels can usually be achieved only with excessive glucocorticoid doses.
GLUCOCORTICOID REPLACEMENT classic mg/m2/24 hr of hydrocortisone (maintain linear growth along percentile lines Pubertal development skeletal maturation 17-hydroxyprogesterone and androstenedione) TID Stress: x2 or 3
simple virilizing disease (delayed diagnosis): spontaneous gonadotropin-dependent puberty (superimposed true precocious puberty gonadotropin hormone-releasing hormone analogue)
Nonclassic not necessary
adrenal rest testicular tumors (↓if steroid dosage ↑ MRI echo)
MINERALOCORTICOID REPLACEMENT fludrocortisone
Infants mg BID + sodium supplementation (1-3 g) -> children mg daily
vital signs; tachycardia and hypertension electrolytes Plasma renin activity
SURGICAL MANAGEMENT OF AMBIGUOUS GENITALIA (4-12 mo )
Testis-sparing surgery for steroid-unresponsive tumors
Nelson Textbook of Pediatrics 19th edition

26. 3ng/ml

27. Take home massage
Classic CAH due to 21-Hydroxylase Deficiency can be classified into salt wasting type which includes electrolytes and simple virilizing type which presents with rapid growth and precocious puberty.
Diagnosis rely on 17-OHP, ACTH, T.T., electrolytes.
Management by Cortisone and Flurinef
Newborn screen can avoid delayed diagnosis and adrenal crisis.
Prenatal genetic screening can prevent female genital virilization by early treament with dexamethasone and also prevent unnecessary exposure to dexamethasone of males.