- Email: [email protected]
Chronic candidiasis, enamel hypoplasia, and pigmentary anomalies
Chronic candidiasis, enamel hypoplasia, and pigmentary anomalies Stephen R. Porter, BSc, PhD, MB, ChB, FDS, RCS, RCSE, Sandip Haria, BDS, MSc, Crispian Scully, PhD, MD, AIDS, FDSRCPS, FFDRCSI, MRCPath, and Andrea Richards, MSc, FDSRCS, Bristol, England CENTRE
FOR THE STUDY OF ORAL DISEASE, BRISTOL
DENTAL
HOSPITAL
AND SCHOOL
This report describes a young male patient who had enamel hypoplasia, persistent oral candidiasis, skin hyperpigmentation, and vitiligo, and was thus suspected of having candidiasis endocrinopathy syndrome. The clinical and laboratory investigations employed to confirm the diagnosis are detailed. (ORAL SURG ORAL MED ORAL PATHOL 1992;74:312-4)
hronic mucocutaneous candidiasis (CMC) is the C term given to a group of rare disorders in which there is persistent candidiasis of the mouth, skin, and nail beds (Table I).‘-’ The present report describes the clinical features of a patient with a variant of CMC and details the clinical diagnosis and problems of confirmatory investigations.
Table
I. Classification of CMC* Type
Early-onset CMC
Autosomal recessive
Diffuse CMC
Autosomal recessive or sporadic
Candidiasis endocrinopathy syndrome
Autosomal recessive or sporadic
Late-onset CMC
Sporadic
CASEREPORT A 17-year-old boy who had been attending the hospital since early childhood for routine dental care was referred to the Centre for Study of Oral Disease, for persistent oral white lesions. The patient had had oral thrush for 10 months, which had failed to respond to topical nystatin. The patient also admitted a 2-year history of decline in general health, with increasing weakness, tiredness, and progressive weight loss. For the previous 2 months he had had postural dizziness. The medical history was apparently otherwise clear, although the patient had had enamel hypoplasia affecting the crowns of the following teeth:
The hypoplasia of all the first permanent molars had been so extensive as to warrant their extraction at 8 years of age. The cause of the enamel hypoplasia was never established, but a systemic chronologic type of hypoplasia was suggested. The patient had no family history of dental hypoplasia.
7/13/34570
312
Inheritance
Principal features
Oral candidiasis, mild cutaneous involvement, occasional iron deficiency Severe oral candidiasis, severe cutaneous involvement including granuloma formation, candidal blepharitis, pharyngitis and laryngitis, occasional bacterial and viral infections, high prevalence of iron deficiency Mild to severe oral and cutaneous candidiasis, hypoparathyroidism, Addison’s disease, autoimmune thyroid disease, diabetes mellitus, vitiligo, other autoimmune disorders, enamel hypoplasia Mild mucosal and cutaneous candidal infection, thymoma, myasthenia gravis, polymyositis, hypogammaglobulinemia, bone marrow changes
*Not includingCMC associated with primary immunodeficiencies.
Volume 74 Number 3
Candidiasis, hypoplasia, pigmentary anomalies
313
Fig. 2. Chronic candidal infection of buccal mucosain CES.
Fig. 1. Vitiligo and hyperpigmentation on face. On general examination the patient was thin with obvious vitiligo and background hyperpigmentation on the forehead (Fig. l), trunk, and abdomen, suggestive of Addison’s disease.Indeed, the blood pressure at sitting was low (95/55 mm Hg), further suggesting Addison’s disease. Leukonychia affected the big toenails of both feet, and a dermatophyte infection of the lateral aspect of the left foot was present. No cervical or submandibular lymphadenopathy was present. The lower lip was slightly swollen and there was bilateral angular stomatitis. Intraorally, extensive adherent homogeneouswhite plaques affected the buccal mucosae(Fig. 2) dorsum of tongue, and the lower labial mucosa.The mucosa of the palate was covered with an adherent speckled white and red lesion. Enamel hypoplasia was noted on the following teeth: 5 +21 123 there were veneers on the labial surfaces of the maxillary incisors and canines. There was no intraoral hyperpigmentation or vitiligo. In view of the presence of the adherent intraoral white plaques, angular stomatitis, and leukonychia, a diagnosis of CMC was considered. In particular, candidiasis endocrinopathy syndrome (CES), a variant of CMC, was believed likely in view of the presence of the enamel hypoplasia (possibly due to hypoparathyroidism), vitiligo, and possible Addison’s diseaseas suggestedby the hypotension, weight loss, hyperpigmentation, and weakness. The patient was given a short adrenocorticotropin (Synacthen) test (250 pg intramuscularly), to which he failed to
respond. He was also found to be hyponatremic (sodium level 126 mmol/L), hyperkalemic (potassium level 5.2 mmol/L), hypocalcemic (calcium level 1.62 mmol/L), and hypoglycemic (glucose level 3.6 mmol/L), confirming the initial diagnosis of adrenocortical hypofunction and possible hypoparathyroidism. Biopsy tissue from the buccal white lesion confirmed chronic hyperplastic candidiasis, and low serum levels of parathyroid hormone confirmed the hypoparathyroidism and thus the diagnosis of CES. There was no evidence of HIV infection. The patient was therefore treated with adrenocorticotrophic hormone, dexamethasone, and fludrocortisone, has respondedwell, and is currently receiving maintenance therapy of hydrocortisone, fludrocortisone, and 1 cu-cholecalciferol (vitamin Ds supplement). The oral candidiasis has cleared in responseto nystatin and miconazole gel. DISCUSSION
This report is of particular interest becausethe patient had had clinical features highly suggestive of CES that had remained undiagnosed for several years. This demonstrates the clear importance of carefully checking the medical history and noting any relevant extraoral features. CES is characterized by chronic candidal infection of the mucosae and occasionally the skin, together with type I polyglandular autoimmune endocrinopathy. Chronic candidal infection of the mouth is often the initial presenting feature, and endocrinopathies may not manifest for another 10 to 15 years; occasionally, however, the sequence is reversed.*-t2 Our patient may have had mild hypoparathyroidism in early childhood, as demonstrated by the enamel hypoplasia,13-17but there appears to have been a rapid onset of Addison’s disease,vitiligo, dermatophyte in-
314
Porter et al.
ORAL SURG ORAL MED ORAL PATHOI. September 1992
fection,18 and oral and cutaneous candidiasis in early adulthood. The precise reason for this subsequent onset of autoimmune phenomena and candidal infection is not known, but defective cell-mediated immunity or immunoregulation seems likely. l9 Simple clinical and laboratory investigations helped confirm the diagnosis of adrenocortical hypofunction (e.g., low blood pressure, hyperkalcemia, hyponatremia, and reduced response to adrenocorticotropin20) and chronic candidal infection (biopsy). However, it is important to note that in our patient these investigations were carried out in reverse, with the biopsy being carried out before any results of serum biochemistry were known or before the adrenocorticotropin test was performed, and furthermore, despite published guidelines21y 22 a corticosteroid cover of only 100 mg hydrocortisone was given, which resulted in the development of an adrenal crisis. Fortunately the patient made a good recovery and is now receiving maintenance therapy of corticosteroids and vitamin D3. Interestingly, his candidiasis has responded to remarkably simple antifungal therapy, an uncommon feature of CES.19 This case underlines the fact that even rare disorders can be diagnosed by carefully taking a medical history and by performing an adequate clinical examination. We thank Mrs. Kath Parkes for her patience
in the effi-
cient processing of this manuscript. REFERENCES 1. Aronson IK, Soltani K. Chronic mucocutaneous candidosis: a review. Mycopathologia 1976;60:17-25. 2. De Villez RL, Lewis CW. Candidiasis seminar. Cutis 1977; 19:69-83. 3. Edwards JE, Lehrer RI, Stiehm ER, Fischer TJ, Young LS. Severe candidal infections. Ann Intern Med 1978:89:91-106. 4. Dwyer JM. Chronic mucocutaneous candidiasis: Ann Rev Med 1981;32:491-7. 5. Jorizzo JL. Chronic mucocutaneous candidosis: an update. Arch Dermatol 1982;!18:963-5.
9.
10. 11. 12.
13.
Cleary TG. Chronic mucocutaneous candidiasis. In: Bodey GP, ed. Candidiasis. New York: Raven Press, !985:241-52. Odds FC. Chronic mucocutaneous candidosis. In: Candida and candidosis. London: Bailliere Tindall, 1988:!43-52. Sutphin A, Albright F, McCune DJ. Five cases (three in siblings) of idiopathic hypoparathyroidism associated with moniliasis. J Clin Endocrinol 1943;3:625-34. Whitaker J, Landing BH, Esselborn VM, Williams RR. Syndrome of familial juvenile hypoadrenocorticism, hypoparathyroidism and superficial moniliasis. J Clin Endocrinol 1956; 16: 1274-87. Mathes-Alguire B, Alguire PC. Autoimmune polyglandular syndromes. Am Fam Physician !984;29: 149-52. Trence DL, Morley JE, Hardwergar BS. Polyglandular autoimmune syndromes. Am J Med 1984;77:107-15. Ahonen P. Autoimmune polyendocrinopathy candidosis ectodermal dystrophy (APEC): autosomal recessive inheritance. Clin Genet 1985;27:535-42. Greenberg M, Brightman V, Lynch M, Ship I. Idiopathic hypoparathyroidism, chronic candidiasis and dental hypoplasia. ORAL SURF ORAL MED ORAL PATHOL
1969;38:42-53.
14. Riley DJ. Dental changes in patients with idiopathic hypoparathyroidism: report of two cases. J Oral Surg !969;27:44-7. 15. Nally FF. Idiopathic juvenile hypoparathyroidism with superficial moniliasis. ORAL SURG ORAL MED ORAL PATHOL 1970; 30:356-65. 16. Myllarniemi S, Perheentupa J. Oral findings in the autoimmune polyendocrinopathy-candidosis syndrome (APECS) and other forms of parathyroidism. ORAL SURG ORAL MED ORAL PATHOL
1978;45:721-9.
17. Porter SR, Scully C. Candidiasis endocrinopathy ORAL SURG ORAL MED ORAL PATHOL
syndrome.
1986;61:573-8.
18. Kirkpatrick CH, Rich RB, Bennett JE. Chronic mucocutaneous candidiasis: model building in cellular immunity. Ann Intern Med !97!;74:955-78. 19. Porter SR, Scully C. Chronic mucocutaneous candidosis and related syndromes. In: Samaranayake L, MacFarlane TW, eds. Oral candidosis. London: Wright, 1990:200-l 2. 20. Lamey PJ, Carmichael F, Scully C. Oral pigmentation, Addison’s disease and the results of screening for adrenocortical insufficiency. Br Dent J 1985;158:297-8. 21. Cawson RA, Scully C. Medical problems in dentistry. 2nd cd. Bristol: Wright, 1987:1-588. 22. Scully C. Patient care: a dental surgeon’s guide, 2nd ed. London: Br Dent J 1989:1-324. Reprint requests: Stephen R. Porter Department of Oral Medicine, Surgery and Pathology Bristol Dental Hospital and School Lower Maudlin Street Bristol BSl 2LY, U.K.
FOR THE STUDY OF ORAL DISEASE, BRISTOL
DENTAL
HOSPITAL
AND SCHOOL
This report describes a young male patient who had enamel hypoplasia, persistent oral candidiasis, skin hyperpigmentation, and vitiligo, and was thus suspected of having candidiasis endocrinopathy syndrome. The clinical and laboratory investigations employed to confirm the diagnosis are detailed. (ORAL SURG ORAL MED ORAL PATHOL 1992;74:312-4)
hronic mucocutaneous candidiasis (CMC) is the C term given to a group of rare disorders in which there is persistent candidiasis of the mouth, skin, and nail beds (Table I).‘-’ The present report describes the clinical features of a patient with a variant of CMC and details the clinical diagnosis and problems of confirmatory investigations.
Table
I. Classification of CMC* Type
Early-onset CMC
Autosomal recessive
Diffuse CMC
Autosomal recessive or sporadic
Candidiasis endocrinopathy syndrome
Autosomal recessive or sporadic
Late-onset CMC
Sporadic
CASEREPORT A 17-year-old boy who had been attending the hospital since early childhood for routine dental care was referred to the Centre for Study of Oral Disease, for persistent oral white lesions. The patient had had oral thrush for 10 months, which had failed to respond to topical nystatin. The patient also admitted a 2-year history of decline in general health, with increasing weakness, tiredness, and progressive weight loss. For the previous 2 months he had had postural dizziness. The medical history was apparently otherwise clear, although the patient had had enamel hypoplasia affecting the crowns of the following teeth:
The hypoplasia of all the first permanent molars had been so extensive as to warrant their extraction at 8 years of age. The cause of the enamel hypoplasia was never established, but a systemic chronologic type of hypoplasia was suggested. The patient had no family history of dental hypoplasia.
7/13/34570
312
Inheritance
Principal features
Oral candidiasis, mild cutaneous involvement, occasional iron deficiency Severe oral candidiasis, severe cutaneous involvement including granuloma formation, candidal blepharitis, pharyngitis and laryngitis, occasional bacterial and viral infections, high prevalence of iron deficiency Mild to severe oral and cutaneous candidiasis, hypoparathyroidism, Addison’s disease, autoimmune thyroid disease, diabetes mellitus, vitiligo, other autoimmune disorders, enamel hypoplasia Mild mucosal and cutaneous candidal infection, thymoma, myasthenia gravis, polymyositis, hypogammaglobulinemia, bone marrow changes
*Not includingCMC associated with primary immunodeficiencies.
Volume 74 Number 3
Candidiasis, hypoplasia, pigmentary anomalies
313
Fig. 2. Chronic candidal infection of buccal mucosain CES.
Fig. 1. Vitiligo and hyperpigmentation on face. On general examination the patient was thin with obvious vitiligo and background hyperpigmentation on the forehead (Fig. l), trunk, and abdomen, suggestive of Addison’s disease.Indeed, the blood pressure at sitting was low (95/55 mm Hg), further suggesting Addison’s disease. Leukonychia affected the big toenails of both feet, and a dermatophyte infection of the lateral aspect of the left foot was present. No cervical or submandibular lymphadenopathy was present. The lower lip was slightly swollen and there was bilateral angular stomatitis. Intraorally, extensive adherent homogeneouswhite plaques affected the buccal mucosae(Fig. 2) dorsum of tongue, and the lower labial mucosa.The mucosa of the palate was covered with an adherent speckled white and red lesion. Enamel hypoplasia was noted on the following teeth: 5 +21 123 there were veneers on the labial surfaces of the maxillary incisors and canines. There was no intraoral hyperpigmentation or vitiligo. In view of the presence of the adherent intraoral white plaques, angular stomatitis, and leukonychia, a diagnosis of CMC was considered. In particular, candidiasis endocrinopathy syndrome (CES), a variant of CMC, was believed likely in view of the presence of the enamel hypoplasia (possibly due to hypoparathyroidism), vitiligo, and possible Addison’s diseaseas suggestedby the hypotension, weight loss, hyperpigmentation, and weakness. The patient was given a short adrenocorticotropin (Synacthen) test (250 pg intramuscularly), to which he failed to
respond. He was also found to be hyponatremic (sodium level 126 mmol/L), hyperkalemic (potassium level 5.2 mmol/L), hypocalcemic (calcium level 1.62 mmol/L), and hypoglycemic (glucose level 3.6 mmol/L), confirming the initial diagnosis of adrenocortical hypofunction and possible hypoparathyroidism. Biopsy tissue from the buccal white lesion confirmed chronic hyperplastic candidiasis, and low serum levels of parathyroid hormone confirmed the hypoparathyroidism and thus the diagnosis of CES. There was no evidence of HIV infection. The patient was therefore treated with adrenocorticotrophic hormone, dexamethasone, and fludrocortisone, has respondedwell, and is currently receiving maintenance therapy of hydrocortisone, fludrocortisone, and 1 cu-cholecalciferol (vitamin Ds supplement). The oral candidiasis has cleared in responseto nystatin and miconazole gel. DISCUSSION
This report is of particular interest becausethe patient had had clinical features highly suggestive of CES that had remained undiagnosed for several years. This demonstrates the clear importance of carefully checking the medical history and noting any relevant extraoral features. CES is characterized by chronic candidal infection of the mucosae and occasionally the skin, together with type I polyglandular autoimmune endocrinopathy. Chronic candidal infection of the mouth is often the initial presenting feature, and endocrinopathies may not manifest for another 10 to 15 years; occasionally, however, the sequence is reversed.*-t2 Our patient may have had mild hypoparathyroidism in early childhood, as demonstrated by the enamel hypoplasia,13-17but there appears to have been a rapid onset of Addison’s disease,vitiligo, dermatophyte in-
314
Porter et al.
ORAL SURG ORAL MED ORAL PATHOI. September 1992
fection,18 and oral and cutaneous candidiasis in early adulthood. The precise reason for this subsequent onset of autoimmune phenomena and candidal infection is not known, but defective cell-mediated immunity or immunoregulation seems likely. l9 Simple clinical and laboratory investigations helped confirm the diagnosis of adrenocortical hypofunction (e.g., low blood pressure, hyperkalcemia, hyponatremia, and reduced response to adrenocorticotropin20) and chronic candidal infection (biopsy). However, it is important to note that in our patient these investigations were carried out in reverse, with the biopsy being carried out before any results of serum biochemistry were known or before the adrenocorticotropin test was performed, and furthermore, despite published guidelines21y 22 a corticosteroid cover of only 100 mg hydrocortisone was given, which resulted in the development of an adrenal crisis. Fortunately the patient made a good recovery and is now receiving maintenance therapy of corticosteroids and vitamin D3. Interestingly, his candidiasis has responded to remarkably simple antifungal therapy, an uncommon feature of CES.19 This case underlines the fact that even rare disorders can be diagnosed by carefully taking a medical history and by performing an adequate clinical examination. We thank Mrs. Kath Parkes for her patience
in the effi-
cient processing of this manuscript. REFERENCES 1. Aronson IK, Soltani K. Chronic mucocutaneous candidosis: a review. Mycopathologia 1976;60:17-25. 2. De Villez RL, Lewis CW. Candidiasis seminar. Cutis 1977; 19:69-83. 3. Edwards JE, Lehrer RI, Stiehm ER, Fischer TJ, Young LS. Severe candidal infections. Ann Intern Med 1978:89:91-106. 4. Dwyer JM. Chronic mucocutaneous candidiasis: Ann Rev Med 1981;32:491-7. 5. Jorizzo JL. Chronic mucocutaneous candidosis: an update. Arch Dermatol 1982;!18:963-5.
9.
10. 11. 12.
13.
Cleary TG. Chronic mucocutaneous candidiasis. In: Bodey GP, ed. Candidiasis. New York: Raven Press, !985:241-52. Odds FC. Chronic mucocutaneous candidosis. In: Candida and candidosis. London: Bailliere Tindall, 1988:!43-52. Sutphin A, Albright F, McCune DJ. Five cases (three in siblings) of idiopathic hypoparathyroidism associated with moniliasis. J Clin Endocrinol 1943;3:625-34. Whitaker J, Landing BH, Esselborn VM, Williams RR. Syndrome of familial juvenile hypoadrenocorticism, hypoparathyroidism and superficial moniliasis. J Clin Endocrinol 1956; 16: 1274-87. Mathes-Alguire B, Alguire PC. Autoimmune polyglandular syndromes. Am Fam Physician !984;29: 149-52. Trence DL, Morley JE, Hardwergar BS. Polyglandular autoimmune syndromes. Am J Med 1984;77:107-15. Ahonen P. Autoimmune polyendocrinopathy candidosis ectodermal dystrophy (APEC): autosomal recessive inheritance. Clin Genet 1985;27:535-42. Greenberg M, Brightman V, Lynch M, Ship I. Idiopathic hypoparathyroidism, chronic candidiasis and dental hypoplasia. ORAL SURF ORAL MED ORAL PATHOL
1969;38:42-53.
14. Riley DJ. Dental changes in patients with idiopathic hypoparathyroidism: report of two cases. J Oral Surg !969;27:44-7. 15. Nally FF. Idiopathic juvenile hypoparathyroidism with superficial moniliasis. ORAL SURG ORAL MED ORAL PATHOL 1970; 30:356-65. 16. Myllarniemi S, Perheentupa J. Oral findings in the autoimmune polyendocrinopathy-candidosis syndrome (APECS) and other forms of parathyroidism. ORAL SURG ORAL MED ORAL PATHOL
1978;45:721-9.
17. Porter SR, Scully C. Candidiasis endocrinopathy ORAL SURG ORAL MED ORAL PATHOL
syndrome.
1986;61:573-8.
18. Kirkpatrick CH, Rich RB, Bennett JE. Chronic mucocutaneous candidiasis: model building in cellular immunity. Ann Intern Med !97!;74:955-78. 19. Porter SR, Scully C. Chronic mucocutaneous candidosis and related syndromes. In: Samaranayake L, MacFarlane TW, eds. Oral candidosis. London: Wright, 1990:200-l 2. 20. Lamey PJ, Carmichael F, Scully C. Oral pigmentation, Addison’s disease and the results of screening for adrenocortical insufficiency. Br Dent J 1985;158:297-8. 21. Cawson RA, Scully C. Medical problems in dentistry. 2nd cd. Bristol: Wright, 1987:1-588. 22. Scully C. Patient care: a dental surgeon’s guide, 2nd ed. London: Br Dent J 1989:1-324. Reprint requests: Stephen R. Porter Department of Oral Medicine, Surgery and Pathology Bristol Dental Hospital and School Lower Maudlin Street Bristol BSl 2LY, U.K.