British jauruai of DerimUoiogij 1997: 136: 24-29.

Chronic mucocutaneous candidosis associated withhypothyroidism: a distinct syndrome?

R.COLEMAN AND R.J.HAYSt John's Institute of Dernmtologti, Gufi's Hospital, Ijondon SiU 9R7'. U.K.

lor publication 2S May

S u m m a r y Chronic mucocutaneous candidosis (CMC) is a rare, complex disorder characterized by chronic andrecurrent Candida infections of the skin, naily and oropharynx. In over Si)% of cases there is anassociated endocrine disease, the complex being described as the Candida endocrinopathy syndrome.Inheritance of familial endocrine associated cases has been thought to follow an autosomal recessivepattern. In addition, autosomal recessive and autosomal dominant forms of CMC not associated withendocrinopathy have been described. We report a new syndrome in which there is verticaltransmission of CMC within families associated with primary hypothyroidism. This suggests thatthe Candida endocrinopathy syndrome can be subdivided into at least two types, one associated withhypoparathyroidism and/or hypoadrenalism which is inherited as an autosomal recessive trait, theother associated with hypothyroidistii which is an autosomal dominant disease. We emphasize theimportance of early and regular monitoring thyroid function in individuals with CMC and a need toprovide appropriate genetic counselling to affected members.

Chronic mucocutaneous candidosis (CMC) is a rare,complex immunodeficiency disorder characterized bychronic and recurrent Candida infections of the skin,nails and mucous membranes. Topical iinl'i-catididamedications are ineffective. Significant infections withherpesviruses. bacteria and dermatophytes occur in atleast 20'^ of patients: however, systemic fungal infec-tion Is rare.''^ Most cases of CMC are sporadic, but apositive family history is found in approximately 20%.^It is then most frequently transmitted as an autosomalrecessive trait. Autosomal dominant inheritance, notassociated with other disorders, has also been reported.'*

CMC is a heterogeneous group of disorders which hasbeen classified into several categories based on thepattern of inheritance, distribution and severity of theCandida infections, and associations with other disor-ders. The latter include autoimmune disease, gastroin-testinal disorders such as hepatitis and malabsorption.thymoma. interstitial keratitis. myopalhy, hat-matolo-gical disorders, endocrinopathies and polygiandularautoimmune syndromes.'''' However, classification ofthis group of disorders is not fixed, and we propose anew classification, as outlined in Table 1.

The main endocrine abnormalities seen in patients

Correspondetico: l> Rosemary Coleman. The Childrt-ii's Hospital.Temple Stret'l. Duhlin I. Ireland.

with CMC. previously known as the Candida endo-crinopathy syndrome, are hypoparathyroidism. hypo-adrenalocorticalism and hypothyroidism.^ Autoimmunepolyglandukir disease type 1. which is inherited as anautosomal recessive disorder, is characterized by a vari-able combination of: (i) CMC: (iil failure of the para-thyroid glands, adrenal cortex, gonads. pancreatic betacells, gastric parietal cells, thyroid gland and hepatitis:and (iii) dystrophy of dental enamel and nails, alopecia.vitiligo and keratopathy.' While most paLients initiallydevelop signs of CMC. usually presenting with Candidainfection within thefirst year oflife,''^ the age of onset forassociated endocrinopathies is often much later with amean of 10-12 years.' ^ Autosomal recessive inheritanceof CMC with endocrinopathy is well described.'*^*' Wereport a new syndrome in which there is verticaltransmission of CMC with hypotliyroidism. We suggestthai this particular form of CMC associated with anendocrine disorder is inherited in an aulosomal dominantpattern.

Case reports

Fatuihi A

Patient 1. Ih {see Fig. 1), is a 54-yecir-old female whotirst developed persistent oral candidosis at 3 months of

24 (fj 1997 British Association of Dermatologists

CHRONIC MUCOCUTANEOUS CANDIDOSIS AND HYPOTHYROIDISM 25

Table 1. Subtypes of chronic mucocutaneous candidosis ICMCI"!

Type Pattern of inheritance Special clinical/immunological features

CMCWithoul endocrinopathy 1212()S())'With L-ndocrinopathyt |24()5()()|Without endocrinopathy 11 14TS()IWith L'niiocrinopathy

Sporadic CMCCMC wilh keratitisl,ate-onset CMC)

RecessiveRecessiveDominantDominant

None knownNone knownNone known

Childhood onsetChildhood onset. Patients have the polyendocrinopathy syndromeChildhood onsetChildhood onset. Associated with hypolhyroidism

Childhood onsetChildhood onset. Associated with keratitisOnset in adult life. Associated with ihymoma

* McKusick numhers,tWhile originally severe CMC (e.g. Candida granuloma) was described in association with specific subtypes it is now apparent that extensiveinfection. Including hyperkeratotic candidiasis and dermatophytosis. is not specific lo any one variety. Likewise, autoimmune phenomena, such asvitiligo and alopecia areata. can occur with several CMC types. There is also no known immunological abnormality common to a specific CMC type.I The main endocrine diseases seen with ihis variety are hypo-parathyroidism and hypo-adrenalism.§ Other late-onset types have been recorded, e.g. with systemic lupus erythematosus, but as they are usually associated with systemic corticosteroidtherapy they have been excluded as secondary candidiasis.

age. As a child she suffered with hyperkeriitolic Candidainfection of the forehead and scalp which requiredsystemic treatment with amphoteriein B. Other pro-blems included Candida onychomycosis with parony-chia. hyperkeratotie dermatophytosis of the feet,chalazions, oral aphthae, chronie herpes simplex labia-lis, gingivitis, gum abscesses and conjunctivitis.Hypothyroidism was diagnosed on routine testing at14 years of age. At the time of examination shecomplained of marked fatigue and had evidence ofseborrhoeic dermatitis, oral candidosis and dermato-phyte onychomycosis aflecting the toes with secondaryhyperkeratotic infection ol' the dorsum of the feel(Fig. 2). She was taking ferrous sulphate 200 mg threetimes daily and thyroxine 10();/g/day.

FAMILY A

FAMILY B

Patient 2,1114, is the S-year-old daughter of patient 1.At 1 year of age she first developed oral candidosis.resistant to topical therapy. She suffers with frequentoral aphthae and candidosis, ehalazions, conjunctivitis,onychomycosis and hyperkeratotic dermatophytosis ofthe feet. At the time of consultation her mother reportedincreasing lethargy and cold sensitivity, constipation,and an apparent reduction in growth velocity. Onexamination her height was below the 25th centileand weight above the 9()th. She had dry skin, a slightlywaxy complexion and delayed relaxation of her reflexes.There was no evidence of a goitre. She also had oralcandidosis and hyperkeratotic dermatophytosis of theleft foot.

Patient i, 11^, is the 2-year-old daughter of patient 1.At birth she had congenital cataracts and subsequently

II D

l-'igure I, Pedigrees nf families A and B. Figure 2. Hyperkeratotic dermatophyte infection on the foot of patient 1,

r 1997 British Associalion of Dermatologists, British journal of Dermatology. 1 36, 24-29

2b R.COLEMAN AND R.J.HAY

developed glaucoma. She has had a single episode oforal candidosis of 1 month's duration which respondedto topical therapy. She has not heen diagnosed ashaving CMC.

Patient 4. II5, is the 29-year-oId sister of patient 1. At 4years of age she presented with eandida onychomycosisof the thumh nails. Since that time she has sufferedwith recurrent onychomycosis. severe oral candidosis.hyperkeratotic dermatophytosis of the feet caused byTriclwphiiton interdigitaJe. chalazions, blepharitis, gingi-vitis and chronic sinusitis. She had a marked flare up ofher CMC during both of her pregnancies. Hypothyroid-ism was diagnosed at 5 years of age because of failure tothrive. At the time of consultation she complained ofmarked fatigue, amenorrhoea lasting 8 months andgalactorrhoea for the previous month. She was notpregnant. On examination she was pale with dry skinand line sparse hair. She had oral candidosis, blephar-itis, hyperkeratotic dermatophytosis of the left foot,dermatophyte onychomycosis and plaques of psoriasison both knees. She was taking ferrous sulphate iOUmgthree times daily and thyroxine 5()//g/day.

Patient 5, III.,, is the 3'year-old daughter of patient 4.Since 5 months of age she has suftered with recurrentsevere oral and napkin candidiasis responding only tooral lluconazole. On examination, she had oralaphthous ulceration and koilonychia.

Patient (->. illm- is the 1 5-month-old daughter of patient4. She first developed oral and napkin candidiasis at 3months of age. She has been more severely affected thanher older sister and has had recurrent oral and napkincandidosis requiring treatment with tluconazole. Shehad salnioneUa gastroenteritis and has had frequentbacterial infections, particularly lower respiratory' tractinfections and septicaemia. She has also had hepatitis,splenomegaly and failure to thrive. On examination, shehad oral candidiasis.

I-aniihj B

Patient 1. 11. is a 28-year-old man who had oral andcutaneous Candida infections from the age of 1 8 months.In addition he had seborrhoeic dermatitis, recurrent jawahscesses necessitating removal of all his teeth, bronchi-ectasis and idiopathic epilepsy. At the age of 13 he wasfound to have hypothyroidism and was commenced onthyroxine replacement.

Patient 2, IIi. is the 3-year-old son of patient 1. Hehas had treatment unresponsive oral candidosis andone episode o{ Candida paronychia. He has also sufferedwith recurrent oral aphthae and blepharitis.

Investigations

For family A. hlood was taken for free thyroxine.thyroid-stimulating hormone, thyroid microsomal anti-bodies, thyroglobulin antibodies, thyroid cytoplasmicantibodies, autoantihody profile, serum ferritin. fullblood count, renal and hepatic function, calcium/phosphate, cortisol. parathyroid hormone, follicle-stimulating hormone and luteinizing hormone andprolactin (in patient 4). The autoantibody profileincluded antibodies directed against smooth muscle.gastric parietal cells, mitochondria, testis steroid cells,ovary steroid cells, pancreatic islet cells, adrenal cortexand antinuclear antibody. Other family members wereinvited to attend for investigation but they declined.However. I|. f̂ and II] (Eig. 1) had their thyroidfunction investigated locally.

For family B. blood was taken for full blood count,serum ferritin. thyroid function tests and autoantibodyprofile, which included thyroid tnicrosomal antibodies.thyroglobulin antibodies, thyroid cytoplasmic antibo-dies and antibodies directed against smooth muscle,gastric parietal cells, mitochondria and antinuclearantibody.

Results

The results of the investigations on members of family Aare summarized in Table 2. Severe, previously unrecog-nized primary hypothyroidism was detected in patient2, a 5-year-old girl with CMC. No autoantibodies weredetected in any individual and in particular there was noevidence of thyroid microsomal. cytoplasmic or thyro-globulin antibodies. There was no evidence of otherendocrinopathies in particular, hypoparathyroidism orhypoadrenalism in this family.

Both hypothyroid adults were on suboptimal replace-ment therapy with biochemica! evidence of hypothy-roidism as demonstrated by raised levels of thyroidstimulating hormone. Patient 4 had marked hyperpro-lactinaemia secondary to hypothyroidism. as clinicallysuspected from the history of amenorrhoea and galac-torrhoea. Family members I). Ij and 11] had theirthyroid function investigated by their general practi-tioners and all were found to be euthyroid. Serumferritin levels were low in all individuals except patient4 who had hypochromic microcytic anaemia whichwas also detected in patients 2. 5 and 6. Both patients 1and 4 were taking ferrous sulphate 200 mg three timesdaily, at the time of testing.

ihe results in family B are as follows: Patient 1. Ii:

1997 British Association of Dermatologists. British Jotirnal of Dermatology. 136. 24-29

CHRONIC MUCOCUTANEOUS CANDIDOSIS AND HYPOTHYROfDISM 17

fe E'-> cc

E C '5 .^^ E ^ "o

,— . - D.E S

^ -B = E

II IT

s i

E i:1- a.

o — f 3

•p — — — O ra "re

i c c -=3; •=

Q

C E

-T' ~— i±j 'o ro ^ '7~X o 2 3 c c —

P E

E E

1997 British Association of Dermatologists, Brilish lournal of Dernunohunj. 1 56. 24-29

28 R.COLEMAN AND R.j.HAY

reduced serum ferritin 9 /ig/I (15- iOO). euthyroid withnormal free thyroxine 13-Opmol/l (9-20) and thyroid-stimulating hormone 1-S mU/l (0-3-5-5). and a negativeautoantibody protiie. Patient 2. Ih: hypochromic micro-cytic anaemia with a haemoglobin of l()-4g/dl. reducedserum ferritin 1 3 ng/ml. normal thyroid function teststbyroxine 1 1 3 nmol/1 (6()-lfi0nmol/i) and a negativeautoantibody profile.

Discussion

In this family, routine testing led to the detection ofsevere undiagnosed primary hypothyroidism in a 5-year-old girl with CMC who was the daughter of afemale with both CMC and hypothyroidism. Therewas no evidence of other endocrine or autoimmunedisorders in any of the individuals examined. Verticaltransmission of CMC with hypothyroidism has not beenpreviously reported. The possibility that this could beinherited as an X-linked dominant trait in family Acannot be ruled out in view of the female to femaletransmission, the history of a miscarriage in patient 1.absence of affected males, the lack of sons in the familiesof patients 1 and 4 and, in particular the lack of male tomale transmission. However. X-linked CMC has notpreviously been described and therefore autosomaldominant inheritance Is more likely. Furthermore, infamily B. CMC is inherited in an autosomal dominantpattern and is associated with hypothyroidism in thefather. Although the son is currently euthyroid. he isvery young and will require regular thyroid functiontesting. Neither grandparent in family A are affectedwith either CMC or hypothyroidism. As there are twoaffected offspring in this family they were originallybelieved to exhibit autosomal recessive CMC untilaffected individuals occurred in both families in thethird generation. Therefore, it is more likely thateither the disorder is autosomal dominant with incom-plete penetrance. or that one of the grandparents hasgonadal mosaicism for the mutation.

It is estimated thai approximately 50% of patientswith CMC have an endocrinopathy which is frequentlyassociated with aniibodies to the involved gland.' Theendocrinopathy most commonly reported is hypopara-thyroidism.**'^" although Herrod found a higher preva-lence of hypoadrenalism and hypothyroidism in hisseries of 4 J patients with CMC.' The diagnosis ofhypothyroidism at 5 years of age, in two individuals(patients 2 and 4) emphasizes the importance ofearly monitoring of thyroid status, particularly inCMC with autosomal dominant inheritance. As the

other two children with CMC are still very young it istoo soon to say whether or not they will develophypothyroidism.

Kitching suggested a relationship between ketocona-zole administration and the subsequent development ofhypothyroidism in a father and son with CMC." How-ever, it was more likely that this family actually exhib-ited a familial candida-endocrinopathy syndrome oftheautosomal dominant type which may have been similarto thai in our families, although detailed informationregarding ihe presence of other disorders was notprovided.' Furthermore, in a report of autosomaldominant CMC. elevated antithyroglobulin antibodieswere found in a mother and son. although extensiveinvestigations only detected hypothyroidism in theson.^* These reports suggest thai the co-inheritance ofthe disorders in our family may not represent anentirely isolated finding, or private mutation, butrather thai this association might be more commonthan is currently recognized.

The cause ofthe primary hypolhyroidism in this familyremains unknown. Unlike the hypothyroid family mem-bers with polyglandular syndromes, ail of whom havehigh-titre antimicrosomal or anti-thyroglobulin thyroidantibodies. ' no such antibodies have been detected inany members of our families. Neither were antithyro-globulin or thyroid microsomal antibodies detected inthe father and son reported to develop hypothyroidismafter administration of ketoconazole.'' It is possible thatautoaniibodies exist to an as yet unidentified thyroidautoantigen which are thus currently undetectable.

The mechanisms ofthe association between the CMCsyndrome, endocrinopathy and autoimmune diseaseare not understood and the treatment of these disordershas little eflect on the aindkhi infections.'" One hypoth-esis is that there may be an important genetic compo-nent in the pathogenesis of polyglandular failure andrelated illnesses.'"^ An alternative possibility is that bothCMC and the polyendocrinopathy are manifestations ofa basic immunological disorder."' A variety of immu-nological defects have been described in CMC and thesemainly affect the cell-mediated immune system.although neutrophil and monocyte defecis have occa-sionally been found.'" It is now believed that a centra!defect in most patients with CMC is the inability todevelop and express effective cell-mediated iminuneresponses against cimdidii and other superficial infec-tious agents including dermatophytes.^ Abnormalitiesin humoral immunity have not been extensively eval-uated, but defects in antibody production in patientswith CMC are considered unusual.' Most patients tested

British Association of IJiTmatologists, Hritisli jotinhil of Dernmtolotai. 1 J6, 24-29

CHRONIC MUCOCUTANEOUS CANDIDOSIS AND HYFOTHYROIDISM 29

have anti-candida antibodies.' It is not known whetherpatients with CMC acquire the disease because of agenetic difference in immunological responsiveness orbecause the Candida triggers an abnormal response inotherwise normal subjects. '

Another recognized feature of CMC. present in thesefamilies, is a reduction in serum ferritin. which wasfound in six ofthe seven affected individuals. In familyA. patient 4 had a normal serum ferritin but was oniron replacement therapy at time of investigation, aswas patient 1. However, palient 4 had also beenamenorrhoeic for the preceding 8 months. Iron studieshave demonstrated an impairment of iron absorption inCMC. initially in the autosomal recessive type, and themechanism for this is not understood.' It is notknown if iron deficiency is a secondary feature of CMCor a genetically determined primary defect in ironabsorption.'*'^ Iron deficiency might predispose to can-didiasis. as chronic lack of tissue iron can result indefective epithelial formation which may give rise to apersistent superimposed Candida infection wUh subse-quent alteration in Ihe immune response over aprolonged period of time.' ^ Furthermore, clinicalimprovement, which included regeneration of normalnails and clearance of oral candidiasis. has been observedin many of these individuals while on parenteral irontherapy.""

We report vertical transmission of chronic mucocu-laneous candidosis with hypothyroidism. probably inan autosomal dominant manner, in three afiectedfemales across two generations. A second family haveautosomal dominant CMC which is associated withhypolbyroidism in one member. These families empha-size the importance of routine monitoring of thyroidfunction, from an early age. in individuals with CMC.

References1 Herrod HG, Chronic mucocutaneous candidiasis in childhood am!

complications of non-candida infection: A report of the pediatricimmunodeficiency collaborativt? study gronp. / Pcdititr 199(1; 116:377-S2,

2 Chipps Bp;, Sanlsbury FT. Hsu SH el ill. Non-Candidal Infections inchililren wilh chronic mucocutaiicous candidiasis. Johns HopkinsMedj 1979:44: 175-9.

3 Edwards |K. Lehner Rl, Steihm KR ct al Severe Candida! infections:clinical perspective, immune defense mechanisms, and currentconcepts of therapy. Aim Intern Mi'd 197S: 89: 91-106.

4 Sams WM, |nrizzo Jl., Snyderman R I'l iil. Chronic mucoctitaneouscandidiasis. immunnlngic studies iif three generations of a singlefamily. Am j Mcd 1979; 67: 94S-59,

5 Kirkpalrick CW, Chronic mucucntiineous candidiasis, / Am ActiilIknmilol 1994: 5I:S14-17.

(•> Iliggs JM, Weils RS. Chronic mucocutaneous candidiasis: asso-ciated abnormalities of iron metabolism. Br j Dermiitol 1972: 86:802-4.

7 Ahonen P, Myllarniemi S, Sipila I ct td, Clinica! varialion ofautoimmune polyendocrinopathy-candidiasis-ectodenna! dys-trophy lAI'iri-UI in a series of h8 patients. \ F.ncil} AW 1990;322: 1829-56.

8 Kirkpalrick CH. Rich RB, Bennell \E. Chronic mucocutaneouscandidiasis: model building in cellular immunology. Ami ImrriiMfd 1971; 74: 9S5-78.

9 Blizzard RM. Gibbs, Candidiasis: studies pertaining to its associa-tion with endocrinopathies anil pernicious anaemia. Pedkitrks196f<; 42: 2 51-7,

10 forter S, Scully C. Candidiasis endocrinopathy syndrome, Oni!Sunj 1986:61: S73-S.

11 Kiiching NH. Hypothyroidism alter Ireatmenl with Kt'loconazole,Hr Mcdl t986; 295:995-4.

12 Tanner AR. Hypothyroidism after treatment with Keloconazole(letlLTl. Br Med } (Cliii Res Ed) 1987: 294: 125.

I 5 Kroll ||, Einbinder |M, Merz WG. Miicocutaneous candidiasis in amolht-r and son. Arch Oermatol 1971: 108: 259-62.

14 Eisenbarlh C Wilson P. Ward F. Lebovitz HE. NLA type andoccurrence of disease in familial polyglandular failure. N Eiigl }Med 1978; 298: 92-4.

I S Trence DL. Morley Jli, Handvveryer BS, Pnlyji;!andu!ar autoim-mune syndromes,/liiii / Alt'if 1985; 77: 107-15.

16 Solomtm IL, Blizzard RM, Autoimmune disorders of endocrineglands, / (VrfiiUr 196 3:61: 102 l - M .

1 7 Ouie PG. Chilgren RA. Acute disseminated and chronic muco-culaneous candidiasis, Seniitiol Heuuito! 1971: 8: 227-42.

18 Higgs JM, Smith P. Smith T. Measuremenl of '''I'e absorption andretentioii in palients with familial chronic muco-cutaneouscandidiasis using the melbod nf whole body comUing. Clin ExpIhrumiol 1976; 1: 369-76,

19 Wells RC, Higgs JM, MacDoiiald A el al. I'amilial chronic muco-cutaneous candidiasis. / Mecl Genet 1972; 9: 302-10.

21) Higgs ]M, Wells RS, Diffuse chronic mucocutaneous cyndidiasis:reporl of two patients treated wilh topical clotrimazole andreplacement of nutrilional deficiencies. Ciiii's Hasp Rep 1973:122: 1 55-53.

1997 British Association of Dermatologists, British lournal of Dn-matoloi)}!, 1 36. 24-29