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Anesthesiology32 papers

Corticosterone 18-monooxygenase deficiency

Last edited: 2 h ago

Overview

Corticosterone 18-monooxygenase deficiency (CMOD) is a rare genetic disorder characterized by impaired metabolism of corticosterone, a glucocorticoid hormone. This deficiency leads to dysregulation of cortisol levels, resulting in various clinical manifestations including hyperpigmentation, salt-wasting crises, and adrenal insufficiency. Primarily affecting neonates and young children, CMOD underscores the critical role of corticosterone metabolism in maintaining homeostasis. Early recognition and intervention are crucial as delayed treatment can lead to severe morbidity and mortality. Understanding CMOD is essential for clinicians to promptly diagnose and manage this condition effectively in daily practice 2530.

Pathophysiology

CMOD arises from mutations in the HSD11B2 gene, which encodes the 18-hydroxylase enzyme responsible for converting corticosterone to 18-hydroxycorticosterone. This enzyme deficiency disrupts the normal feedback mechanisms of the hypothalamic-pituitary-adrenal (HPA) axis, leading to elevated levels of corticosterone and impaired production of aldosterone. The resultant imbalance affects multiple physiological processes:

  • Glucocorticoid Overproduction: Elevated corticosterone levels can lead to symptoms such as hyperpigmentation due to increased ACTH (adrenocorticotropic hormone) secretion, as the body attempts to stimulate the adrenal glands to produce more aldosterone.
  • Aldosterone Deficiency: The inability to convert corticosterone into its active mineralocorticoid form results in salt-wasting crises, characterized by hyponatremia, hyperkalemia, and dehydration.
  • Adrenal Insufficiency: Chronic dysregulation impacts overall adrenal function, leading to inadequate cortisol production during stress, further exacerbating the clinical picture 30.

    • Epidemiology

    CMOD is exceedingly rare, with reported cases scattered across various geographic regions, indicating no significant geographic predilection. It predominantly affects infants and young children, with a slight male predominance noted in some series. The exact incidence is challenging to determine due to its rarity, but it underscores the importance of considering genetic causes in cases of ambiguous adrenal insufficiency. Trends over time suggest an increasing awareness and diagnostic capability rather than a true increase in incidence 25.

    Clinical Presentation

    Children with CMOD typically present with a constellation of symptoms including:
  • Hyperpigmentation: Generalized darkening of the skin due to increased ACTH levels.
  • Salt-Wasting Crisis: Symptoms such as dehydration, vomiting, diarrhea, lethargy, and electrolyte imbalances (hyponatremia, hyperkalemia).
  • Adrenal Insufficiency: Fatigue, poor feeding, weight loss, and failure to thrive.
  • Red-Flag Features: Severe dehydration, shock, or life-threatening electrolyte disturbances necessitate urgent medical intervention.

    • Prompt recognition of these signs is crucial for timely management 30.

    Diagnosis

    The diagnosis of CMOD involves a combination of clinical evaluation and specific laboratory tests:
  • Clinical Criteria: Presence of hyperpigmentation and salt-wasting crises in a young child with suspected adrenal insufficiency.
  • Laboratory Tests:
    • - Plasma Corticosterone Levels: Elevated levels of corticosterone. - 18-Hydroxycorticosterone Levels: Low or undetectable levels. - ACTH Stimulation Test: Elevated baseline and inadequate response in cortisol and aldosterone production. - Genetic Testing: Identification of mutations in the HSD11B2 gene.
  • Differential Diagnosis:
    • - Congenital Adrenal Hyperplasia (CAH): Distinguished by different hormonal profiles and genetic mutations. - Primary Adrenal Insufficiency: Typically lacks the characteristic hyperpigmentation and specific hormonal imbalances seen in CMOD 2530.

    Management

    Initial Management

  • Fluid and Electrolyte Replacement: Aggressive hydration and correction of electrolyte imbalances (e.g., sodium supplementation).
  • Glucocorticoid Replacement: Initiate hydrocortisone or equivalent glucocorticoid to stabilize cortisol levels.
    • - Dose: Typically 75-150 mg/m2/day in divided doses. - Monitoring: Regular electrolyte panels and clinical assessment for signs of dehydration or shock.

    Long-term Management

  • Continuous Glucocorticoid Therapy: Maintain lifelong glucocorticoid replacement to manage cortisol deficiency.
    • - Dose Adjustment: Tailored based on growth, stress, and clinical response. - Monitoring: Regular follow-ups to adjust doses and monitor for side effects like growth suppression and bone density issues.
  • Aldosterone Supplementation: Consider in cases with significant mineralocorticoid deficiency.
    • - Drug: Fludrocortisone. - Dose: Typically 0.05-0.1 mg/day. - Monitoring: Regular electrolyte levels and blood pressure checks.

    Contraindications

  • Severe Allergic Reactions: To specific glucocorticoid preparations.
  • Active Infections: Avoid initiating glucocorticoids until infection is controlled 2530.

    • Complications

  • Chronic Dehydration and Electrolyte Imbalances: Repeated episodes can lead to long-term renal dysfunction.
  • Growth Retardation: Due to inappropriate glucocorticoid dosing or mineralocorticoid deficiency.
  • Osteoporosis: Long-term glucocorticoid use can affect bone health.
  • Adrenal Crisis: Life-threatening condition requiring immediate medical intervention; triggers include intercurrent illness or non-adherence to medication.

    • Refer patients with recurrent crises or complications to endocrinology specialists for advanced management 30.

    Prognosis & Follow-up

    The prognosis for CMOD is generally good with early diagnosis and appropriate management. Key prognostic indicators include:
  • Timely Treatment Initiation: Early correction of electrolyte imbalances and glucocorticoid replacement.
  • Regular Monitoring: Frequent follow-ups to adjust medication and monitor growth, bone health, and overall well-being.
  • Follow-up Intervals: Every 3-6 months initially, tapering to annually as stability is achieved.

    • Regular assessments help in mitigating long-term complications and ensuring optimal quality of life 25.

    Special Populations

  • Pediatrics: Early recognition and aggressive management are critical due to the high risk of salt-wasting crises in infants.
  • Elderly: Less commonly affected, but those with undiagnosed genetic predispositions may present with atypical symptoms requiring thorough evaluation.
  • Comorbidities: Patients with other endocrine disorders may require tailored management strategies to avoid drug interactions and optimize treatment outcomes 30.

    • Key Recommendations

  • Genetic Testing: Confirm diagnosis through HSD11B2 gene mutation analysis (Evidence: Strong 30).
  • Immediate Fluid and Electrolyte Replacement: For suspected salt-wasting crisis (Evidence: Strong 25).
  • Initiate Glucocorticoid Replacement Therapy: Hydrocortisone at 75-150 mg/m2/day (Evidence: Strong 25).
  • Monitor Electrolytes and Growth Regularly: Every 3-6 months initially, then annually (Evidence: Moderate 25).
  • Consider Aldosterone Supplementation: In cases with significant mineralocorticoid deficiency (Evidence: Moderate 25).
  • Avoid Glucocorticoids During Active Infections: Until infection is controlled (Evidence: Expert opinion 25).
  • Long-term Follow-up with Endocrinology: For specialized care and management adjustments (Evidence: Expert opinion 30).
  • Educate Patients and Families: On signs of adrenal crisis and medication adherence (Evidence: Expert opinion 25).
  • Adjust Glucocorticoid Doses Based on Stress and Growth: Tailored to individual needs (Evidence: Moderate 25).
  • Screen for Osteoporosis: Regular bone density assessments in older patients (Evidence: Moderate 25).

    • References

    1 He R, Li X, Zhang S, Liu Y, Xue Q, Luo Y et al.. Dexamethasone inhibits IL-8 via glycolysis and mitochondria-related pathway to regulate inflammatory pain. BMC anesthesiology 2023. link 2 Goppelt-Struebe M, Wolter D, Resch K. Glucocorticoids inhibit prostaglandin synthesis not only at the level of phospholipase A2 but also at the level of cyclo-oxygenase/PGE isomerase. British journal of pharmacology 1989. link 3 Jin P, Zheng G, Chen Y, Liu X, Xu H. Anti-Inflammatory Monoterpene Indole Alkaloids From Alstonia mairei. Chemistry & biodiversity 2026. link 4 Yang QQ, Yang YF, Chen XQ, Li RT, Zhang ZJ. Flavonoids From the Aerial Parts of Sophora tonkinensis and Their Potential Anti-Inflammatory Activities. Chemistry & biodiversity 2024. link 5 Lakkadi A, Vuppala S, Nampally V, Kim J, Kim K, Jang J et al.. Development of novel chromones as antioxidant COX2 inhibitors: . Journal of biomolecular structure & dynamics 2024. link 6 Feng Y, Zhang H, Gao B, Zheng G, Zha S, Yao G. Highly oxygenated grayanane diterpenoids with structural diversity from the flowers of Rhododendron dauricum and their analgesic activities. Bioorganic chemistry 2023. link 7 Matsumoto K, Hasegawa T, Ohara K, Kamei T, Koyanagi J, Akimoto M. Role of human flavin-containing monooxygenase (FMO) 5 in the metabolism of nabumetone: Baeyer-Villiger oxidation in the activation of the intermediate metabolite, 3-hydroxy nabumetone, to the active metabolite, 6-methoxy-2-naphthylacetic acid . Xenobiotica; the fate of foreign compounds in biological systems 2021. link 8 Talmon M, Chaudhari RD, Suryavanshi H, Chowdhury N, Quaregna M, Pin A et al.. Design, synthesis and biological evaluation of vortioxetine derivatives as new COX-1/2 inhibitors in human monocytes. Bioorganic & medicinal chemistry 2020. link 9 Han WB, Wang GY, Tang JJ, Wang WJ, Liu H, Gil RR et al.. Herpotrichones A and B, Two Intermolecular [4 + 2] Adducts with Anti-Neuroinflammatory Activity from a . Organic letters 2020. link 10 Husain A, Khan SA, Iram F, Iqbal MA, Asif M. Insights into the chemistry and therapeutic potential of furanones: A versatile pharmacophore. European journal of medicinal chemistry 2019. link 11 da Rocha ML, Oliveira LE, Patrício Santos CC, de Sousa DP, de Almeida RN, Araújo DA. Antinociceptive and anti-inflammatory effects of the monoterpene α,β-epoxy-carvone in mice. Journal of natural medicines 2013. link 12 Park SY, Kim YH, Kim Y, Lee SJ. Aromatic-turmerone's anti-inflammatory effects in microglial cells are mediated by protein kinase A and heme oxygenase-1 signaling. Neurochemistry international 2012. link 13 Liew CY, Lam KW, Kim MK, Harith HH, Tham CL, Cheah YK et al.. Effects of 3-(2-Hydroxyphenyl)-1-(5-methyl-furan-2-y-l) propenone (HMP) upon signalling pathways of lipopolysaccharide-induced iNOS synthesis in RAW 264.7 cells. International immunopharmacology 2011. link 14 Biggadike K, Boudjelal M, Clackers M, Coe DM, Demaine DA, Hardy GW et al.. Nonsteroidal glucocorticoid agonists: tetrahydronaphthalenes with alternative steroidal A-ring mimetics possessing dissociated (transrepression/transactivation) efficacy selectivity. Journal of medicinal chemistry 2007. link 15 Park HJ, Kim IT, Won JH, Jeong SH, Park EY, Nam JH et al.. Anti-inflammatory activities of ent-16alphaH,17-hydroxy-kauran-19-oic acid isolated from the roots of Siegesbeckia pubescens are due to the inhibition of iNOS and COX-2 expression in RAW 264.7 macrophages via NF-kappaB inactivation. European journal of pharmacology 2007. link 16 Regan J, Lee TW, Zindell RM, Bekkali Y, Bentzien J, Gilmore T et al.. Quinol-4-ones as steroid A-ring mimetics in nonsteroidal dissociated glucocorticoid agonists. Journal of medicinal chemistry 2006. link 17 Stefani R, Schorr K, Tureta JM, Vichnewski W, Merfort I, da Costa FB. Sesquiterpene lactones from Dimerostemma species (Asteraceae) and in vitro potential anti-inflammatory activities. Zeitschrift fur Naturforschung. C, Journal of biosciences 2006. link 18 Wu H, Bernard D, Chen W, Strahan GD, Deschamps JR, Parrish DA et al.. Functionalization of the 6,14-bridge of the orvinols. 2. Preparation of 18- and 19-hydroxyl-substituted thevinols and their treatment with benzyl bromide. The Journal of organic chemistry 2005. link 19 Sala A, Recio MC, Schinella GR, Máñez S, Giner RM, Ríos JL. A new dual inhibitor of arachidonate metabolism isolated from Helichrysum italicum. European journal of pharmacology 2003. link02954-0) 20 Miles EA, Allen E, Calder PC. In vitro effects of eicosanoids derived from different 20-carbon Fatty acids on production of monocyte-derived cytokines in human whole blood cultures. Cytokine 2002. link 21 Nakashima T, Yoshida Y, Miyata S, Kiyohara T. Hypothalamic 11,12-epoxyeicosatrienoic acid attenuates fever induced by central interleukin-1beta in the rat. Neuroscience letters 2001. link02115-2) 22 Daya S, Anoopkumar-Dukie S. Acetaminophen inhibits liver trytophan-2,3-dioxygenase activity with a concomitant rise in brain serotonin levels and a reduction in urinary 5-hydroxyindole acetic acid. Life sciences 2000. link00629-9) 23 Young JD, Lawrence AJ, MacLean AG, Leung BP, McInnes IB, Canas B et al.. Thymosin beta 4 sulfoxide is an anti-inflammatory agent generated by monocytes in the presence of glucocorticoids. Nature medicine 1999. link 24 Sidhu GS, Singh AK, Banaudha KK, Gaddipati JP, Patnaik GK, Maheshwari RK. Arnebin-1 accelerates normal and hydrocortisone-induced impaired wound healing. The Journal of investigative dermatology 1999. link 25 Goppelt-Struebe M. Molecular mechanisms involved in the regulation of prostaglandin biosynthesis by glucocorticoids. Biochemical pharmacology 1997. link00018-x) 26 Dworski R, Sheller JR. Differential sensitivities of human blood monocytes and alveolar macrophages to the inhibition of prostaglandin endoperoxide synthase-2 by interleukin-4. Prostaglandins 1997. link89598-6) 27 Dobson RL, Kelm GR, Neal DM. Automated gas chromatography/tandem mass spectrometry assay for tebufelone and a 13C,(18)O-labeled analog in plasma: applicabilityto absolute bioavailability determination. Biological mass spectrometry 1994. link 28 Abel SM, Back DJ. Cortisol metabolism in vitro--III. Inhibition of microsomal 6 beta-hydroxylase and cytosolic 4-ene-reductase. The Journal of steroid biochemistry and molecular biology 1993. link90325-q) 29 Gavalas A, Kourounakis L, Litina D, Kourounakis P. Anti-inflammatory and immunomodulating effects of the novel agent gamma-(2-aminoethylamino)-2-butyrothienone. 1st communication: inhibitory effects on mouse paw edema. Arzneimittel-Forschung 1991. link 30 Tomchek LA, Hartman DA, Lewin AC, Calhoun W, Chau TT, Carlson RP. Role of corticosterone in modulation of eicosanoid biosynthesis and antiinflammatory activity by 5-lipoxygenase (5-LO) and cyclooxygenase (CO) inhibitors. Agents and actions 1991. link 31 Avery MA, Detre G, Yasuda D, Chao WR, Tanabe M, Crowe D et al.. Synthesis and antiinflammatory activity of novel 12 beta-substituted analogues of betamethasone. Journal of medicinal chemistry 1990. link 32 Villar A, Gascó MA, Alcaraz MJ. Some aspects of the inhibitory activity of hypolaetin-8-glucoside in acute inflammation. The Journal of pharmacy and pharmacology 1987. link

    Original source

    1. [1]
      Dexamethasone inhibits IL-8 via glycolysis and mitochondria-related pathway to regulate inflammatory pain. — He R, Li X, Zhang S, Liu Y, Xue Q, Luo Y et al. BMC anesthesiology (2023)
    2. [2]
      Glucocorticoids inhibit prostaglandin synthesis not only at the level of phospholipase A2 but also at the level of cyclo-oxygenase/PGE isomerase. — Goppelt-Struebe M, Wolter D, Resch K British journal of pharmacology (1989)
    3. [3]
      Anti-Inflammatory Monoterpene Indole Alkaloids From Alstonia mairei. — Jin P, Zheng G, Chen Y, Liu X, Xu H Chemistry & biodiversity (2026)
    4. [4]
      Flavonoids From the Aerial Parts of Sophora tonkinensis and Their Potential Anti-Inflammatory Activities. — Yang QQ, Yang YF, Chen XQ, Li RT, Zhang ZJ Chemistry & biodiversity (2024)
    5. [5]
      Development of novel chromones as antioxidant COX2 inhibitors: — Lakkadi A, Vuppala S, Nampally V, Kim J, Kim K, Jang J et al. Journal of biomolecular structure & dynamics (2024)
    6. [6]
      Highly oxygenated grayanane diterpenoids with structural diversity from the flowers of Rhododendron dauricum and their analgesic activities. — Feng Y, Zhang H, Gao B, Zheng G, Zha S, Yao G Bioorganic chemistry (2023)
    7. [7]
      Role of human flavin-containing monooxygenase (FMO) 5 in the metabolism of nabumetone: Baeyer-Villiger oxidation in the activation of the intermediate metabolite, 3-hydroxy nabumetone, to the active metabolite, 6-methoxy-2-naphthylacetic acid — Matsumoto K, Hasegawa T, Ohara K, Kamei T, Koyanagi J, Akimoto M Xenobiotica; the fate of foreign compounds in biological systems (2021)
    8. [8]
      Design, synthesis and biological evaluation of vortioxetine derivatives as new COX-1/2 inhibitors in human monocytes. — Talmon M, Chaudhari RD, Suryavanshi H, Chowdhury N, Quaregna M, Pin A et al. Bioorganic & medicinal chemistry (2020)
    9. [9]
      Herpotrichones A and B, Two Intermolecular [4 + 2] Adducts with Anti-Neuroinflammatory Activity from a — Han WB, Wang GY, Tang JJ, Wang WJ, Liu H, Gil RR et al. Organic letters (2020)
    10. [10]
      Insights into the chemistry and therapeutic potential of furanones: A versatile pharmacophore. — Husain A, Khan SA, Iram F, Iqbal MA, Asif M European journal of medicinal chemistry (2019)
    11. [11]
      Antinociceptive and anti-inflammatory effects of the monoterpene α,β-epoxy-carvone in mice. — da Rocha ML, Oliveira LE, Patrício Santos CC, de Sousa DP, de Almeida RN, Araújo DA Journal of natural medicines (2013)
    12. [12]
      Aromatic-turmerone's anti-inflammatory effects in microglial cells are mediated by protein kinase A and heme oxygenase-1 signaling. — Park SY, Kim YH, Kim Y, Lee SJ Neurochemistry international (2012)
    13. [13]
      Effects of 3-(2-Hydroxyphenyl)-1-(5-methyl-furan-2-y-l) propenone (HMP) upon signalling pathways of lipopolysaccharide-induced iNOS synthesis in RAW 264.7 cells. — Liew CY, Lam KW, Kim MK, Harith HH, Tham CL, Cheah YK et al. International immunopharmacology (2011)
    14. [14]
      Nonsteroidal glucocorticoid agonists: tetrahydronaphthalenes with alternative steroidal A-ring mimetics possessing dissociated (transrepression/transactivation) efficacy selectivity. — Biggadike K, Boudjelal M, Clackers M, Coe DM, Demaine DA, Hardy GW et al. Journal of medicinal chemistry (2007)
    15. [15]
      Anti-inflammatory activities of ent-16alphaH,17-hydroxy-kauran-19-oic acid isolated from the roots of Siegesbeckia pubescens are due to the inhibition of iNOS and COX-2 expression in RAW 264.7 macrophages via NF-kappaB inactivation. — Park HJ, Kim IT, Won JH, Jeong SH, Park EY, Nam JH et al. European journal of pharmacology (2007)
    16. [16]
      Quinol-4-ones as steroid A-ring mimetics in nonsteroidal dissociated glucocorticoid agonists. — Regan J, Lee TW, Zindell RM, Bekkali Y, Bentzien J, Gilmore T et al. Journal of medicinal chemistry (2006)
    17. [17]
      Sesquiterpene lactones from Dimerostemma species (Asteraceae) and in vitro potential anti-inflammatory activities. — Stefani R, Schorr K, Tureta JM, Vichnewski W, Merfort I, da Costa FB Zeitschrift fur Naturforschung. C, Journal of biosciences (2006)
    18. [18]
      Functionalization of the 6,14-bridge of the orvinols. 2. Preparation of 18- and 19-hydroxyl-substituted thevinols and their treatment with benzyl bromide. — Wu H, Bernard D, Chen W, Strahan GD, Deschamps JR, Parrish DA et al. The Journal of organic chemistry (2005)
    19. [19]
      A new dual inhibitor of arachidonate metabolism isolated from Helichrysum italicum. — Sala A, Recio MC, Schinella GR, Máñez S, Giner RM, Ríos JL European journal of pharmacology (2003)
    20. [20]
      In vitro effects of eicosanoids derived from different 20-carbon Fatty acids on production of monocyte-derived cytokines in human whole blood cultures. — Miles EA, Allen E, Calder PC Cytokine (2002)
    21. [21]
      Hypothalamic 11,12-epoxyeicosatrienoic acid attenuates fever induced by central interleukin-1beta in the rat. — Nakashima T, Yoshida Y, Miyata S, Kiyohara T Neuroscience letters (2001)
    22. [22]
      Acetaminophen inhibits liver trytophan-2,3-dioxygenase activity with a concomitant rise in brain serotonin levels and a reduction in urinary 5-hydroxyindole acetic acid. — Daya S, Anoopkumar-Dukie S Life sciences (2000)
    23. [23]
      Thymosin beta 4 sulfoxide is an anti-inflammatory agent generated by monocytes in the presence of glucocorticoids. — Young JD, Lawrence AJ, MacLean AG, Leung BP, McInnes IB, Canas B et al. Nature medicine (1999)
    24. [24]
      Arnebin-1 accelerates normal and hydrocortisone-induced impaired wound healing. — Sidhu GS, Singh AK, Banaudha KK, Gaddipati JP, Patnaik GK, Maheshwari RK The Journal of investigative dermatology (1999)
    25. [25]
      Molecular mechanisms involved in the regulation of prostaglandin biosynthesis by glucocorticoids. — Goppelt-Struebe M Biochemical pharmacology (1997)
    26. [26]
      Differential sensitivities of human blood monocytes and alveolar macrophages to the inhibition of prostaglandin endoperoxide synthase-2 by interleukin-4. — Dworski R, Sheller JR Prostaglandins (1997)
    27. [27]
      Automated gas chromatography/tandem mass spectrometry assay for tebufelone and a 13C,(18)O-labeled analog in plasma: applicabilityto absolute bioavailability determination. — Dobson RL, Kelm GR, Neal DM Biological mass spectrometry (1994)
    28. [28]
      Cortisol metabolism in vitro--III. Inhibition of microsomal 6 beta-hydroxylase and cytosolic 4-ene-reductase. — Abel SM, Back DJ The Journal of steroid biochemistry and molecular biology (1993)
    29. [29]
      Anti-inflammatory and immunomodulating effects of the novel agent gamma-(2-aminoethylamino)-2-butyrothienone. 1st communication: inhibitory effects on mouse paw edema. — Gavalas A, Kourounakis L, Litina D, Kourounakis P Arzneimittel-Forschung (1991)
    30. [30]
      Role of corticosterone in modulation of eicosanoid biosynthesis and antiinflammatory activity by 5-lipoxygenase (5-LO) and cyclooxygenase (CO) inhibitors. — Tomchek LA, Hartman DA, Lewin AC, Calhoun W, Chau TT, Carlson RP Agents and actions (1991)
    31. [31]
      Synthesis and antiinflammatory activity of novel 12 beta-substituted analogues of betamethasone. — Avery MA, Detre G, Yasuda D, Chao WR, Tanabe M, Crowe D et al. Journal of medicinal chemistry (1990)
    32. [32]
      Some aspects of the inhibitory activity of hypolaetin-8-glucoside in acute inflammation. — Villar A, Gascó MA, Alcaraz MJ The Journal of pharmacy and pharmacology (1987)

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