21-hydroxylase deficiency history and symptoms
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Mehrian Jafarizade, M.D [2]
Overview
Classic CAH salt-wasting CAH Baby girls with ambiguous genitalia with life-threatening cases of vomiting, weight loss and dehydration in a baby’s first few weeks of life or simple virilizing CAH but girls will have ambiguous genitalia. baby boys may have enlarged penises. nonclassic or late onset CAH Patients don't show any signs in early life but show premature pubarche, acne, hirsutism.
History and Symptoms
Symptom of 21-hydroxylase deficiency ranges from severe to mild or asymptomatic forms, depending on the degree of 21-hydroxylase enzyme deficiency. There are three main clinical phenotypes: classic salt-wasting, classic non-salt-wasting (simple virilizing), and non-classic (late-onset):
| 21-OH deficiency type | Common symptoms | Less common symptoms | ||||
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| Child | Female | Male | Child | Female | Male | |
| Classical salt wasting |
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| Classical non-salt wasting |
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| Late onset disease |
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in the ovary are rare [72], unlike in male patients, who often have testicular adrenal rest tumors (see 'Testicular adrenal rests' below). In addition to the ovary, adrenal rest tumors have been found in the paraovarian/adnexal area. The tumors are difficult to identify by imaging, and most have been identified during surgery or at autopsy. Imaging with 18FDG-PET/CT localized rest tissue in three women [73-75] (including one with Nelson’s syndrome); in one case, tumors were only visible after administration of cosyntropin [74]. The etiology appears related to sustained elevations in ACTH. Male reproduction — Reproductive function may be impaired in men with 21-hydroxylase deficiency. Affected boys or young men may have no symptoms or signs of androgen excess. However, they may have testicular masses composed of adrenal tissue. Testicular adrenal rests — Testicular adrenal rest tumors, which are testicular masses composed of adrenal-like tissue, are common in male patients with 21-hydroxylase deficiency [76-78]. Confirmation that these tumors resemble adrenal tissue comes from a study of eight adult patients who underwent testis-sparing surgery [79]. Adrenal-specific steroid secretion was documented with preoperative spermatic vein sampling, and expression of adrenal-specific enzymes and ACTH receptors was confirmed in tumor tissue. The clinical features of testicular rest tumors include: ● They are usually diagnosed between the ages of 10 and 20 years, but may be found as early as age five [80-82]. In one report of 34 boys with classic 21-hydroxylase deficiency between the ages of 2 and 18 years who were undergoing testicular ultrasonography, eight (24 percent) were diagnosed with testicular adrenal rests; two of the boys were age seven [82]. A similar prevalence was reported in a second report of 19 boys (mean age 5.6 years, range 2 to 10 years) [83]. Inhibin B and anti-müllerian hormone concentrations were lower in patients compared with age-matched controls, suggesting that gonadal dysfunction was also present.
● Ultrasound studies suggest that the majority of adolescent and adult males with 21-hydroxylase deficiency have testicular adrenal rests (18 of 21 [86 percent] and 16 of 17 [94 percent] in two reports) [77,78,84].
● They are more common in patients with the salt-losing form than the simple virilizing form, as the former tend to have poorer control and higher ACTH concentrations [85]. However, a correlation between ACTH levels and tumor growth is not always seen [76,77].
● They are typically bilateral and vary in size from 2 to 40 mm in diameter [78].
● They may lead to obstruction of seminiferous tubules, gonadal dysfunction, and infertility (see 'Infertility' below).
● Some, but not all, regress during glucocorticoid therapy [86,87]. A minority of patients with large adrenal rest tumors eventually requires surgery for pain relief. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults", section on 'Testicular adrenal rest tumors'.)
Because of the high prevalence of testicular adrenal rests and their association with infertility in male patients with 21-hydroxylase deficiency, we suggest screening testicular ultrasonography in adolescence or early adulthood [78]. Infertility — Most men with 21-hydroxylase deficiency are fertile as adults, but others have evidence of Leydig cell failure or impaired spermatogenesis [77,78,88]. As noted above, testicular adrenal rests may be associated with seminiferous tubule obstruction, gonadal dysfunction, and infertility. (See 'Testicular adrenal rests' above.) In one study of 17 adolescent and adult men, serum testosterone concentrations were low in six, and seven had abnormal semen analyses [77]. In a second report of 30 men, those with adrenal rests in the testes were more likely to be infertile [76]. Epinephrine deficiency — Adrenomedullary function is compromised in patients with classic CAH, as illustrated in a study of 38 children with classic 21-hydroxylase deficiency. Plasma epinephrine and metanephrine concentrations and urinary epinephrine excretion were 40 to 80 percent lower than in normal subjects [89]. In three patients who underwent bilateral adrenalectomy, the adrenal medulla was poorly formed and the cells contained few vesicles. In a second study, the epinephrine response to exercise was significantly reduced in patients with classic 21-hydroxylase deficiency compared with healthy volunteers [90], and stress doses of hydrocortisone did not improve the response [91]. Thus, 21-hydroxylase deficiency compromises both the development and subsequent functioning of the adrenomedullary system in severely affected cases. The combination of cortisol deficiency and epinephrine deficiency puts patients at risk for hypoglycemia with illness or prolonged fasting [90]. Adrenomedullary function has not been studied in patients with nonclassic CAH. Other findings — Other clinical findings that have been described include adrenal incidentalomas, pituitary adenomas, insulin resistance, and hyperleptinemia. ● Although 60 percent of patients with unilateral adrenal incidentalomas, and even more of those with bilateral incidentalomas, have exaggerated serum 17-hydroxyprogesterone responses to ACTH stimulation [1], the prevalence of germline CYP21A2 mutations is low. However, unilateral and bilateral adrenal incidentalomas were found in 10 of 12 patients with simple virilizing and five of seven patients with late-onset CAH, as well as 9 of 10 heterozygotic siblings [92]. Most tumors had a diameter of less than 2 cm, but three patients had masses more than 5 cm in size. Adrenal masses in children with CYP21A2 deficiency are usually benign [1].
● Pituitary microadenomas or empty sella may be found, but symptomatic corticotroph tumors have not been reported [1,93].
● Insulin resistance has been reported in patients with both classic [94] and nonclassic [95] 21-hydroxylase deficiency. Hyperandrogenism, glucocorticoid therapy, and epinephrine deficiency have all been implicated as possible risk factors for insulin resistance [14,94,95]. Hyperleptinemia has also been reported [94,96].
Congenital adrenal hyperplasia symotpms differ according to type of disease and gender of patient:
Classic CAH or early onset:
Classic cases of congenital adrenal hyperplasia come in two forms:
Salt-wasting CAH
- Baby girls with ambiguous genitalia.
- Baby boys may have enlarged penises and develop masculine features before puberty.
- Salt-wasting CAH can lead to life-threatening cases of vomiting, weight loss and dehydration in a baby’s first few weeks of life.
simple virilizing CAH
- Patients don't show hypotension, hyperkalemia and acidosis crisis but:
- Girls will have ambiguous genitalia.
- Baby boys may have enlarged penises.
Nonclassic or late onset CAH
Patients don't show any signs in early life but show premature puberty, acne, hirsutism, and menstrual irregularity.
- Children with CAH are at risk for adult short stature due to high levels of sex hormones causing premature epiphyseal closure.[1]
- Female patients with classic CAH have more male-typical palying[2]and greater aggressive tendencies.
- Fertility rates in women are low.[3]Hyperandrogenism results in anovulatory cycles.[4]Genital malformations from congenital ambiguous genitals may contribute to low fertility.[5]Careful management with monitoring of androgen levels during gestation is indicated.[6]
- Males show testicular adrenal tumors which are testicular masses of adrenal-like tissue.[7]They are more common in patients with the salt-losing form than the simple virilizing form.[8]They may lead to obstruction of seminiferous tubules and infertility. Other causes of low fertility is impaired spermatogenesis.[9]
- Fertility rates are related to the severity of the mutation.[10]
References
- ↑ Eugster EA, Dimeglio LA, Wright JC, Freidenberg GR, Seshadri R, Pescovitz OH (2001). "Height outcome in congenital adrenal hyperplasia caused by 21-hydroxylase deficiency: a meta-analysis". J Pediatr. 138 (1): 26–32. doi:10.1067/mpd.2001.110527. PMID 11148508.
- ↑ Mathews GA, Fane BA, Conway GS, Brook CG, Hines M (2009). "Personality and congenital adrenal hyperplasia: possible effects of prenatal androgen exposure". Horm Behav. 55 (2): 285–91. doi:10.1016/j.yhbeh.2008.11.007. PMC 3296092. PMID 19100266.
- ↑ Mulaikal RM, Migeon CJ, Rock JA (1987). "Fertility rates in female patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency". N Engl J Med. 316 (4): 178–82. doi:10.1056/NEJM198701223160402. PMID 3491959.
- ↑ Stikkelbroeck NM, Hermus AR, Braat DD, Otten BJ (2003). "Fertility in women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency". Obstet Gynecol Surv. 58 (4): 275–84. doi:10.1097/01.OGX.0000062966.93819.5B. PMID 12665708.
- ↑ Hagenfeldt K, Janson PO, Holmdahl G, Falhammar H, Filipsson H, Frisén L; et al. (2008). "Fertility and pregnancy outcome in women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency". Hum Reprod. 23 (7): 1607–13. doi:10.1093/humrep/den118. PMID 18420648.
- ↑ Lo JC, Schwitzgebel VM, Tyrrell JB, Fitzgerald PA, Kaplan SL, Conte FA; et al. (1999). "Normal female infants born of mothers with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency". J Clin Endocrinol Metab. 84 (3): 930–6. doi:10.1210/jcem.84.3.5565. PMID 10084573.
- ↑ Stikkelbroeck NM, Suliman HM, Otten BJ, Hermus AR, Blickman JG, Jager GJ (2003). "Testicular adrenal rest tumours in postpubertal males with congenital adrenal hyperplasia: sonographic and MR features". Eur Radiol. 13 (7): 1597–603. doi:10.1007/s00330-002-1786-3. PMID 12835972.
- ↑ Stikkelbroeck NM, Hermus AR, Suliman HM, Jager GJ, Otten BJ (2004). "Asymptomatic testicular adrenal rest tumours in adolescent and adult males with congenital adrenal hyperplasia: basal and follow-up investigation after 2.6 years". J Pediatr Endocrinol Metab. 17 (4): 645–53. PMID 15198296.
- ↑ Stikkelbroeck NM, Suliman HM, Otten BJ, Hermus AR, Blickman JG, Jager GJ (2003). "Testicular adrenal rest tumours in postpubertal males with congenital adrenal hyperplasia: sonographic and MR features". Eur Radiol. 13 (7): 1597–603. doi:10.1007/s00330-002-1786-3. PMID 12835972.
- ↑ Nordenskjöld A, Holmdahl G, Frisén L, Falhammar H, Filipsson H, Thorén M; et al. (2008). "Type of mutation and surgical procedure affect long-term quality of life for women with congenital adrenal hyperplasia". J Clin Endocrinol Metab. 93 (2): 380–6. doi:10.1210/jc.2007-0556. PMID 18029470.
Symptoms of 21-hydroxylase deficient congenital adrenal hyperplasia include:
Symptoms of adrenal hyperplasia in infants
In this form of congenital adrenal hyperplasia, newborns develop severe symptoms shortly after birth due to loss of salt, which include:
Symptoms of adrenal hyperplasia in children
- Ambiguous genitalia or virilizing genitalia in girls (often appearing more male than female: deep voice, early appearance of pubic and armpit hair, and excessive hair growth and facial hair)
- Early appearance of masculinization characteristics in boys (deep voice, early appearance of pubic and armpit hair, enlarged penis, small testes, and well-developed muscles)
Symptoms of adrenal hyperplasia in adults
Symptoms of adrenal hyperplasia in children and adults may include:
- Metrorrhagia and amenorrhea in girls
- Infertility