journal club 2006.11.30 diabetes and endocrine department kameda medical center masahiro, masuzawa

Journal Club 2006.11.30

Diabetes and Endocrine Department

Kameda Medical Center

Masahiro, Masuzawa

Extensive clinical experienceNon-classical 21-Hydroxylase

deficiency

Maria I, NewDepartment of Pediatrics Mount Sinai School of Medicine, New York,

New York 10029

JCEM 2006 91(11):4205-4214

Copyright ©2006 The Endocrine Society

New, M. I. J Clin Endocrinol Metab 2006;91:4205-4214

FIG. 1. Scheme of adrenal steroid synthesis

Figure 1. Pathways of steroid biosynthesis. The pathways for synthesis of progesterone and mineralocorticoids (aldosterone), glucocorticoids (cortisol), androgens (testosterone and dihydrotestosterone), and estrogens (estradiol) are arranged from left to right. The enzymatic activities catalyzing each bioconversion are written in boxes. For those activities mediated by specific cytochromes P450, the systematic name of the enzyme ("CYP" followed by a number) is listed in parentheses. CYP11B2 and CYP17 have multiple activities. The planar structures of cholesterol, aldosterone, cortisol, dihydrotestosterone, and estradiol are placed near the corresponding labels. 　 Endocrine Review 2000;21(3) 245-291

Disease

21-Hydroxylase deficiency

11ß-Hydroxylase deficiency

Aldosterone synthase deficiency

17 -Hydroxylase deficiency

3ß-Hydroxysteroid dehydrogenase deficiency

Lipoid hyperplasi

a

Defective gene CYP21 CYP11B1 CYP11B2 CYP17 HSD3B2 STAR

Alias P450c21 P450c11 P450aldo P450c17 3ß-HSDChromosomal location

6p21.3 8q24.3 8q24.3 10q24.3 1p13.1 8p11.2

Ambiguous genitalia

+ in ♀ + in ♀ No + in♂ + in ♂ + in♂

No puberty in♀ Mild in ♀ No puberty in♀

Addisonian crisis

+ Rare Salt wasting only No + ++

Incidence (gen. pop.)

1:10–18,000 1:100,000 Rare Rare Rare Rare

HormonesGlucocorticoids ↓ ↓ Normal Corticosterone

normal ↓ 　↓

Mineralocorticoids

↓ ↑ ↓ ↑ ↓ ↓

Androgens ↑ 　↑ Normal ↓ ↓in ♂ ↓ ↑in ♀

Estrogens Relatively ↓ in ♀

Relatively↓ in ♀

Normal ↓ ↓ ↓

PhysiologyBlood pressure ↓ ↑ ↓ ↑ ↓ ↓

Na balance ↓ ↑ ↓ ↑ ↓ 　↓ K balance ↑ ↓ ↑ ↓ ↑ ↑

Acidosis + ± Alkalosis + ± Alkalosis + +

Elevated metabolites

17-OHP DOC, 11-deoxycortisol

Corticosterone,±18-hydroxy-corticosterone

DOC corticosterone,

DHEA, 17Δ 5Preg None

17-OHP, 17-Hydroxyprogesterone; DOC, deoxycorticosterone; DHEA, dehydroepiandrosterone; 17Δ5Preg, 17-Δ5-hydroxypregnenolone.

Table 2. Characteristics of different forms of congenital adrenal hyperplasia

Endocrine Reviews 21 (3): 245-291

Phenotype:Classic salt wasting Classic simple virilizing Nonclassic

♂ ♀ ♂ ♀ ♂ ♀

Age at diagnosis Newborn-6m Newborn-1m 2–4 y Newborn-2 y Child-adult Child-adult

Genitalia Normal Ambiguous Normal Ambiguous Normal +/- ↑ clitoris

Aldosterone↓ Normal Normal

Renin↑ 　　 May be↑ Normal

Cortisol ↓ ↓ Normal

17-OH-progesterone>20,000 ng/dl >10,000–20,000 ng/dl 1,500–10,000 ng/dl (ACTH-stimulated)

Testosterone 　↑ In pre-puberty only 　　　　↑

↑In pre-puberty ↑only

Variably ↑in pre-puberty only

Variably↑

Treatment Glucocorticoid+ mineralocorticoid (+ sodium) Glucocorticoid (+ mineralocorticoid) Glucocorticoid, if symptomatic

Somatic growth1 -2-3 SD, husky-obese -1-2 SD ?-1 SD

Incidence21/20,000 1/60,000 1/1000

Typical mutations3

Deletion I172N V281LLarge conversion nt 656g P30L

nt 656g ("intron 2 g")G110Δ8nt

I236N/V237E/M239KQ318XR356W

% Enzymatic activity4 0 1 20–50

1 SD, Standard deviation scores. 2 Incidence in general white population. See Table 3 for incidence of classic disease (salt wasting plus simple virilizing) from neonatal screening in various populations. 3 See Table 4 and Section VI.F. 4 Enzymatic activity predicted from in vitro expression studies (see Section VI.F). Endocrine Reviews 21 (3): 245-291

Table 1. Characteristics of different clinical forms of 21-hydroxylase deficiency

Copyright ©2006 The Endocrine SocietyNew, M. I. J Clin Endocrinol Metab 2006;91:4205-4214

FIG. 2. Clinical spectrum of classical and nonclassical 21OHD

PCO diagnostic criteria

(1) polycystic ovaries by sonography(2) clinical or biochemical evidence of androgen

excess(3) chronic menstrual abnormalities or anovulation,

in addition to exclusion of other known disorders

• Dr Geoffrey Hendy reported 10% of PCOS patients were proven to have

NC21OHD.



FIG. 6. HLA region of chromosome 6p

21B is the active gene, whereas 21A is the pseudogene. I, II, III, Major Histocompatibility Complex I, II, and III; DP, DP-antigen gene; DR, DR-antigen gene; DQ, DQ-antigen gene; C4, C4 complement genes; Bf, complement factor B gene; C2, C2 complement genes; B, B-antigen gene; C, C-antigen gene; A, A-antigen gene.



FIG. 7. The two homologs: CYP21A2 (the active gene) and CYP21A1P (the pseudogene)

Noncorrespondent bases number less than 90 over a distance of 5.1 kb of DNA. Numbered are the pseudogene base changes that are frequently identified on mutant CYP21A2 genes responsible for 21OHD. Mutations associated with NC21OHD are indicated with black squares (exons 1, 7, 8, and 10).

Region Incidence No. detected/ no. screened Reference1

Alaska, Yupik Eskimos 1:280 5/1,131 (221)

France, La Reunion 1:2,100 7/14,987 (81)

Sweden 1:9,800 73/not given (225)

United States, Wisconsin 1:11,000 14/149,684 (217)

France, Lille 1:13,000 31/408,138 (539)

Japan 1:18,000 Not given/4,500,000 (232)

United States, Texas 1:16,000 121/1,936,998 (218)

Scotland 1:17,000 7/119,960 (81)

Italy 1:18,000 27/420,960 (224)

New Zealand 1:23,000 23/536,915 (223)

Table 3. Frequency of classic 21-hydroxylase deficiency determined from neonatal screening (representative populations)

Endocrine Reviews 21 (3): 245-291

TABLE 1. Common gene mutations of the 21-hydroxylase gene CYP21A2 (75 )

Exon/intron Mutation type MutationPhenoty

peSeverity of enzyme defect (% enzyme

activity) Ref.

Nonclassical mutations

Exon 1 Missense mutation P30L NC Mild (30–60%) 3

Exon 7 Missense mutation V281L NC Mild (20–50%) 5

Exon 81 Missense mutation R339H1 NC Mild (20–50%) 4

Exon 101 Missense mutation P453S1 NC Mild (20–50%) 4

Classical mutations

Deletion 30-kb deletion SW Severe (0%) 66

Intron 2 Aberrant splicing of intron 2

656 A/C-G SW, SV Severe (ND) 76

Exon 3 Eight-base deletion G110 Δ 8nt SW Severe (0%) 93

Exon 4 Missense mutation I172N SV Severe (1%) 79 80

Exon 6 Cluster I236N, V237E, M239K

SW Severe (0%) 79 80

Exon 8 Nonsense mutation Q318X SW Severe (0%) 87

Exon 8 Missense mutation R356W SW, SV Severe (0%) 81

Exon 101 Missense mutation R483P1 SW Severe (1–2%) 42

SW, Salt wasting; SV, simple virilizing; NC, nonclassical; ND, not determined. 1 Not routinely assayed.

TABLE 3. Disease frequencies in various ethnic groups

Ethnic group nDisease

frequencyCarrier

frequency

Ashkenazi Jews 56 1:27 1:3

Hispanics 9 1:40 1:4

Slavics1 8 1:50 1:5

Italians 12 1:300 1:10

Heterogeneous population of New York City

249

1:100 1:6

1 From Croatia.

TABLE 4. Ethnic-specific genotype frequencies (%) of NC21OHD probands

Ethnic group n Exon 7/Exon 7 Exon 7/Intron 2 Deletion/Exon 7 Other

Ashkenazi Jews 140 50 18 18 14

African-Americans 4 25 0 0 75

Hispanics 33 24 27 21 28

Italian-Americans 48 17 19 15 49

Non-Jewish Caucasians 92 17 16 7 60

Total 317 31 18 15 36



FIG. 8. Disease frequencies in different ethnic groups

TABLE 2. Hormonal measurements of NC21OHD patients in neonates (unpublished data)

Normal values (ng/dl)0-d-old female 0-d-old male

Female treated until term

17-OHP Males and females: <420

458 2094 212

Δ 4-Androstenedione Males and females: <290

368 125 20

Testosterone Males: <187 56

Females: <24 60 Blank

Mutations in 21-OH gene

V281L/V281L

V281L/R356W

Unknown

Figure 7. Levels of 17-OHP in dried blood samples from the Wisconsin neonatal screening program, plotted against birth weight. The heavy line represents mean values and the dotted lines represent 95% confidence limits. The heavy dashed line denotes threshold notification values in the Wisconsin program for infants of various birth weights. [Adapted from Ref. 217]. Endocrine Reviews 21 (3): 245-291



FIG. 5. Nomogram relating baseline to ACTH-stimulated serum concentrations of 17-OHP

Figure 8. Nomogram for comparing 17-OHP levels before and 60 min after a 0.25 mg iv bolus of cosyntropin in subjects with or without 21-hydroxylase deficiency. Note that the values for normals and heterozygotes (carriers) overlap. [Adapted from Ref. 35.] Endocrine Reviews 21 (3): 245-291

TABLE 5. NC21OHD females with prenatal diagnosis and treatment

Patient

Dex

Birth year

Prader score

Dex treatment (wk)

Diagnosis procedure

Paternal mutation

Maternal mutation

1 No

2002 F Amnio Exon 7 Exon 7

2 No


3 No


4 No


5 Yes

1991 F 10–40 CVS HLA HLA

6 Yes

1997 F 4–41 Amnio Exon 7 Deletion

7 Yes

1997 F 10–40 Amnio Exon 1 Exon 7

8 Yes

2005 F 9–40 CVS Exon 7 Exon 7

Dex, Prenatal dexamethasone treatment; Amnio, amniocentesis; CVS, chorionic villus sampling.

TABLE 6. NC21OHD males with prenatal diagnosis and treatment

Patient

Dex

Birth year Dex treatment (wk) Diagnosis procedure Paternal mutation Maternal mutation

1 No 1986 CVS Exon 7 Exon 8356

2 No 1999 Amnio Exon 1 Intron 2

3 No 2000 Amnio Exon 7 Exon 7



6 Yes

1994 8–11.7 CVS Exon 7 Deletion

7 Yes

1995 3–7 CVS Exon1, intron 2 Exon 7

8 Yes

1995 7–18 Amnio Exon 7 Deletion

9 Yes

2000 1–40 CVS Exon 7 Exon 8318

10 Yes

2001 4–13 CVS Exon 7 Exon 8318

Dex, Prenatal dexamethasone treatment; Amnio, amniocentesis; CVS, chorionic villus sampling.

FIG. 10. Algorithm for prenatal diagnosis and treatment of 21-OHD. The mother comes for prenatal diagnosis, and dexamethasone treatment is started blind to the sex or affection status of the fetus. Dexamethasone treatment would be terminated if the fetus has a male sex, is an unaffected female fetus, or is a nonclassical patient based on genotype. A female fetus with classical 21OHD is treated until term. hCG, Human chorionic gonadotropin; GA, gestational age.



FIG. 9. Prenatal genetic diagnosis and treatment of pregnancies for classical 21OHD

Figure 6. Flowchart for decisions pertaining to newborn screening for 21-hydroxylase deficiency. ACTH stim 17-OHP, 17-Hydroxyprogesterone level after cosyntropin stimulation; 'lytes, electrolytes. Endocrine Reviews 21 (3): 245-291



FIG. 11. Reversibility of symptoms in patients with NC21OHD (n = 20)

TABLE 7. National health care burden for treatment of hyperandrogenic signs associated with NC21OHD

Annual expenditure on remedies Cost Source

Total skin care $5 billion to $6 billion annually Richard Granstein, M.D., Chairman of Dermatology, NYPH-WMC

Acne over-the-counter treatment

$324 million annually www.drugtopics.com

(D. P. Hamacher & Associates)

Acne prescription drugs

$350 per 2 wk of Benzaclin, topical retinoid, and antibiotics

Diane Berson, M.D., Dermatologist, Women’s Center, NYPH-WMC

Hirsutism

Laser treatment $2000 per five sessions Diane Berson, M.D., Dermatologist, Women’s Center, NYPH-WMC

Electrolysis $1200/yr (12 sessions/yr) American Electrolysis Association

NYPH-WMC, New York Presbyterian Hospital-Weill Medical College.

http://www.drugtopics.com/

Figure 2. Time course of prenatal sexual differentiation in male and female fetuses. Top, Amniotic fluid levels of 17-OHP at various ages of gestation. The scale is logarithmic. Open squares denote mean values in fetuses affected with 21-hydroxylase deficiency, and closed circles denote mean values in normal infants. Vertical lines denote 95% confidence limits [adapted from Ref. 500]. Bottom, Timelines for five aspects of sexual differentiation [adapted from Ref. 541]. Note that 17-OHP levels are already markedly elevated in affected fetuses during development of the external genitalia. Endocrine Reviews 21 (3): 245-291

Figure 3. Normal and abnormal differentiation of the urogenital sinus and external genitalia (cross-sectional view). Diagrams of normal female and male anatomy flank a series of schematic representations of different degrees of virilization of females, graded using the scale developed by Prader (64 ). [Adapted from Refs. 64 and 213]. Note that the uterus persists in virilized females even when the external genitalia have a completely masculine appearance (Prader grade 5). Endocrine Reviews 21 (3): 245-291

Figure 4. Normal and abnormal differentiation of the external genitalia (external view). Diagrams of normal female and male anatomy flank a series of schematic representations of different degrees of virilization, graded using the scale developed by Prader (64 ). [Adapted from Refs. 64 and 213]. Endocrine Reviews 21 (3): 245-291

Figure 5. Simplified flowchart for initial evaluation of ambiguous genitalia. Decision points are denoted by diamonds, and endpoints by rectangles. Note that a karyotype is almost invariably performed, although palpation of gonads and a pelvic sonogram permit a tentative sex assignment in many cases. Endocrine Reviews 21 (3): 245-291

journal club 2006.11.30 diabetes and endocrine department kameda medical center masahiro, masuzawa

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